Clinical Trials

Eligibility

Eligibility

Eligibility

Inclusion Criteria:

• Patients (females and males) with clinical stage T1c-T3 (or Tx) and nodal stage N0-N1 (except T3N1 tumors, which are not eligible)
• Patients must have no residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Patients with residual isolated tumor cells at surgery are considered node-positive and are not eligible
• HER2+ by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Central pathology review is not required. In cases where there were multiple tumor sites in breast/nodes that had HER2 testing at diagnosis, at least one site must have been HER2+ AND the treating investigator must feel it is in the patient's best interest to be treated as having HER2+ breast cancer
• Known hormone receptor status as defined by ASCO/CAP guidelines. Estrogen receptor (ER) and progesterone receptor (PR) of any values are allowed. Hormone receptor positive status can be determined by either known positive ER or known positive PR status; hormone receptor negative status must be determined by both known negative ER and known negative PR
• If invasive disease was present in both breasts, participation in the study is permitted as long as the eligibility criteria are met for both tumors/breasts (including the requirement that at least one biopsied site on each side must have been HER2+)
• Age ? 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Patients must have received neoadjuvant chemotherapy in combination with trastuzumab with or without pertuzumab for a minimum of 12 weeks. All chemotherapy must have been completed preoperatively

  • Patient must complete a minimum of 12 weeks of coverage with trastuzumab and a maximum of 24 weeks in the combined neoadjuvant and adjuvant setting prior to trial registration. Trastuzumab may have been administered either weekly or once every 3 weeks (q3weeks). (For purposes of this eligibility criterion, a single dose of q3week trastuzumab would provide 3 weeks of coverage; a single dose of once a week (q1week) trastuzumab would provide 1 week of coverage. If a q3week dose of trastuzumab were administered and then the subsequent dose was delayed for any period of time, that would still count as 3 weeks of coverage.)
  • Administration of endocrine therapy for treatment of this breast cancer is allowed prior to trial registration. If a patient received prior breast cancer endocrine therapy (eg tamoxifen or aromatase inhibitor) for DCIS or preventive indication, and endocrine therapy is indicated for treatment of their current breast cancer, then prior endocrine therapy must have been stopped > 12 months prior to registration on this protocol
  • No use of investigational anti-cancer agents at time of registration
• Patient must register within 14 weeks of final surgery

• Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

  • Breast surgery: Total mastectomy with grossly negative margins (in the opinion of the surgeon there is no disease grossly at the margins) or breast-conserving surgery with histologically negative margins (no ink on tumor, including DCIS) unless those margins are anterior at the skin or posterior at the chest wall and no additional margin re-excision can be performed
  • Lymph node surgery: Lymph node surgery must have been performed and can include sentinel lymph node biopsy, targeted axillary dissection, or axillary dissection, at the discretion of the breast surgeon

• Adequate radiation: Patients who completed breast-conserving surgery (i.e. lumpectomy) must have received or plan to receive adjuvant radiation. If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible. Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation) are not eligible

  • Adjuvant radiation can be given on study, and in this case is encouraged to be given concurrently with adjuvant HER2-directed therapy, per investigator discretion
  • Targeting of the regional nodal basins will be at treating investigator discretion
• Not pregnant and not nursing, because this study involves agents with known teratogenic potential. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test should be performed prior to receiving HER2-directed therapy according to local standard practice
• Adequate hepatic, renal and bone marrow function to receive adjuvant HER2-directed therapy in the opinion of the treating investigator. There are no specific required laboratory values for eligibility
• No stage IV (metastatic) breast cancer
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• No history of any prior (ipsilateral [ipsi-] or contralateral) invasive breast cancer. Prior DCIS is allowed
• No evidence of recurrent disease following preoperative therapy and surgery
• Patients living with HIV who are healthy and deemed by their medical team to have a low risk of AIDS-related illnesses are included in this trial. Patients with Hepatitis B or Hepatitis C virus who are healthy and deemed by their medical team to meet all other enrollment criteria are included in this trial.
• Patients with inadequate cardiac function on most recent assessment of left ventricular ejection fraction (LVEF) are not eligible for this trial. Inadequate cardiac function is defined as LVEF < 50% on echocardiogram (echo) or multiple-gated acquisition (MUGA)
• No history of grade 3 or 4 toxicity related to trastuzumab. If pertuzumab is planned to be given on trial, patient must also have no history of grade 3-4 toxicity related to pertuzumab
• No contraindication to receipt of further HER2-directed therapy
• No patients with severe, uncontrolled systemic disease that may interfere with planned trial therapy.

Exclusion Criteria:

Eligibility

Eligibility

Eligibility

Inclusion Criteria:

• STEP 1: REGISTRATION (SCREENING): Participants must have histologically confirmed estrogen receptor (ER) positive and/or progesterone receptor (PR) positive (hormone receptor positive) and HER2 negative breast cancer, as per American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines

  • NOTE: Participants with HER2 positive disease by ASCO CAP guidelines are ineligible. HER2 negative and HER2 low or equivocal cases as per ASCO CAP guidelines that do not receive HER2 targeted therapy are eligible

• STEP 1: REGISTRATION (SCREENING): Participants must have clinical stage II or III breast cancer

  • NOTE: Participants with inflammatory breast cancer are eligible
• STEP 1: REGISTRATION (SCREENING): Participants must not have metastatic disease (i.e., must be clinically M0 or Mx) Systemic staging studies with imaging should follow routine practice as per National Comprehensive Cancer Network (NCCN) and ASCO guidelines
• STEP 1: REGISTRATION (SCREENING): Participants must not have locally recurrent breast cancer
• STEP 1: REGISTRATION (SCREENING): Participants with multifocal disease or synchronous primary tumors are eligible, however, all tumors must be hormone receptor positive and HER2 negative per ASCO CAP guidelines. It is sufficient to have MP2 status on at least one of the lesions

• Participants must have either adequate tissue available to submit on-study or a prior known MammaPrint Index Score that is MP2 status

  • Submitting tissue for on-study MammaPrint testing:

    • Participants must have a minimum of ten, unstained formalin-fixed paraffin-embedded (FFPE) slides (4-5 micron thickness) available from initial tumor biopsy for MammaPrint assessment

      • NOTE: Participants must agree to have this tissue submitted to Agendia for MammaPrint Index Scoring and to have subsequent results disclosed to SWOG Cancer Research Network OR

  • Submitting prior known MammaPrint Index Score:

    • If a MammaPrint Index Score report from within the last 12 weeks is already known and is MP2 status, the participant must be registered to Step 2 immediately following Step 1 registration provided they meet all other criteria. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) tested from initial tumor biopsy

      • NOTE: Participants must agree to have their commercial MammaPrint Index Score disclosed to Southwest Oncology Group (SWOG) Cancer Research Network
      • NOTE: Participants with prior known MammaPrint result that is not MP2 status should not be enrolled to either step of this study
• STEP 1: REGISTRATION (SCREENING): Participants must not have received any prior treatment for their current breast cancer, including chemotherapy, immunotherapy, biologic or hormonal therapy, and must be candidates for doxorubicin, paclitaxel, and durvalumab therapy
• STEP 1: REGISTRATION (SCREENING): Participants must be >= 18 years old at the time of registration
• STEP 1: REGISTRATION (SCREENING): Participants must have a complete medical history and physical exam within 28 days prior to Step 1 Registration
• STEP 1: REGISTRATION (SCREENING): Participants must have body weight > 30 kg
• STEP 1: REGISTRATION (SCREENING): Participants must have Zubrod Performance Status of 0-2
• STEP 1: REGISTRATION (SCREENING): Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• STEP 1: REGISTRATION (SCREENING): Participant must not have medical contraindications to receiving immunotherapy, including history of non-infectious pneumonitis that required steroids or active autoimmune disease that has required systemic treatment with disease modifying agents, corticosteroids or immunosuppressive drugs in the past two years. Replacement therapy (e.g. thyroxine for pre-existing hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Intra-articular steroid injections are allowed

• STEP 1: REGISTRATION (SCREENING): NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

  • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
  • For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
• STEP 2: RANDOMIZATION: Participants must have met all eligibility criteria for Step 1 Registration

• STEP 2: RANDOMIZATION: Participants must have MP2 MammaPrint result

  • For participants submitting tissue for on-study MammaPrint testing:

    • Participants must be registered to Step 2: Randomization within 84 calendar days (12 weeks) after receiving an MP2 status from the MammaPrint Index score. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) from initial tumor biopsy OR

  • Submitting commercial MammaPrint Index Score:

    • If a MammaPrint Index Score report from within the last 12 weeks is already known and is MP2 status, the participant must be registered to Step 2 immediately following Step 1 registration provided they meet all other criteria. MP2 status is defined as a MammaPrint Index score between negative 1.0 and negative 0.57 (-1.0 to -0.57, including negative 0.57) tested from initial tumor biopsy
• STEP 2: RANDOMIZATION: Participants must not have received live vaccines within 28 days prior to study Step 2: Randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines and coronavirus disease 2019 (COVID-19) vaccines are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and are not allowed
• STEP 2: RANDOMIZATION: Participants must not be planning to receive any concurrent non-protocol directed chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study
• STEP 2: RANDOMIZATION: Participant must have Zubrod Performance Status of 0-2
• STEP 2: RANDOMIZATION: Participants must not have a history of (non-infectious) pneumonitis that required steroids or evidence of active pneumonitis within two years prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants must not have active autoimmune disease that has required systemic treatment in the past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) prior to Step 2: Randomization. Replacement therapy (e.g. thyroxine for pre-existing hypothyroidism, insulin for type I diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Intra-articular steroid injections are allowed
• STEP 2: RANDOMIZATION: Participant must have a complete medical history and physical exam within 28 days prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Leukocytes >= 3 x 10^3/uL (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Absolute neutrophil count >=1.5 x 10^3/uL (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Platelets >= 100 x 10^3/uL (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Total bilirubin =< institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: AST/ALT =< 3 × institutional ULN (within 28 days prior to Step 2: Randomization)
• STEP 2: RANDOMIZATION: Participants must have a calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• STEP 2: RANDOMIZATION: Participants must not have uncontrolled diabetes defined as hemoglobin A1c of 9.0% or greater, within 28 days prior to Step 2: Randomization.
• STEP 2: RANDOMIZATION: Participants with history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have an undetectable viral load on the most recent test results obtained within 6 months prior to Step 2: Randomization
• STEP 2: RANDOMIZATION: Participants with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on the most recent test results obtained while on suppressive therapy within 6 months prior to Step 2: Randomization, if indicated
• STEP 2: RANDOMIZATION: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load on the most recent test results obtained within 6 months prior to Step 2: Randomization, if indicated
• STEP 2: RANDOMIZATION: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method during protocol therapy and for 6 months following completion of protocol therapy with details provided as a part of the consent process and must have a negative pregnancy test at screening. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. Participants should not breastfeed during protocol therapy and for 6 months following completion of protocol therapy.
• STEP 2: RANDOMIZATION: Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System
• STEP 2: RANDOMIZATION: Participants who can complete questionnaires in English, or Spanish must be offered the opportunity to participate in the Quality of Life study
• STEP 2: RANDOMIZATION: NOTE: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• STEP 2: RANDOMIZATION: Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

Eligibility

Inclusion Criteria:

• Participants must have histologically confirmed estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative breast cancer (TNBC) defined as ER < 5%, PR < 5%, and HER2 negative (per 2020 American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines)

  • NOTE: Participants with weakly ER or PR positive disease, defined as ER and/or PR between 1-4% by immunohistochemistry, are eligible if adjuvant endocrine therapy is not recommended/planned by the treating physician

• Participants must have American Joint Committee on Cancer (AJCC) 8 anatomic tumor clinical stage either

  • T2-T4, N0, M0 or
  • T1-T3, N1-2, M0
  • Note: All participants with clinically suspicious nodes must undergo core needle biopsy or fine needle biopsy per standard clinical practice to pathologically confirm nodal status

• Participants must have breast and axillary imaging with mammogram and/or ultrasound and/or magnetic resonance imaging (MRI) within 49 days prior to randomization

  • Note: Participants with bilateral invasive breast cancer are eligible if both breast cancers are ER-negative, PR-negative, and HER2-negative provided they meet the other eligibility criteria
• Participants must not have T4/N+, any N3, or inflammatory breast cancer
• Participants must not have metastatic disease (M1)
• Participants must not have received prior systemic therapy or radiation therapy with curative intent for the current breast cancer
• Participants must not have had previous definitive ipsilateral breast surgery for the current breast cancer
• Participants must not have current or anticipated use of other investigational agents while participating in this study
• Participants must not have history of allergic reactions attributed to compounds of similar chemical or biologic composition as study agents
• Participants must not have severe hypersensitivity (>= grade 3) to pembrolizumab or any of its excipients
• Participants must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137)
• Participants must not be currently participating in or have participated in a study of an investigational agent or used an investigational device within 28 days prior to randomization
• Participants must be >= 18 years old
• Participants must have Zubrod performance status of 0-2
• Participants with evidence of peripheral neuropathy must have it at =< grade 1, by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0, within 28 days prior to randomization
• Participants must have a complete medical history and physical exam within 28 days prior to randomization

• Hemoglobin >= 9.0 g/dL or >= 5.6 mol/L (within 28 days prior to randomization)

  • (Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks)
• Leukocytes >= 3 x 10^3/uL (within 28 days prior to randomization)
• Absolute neutrophil count >= 1.5 x 10^3/uL (within 28 days prior to randomization)
• Platelets >= 100 x 10^3/uL (within 28 days prior to randomization)
• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN), OR direct bilirubin =< IULN for participants with total bilirubin > 1.5 x IULN (unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional IULN) (within 28 days prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional upper limit of normal (ULN) (within 28 days prior to randomization)
• Participants must have a serum creatinine =< the IULN OR calculated creatinine clearance >= 50 mL/min/1.73m^2 using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration
• Participants must have adequate cardiac function. Participants must have left ventricular ejection fraction >= 50% as assessed by either echocardiography (ECHO) or multigated acquisition scan (MUGA) assessed within 28 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification and must be class 2B or better
• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at randomization and have undetectable viral load test on the most recent test results obtained within 6 months prior to randomization

• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to randomization, if indicated

  • Note: No testing for Hepatitis B is required unless mandated by local health authority

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to randomization, if indicated

  • Note: No testing for hepatitis C is required unless mandated by local health authority
• Participants with history of diabetes must not have uncontrolled diabetes in the opinion of the treating investigator
• Participants must not have uncontrolled hypertension in the opinion of the treating investigator
• Participants must not have had a major surgery within 14 days prior to randomization. Participants must have fully recovered from the effects of prior major surgery in the opinion of the treating investigator
• Participants must not have severe or active infections within 14 days prior to Randomization, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia
• Participants must not have a diagnosis of immunodeficiency and be receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
• Participants must not have active autoimmune disease that has required systemic treatment in 2 years prior to randomization (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
• Participants must not have a history of (non-infectious) pneumonitis that required steroids, or has current (non-infectious) pneumonitis
• Participants must not have received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist [registered trademark]) are live attenuated vaccines and are not allowed
• Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the treatment regimen
• Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
• Participants must have one (1) physical 4-5-micron single hematoxylin and eosin (H&E) slide from the archival pretreatment diagnostic biopsy available for submission
• Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• Participants who can complete questionnaires in English, Spanish, or French must be offered the opportunity to participate in the Patient-Reported Outcome study

• NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

  • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
  • For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
• As part of the registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Eligibility

5.1.      Inclusion Criteria

1. Must be at least 18 years of age.

2. An ECOG performance status of ≤ 2.

3. Life expectancy of ≥ 9 months.

4. Able to eat and digest food normally. Patients with colostomies are allowed.

5. Must meet the following:

• Newly diagnosed metastatic or unresectable locally advanced (i.e., surgery with curative intent is not an option) colorectal adenocarcinoma and about to start first line chemotherapy. Patients must not have relapsed within 6 months after completing prior treatment for early-stage disease.

• Determined by the Investigator to be ready to receive their second dose of chemotherapy.

• If currently participating in the clinical trial under the original protocol and the patient is willing to continue the study drug for a maximum total of 12-weeks of study drug treatment once Amendment #1 is IRB / IEC approved, the updated consent has been signed during the patient’s participation, and the patient is still receiving study drug treatment as part of the 28-day study.

6. Starting chemotherapy routines allowed are: FOLFOX, FOLFIRI, or FOLFIRINOX with or without bevacizumab, or other monoclonals or other FDA approved agents to be dosed every 2 weeks. The primary cancer therapy (dose, schedule, or drugs) may be changed as medically indicated.

7. Must have a BMI ≤ 33 kg/m2.

8. Must be able and willing to safely self-inject daily or be injected by a caregiver.

9. Must have evaluable disease by RECIST 1.1.

10. Must have adequate end organ function as defined by:

• Bone marrow function

o Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

o Platelets ≥ 100 × 109/L, or adequate as determined by the medical judgement of the investigator; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by the Medical Monitor/Sponsor

o Hemoglobin ≥ 9 g/dL, or adequate as determined by the medical judgement of the investigator; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor

• Hepatic function

o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); if liver metastases, then ≤ 5 × ULN; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor.

o Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s Syndrome; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor unless approved by Medical Monitor/Sponsor

o Albumin between 3.4 and 5.4 gm/dL or within institutional normal limits, or not considered clinically significant by the investigator; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor

• Renal function

o Creatinine clearance ≥ 50 mL/min (calculated by methodology selected at the local lab); lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor. See Appendix 2 [Section 10.2]).

• Metabolic function

o Normal hemoglobin A1c levels based on institutional normal limits, or not considered clinically significant by the investigator; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor.

11. NT-Pro-BNP and Troponin (TnI or TnT) are within normal limits or not considered to be clinically significant by the investigator; lab may be repeated as needed to rule out initial transient lab abnormality that does not require medical intervention unless approved by Medical Monitor/Sponsor.

12. If a female of childbearing capability, must have a negative pregnancy test within 2 weeks of starting treatment.

13. Fertile men and women must agree to use adequate contraception for the duration of the trial.

14. Willing and able to sign informed consent.

5.2. Exclusion Criteria

Patients are excluded from the study if any of the following criteria apply:

1. Patients receiving second line or later systemic treatment .

2. Patients with swallowing abnormalities, malabsorption syndromes, short or inflammatory bowel syndromes, or other conditions that in the Investigator’s opinion could impair food consumption or metabolism.

3. History of weight loss surgery including gastric stapling, or bypass surgery.

4. Unintentional weight loss ≥ 10% of usual body weight in 4 months prior to Screening or other weight loss considered significant by the Investigator.

5. Currently using any new agent designed to increase appetite or otherwise affect weight (increase or decrease). Antiemetics to control nausea are acceptable.

• THC containing agents (e.g., dronabinol, cannabis) or other weight promoting agents including androgenic compounds (e.g., testosterone, oxandrolone), dopamine antagonists, or megestrol acetate within the past 6 months is excluded. Chronic (> 6 months) use is allowed for THC.

• Newly prescribed glucocorticoids for less than four weeks at the time of Screening and whose weight is not yet stable are excluded. Stable (dose unchanged for 4 weeks or more) and low dose (<5 mg per day) corticosteroids are permissible, as are inhaled corticosteroids.

• Drugs like Olanzapine are allowed and only when used as an antiemetic, as needed (PRN). If used for treating cachexia, drugs like Olanzapine are not allowed.

6. Chronic and ongoing use of corticosteroids at a dose of ≥ 5 mg of prednisone or equivalent per day.

7. History of bulimia or anorexia.

8. Pregnancy, lactation, or plans to become pregnant.

9. History of another malignancy except basal cell carcinoma of the skin, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy that has previously undergone potentially curative therapy.

10. Concurrent participation in any other clinical trial.

11. Patients with known brain or CNS metastases.

12. Impaired cardiac function or significant cardiac issues including, but not limited to, any of the following:

a. Greater than class II NYHA congestive heart failure

b. Congenital long QT syndrome

c. QTc > 470 msec (as calculated by institution standards) confirmed by two ECGs ≥ 1 minute apart (interval corrected using [Bazett’s formula [QTcB])

d. Unstable angina pectoris

e. Acute myocardial infarction ≤ 6 months prior to study entry (ie, screening and enrollment)

13. Known hypersensitivity to B07 or its formulation.

14. Known diagnosis of HIV infection (HIV testing is not mandatory).

15. Active infection with Hepatitis B, Hepatitis C, or active systemic viral disease or active severe infection. Patients with a history of HIV regardless of viral load are excluded.

16. Unwilling or unable to comply with the protocol.

17. Any condition that, in the Investigator’s opinion, would impair the patients’ ability to participate in this study.

Eligibility

1. Provision to sign and date the consent form
2. Able to comply with all study procedures and be available for the duration of the study in the investigator's judgment
3. Age ?18
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of ? 1
5. Histologically or cytologically confirmed advanced or metastatic colorectal adenocarcinoma

6. Prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab (unless contraindicated) and cetuximab/panitumumab (for RAS-wild type disease) for the treatment of advanced or metastatic colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen.

   1. Patients who progressed on irinotecan- and oxaliplatin-based regimens previously for metastatic disease should not be retreated with these agents prior to enrolling on this study.
   2. Patients who developed locally advanced/metastatic disease during or within 6 months of completing adjuvant therapy are eligible and the adjuvant/neoadjuvant therapy can be counted as one regimen of chemotherapy for advanced disease. Patients who developed locally advanced/metastatic disease > 6 months after completion of adjuvant therapy must be treated with the above therapies in the advanced setting to be eligible.
7. Mismatch repair proficient (MMRp) status documented by local IHC testing
8. RAS and BRAF status documented
9. Measurable disease according to RECIST v1.1
10. Able to swallow and absorb oral medication

11. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 72 hours prior to first dose of study drug treatment:

    1. ANC ? 1.5 Ã? 109/L
    2. Platelet count ? 70 Ã? 109/L
    3. Hemoglobin ? 9 g/dL in the previous week
    4. Serum bilirubin ? 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ? 3.0 Ã?ULN
    5. Aspartate aminotransferase (AST) and alanine aminotransferase ALT) < 3 Ã? upper limit of normal (ULN) (in the presence of liver metastases ? 5 Ã? ULN)
    6. Estimated creatinine clearance ? 30 mL/min by Cockcroft-Gault Equation (or similar formula) or as calculated using a timed urine collection
12. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (? 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
13. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion criteria:

1. Patients with known MSI-high or mismatch repair deficient (dMMR) status or in whom the status of both are unknown
2. Patients with BRAF V600 mutations
3. Prior treatment with regorafenib, trifluridine-tipiracil (TAS-102), or fruquintinib.
4. Major surgery within 14 days of C1D1. Minor procedures (e.g. biopsies, central venous catheters) are not considered major surgery.
5. Patients must have recovered from clinically significant AEs of their most recent prior therapy/intervention prior to enrollment as determined by relevant clinical and laboratory parameters.
6. Untreated CNS metastases or known leptomeningeal disease. Patients with treated CNS metastases (either by surgical or radiation techniques) are eligible provided there is no evidence of progression for at least 4 weeks after CNS-directed therapy as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
7. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessments of the investigational regimen. Patients whose prior or concurrent malignancy natural history and/or treatment does NOT have the potential to impact safety or study assessments are eligible.

8. Uncontrolled intercurrent illness (defined as but not limited to others in the opinion of the treating investigator):

   1. Uncontrolled pleural effusion, pericardial effusion or ascites defined as requiring recurrent drainage procedures within 3 weeks of C1D1
   2. Uncontrolled arrhythmia or any ventricular arrhythmia requiring treatment
   3. Uncontrolled hypertension (? 160 mmHg systolic or ? 100mmHg diastolic in spite of maximal medical therapy)
   4. Urine dipstick or urinalysis with protein ? 2+ or 24-hour urine protein ? 1.0g/24 hours. Patients with 1+ proteinuria must undergo a urine protein creatinine ratio (UPCR) or 24-hour urine collection to assess protein level. For interpretation of lab values for proteinuria please see Appendix E.
   5. New York Heart Association (NYHA) Functional Classification class 3 or 4 congestive heart failure or left ventricular ejection fraction < 50%
   6. Severe or unstable angina within 3 months prior to C1D1
   7. Active infection requiring IV antibiotics within 1 week prior to C1D1. Antibiotics used for prophylactic purposes are allowed.
   8. Corrected QT interval using the Fridericia method > 470 msec (repeated demonstration of the QTcF interval if > 470 msec during first assessment) or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as congenital long QT syndrome or family history of long QT syndrome
9. History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of obstruction, perforation or fistulas, and any other condition that could, in the investigator's judgment, result in significant gastrointestinal hemorrhage or perforation, within 6 months prior to C1D1.
10. History or presence of hemorrhage from any other site (e.g. hemoptysis or hematemesis) within 3 months prior to C1D1.
11. History of a venous thromboembolic event (e.g. deep vein thrombosis or pulmonary embolism) within 3 months prior to C1D1.
12. History of an arterial thromboembolic event (e.g. stroke/CVA, transient ischemic event, unstable angina, acute myocardial infarction/coronary artery bypass surgery) within 6 months prior to C1D1.
13. Tumor invasion of a large vascular structure (e.g. pulmonary artery, superior or inferior vena cava).
14. Inability to discontinue medications with a known risk of causing QT prolongation and/or torsades de pointes within 7 days of C1D1.
15. Use of strong or moderate inducers of CYP3A within 7 days of C1D1.
16. Patients with AIDS. HIV-infected patients on effective anti-retroviral therapy with an undetectable viral load during the screening period are eligible.
17. For patients with known chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy during the screening period. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load during the screening period.
18. Recent COVID-19 diagnosis (symptomatic or asymptomatic). To become eligible (following symptomatic infection), the patient must not have fever for 24 hours (without using medicine to reduce fever), other symptoms have improved, and at least 10 days have passed since onset of symptoms. To become eligible (following asymptomatic infection, e.g. positive test only), at least 10 days have passed since the positive test. In either case, a repeat COVID-19 test is not required. Likewise, a persistently positive test (if obtained) does not continue to exclude the patient should the other criteria be satisfied.
19. History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications or their classes
20. Inability to swallow, retain and/or absorb oral medications
21. Pregnant or lactating or intending to become pregnant during the study interval
22. Other uncontrolled serious medical or psychiatric illness that would impact study participation and/or follow up in the opinion of the treating investigator

Eligibility

Inclusion Criteria:

• Histologically confirmed diagnosis of endometrioid endometrial carcinoma.
• Documented evidence of advanced or recurrent endometrial cancer that is not amenable to surgery/radiation for curative intent.
• Participant has received at least 1 but not more than 3 prior systemic therapies. Prior therapy must include platinum-based chemotherapy and a checkpoint inhibitor, either separately or in combination.
• PI3K/AKT/mTOR pathway gene alteration identified.
• At least 1 measurable target lesion according to RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of ? 1 at Screening.
• Non-pregnant, non-lactating females who are postmenopausal, surgically sterile or who agree to use effective contraceptive methods..

Exclusion Criteria:

• Participants with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study
• Active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas [e.g., breast, cervix, bladder], or basal or squamous cell carcinoma of the skin) within the past 24 months prior to treatment. Fully resected localized malignancies are eligible.
• Gastrointestinal malabsorption, gastrointestinal anastomosis, bowel obstruction, or any other condition that might affect the absorption of study treatment.
• Clinically significant hemoptysis or tumor bleeding.
• Significant cardiovascular impairment.
• Active, uncontrolled (requiring systemic antimicrobial therapy) infection.
• Concurrent participation in another therapeutic clinical trial.
• Prior radiation therapy within 21 days prior to start of study treatment.
• Strong CYP3A4 inhibitors, strong CYP1A2 inhibitors or CYP1A2 inducers, or clinically significant CYP3A4 inducers within 7 days before the first dose of study intervention, or participants who require treatment with strong CYP3A4 inhibitors or inducers during the study.
• Participants who require PPIs or chronic use of antacids, histamine H2 receptor blockers, or other treatments to raise gastric pH.
• Prolongation of QTc interval to >480 ms.
• HbA1c ? 8.0%, fasting serum glucose > 160 mg/dL, fasting triglycerides > 300 mg/dL or receiving treatment with insulin.

Eligibility

Key inclusion criteria include but are not limited to:

• Has a histologically confirmed diagnosis of primary advanced or recurrent endometrial carcinoma that has been confirmed as proficient mismatch repair (pMMR)
• Has radiographically evaluable disease, with measurable Stage III or either measurable or non-measurable Stage IV or recurrent disease per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1), as assessed by the investigator.
• Has received no prior systemic therapy for endometrial carcinoma except the following conditions as pre-specified by the protocol: 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of curative-intent, prior radiation with or without radiosensitizing chemotherapy if >2 weeks before the start of induction treatment, or prior hormonal therapy for treatment of endometrial carcinoma that was discontinued ?1 week before the start of induction treatment

Key exclusion criteria include but are not limited to:

• Has carcinosarcoma, neuroendocrine tumors or endometrial sarcoma, including stromal sarcoma, leiomyosarcoma, adenosarcoma, or other types of sarcomas
• Has endometrial carcinoma of any histology that is mismatch repair deficient (dMMR)
• Is a candidate for curative-intent surgery or curative-intent radiotherapy at the time of enrollment
• Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
• Human Immunodeficiency Virus-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Received prior therapy in any setting with any of the following: anti-programmed cell death 1 protein, anti-programmed cell death ligand 1, anti-programmed cell death ligand 2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor; trophoblast cell surface antigen 2-targeted antibody drug conjugate; or topoisomerase I inhibitor-containing antibody drug conjugate

Eligibility

Eligibility

Inclusion Criteria:

• PRE-REGISTRATION: Histological or cytological evidence of prostate cancer. Patients with variant histologies including neuroendocrine, small cell and sarcomatoid prostate cancer are allowed to enroll and these will not be used as selection criteria for individual arms. Central pathology review is not required.
• PRE-REGISTRATION: Measurable disease and/or non-measurable metastatic disease per RECIST version 1.1.
• PRE-REGISTRATION: Tissue procured within 12 months of pre-registration (metastatic disease preferred over primary tissue, though both are acceptable) available for submission per Section 6.2. For patients who have progressed on A032102 and are pre-registering again, repeat tissue procurement will not be mandated.
• PRE-REGISTRATION: Molecular report available performed as part of standard of care testing via any Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing (NGS) assay. Patients may be assigned based on pre-determined qualifying molecular/DNA alterations as stated in Section 4.8 after receipt of local molecular testing by the A032102 molecular tumor board (MTB). Final determination of arm assignment will be determined by the MTB. For qualifying DNA alteration determined by the MTB, testing may be from tumor tissue collected at any time or circulating tumor DNA (ctDNA) within 12 months of pre-registration. If no qualifying DNA alteration is identified based on the CLIA-certified next generation sequencing assay and MTB review, Caris testing, should be performed for both DNA/RNA profiling. Arm assignment based RNA requires testing of tumor tissue collected within 12 months of pre-registration and MTB review.
• PRE-REGISTRATION: Age ≥ 18 years.

• REGISTRATION: Progressive mCRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND one or more of the following criteria (choose all the apply):

  • PSA progression, defined by at least 2 consecutive rising PSA values at a minimum of 1-week intervals with the most recent PSA value being 2.0 ng/mL or higher, if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal of anti-androgen therapy.
  • Radiographic progression per RECIST 1.1 criteria for soft tissue lesions
  • Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3) criteria.
• REGISTRATION: Patients selected to receive lutetium Lu 177 vipivotide tetraxetan treatment are required to have prostate-specific membrane antigen (PSMA) positive mCRPC as determined by investigator assessment. For reference, in the VISION trial this was defined as at least 1 PSMA+ metastatic lesion (defined as uptake greater than that of liver parenchyma in lesions of any size in any organ system) and no PSMA- lesions (defined as uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any solid organ lesion with a short axis of at least 1.0 cm, or in any bone lesion with a soft-tissue component of at least 1.0 cm in the short axis).
• REGISTRATION: Prior treatment with androgen receptor signaling inhibitor (ARSI) in either the metastatic hormone sensitive setting or mCRPC is required. Prior taxane therapy in either metastatic hormone sensitive setting or mCRPC is mandated unless patient is taxane ineligible or the patient refuses taxane therapy. Prior lutetium LU177 vipivotide tetraxetan treatment is permitted but not mandated. Patients with known germline or somatic deleterious BRCA 1/2 mutations must have received a prior PARPi.

• REGISTRATION: Resolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 for at least 3 months prior to registration and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, comprised of:

  • Chemotherapy-induced neuropathy
  • Fatigue
  • Residual toxicities from prior treatment: Grade 1 or grade 2 endocrinopathies which may include: Hypothyroidism/hyperthyroidism. type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo)
• REGISTRATION: No cytotoxic, biologic, radiopharmaceutical or other non-kinase inhibitor investigational agent within 4 weeks of registration. Treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitor) within 2 weeks of registration. Treatment with abiraterone acetate, apalutamide, or darolutamide within 2 weeks of registration. Treatment with enzalutamide within 4 weeks of registration. No treatment with radiation therapy within 2 weeks of registration.
• REGISTRATION: No major surgery within 4 weeks of registration.
• REGISTRATION: No prior treatment with EZH inhibitors.
• REGISTRATION: Prior treatment with cabazitaxel + carboplatin.

• REGISTRATION: None of the following conditions:

  • Current use of moderate or strong cytochrome P450 (CYP)3A inducers.
  • Known or suspected hypersensitivity to valemetostat tosylate (DS-3201b) or any of the excipients.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

  * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

  • Imminent or established spinal cord compression based on clinical and/or imaging findings.
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to registration after radiotherapy or at least 4 weeks prior to registration after major surgery (e.g., removal or biopsy of brain metastasis). Patients must have complete wound healing from major surgery or minor surgery before registration.
  • Significant cardiovascular defined as:
  • Myocardial infarction within 6 months prior to enrollment.
  • Uncontrolled angina pectoris within 6 months prior to enrollment.
  • New York Heart Association Class 3 or 4 congestive heart failure.
  • Corrected QT interval calculated by the Fridericia's formula (QTcF) ≥ 470 ms per electrocardiogram (ECG) within 42 days before randomization in any individual with any history of any cardiac disease or medication which can impact QTcF. Patients with known history or current symptoms of cardiac disease, history of treatment with cardiotoxic agents, or agents/conditions known to impact QTcF should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification and ECG.
  • Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or diastolic blood pressure > 100 mmHg).
  • Clinically significant acute infection requiring systemic antibacterial, antifungal or antiviral therapy.
  • Moderate to severe hepatic impairment (Child-Pugh Class C)
• REGISTRATION: No freezing or donating sperm ≤ 14 days prior to registration.
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• REGISTRATION: No granulocyte colony-stimulating factor (GCSF) within 2 weeks of registration.
• REGISTRATION: No red blood cell (RBC) transfusions within 2 weeks of registration.
• REGISTRATION: No platelet transfusions within 2 weeks of registration.
• REGISTRATION: No bleeding diathesis.
• REGISTRATION: White blood cell count (WBC) ≥ 2,500/mcL.
• REGISTRATION: Absolute neutrophil count (ANC) ≥ 1,500/mcL.
• REGISTRATION: Hemoglobin ≥ 9 g/dL.
• REGISTRATION: Platelet count ≥ 100,000/mcL.
• REGISTRATION: Creatinine clearance ≥ 30 mL/min as defined by Cockcroft-Gault equation.
• REGISTRATION: Total bilirubin ≤ 1.5 x ULN (? 3 x upper limit of normal [ULN] for subjects with documented Gilbert's disease).
• REGISTRATION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.
• REGISTRATION: Albumin ≥ 2.8 g/dL.
• REGISTRATION: The A032102 molecular tumor board will review the local pathology report and molecular sequencing report, and the Alliance registration/randomization office will relay the assignment to the submitting site. Once the site receives this assignment, they can register the patient to A032102. Any questions about the molecular board treatment assignments can be directed to A032102@alliancenctn.org.
• RE-REGISTRATION: Progressive mCRPC (after receiving the tumor board assigned therapy) as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND 2) progressive disease defined by radiographic progression on conventional imaging (CT/MRI chest, abdomen and pelvis and bone scan within 42 days of re-registration).

• RE-REGISTRATION: Resolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) resolved to CTCAE version 5.0, grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 for at least 3 months prior to registration and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, comprised of:

  • Chemotherapy-induced neuropathy
  • Fatigue
  • Residual toxicities from prior treatment: Grade 1 or grade 2 endocrinopathies which may include: Hypothyroidism/hyperthyroidism. type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo).

• RE-REGISTRATION: None of the following conditions:

  • Imminent or established spinal cord compression based on clinical and/or imaging findings.
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to registration after radiotherapy or at least 4 weeks prior to re-registration after major surgery (e.g., removal or biopsy of brain metastasis). Patients must have complete wound healing from major surgery or minor surgery before re-registration.
  • Corrected QT interval calculated by the Fridericia's formula (QTcF) < 470 ms per ECG within 42 days before randomization in any individual with any history of any cardiac disease or medication which can impact QTcF.
  • Significant cardiovascular defined as:
  • Myocardial infarction within 6 months prior to enrollment.
  • Uncontrolled angina pectoris within 6 months prior to enrollment.
  • New York Heart Association Class 3 or 4 congestive heart failure.
  • Uncontrolled hypertension (resting systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg).
• RE-REGISTRATION: ECOG Performance Status 0-2.
• RE-REGISTRATION: No GCSF within 2 weeks of registration.
• RE-REGISTRATION: No RBC transfusions within 2 weeks of registration.
• RE-REGISTRATION: No platelet transfusions within 2 weeks of registration.
• RE-REGISTRATION: WBC ≥ 2,500/mcL.
• RE-REGISTRATION: ANC ≥ 1,500/mcL.
• RE-REGISTRATION: Hemoglobin ≥ 9 g/dL (transfusions permitted).
• RE-REGISTRATION: Platelet count ≥ 100,000/mcL.
• RE-REGISTRATION: Creatinine clearance ≥ 30 mL/min as defined by Cockcroft-Gault equation.
• RE-REGISTRATION: Total bilirubin ≤ 1.5 x ULN (? 3 x ULN for subjects with documented Gilbert's disease).
• RE-REGISTRATION: AST and ALT ≤ 3 x ULN.
• RE-REGISTRATION: Albumin ≥ 2.8 g/dL.
• RE-REGISTRATION: QT Interval (QTcF) < 470 ms (in individuals with any cardiac history of any medication or condition known to impact QTcF).
• RE-REGISTRATION: The A032102 molecular tumor board will review the CARIS molecular sequencing report, the Alliance registration/randomization office will relay the assignment to the site. Any questions about the molecular board treatment assignments can be directed to A032102@alliancenctn.org.

Eligibility

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Has one of the following cancers:

  • Unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC)
  • Unresectable or metastatic adenocarcinoma of the biliary tract [intra- or extrahepatic holangiocarcinoma (CCA) or gallbladder cancer (GBC)]
  • Unresectable or metastatic colorectal adenocarcinoma
  • Unresectable or metastatic gastric adenocarcinoma
  • Gastroesophageal junction adenocarcinoma (GEJAC)
  • Esophageal adenocarcinoma (EAC)
• Has received prior therapy for the cancer
• Has a life expectancy of at least 3 months
• If human immunodeficiency virus (HIV) infected, must have well controlled HIV on antiretroviral therapy (ART)

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids or has current ILD/pneumonitis, and/or suspected ILD/pneumonitis
• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
• Has uncontrolled or significant cardiovascular disease
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Has not adequately recovered from major surgery or has ongoing surgical complications
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

Eligibility

Eligibility

Inclusion Criteria:

• Participants must have advanced or locally unresectable gastric, gastroesophageal junction or esophageal adenocarcinoma
• Participants must have PD-L1 CPS (Combined Positive Score) ? 1. This test would have been performed as part of standard of care (SOC) pathology testing, using tissue obtained within two years prior to registration and collected prior to or after a frontline regimen
• Participants must have a histologically confirmed diagnosis of microsatellite stable (MSS) and HER2 negative gastric, gastroesophageal junction, or esophageal adenocarcinoma
• Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging completed prior to registration. Imaging must have been completed within 28 days prior to registration for participants with measurable disease. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form
• Participants with treated brain metastases must have no evidence of progression on the follow-up brain imaging after central nervous system (CNS)-directed therapy. All treatment for brain metastases must have been completed at least 28 days prior to registration
• Participants must have disease progression or intolerance to frontline standard of care (SOC) chemotherapy plus either nivolumab, pembrolizumab or any other PD-1 or PD-L1 inhibitor. Peri-operative chemotherapy plus nivolumab, pembrolizumab or any other PD-1 or PD-L1 inhibitor will count as one line if disease progression occurs while on the therapy or within 6 months of completing the chemotherapy plus nivolumab or pembrolizumab or other PD-1/PD-L1 inhibitor cycle
• Participants must not have received more than one prior line of systemic therapy
• Participants must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as long as there has been a washout period for corticosteroids of ? 7 days prior to registration
• Participants must not have prior significant immunotherapy related adverse events requiring permanent discontinuation of the immunotherapy agent including events like pneumonitis, myocarditis, renal failure, Guillain barre syndrome, or myasthenia gravis. Participants with endocrinopathy events leading or not to replacement steroids, thyroid hormone, insulin, or cortisol are eligible
• Participants must not have received a live attenuated vaccination within 28 days prior to registration
• Participants must not have had a major surgery within 28 days or subcutaneous venous access device placement within 7 days prior registration
• Participants must have fully recovered from the effects of prior surgery in the opinion of the treating investigator. Any participants with postoperative bleeding complications or wound complications from a surgical procedure performed in the last eight weeks should be excluded
• Participants must not have plans to undergo elective or planned major surgery during the clinical trial
• Participants must not have active bleeding or prior history of gastrointestinal (GI) perforation, fistula or significant GI bleeding (requiring transfusion, endoscopic or surgical intervention) within 84 days prior to registration
• Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, investigational agents, biologic or hormonal therapy for cancer treatment while receiving treatment on this study
• Participants must not have a history of a grade 3 or 4 allergic reaction attributed to humanized or human monoclonal antibody therapy
• Participants must not have a history of grade 3 or 4 immunotherapy related toxicities with the exception of hormonal abnormalities like thyroiditis or thyroid derangements
• Participants must be ? 18 years old
• Participants must have Zubrod Performance Status of 0-2
• Participants must have a complete medical history and physical exam within 28 days prior to registration
• Leukocytes ? 2 x 10^3/uL within 28 days prior to registration
• Absolute neutrophil count ? 1.2 x 10^3/uL within 28 days prior to registration
• Hemoglobin ? 9.0 g/dL within 28 days prior to registration
• Platelets ? 100 x 10^3/uL within 28 days prior to registration
• Total bilirubin ? 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to registration) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin ? 5 x institutional ULN
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ? 3 Ã? institutional ULN (within 28 days prior to registration) (unless liver metastases are present, in which case they must be ? 5 x ULN)
• Participants must have a creatinine ?1.5 x the institutional ULN OR calculated creatinine clearance ? 40 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration
• Participants' urinary protein must be ? 1+ on dipstick or routine urinalysis (UA) within 28 days of registration. Random analysis of urine protein with a normal value is sufficient. If urine dipstick or routine analysis indicated proteinuria ? 2+, then a 24-hour urine is to be collected and demonstrate < 1000 mg of protein in 24 hours to allow participation in the study
• Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2 or better
• Participants must have recovered to baseline or < grade 2 CTCAE version (v) 5.0 from toxicities related to any prior treatments, unless AE(s) are clinically stable on supportive therapy
• Participants must not have experienced arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to registration
• Participants must not have uncontrolled blood pressure within 28 days prior to registration as determined by the treating investigator
• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load on the most recent test results obtained within 6 months prior to registration
• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load on the most recent test results obtained within 6 months prior to registration, if indicated
• Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
• Participants must not have a history of inflammatory bowel disease, (including ulcerative colitis and Crohn's disease), symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis). Note: Participants with Graves' disease will be allowed
• Participants must not have a history of pneumonitis that has required oral or IV steroids within the last 12 months prior to registration
• Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• Participants who can complete patient reported outcomes (FACT-Ga and PRO-CTCAE) questionnaires in English or Spanish must participate in the quality of life studies
• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations

Eligibility

Inclusion Criteria:

• Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is metastatic and/or unresectable

• Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obtained prior to treatment initiation to a central laboratory

  • If archival tissue is not available, a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to start of study treatment
• HER2+ disease as determined by a tissue based assay performed at a central laboratory.
• Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease as determined by local or central testing

• Radiographically measurable disease per RECIST v1.1 with:

  • At least one site of disease that is measurable and that has not been previously irradiated, or
  • If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• CNS Inclusion - based on contrast brain magnetic resonance imaging, participants may have any of the following:

  • No evidence of brain metastases
  • Previously treated brain metastases which are asymptomatic

Exclusion Criteria:

• Prior systemic anticancer therapy for colorectal cancer (CRC) in the metastatic setting

  • May have received chemotherapy for CRC in the adjuvant setting if it was completed >6 months prior to enrollment
• Radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of stereotactic radiosurgery)
• Previous treatment with anti-HER2 therapy
• Ongoing Grade 3 or higher neuropathy
• GI perforation within 12 months of enrollment

Eligibility

Inclusion Criteria:

• PRE-REGISTRATION: Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Variant histology, including neuroendocrine differentiation, is allowed if urothelial cancer is predominant histology (any amount of squamous differentiation is allowed provided the tumor is not a pure squamous cell cancer)
• PRE-REGISTRATION: Patient must have had radical cystectomy and lymph node dissection >= 3 weeks, but =< 12 weeks prior to pre-registration. Patients who have had a partial cystectomy as definitive therapy are not eligible
• PRE-REGISTRATION: No gross cancer at the surgical margins. Microscopic invasive urothelial carcinoma at the surgical margins (i.e., "positive margins") are allowed. Carcinoma in situ (CIS) at margins is considered negative margins
• PRE-REGISTRATION: No evidence of residual cancer or metastasis after cystectomy (imaging is not required prior to pre-registration but is required prior to registration)

• PRE-REGISTRATION: Have undergone a radical cystectomy with pathological evidence of urothelial carcinoma of the bladder at high risk of recurrence as described in one of the two scenarios below (i or ii). The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized.:

  • (i) Patients who have not received neoadjuvant cisplatin-based chemotherapy: pT3-pT4* or pT0/x-pT4/N+ on cystectomy and are not eligible for adjuvant cisplatin chemotherapy

    • (i) Patients ineligible for cisplatin due to at least one of the following criteria and reason for ineligibility should be documented:

      • (i) Creatinine Clearance (using Cockcroft-Gault): < 60 mL/min
      • (i) Common Terminology Criteria for Adverse Events (CTCAE) version 5, grade >= 2 audiometric hearing loss
      • (i) CTCAE version 5, grade >= 2 or above peripheral neuropathy
      • New York Heart Association Class III heart failure
      • (i) Eastern Cooperative Oncology Group (ECOG) performance status = 2

    • (i) Patients who are eligible for cisplatin may be candidates if they refuse available adjuvant chemotherapy, despite being informed by the investigator about the treatment options. The patient's refusal must be documented.

      • (i) Patients with pT2N0 urothelial cancer on cystectomy (without prior neoadjuvant chemotherapy) with ctDNA(+) Signatera results based on an assay performed post-cystectomy as part of routine care outside of the study may proceed with pre-registration but require confirmation of ctDNA(+) Signatera testing on repeat "central testing" in the context of A032103 testing. Patients with pT2N0 with central testing not confirming ctDNA(+) will not be eligible for A032103 (Note: this is distinct from patients with ypT2N0 who are eligible based on ii).
  • (ii) Patients who received cisplatin-based neoadjuvant chemotherapy: ypT2-ypT4 or ypT0/x-pT4/N+ on cystectomy
• PRE-REGISTRATION: Available tumor tissue for central Signatera testing to be submitted after pre-registration. Central testing is defined as testing performed as part of the A032103 study prior to registration and is provided by the study and not routine standard commercial testing. Patients who have already had Signatera testing performed as part of routine care will require repeat central testing as part of the A032103 study to be eligible for registration/randomization. Tumor tissue from the cystectomy is preferred over tissue from prior transurethral resection
• PRE-REGISTRATION: Age >= 18 years
• PRE-REGISTRATION: ECOG Performance Status 0-2
• PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
• PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after cystectomy
• PRE-REGISTRATION: No adjuvant radiation after cystectomy
• PRE-REGISTRATION: No treatment with any other type of investigational agent =< 4 weeks before pre-registration
• PRE-REGISTRATION: Not have ever received prior treatment with PD-1/PD-L1 blockade.
• PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade.
• PRE-REGISTRATION: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• PRE-REGISTRATION: Absolute Neutrophil Count (ANC) >= 1,200/mm^3
• PRE-REGISTRATION: Platelet count >= 100,000/mm^3
• PRE-REGISTRATION: Hemoglobin >= 8 g/dL
• PRE-REGISTRATION: Creatinine =< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine clearance > 30 mL/min (using either Cockcroft-Gault formula or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN
• PRE-REGISTRATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• PRE-REGISTRATION: For women of childbearing potential only: A negative urine or serum pregnancy test done =< 14 days prior to pre-registration is required
• PRE-REGISTRATION: Not currently requiring hemodialysis
• PRE-REGISTRATION: No current or prior history of myocarditis
• PRE-REGISTRATION: No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
• PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
• PRE-REGISTRATION: Patients with rheumatoid arthritis and other arthropathies, Sjo?gren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years.
• PRE-REGISTRATION: No known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
• PRE-REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• PRE-REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible.
• PRE-REGISTRATION: No concurrent antineoplastic therapy.
• PRE-REGISTRATION: No current immunosuppressive agents (with the exception of corticosteroids as described below).
• PRE-REGISTRATION: No condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of pre-registration (with the exception of steroid pre-medications for contrast allergies). Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• REGISTRATION: Patient must have had radical cystectomy and lymph node dissection =< 18 weeks prior to registration.

• REGISTRATION: Must have evaluable ctDNA Signatera assay result (i.e., ctDNA[+]or ctDNA[-]) based on test performed as part of central testing after pre-registration to A032103. Central testing is defined as testing performed as part of the A032103. Local/commercial testing results may not be used for registration to A032103

  • Cisplatin-ineligible (or cisplatin-declining) patients with a pT2N0 urothelial cancer on cystectomy who were pre-registered based on routine standard care ctDNA(+) Signatera testing must have confirmed ctDNA(+) Signatera testing on central testing. If central Signatera testing yields a ctDNA(-) result, these patients are ineligible. NOTE: This is a distinct consideration from patients with ypT2-4 and/or ypN+ urothelial cancer (i.e., patients who had received neoadjuvant cisplatin-based chemotherapy) who are eligible with either ctDNA(+) or ctDNA(-) central Signatera testing
• REGISTRATION: All patients must have confirmed disease-free status defined as no measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or definitive non-measurable radiographic metastatic disease, within 60 days prior to registration. Patients with equivocal nodes less than 15 mm in short axis, or < 10 mm in long axis for non-lymph node lesions, not considered by the investigator to represent malignant disease will be eligible. Attempts should be made to resolve the etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.
• REGISTRATION: No major surgery =< 3 weeks before registration.
• REGISTRATION: No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist [registered trademark]) are live attenuated vaccines and are not allowed. Coronavirus disease 2019 (COVID-19) vaccines are not live vaccines and are allowed

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

  • Patient must have converted to ctDNA(+) during serial monitoring performed centrally in the setting of the A032103 study

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

  • No evidence of metastatic disease on the most recent scheduled imaging assessment as outlined in the study calendar (no repeat imaging is necessary specifically at the time of the conversion from ctDNA[-] to ctDNA[+]).

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

  • No change in clinical condition and/or laboratory tests that would impact the safety of nivolumab in the opinion of the treating investigator

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

  • =< 6 weeks from reporting of ctDNA(+) result by Natera.

Eligibility

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology
• Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease shown by computed tomography scan (CT)/magnetic resonance imaging (MRI)
• Has prostate cancer progression while receiving androgen deprivation therapy (ADT) (or post bilateral orchiectomy) within 6 months before screening
• Has disease that progressed during or after treatment with one next-generation hormonal agent (NHA) for hormone sensitive prostate cancer (HSPC) metastatic hormone sensitive prostate cancer (mHSPC) or non metastatic hormone sensitive prostate cancer (nmHSPC), for at least 8 weeks (at least 14 weeks for participants with bone progression) Note: Participants may have received abiraterone acetate and docetaxel or darolutamide and docetaxel for HSPC. However, participants must have received no more than six cycles of docetaxel and had no radiographic disease progression while receiving docetaxel
• Has an eastern clinical oncology group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM)
• Has had prior treatment with Poly polymerase inhibitors (PARPi) or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment
• Has adequate organ function
• Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated. Samples from tumors progressing at a prior site of radiation are allowed
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening
• Participants who have adverse event (AEs) due to previous anticancer therapies must have recovered to ?Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy (HRT) or participants who have ?Grade 2 neuropathy are eligible
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has presence of gastrointestinal condition
• Is unable to swallow capsules/tablets
• Has history of pituitary dysfunction
• Has poorly controlled diabetes mellitus
• Has a history of active or unstable cardio/cerebro-vascular disease, including thromboembolic events
• Has clinically significant abnormal serum potassium or sodium level
• Has any of the following at screening visit: Hypotension: systolic blood pressure (BP) <110 mmHg, or Uncontrolled hypertension: systolic BP >160mmHg or diastolic blood BP >90 mmHg, in 2 out of the 3 recordings with optimized antihypertensive therapy
• History or family history of long QTc syndrome
• Has a history of seizure(s) within 6 months prior to signing the informed consent (IC) or has any condition that may predispose to seizure within 12 months prior to the date of enrollment
• Has a history of clinically significant ventricular arrhythmias or Mobitz II second degree or third-degree heart block without a permanent pacemaker in place
• Has received a taxane-based chemotherapy and or NHA for metastatic castration-resistant prostate cancer (mCRPC)
• Has not adequately recovered from major surgery or have ongoing surgical complications
• Has received prior treatment with radium for prostate cancer
• Is currently being treated with Cytochrome P450 (CYP450)-inducing antiepileptic drugs for seizures
• Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention
• Receives prior radiotherapy within 2 weeks before the first dose of study intervention, or radiation-related toxicities, requiring corticosteroids
• Receives prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
• Has systemic use of strong Cytochrome P450 3A4 (CYP3A4) inducers and P-glycoprotein (P-gp) inhibitors within 2 weeks before the first dose of study intervention
• Has received prior targeted small molecule therapy or NHA treatment within 4 weeks before the first dose of study intervention
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Has known hypersensitivity to the components or excipients in abiraterone acetate, prednisone or prednisolone, enzalutamide, fludrocortisone, dexamethasone, or opevesostat.
• Has a "superscan" bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days prior to the first dose of study intervention
• Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is allowed
• Active infection requiring systemic therapy
• Has concurrent active Hepatitis B virus and Hepatitis C virus infection

Eligibility

Inclusion criteria:

1. Informed consent

2. ≥18 years of age

3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

4. Histologic documentation of prostate adenocarcinoma

5. Metastatic disease, documented by imaging. Imaging performed within 56 days prior to Screening is acceptable

6. Evaluable disease demonstrated by at least 1 of the following:

a. Bone scan

b. Whole-body imaging by computed tomography (CT) or magnetic resonance imaging (MRI)

c. Evidence of mCRPC by prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scan using Food

and Drug Administration or European Medicines Agency or equivalent approved PSMA imaging agents

7. Progressive disease defined by rising PSA at study entry while the participant is on continuous androgen-deprivation therapy (ADT) or status post orchiectomy. Note: A rising PSA requires at least 3 measurements obtained at least 1 week apart showing increase from nadir with the last level >2 ng/mL by local testing.

8. Receipt of prior androgen receptor signaling inhibitor (ie, enzalutamide, apalutamide, abiraterone acetate, or darolutamide) with progression while on therapy

9. Life expectancy ≥12 months

10. Serum testosterone concentration ≤50 ng/dL

11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 Ã? upper limit of normal (ULN) in the absence of liver metastases (ALT and AST ≤5 Ã? ULN in the presence of suggested liver metastases)

12. Total bilirubin ≤1.5 Ã? ULN (≤3 Ã? ULN for Gilbertâ??s syndrome)

13. Creatinine clearance ≥50 mL/min

14. Absolute neutrophil count ≥1.5 Ã? 109/L without any growth factors 7 days prior to Screening

15. Hemoglobin ≥9.0 g/dL with no blood transfusion 14 days prior to Screening

16. Platelet count ≥100 Ã? 109/L with no platelet transfusion 7 days prior to Screening

17. Hemoglobin A1c <6.5%

18. Left ventricular ejection fraction ≥40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan

19. Sexually active male participants must agree to use condoms as an effective barrier method and refrain from sperm donation and/or their female partners of reproductive potential must agree to use a medically acceptable method of effective birth control during the study and for 90 days after the end of the study treatment. Reproductive potential in a sexually mature woman is defined as having not undergone a hysterectomy, bilateral oophorectomy, or bilateral tubal occlusion, and having menstruated at least once in the preceding 24 consecutive months.

20. Ability and willingness to adhere to the study visit schedule and all protocol requirements, including tumor biopsy unless participant has sufficient archival tumor tissue collected within 6 months prior to Screening, has no accessible tumors amenable to biopsy, or biopsy is clinically contraindicated (review with Medical Monitor)

21. Ability to swallow study drug capsules

Inclusion criterion specifically for the Phase 2a pocenbrodib + abiraterone acetate cohort (Cohort 2B)

22. Considered by the Investigator to be sensitive to abiraterone acetate retreatment despite prior therapy

Inclusion criterion specifically for the Phase 2a pocenbrodib + olaparib cohort (Cohort 2C)

23. Evidence of deleterious or suspected deleterious germline or somatic homologous recombination repair geneâ??mutated mCRPC based on an approved companion diagnostic

Inclusion criteria specifically for the Phase 2a pocenbrodib + 177Lu-PSMA-617 cohort (Cohort 2D)

24. Prior treatment with taxane-based chemotherapy

25. Laboratory criteria:

a. White blood cell count ≥3000 µL

b. Serum albumin ≥2.5 g/dL

c. Prothrombin time <1.3 Ã? laboratory ULN or international normalized ratio <1.5 AND activated partial thromboplastin time <1.3 Ã? laboratory ULN

d. Urine protein/creatinine ratio ≤1 mg/mg or 24-h urine protein ≤1 g

Inclusion criteria specifically for biomarker-selected participants in Phase 2a

26. Tissue submission, archive or fresh biopsy, is required.

27. Detection of exploratory biomarker as defined by the Sponsor. Prescreening under separate consent for biomarker should be performed prior to full study consent.

Exclusion criteria:

1. Current or prior evidence of any small cell or neuroendocrine histology on the most recent prostate biopsy

2. Any liver metastases confirmed by biopsy or evidence of lesions >1 cm consistent with liver metastases on imaging

3. Intervention with any chemotherapy, investigational agent, or other anticancer drug, including enzalutamide, apalutamide, or darolutamide, 14 days prior to Screening or 5 half-lives from the last dose (whichever is shorter)

4. More than 2 prior therapies with taxane-based chemotherapy

5. Current use of systemic prednisone >10 mg/day equivalent dose for underlying condition

6. Concomitant medication(s) known to cause Torsades de Pointes initiated less than the duration required to reach steady-state plasma concentration (approximately 5 half-lives) before first dose of pocenbrodib. Note: Medications used as needed (eg, PRN ondansetron) are permitted with close monitoring.

7. Baseline QT interval corrected with Fridericiaâ??s method (QTcF) >480 ms (average of triplicate readings). Note: Criterion does not apply to participants with a right or left bundle branch block; a cardiologist should review the electrocardiogram (ECG) and determine eligibility.

8. Concomitant medication(s) known to be a strong inhibitor or inducer of CYP3A4 or P-glycoprotein

9. Prior history or current evidence of Type 1 or Type 2 diabetes

10. Gastrointestinal disorders likely to interfere with absorption of an oral (PO) medication

11. Symptomatic, untreated, or actively progressing central nervous system metastasis or leptomeningeal disease. Note: Treated disease that has been stable for 28 days prior to Screening is permitted.

12. Other malignancy within 3 years prior to Screening, except adequately treated non-melanoma skin cancer or in situ carcinoma or nonâ??muscle-invasive bladder cancer

13. Clinical or radiological evidence of current spinal cord compression or treated for the same condition within 14 days prior to Screening

14. Major surgery requiring general anesthesia within 4 weeks prior to Screening. Note: A limited biopsy or line placement is permitted.

15. Previous solid organ transplant

16. Any clinical, laboratory, or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of enrollment

17. Known to be human immunodeficiency virus (HIV) positive or on antiviral therapy

18. Known current/active infection with hepatitis B or hepatitis C virus or hepatitis B surface antigen positivity

19. Any known or suspected contraindications or hypersensitivity to pocenbrodib or partner drug, if applicable

20. Any other serious underlying medical, psychiatric, psychological, familial, or geographical condition, which in the judgment of the Investigator may interfere with study participation and compliance or place the participant at high risk from treatment-related complications

21. Site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or Pathos employees directly involved in the conduct of the study or their family members

Eligibility

Eligibility

Inclusion Criteria:

Arms A and B

• Histologic diagnosis of epithelial ovarian, primary peritoneal, or fallopian-tube carcinoma
• Arm A Only: Platinum-resistant disease
• Arm B Only: Platinum-sensitive disease who had progression while receiving treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor
• Life expectancy of ?3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Able to swallow and retain oral medication
• 1 to 3 lines of prior systemic anticancer therapy
• Adequate organ function
• Negative pregnancy test for patients of childbearing potential

Arm C

• Stage III or IV, recurrent, or metastatic endometrial cancer
• Life expectancy of ?3 months
• ECOG performance status of 0 or 1
• Able to swallow and retain oral medication
• Prior treatment with a platinum agent and an approved anti-Programmed Cell Death Ligand 1 (PD[L]1) antibody
• 1 to 2 lines of prior systemic anticancer therapy for endometrial cancer
• Must consent to provide an available formalin-fixed paraffin-embedded (FFPE) tumor tissue block or recently cut sections
• Adequate organ function
• Negative pregnancy test for patients of childbearing potential

Exclusion Criteria:

Arm A and B

• Arm A Only: Has progressed while receiving weekly paclitaxel or nab-paclitaxel
• Prior enrollment in a clinical trial of relacorilant
• Prior anticancer therapy related toxicities not resolved to grade ?1
• Any surgery within 4 weeks prior to enrollment
• Wide-field radiation to more than 25% of marrow-bearing areas
• Medical conditions requiring chronic or frequent treatment with corticosteroids
• Concurrent treatment with mifepristone or other glucocorticoid receptor modulators
• Peripheral neuropathy from any cause >Grade 1
• Hypertension: ?150 mm Hg systolic or ?100 mm Hg diastolic
• Uncontrolled condition(s) which, may confound the results of the trial or interfere with the patient's safety or participation
• Bowel obstruction ?12 weeks prior to study entry
• Ascites or pleural effusions requiring therapeutic paracentesis
• Untreated or symptomatic central nervous system metastases
• History of other malignancy within 3 years prior to enrollment
• Has received a live vaccine within 30 days prior to the study start date

Arm C

• Has progressed while receiving weekly paclitaxel or nab-paclitaxel
• Prior enrollment in a clinical trial of relacorilant
• Prior anticancer therapy related toxicities not resolved to grade ?1
• Any surgery within 4 weeks prior to enrollment
• Wide-field radiation to more than 25% of marrow-bearing areas
• Medical conditions requiring chronic or frequent treatment with corticosteroids
• Concurrent treatment with mifepristone or other glucocorticoid receptor modulators
• Peripheral neuropathy from any cause >Grade 1
• Uncontrolled condition(s) which, may confound the results of the trial or interfere with the patient's safety or participation
• Bowel obstruction ?12 weeks prior to study entry
• Ascites or pleural effusions requiring therapeutic paracentesis
• History of other malignancy within 3 years prior to enrollment
• Has received a live vaccine within 30 days prior to the study start date
• Patients with central nervous system metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study.

Eligibility

Inclusion Criteria:

• Sign and date the informed consent form prior to the start of any study-specific qualification procedures.
• Age ?18 years or the minimum legal adult age (whichever is greater) at the time the informed consent form is signed.
• Participants with histologically or cytologically documented high-grade serous ovarian cancer (OVC), high-grade endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer.
• Participants must have at least 1 lesion, not previously irradiated, amenable to biopsy, and must consent to provide a pretreatment biopsy and on-treatment biopsy tissue sample (on-treatment biopsy sample not required for the Phase 3 part of the study). Fresh pretreatment biopsy may be waived for subjects who consent to provide an archival tumor tissue sample from a lesion not previously irradiated, performed within 6 months of consent, and performed after treatment with their most recent cancer therapy regimen.

• Has received at least 1 but no more than 3 prior systemic lines of anticancer therapy:

  • Neoadjuvant +/-adjuvant considered 1 line of therapy.
  • Maintenance therapy (eg, bevacizumab, poly-ADP ribose polymerase [PARP] inhibitors) will be considered part of the preceding line of therapy.
  • Therapy changed due to toxicity in the absence of progression will be considered part of the same line.
  • Hormonal therapy will be counted as a separate line of therapy, unless it was given as maintenance.
  • At least 1 line of therapy containing bevacizumab, unless the subject is not eligible for treatment with bevacizumab due to precautions/intolerance. Note: Subjects must have progressed radiologically on or after their most recent line of systemic therapy. Biochemical progression will not be considered progression for this study.
• Has platinum-resistant disease. If a subject had only 1 line of platinum therapy, must have received at least 4 cycles of platinum, must have had a best response of not PD, and then progressed between >90 and ?180 days after the date of the last dose of platinum If a subject had 2 or 3 lines of platinum therapy, must have received at least 2 cycles of platinum and have progressed on or within 180 days after the date of the last dose of platinum.
• Has had prior poly-ADP ribose polymerase (PARP) inhibitors for participants with documented breast cancer gene mutation (germline and/or somatic), unless the participant is not eligible for treatment with a PARP inhibitor.
• Has had prior treatment with mirvetuximab soravtansine for participants with documented high-folate receptor alpha expression, unless the participant is not eligible for treatment with mirvetuximab soravtansine due to precautions/intolerance, or if the treatment is not approved or available locally.
• Has at least 1 measurable lesion evaluated by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per investigator assessment.
• Eastern Cooperative Oncology Group performance status of 0 or 1.

• Required baseline local laboratory data (within 7 days before start of study drug administration):

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

    • 3.0 × upper limit of normal (ULN) in subjects with no liver metastasis and
    • 5.0 × ULN in subjects with liver metastasis
  • Total bilirubin (TBL) ?1.5 × ULN (<3 × ULN for subjects with Gilbert's syndrome or liver metastasis at baseline)
  • Absolute neutrophil count ?1.5 × 109/L (growth factor support allowed up to 14 days before laboratory assessment for eligibility)
  • Platelet count ?100 × 109/L (transfusion allowed up to 14 days before laboratory assessment for eligibility)
  • Hemoglobin ?9.0 g/dL (transfusion and/or growth factor support allowed up to 14 days before laboratory assessment for eligibility)
  • Creatinine clearance ?30 mL/min as calculated using the Cockcroft-Gault equation
  • Serum albumin ?2.5 g/dL
  • Adequate blood clotting function: International normalized ratio and either activated partial thromboplastin time or partial thromboplastin time ?1.5 × ULN, unless the subject is receiving anticoagulant therapy as long as activated partial thromboplastin time or partial thromboplastin time is within the therapeutic range of intended use of anticoagulants
• If the participant is a female of childbearing potential, she must have a negative serum pregnancy test at 72 hours before the first dose of study drug and must be willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 7 months following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by follicle-stimulating hormone test.
• Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
• Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
• For Phase 3 (Part B) only: Participants must be eligible for one of the treatments included in the Investigator's choice of chemotherapy arm and must not have received it previously for OVC.

Exclusion Criteria

• Has clear cell, mucinous, or sarcomatous histology, mixed tumors containing any histology, or low-grade/borderline OVC.

• Inadequate washout period before Cycle 1 Day 1, defined as follows:

  • Major surgery <28 days
  • Radiation therapy <28 days (if palliative stereotactic radiation therapy without abdominal radiation, ?14 days)
  • Systemic anticancer therapy (including antibody-drug therapy, retinoid therapy, and hormonal therapy) <28 days or 5 half-lives, whichever is shorter, before starting study drug
  • Chloroquine/hydroxychloroquine <14 days
  • Exposure to another investigational drug within 28 days prior to start of study treatment or current participation in other therapeutic investigational procedures
• Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with untreated and asymptomatic brain metastases or subjects with treated brain metastases who are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy, at the investigator's discretion. Note: If there is a history or suspicion of central nervous system metastasis, a CT scan of the head or MRI of the brain must be performed at baseline.
• Any of the following within the past 6 months prior to randomization: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.

• Uncontrolled or significant cardiovascular disease, including the following:

  • QT interval corrected with Fridericia's formula interval >470 ms (average of triplicate determinations).
  • Diagnosed or suspected long QT syndrome or known family history of long QTsyndrome.
  • History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
  • The participant has bradycardia of less than 50 bpm (as determined by central reading), unless the subject has a pacemaker.
  • History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
  • Myocardial infarction within 6 months prior to screening.
  • Uncontrolled angina pectoris within 6 months prior to screening.
  • New York Heart Association Class 3 or 4 congestive heart failure.
  • Left ventricular ejection fraction <50% or institutional lower limit of normal as measured by echocardiography or multigated acquisition (MUGA) scan.
  • Coronary/peripheral artery bypass graft within 6 months prior to screening
  • Uncontrolled hypertension (resting systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)
  • Complete left or right bundle branch block.
• Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc) and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc), or prior pneumonectomy.

• Chronic steroid treatment (>10 mg/day), with the exception of the following:

  • Inhaled steroids for asthma or COPD
  • Mineralocorticoids (eg, fludrocortisone) for subjects with orthostatic hypotension
  • Topical steroids for mild skin conditions
  • Low-dose supplemental corticosteroids for adrenocortical insufficiency
  • Premedication for treatment groups and/or premedication in case of any hypersensitivity
  • Intra-articular steroid injections
• History of malignancy other than epithelial OVC, primary peritoneal cancer, or fallopian tube cancer within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS rate >90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, ductal carcinoma in situ, or Stage 1 uterine cancer).

• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Version 5.0, Grade ?1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for 3 months prior to randomization and managed with SOC treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor, such as the following:

  • Chemotherapy-induced neuropathy
  • Fatigue
  • Endocrinopathies, which may include hypothyroidism, hyperthyroidism, Type 1 diabetes, hyperglycemia, and adrenal insufficiency
  • Skin pigmentation (vitiligo)
• Prior exposure to other CDH6-targeted agents or an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan or datopotamab deruxtecan).
• History of hypersensitivity to any excipients in the R-DXd or any known contraindication to treatment with, including hypersensitivity to, the study drug(s).
• Has a known human immunodeficiency virus (HIV) infection that is not well controlled. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or institutional review boards (IRBs)/ethics committees (ECs). All the following criteria are required to define an HIV infection that is well controlled: undetectable viral ribonucleic acid (RNA) load, CD4+ counts/levels of >350 cells/?L, no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, and stable for at least 3 weeks on the same anti-HIV retroviral medications. If an HIV infection meets the above criteria, the subject's viral RNA load and CD4+ cell count should be monitored per local SOC (eg, Q3M).
• Has any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses or active infection, substance abuse) or other factors that, in the investigator's opinion, makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.

• Has an active or uncontrolled hepatitis B and/or hepatitis C infection. Subjects must be tested for hepatitis B (hepatitis B virus surface antigen [HBsAg] and anti-hepatitis B core antigen [HBc]) and hepatitis C virus antibody (HCV Ab) during the Screening Period. Subjects are eligible if they meet the following conditions:

  1. Have been curatively treated for hepatitis C virus (HCV) infection as demonstrated by undetectable HCV RNA
  2. Have received hepatitis B virus (HBV) vaccination with only anti-hepatitis B surface antibody (HBs) positivity and no clinical signs of hepatitis
  3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i to iii of criterion "d" below
  4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i to iii below: (i) HBV DNA viral load <2000 IU/mL (ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN that are not attributable to HBV infection (iii) Start or maintain antiviral treatment if clinically indicated as per the Investigator
• Female who is pregnant or breastfeeding or intends to become pregnant during the study.
• Psychological, social, familial, or geographical factors that would prevent regular follow-up.
• Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
• Has a history of receiving live-attenuated vaccine (messenger RNA [mRNA] and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention.
• For Phase 3 (Part B) only: Subjects are ineligible if they have a history of any contraindication included in the approved local label for the control group treatment.

Eligibility

Key Inclusion Criteria:

1. Sign and date the tissue prescreening informed consent form (ICF), prior to HER2 central testing. Sign and date the main ICF, prior to the start of any trial- specific qualification procedures. Consent to optional PGx prior to any PGx procedures. For participants in the safety run-in phase, a safety run-in ICF needs to be signed and dated prior to the start of any trial-specific qualification procedures.
2. Adults ?18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.
3. Has histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube or primary peritoneal carcinoma (including but not limiting to serous, endometrioid, clear cell, carcinosarcoma, mucinous).
4. Is newly diagnosed FIGO Stage III or IV.
5. Has HER2 expression per 2016 ASCO-CAP gastric cancer IHC scoring (3+/2+/1+) guidelines1 by prospective central testing. For participants in the safety run-in phase, HER2 expression assessed by either local (require using ASCO-CAP gastric cancer IHC scoring [IHC 3+/2+/1+] guidelines) or central assessment (if available) is acceptable. Submission of the pathology report is required for participants enrolled based on local HER2 IHC results.
6. Has adequate tumor tissue sample available for assessment of HER2 by central laboratory. Tumor tissue block or sufficient tissue slides are required for HER2 testing and retrospective HRD status determination. Participants in the safety run-in phase who are enrolled based on local HER2 IHC results are recommended to provide tumor tissue sample from the same specimen for central assessment.
7. Has a local HRD or breast cancer gene (BRCA) test result available. Participants with BRCA wildtype will have a local HRD test results, as applicable.
8. Has received standard of care bevacizumab in combination with front line platinum based chemotherapy as per approved indication and clinical guidelines and is eligible to continue single agent bevacizumab maintenance per standard of care and investigator discretion.

Key Exclusion Criteria:

1. Has ovarian, fallopian tube, or peritoneal cancer of non-epithelial origin.
2. Has a BRCA mutation as per local test.
3. Participant to receive PARP inhibitor as maintenance per standard of care and investigator discretion. Reasons for which the participant is not eligible for PARP inhibitor will be recorded in the eCRF as follows: HRD negative HRD positive with SD as best response after platinum HRD positive non-serous histology HRD tested, but inconclusive HRD positive but safety concern (safety concern to be specified).
4. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products and other monoclonal antibodies.
5. Previous Cerebral-Vascular Accident, Transient Ischemic Attack or Sub- Arachnoids Hemorrhage within 6 months prior to randomization.
6. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation therapy).
7. Has a history of hemorrhagic disorders, abdominal fistula, gastrointestinal perforation, or active gastrointestinal bleeding within 6 months before randomization.
8. Evidence of active or ongoing bowel obstruction.
9. Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, pneumonectomy, etc.)
10. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
11. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie pulmonary emboli within three months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (ie Rheumatoid arthritis, Sjogren's, sarcoidosis etc.), or prior pneumonectomy.

Eligibility

Key Inclusion Criteria:

• Must have histologically or cytologically confirmed high-grade serous or endometrioid epithelial ovarian cancer (EOC), primary peritoneal cancer, or fallopian tube cancer.
• Must have PSOC defined as progressive disease > 6 months (ie, 183 days) from the last dose of primary (first-line [1L]) platinum therapy.
• Participants with known breast cancer (BRCA)-mutated (somatic or germline) or homologous recombination deficiency (HRD)-positive ovarian cancer who achieved complete response (CR)/no clinical evidence of disease (NED) or partial response (PR) following 1L platinum-based chemotherapy regimen must have previously received PARPi maintenance therapy as part of their 1 L treatment.
• Must have completed platinum-based chemotherapy in the 2L treatment for recurrent PSOC.
• Must have received platinum-based chemotherapy in the 1L treatment and received platinum-based chemotherapy in the 2L treatment.
• Must be randomized no later than 8 weeks from the last dose of the 2L platinum-based therapy.
• Participants must have achieved a CR/NED, PR, or SD, as assessed by the investigator, following completion of 2L platinum-based chemotherapy.

Key Exclusion Criteria:

• Participants with clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade/borderline ovarian tumors
• More than 2 prior lines of systemic therapy.
• Progression while on or following 2L platinum-based regimen prior to randomization.
• Participants who receive an intervening systemic anticancer treatment (excluding bevacizumab) after the last dose of 2L platinum-based chemotherapy and prior to randomization.

Note: Other protocol-defined Inclusion and Exclusion criteria may apply.

Eligibility

Inclusion Criteria:

• Histological diagnosis of a high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer.

• Have platinum-resistant disease:

  • Participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of a platinum-containing regimen.
  • Participants who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 6 months after the last dose of platinum.
• Archival FFPE tumor tissue block or slides from a specimen no older than 5 years must be available. If not available, participant must be willing to undergo a pretreatment tumor biopsy.
• Received at least 1 and no more than 4 prior lines of systemic therapy following the initial diagnosis, after which single-agent therapy is considered an appropriate next therapeutic option.
• Must have received bevacizumab unless there was a contraindication for its use.
• If the tumor tests positive for FR?, participants must have received mirvetuximab soravtansine unless there is an exception for its use on medical grounds.

Exclusion Criteria:

• Have endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of these histologies, or low-grade/borderline ovarian cancer.
• Have primary platinum-refractory disease: either did not respond (CR or PR) to first-line platinum-containing therapy or progressed on or within 3 months after the last dose of the first line platinum-containing therapy.
• The tumor tests positive for FR? but the participant has not received mirvetuximab soravtansine for any reason other than medical contraindication.
• Clinically significant or uncontrolled cardiac disease within 6 months before the first dose of study drug.
• Known active CNS metastases and/or carcinomatous meningitis.
• Known additional malignancy that is progressing or requires active treatment.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Eligibility

Eligibility

The main inclusion criteria include but are not limited to the following:

• Has histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube cancer.
• Has completed primary debulking surgery or interval debulking surgery.
• Has completed first-line (1L) platinum-based chemotherapy, with a response of stable disease, partial response, or complete response per protocol.
• Has provided tumor tissue that is not previously irradiated.
• If human immunodeficiency virus (HIV) infected, has well-controlled HIV on antiretroviral therapy.
• Has undetectable hepatitis B virus (HBV) viral load and received HBV antiviral therapy if hepatitis B surface antigen (HBsAg)-positive.
• Has undetectable hepatitis C virus (HCV) viral load if has a history of HCV infection.

The main exclusion criteria include but are not limited to the following:

• Has nonepithelial cancers, borderline tumors mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor, and undifferentiated carcinoma.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has a history of severe eye disease.
• Has active inflammatory bowel disease requiring immunosuppressive medication or a previous history of inflammatory bowel disease.
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease.
• Has a history of (noninfectious) pneumonitis/interstitial lung disease (ILD), which required steroids, or has current pneumonitis/ILD.
• Received prior systemic anticancer therapy, with the exception of the first-line platinum-based chemotherapy required by the inclusion criteria.
• Had a live or live-attenuated vaccine within 30 days of randomization.
• Has a known additional malignancy that is progressing or required active treatment within the past 3 years.
• Has active infection requiring systemic therapy.
• Has concurrent and active HBV and HCV infections.
• Has HIV infection and a history of Kaposi's sarcoma and/or multicentric Castleman's disease.
• Has not recovered from major surgery or has ongoing surgical complications.

Eligibility

Inclusion Criteria:

• Has histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
• Has received 4 or more cycles of platinum-based doublet chemotherapy in first-line and a total of 6 cycles of carboplatin-based doublet chemotherapy in second-line setting for ovarian cancer (OC).
• Has platinum-sensitive epithelial OC,
• Has provided tissue of a tumor lesion that was not previously irradiated
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy
• Participants who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to allocation (Part 1) or randomization (Part 2)
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
• Has an ECOG performance status of 0 to 1 assessed within 7 days before allocation (Part 1) or randomization (Part 2)

Exclusion Criteria:

• Has nonepithelial cancers (germ cell tumors and sex cord-stromal tumors), borderline tumors (low malignant potential), mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor and undifferentiated carcinoma
• Has platinum-resistant OC or platinum-refractory OC
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis, or chronic diarrhea)
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease.
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has received more than 2 prior lines of systemic therapy for OC.
• Has received prior systemic anticancer therapy within 3 weeks or 5 half-lives (whichever is shorter) before allocation (Part 1) or randomization (Part 2)
• Has received prior radiotherapy within 2 weeks of allocation (Part 1) or randomization (Part 2), or has radiation related toxicities, requiring corticosteroids
• Has an additional malignancy that is progressing or has required active treatment within the past 3 years
• Has active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active infection requiring systemic therapy

Eligibility

Inclusion criteria

· Histological confirmed primary SCC of the vulva

· T1 tumor, not encroaching urethra/vagina/anus

· Depth of invasion > 1mm

· Tumor diameter < 4cm

· Unifocal tumor

· No enlarged (>1.5cm) or suspicious inguinofemoral lymph nodes at imaging (CT/MRI/ultrasound)

· Possibility to obtain informed consent

· Metastatic sentinel lymph node; size of metastasis > 2mm and / or extracapsular extension, or

· Metastatic sentinel lymph node: more than 1 SN with metastasis ≤ 2mm

· Patients are able to understand requirements of study, provide written informed consent and comply with the study and follow-up procedures

· Adequate bone marrow, renal and liver function:

· Absolute neutrophil count ≥ 1.5 x 109 /L

· Platelet count ≥ 100 x 109 /L

· Creatinine clearance ≥ 40 ml/min measured by the Cockroft Gault formula

· Total bilirubin < 1.25 x ULN

· Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN

Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale

Age 18 years or older

Life expectancy of ≥ 12 weeks

Written informed consent

Exclusion criteria

· Inoperable tumors and tumors > 4cm

· Multifocal tumors

· Tumors with other pathology than squamous cell carcinoma

· Patients with enlarged / suspicious lymph nodes which are proven metastatic after fine needle aspiration cytology

· No other carcinomas, other than basal cell carcinomas, within last 5 years

· History of pelvic radiotherapy

· History of any infection requiring hospitalization or antibiotics within 2 weeks before enrollment

· Pregnant female or nursing mother

· Desire to become pregnant

· Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids

· Unstable angina, myocardial infarction, cerebrovascular accident, > Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment

Eligibility

Inclusion Criteria:

• Written informed consent provided prior to any screening procedures.
• Male or female patients, ?18 years of age at the time of obtaining informed consent.
• Patients with histologically or cytologically confirmed advanced solid tumors previously treated with standard of care systemic therapy, or for whom no standard therapy is available.
• Willingness to provide archival tumor tissue, when available. If no archival tissue is available, willingness to undergo a pretreatment biopsy if medically feasible and safe.
• Measurable disease per RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy of ?12 weeks.

• Adequate organ function as defined by:

  • Absolute neutrophil count (ANC) ?1.5 x 109/L (1500/µL), without colony-stimulating factor support for the past 14 days.
  • Platelets ?100.0 x 109/L (100 000/µL).
  • Hemoglobin ?9.0 g/dL (without blood transfusion in 2-week period prior to screening).
  • Creatinine clearance (CrCl) ?45 mL/min as calculated by the Cockcroft-Gault method.
  • Serum total bilirubin ? 1.5 x the upper limit of normal (ULN).
  • Aspartate aminotransferase (AST) ?2.5 x ULN; alanine aminotransferase (ALT) ? 2.5 x ULN.
  • International normalized ratio (INR) ? 1.5; activated partial thromboplastin time (aPTT) ? 1.5 x ULN.
  • Left ventricular ejection fraction (LVEF) ?50% as per echocardiography (ECHO) or multi-gated acquisition scan (MUGA).
  • Q wave to T wave (QT) interval corrected for heart rate (QTc) ?480 ms (Fridericia's formula).
  • Baseline oxygen saturation on room air ? 92%
  • Albumin ? 3.0 g/dL
• Women of child-bearing potential (WOCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months must agree to use a highly effective contraceptive method
• Patients must be willing and able to sign the informed consent form, and to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

• Prior treatment with an ADC with a topoisomerase I (TOP1) payload.
• Active or progressing brain metastases or evidence of leptomeningeal disease. Stable/treated brain metastases are permitted (defined as history of brain metastases previously treated with surgical resection or stereotactic radiosurgery, stable on baseline screening study MRI brain for at least 2 months (compared to comparator MRI brain) and asymptomatic without requirement for steroids or antiseizure medications.
• Persistent toxicities from previous systemic antineoplastic treatments of Grade >1, excluding alopecia and vitiligo.
• Systemic antineoplastic therapy or prohibited co-medications within 5 half-lives or 4 weeks, whichever is shorter, prior to first dose of the study drug, including investigational agents.
• Wide-field radiotherapy (e.g., >30% of marrow-bearing bones) within 4 weeks, or focal radiation with palliative intent outside the field of measurable disease within 2 weeks prior to first dose of the study drug.
• Major surgery within 4 weeks prior to first dose of study drug, or no recovery from side effects of such intervention.
• Has had clinically significant lung disease requiring systemic corticosteroid treatment within the last 6 months of randomization/registration (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are suspected to have such diseases by imaging at screening period.
• Patients with acute or chronic pancreatitis and/or liver cirrhosis except well compensated cirrhosis (Child-Pugh class A).
• Hepatic insufficiency manifesting as clinical jaundice, hepatic encephalopathy, and/or variceal bleed within 60 days prior to study entry.
• History of liver transplant.
• Prior allogeneic bone marrow transplantation.
• Significant cardiac disease, such as recent (within 6 months prior to first dose of the study drug) myocardial infarction or acute coronary syndromes (including unstable angina pectoris), congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension, uncontrolled cardiac arrhythmias, severe aortic stenosis.
• History of thromboembolic or cerebrovascular events, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, or pulmonary emboli within 3 months prior to first dose of the study drug.

• Acute and/or clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV).

  • Note: patients with chronic HBV, HCV or HIV infection will be eligible if they are considered upon a mutual agreement of the Investigator and the Medical Monitor as safe for enrollment and meet one of the following additional conditions:
  • Patients with HIV infection are on an established antiretroviral therapy for at least 4 weeks, and have CD4+ T-cell counts ?350 cells/µL and HIV viral load <50 copies/mL,
  • Patients with serologic evidence of chronic HBV infection receive concurrent anti-HBV therapy and have HBV viral load below the limit of quantification,
  • Patients with a history of HCV infection must have completed curative anti-HCV therapy and have HCV viral load below the limit of quantification,
  • Patients on concurrent anti-HCV therapy have HCV viral load below the limit of quantification.
• Known or suspected allergy to the study drug or any component of the study drug.
• Concurrent participation in another investigational clinical trial.
• Pregnant or breast-feeding females.

• Prior history of malignancy other than inclusion diagnosis within 3 years prior to first dose of the study drug.

  • Note: excluding patients with adequately treated basal cell or squamous cell skin cancer, non-invasive superficial bladder cancer, in situ cervical cancer, in situ breast cancer, and in situ prostate cancer. Other malignancies with low risk of recurrence may also be considered following discussion with the Medical Monitor.
• Any other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or the study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for enrollment in this study.
• Chest irradiation within 1 year prior to first dose of study drug.
• Gastrointestinal obstruction or radiographic evidence of gastrointestinal obstruction within 4 weeks prior to the first dose of study drug.
• Vaccination with a live vaccine ?30 days prior to first dose of study drug.
• Use of a strong cytochrome P450 (CYP)3A4 or CYP1A2 inducer or inhibitor ?14 days prior to first dose of study drug or inability to discontinue use of a strong CYP3A4 or CYP1A2 inducer or inhibitor for the duration of the study.
• Ascites requiring frequent paracentesis for symptomatic management.

Eligibility

Inclusion criteria:

1. Must have recurrent or metastatic cervical cancer with disease progression on or after chemotherapy
2. Treating physician has determined that treatment with Tivdak is appropriate for the participant according to US Prescribing Information
3. Must sign an informed consent form indicating that the participant understands the purpose and procedures required for the study and are willing to participate
4. Must be willing to undergo repeated ocular assessments as required by the study and regular clinic visits according to local standard practice of the study site
5. Must agree to use effective contraception according to the US Prescribing Information

Exclusion criteria:

1. Active ocular disease at baseline per investigator assessment
2. Previous treatment with Tivdak
3. Previous administration of an investigational drug within 30 days
4. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may, in the investigator's judgment, increase the risk of study participation or make the participant inappropriate for the study.
5. Patients who are breastfeeding, pregnant, or planning to become pregnant based on criteria as indicated in the US Prescribing Information
6. Known allergies, hypersensitivity, or intolerance to Tivdak or its excipients

Eligibility

Inclusion Criteria:

Patients may be eligible for inclusion in the study if they meet the following criteria:

1. Histologically proven LGSOC (ovarian, fallopian, peritoneal)
2. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.
3. Measurable disease according to RECIST v1.1.
4. An Eastern Cooperative Group (ECOG) performance status ? 1.
5. Adequate organ function
6. Adequate recovery from toxicities related to prior treatments.
7. For patients with reproductive potential, Agreement to use highly effective method of contraceptive.
8. Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
2. Co-existing high-grade ovarian cancer or another histology.
3. Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
4. History of prior malignancy with recurrence <3 years from the time of enrollment.
5. Major surgery within 4 weeks.
6. Symptomatic brain metastases or spinal cord compression.
7. An active skin disorder that has required systemic therapy within one year of signing informed consent.
8. History of medically significant rhabdomyolysis.
9. For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor.
10. Symptomatic bowel obstruction within 3 months.
11. Concurrent ocular disorders.
12. Concurrent heart disease or severe obstructive pulmonary disease.
13. Subjects with the inability to swallow oral medications.
14. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Eligibility

Eligibility

Inclusion Criteria:

• Confirmed diagnosis of CLL or SLL, requiring treatment, based on 2018 iwCLL criteria
• Previously received treatment for CLL/SLL with a covalent Bruton tyrosine kinase inhibitor (cBTKi). Patients should have disease relapsed after or refractory to at least 1 line of therapy including a cBTKi.
• Participants with SLL must have measurable disease by computed tomography/magnetic resonance imaging, defined as ? 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters.

Exclusion Criteria:

• Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation.
• History of known bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
• History of ischemic stroke or intracranial hemorrhage within 6 months before first dose of study drug
• Prior exposure to any Bruton tyrosine kinase (BTK) protein degraders or noncovalent Bruton tyrosine kinase inhibitor (ncBTKi).
• Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by CLL/SLL

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility

Inclusion Criteria:

• Diagnosis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) as per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 diagnostic criteria
• For ibruinib + venetocIax (I+V) cohorts: eastern cooperative oncology group (ECOG) performance status of 0-1. For ibrutinib monotherapy cohorts: ECOG performance status of 0-2
• Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node greater than and equal to (>=) 1.5 centimeters (cm) in longest diameter
• A participant using oral contraceptives must use an additional contraceptive method
• A participant must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or until 1 month after last dose or per local label if more conservative (for example, 3 months in European Union or Canada and 1 month in United States)

Exclusion Criteria:

• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as those participants with a declining hemoglobin level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study treatment, or the need for prednisone greater than (>) 20 milligrams (mg) daily (or corticosteroid equivalent) to treat or control the autoimmune disease
• Known bleeding disorders (example, von Willebrand's disease or hemophilia)
• Stroke or intracranial hemorrhage within 6 months prior to enrollment
• Known or suspected Richter's transformation or central nervous system (CNS) involvement
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class II, III, or IV congestive heart failure as defined by the New York Heart Association Functional Classification

Eligibility

Inclusion Criteria:

1. - Age ? 18 years.
2. . Patients that have documented CLL/SLL who meet iwCLL 2018 criteria for CLL treatment guidelines are eligible for treatment and must be receiving BTKi monotherapy for at least 12 months
3. ECOG Performance Status grade 0-2

4. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows:

   • Absolute neutrophil count ? 1.0 × 109/L
   • Platelet counts ? 75 × 109/L; in cases of thrombocytopenia
   • Total hemoglobin ? 9 g/dL,

5. Adequate renal function

   • Creatinine clearance must be > 50 ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ? ((140 - age) x actual body weight)/(72 x creatinine), for women x 0.85) or an equally accurate method.
   • For patients with creatinine values within the normal range, the calculation of clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 50 ml/min may be eligible if a repeat estimate after adequate hydration is > 50 ml/min.

6. Adequate liver function as indicated by:

   • Total bilirubin ? 1.5 x ULN, except patients with known Gilbert's Syndrome
   • Aspartate aminotransferase (AST) ? 2.5 x the institutional ULN value
   • Alanine aminotransferase (ALT) ? 2.5 x the institutional ULN value,
   • International normalized Ratio (INR), Prothrombin Time (PT) or Activated Partial Thromboplastin time (APTT) ? 1.5×ULN.
7. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Eligibility

Inclusion Criteria:

• Patients must be 5 to 60 years of age at the time of enrollment
• Patients with newly diagnosed untreated histologically confirmed classic Hodgkin lymphoma (cHL) (nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]) with stage I or II disease
• Patients must have bidimensionally measurable disease (at least one lesion with longest diameter >= 1.5 cm)
• Patients must have a whole body or limited whole body PET scan performed within 42 days prior to enrollment. PET-CT is strongly preferred. PET-MRI allowed if intravenous contrast enhanced CT is also obtained
• Pediatric patients (age 5-17 years) must have an upright posteroanterior (PA) chest X-ray (CXR) for assessment of bulky mediastinal disease. Adult patients must have either a CXR or CT chest
• Patients >= 18 years must have a performance status corresponding to Zubrod scores of 0, 1 or 2
• Patients =< 17 years of age must have a Lansky performance score of >= 50

• Pediatric patients (age 5-17 years): A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

  • 2 to < 6 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female)
  • 6 to < 10 years (age): 1 mg/dL (male), 1 mg/dL (female)
  • 10 to < 13 years (age): 1.2 mg/dL (male), 1.2 mg/dL (female)
  • 13 to < 16 years (age): 1.5 mg/dL (male), 1.4 mg/dL (female)
  • >= 16 years (age): 1.7 mg/dL (male), 1.4 mg/dL (female) OR a 24 hour urine creatinine clearance >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment). GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
  • Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• For adult patients (age 18 years or older) (within 7 days prior to enrollment): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight

• Total bilirubin =< 2 x upper limit of normal (ULN) (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome

• Aspartate aminotransferase (AST) =< 3 x ULN (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome

• Alanine aminotransferase (ALT) =< 3 x ULN (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
• Shortening fraction of >= 27% by echocardiogram (ECHO), multigated acquisition scan (MUGA), or functional cardiac imaging scan (within 7 days prior to enrollment) or ejection fraction of >= 50% by radionuclide angiogram, ECHO, MUGA, or cardiac imaging scan (within 7 days prior to enrollment)
• Diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted value as corrected for hemoglobin by pulmonary function test (PFT) (within 7 days prior to enrollment). If unable to obtain PFTs, the criterion is: a pulse oximetry reading of > 92% on room air
• Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria:

• Patients with nodular lymphocyte predominant Hodgkin lymphoma
• Patients with a history of active interstitial pneumonitis or interstitial lung disease
• Patients with a diagnosis of inherited or acquired immunodeficiency that is poorly controlled or requiring active medications, such as primary immunodeficiency syndromes or organ transplant recipients
• Patients with any known uncontrolled intercurrent illness that would jeopardize the patient's safety such as infection, autoimmune conditions, cardiac arrhythmias, angina pectoris, and gastrointestinal disorders affecting swallowing and/or absorption of pills

• Patients with a condition requiring systemic treatment with either corticosteroids (defined as equivalent to > 10 mg daily prednisone for patients >= 18 years or > 0.5 mg/kg [up to 10 mg/day] for patients < 18 years) or other immunosuppressive medications within 14 days prior to enrollment

  • Note: Replacement therapy such as thyroxine, insulin, or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment. Inhaled or topical steroids, and adrenal replacement doses (=< 10 mg daily for patients >= 18 years or =< 0.5 mg/kg [up to 10 mg/day] prednisone equivalents) are permitted in the absence of active autoimmune disease
  • Note: Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued by cycle 1, day 1
• Patients with peripheral neuropathy > grade 1 at the time of enrollment or patients with known Charcot-Marie-Tooth syndrome
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Administration of prior chemotherapy, radiation, or antibody-based treatment for cHL
• Prior solid organ transplant
• Prior allogeneic stem cell transplantation
• Live vaccine within 30 days prior to planned day 1 of protocol therapy (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, bacillus calmette guerin [BCG], oral polio vaccine, and oral typhoid). Administration of messenger ribonucleic acid (mRNA) vaccines are permitted
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test within 28 days prior to enrollment is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last treatment

• Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study drug therapy. Following therapy, patients will be advised to use contraception as per institutional practice or as listed below for investigational agents, whichever is longer

  • Men and women of childbearing potential must continue contraception for a period of 6 months after last dose of brentuximab vedotin
  • Women of child-bearing potential (WOCBP) must continue contraception for a period of at least 5 months after the last dose of nivolumab
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Eligibility

Inclusion Criteria:

• Age ?18 years
• Provided written informed consent
• Histologically confirmed B-cell malignancy, including CLL/SLL, WM, MCL, MZL, or FL. Patients must have failed or are intolerant to ?2 prior lines of systemic therapy
• ECOG Performance Status 0 to 2
• Absolute neutrophil count ?0.75 × 10?/L
• Platelet count ?50 × 10?/L
• Hemoglobin ?8 g/dL
• Adequate hepatic function
• Adequate renal function
• Ability to swallow tablets and comply with study requirements for the duration of study participation.
• Male and female patients of reproductive potential: Willing to observe conventional and effective birth control methods

Exclusion Criteria:

• Transformed disease (eg, Richter's transformation) prior to or during Screening
• Investigational agent or anticancer therapy within 5 half-lives before the planned start of AS-1763, except therapeutic monoclonal antibody treatment which must be discontinued at least 4 weeks before the start of AS-1763. Current treatment with investigational therapy or planned investigational therapy which would be concurrent with this study.
• Requiring therapeutic anticoagulation with warfarin.
• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers
• Treatment with proton pump inhibitors within 7 days before first dose of AS-1763
• Current treatment with strong P-glycoprotein inhibitors or strong breast cancer resistance protein (BCRP) inhibitors.
• Refractory to transfusion support.
• Major surgery within 4 weeks before planned start of AS-1763.
• Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 2 at the time of starting study treatment except for alopecia.
• History of allogeneic or autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy within the last 30 days.
• Active second malignancy unless in remission with life expectancy >2 years
• Known central nervous system (CNS) involvement by systemic lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented Sponsor approval.
• Active uncontrolled autoimmune cytopenia (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura) where new therapy introduced or concomitant therapy escalated within the 4 weeks before study enrollment is required to maintain adequate blood counts.
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months before planned start of AS-1763, or prolongation of the QT interval corrected for heart rate using Fridericia's Formula (QTcF) >470 msec on at least 2 of 3 consecutive ECGs, and mean QTcF >470 msec on all 3 ECGs, during Screening.
• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection
• Positive for human immunodeficiency virus (HIV). For patients with unknown HIV status, HIV testing will be performed at Screening.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of AS-1763
• Pregnant or lactating.
• Known hypersensitivity to any component or excipient of AS-1763.
• Prior treatment with AS-1763 or other noncovalent BTKi such as pirtobrutinib or nemtabrutinib

Eligibility

Inclusion Criteria:

• Histologically confirmed DLBCL, not otherwise specified (NOS)
• R/R disease, defined as: relapsed = disease that has recurred following a response that lasted >/= 6 months after completion of the last line of therapy; refractory = disease that did not respond to or that progressed < 6 months after completion of the last line of therapy
• At least one line of prior systemic therapy
• Participants who have failed only one prior line of therapy must not be a candidate for high-dose chemotherapy followed by autologous stem cell transplant (ASCT)
• At least one bi-dimensionally measurable (> 1.5 cm) nodal lesion, or one bi-dimensionally measurable (> 1 cm) extranodal lesion, as measured on CT scan
• Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2
• Adequate hematologic and renal function

Exclusion Criteria:

• Prior enrollment in Study GO41943 (NCT04313608), GO41944 (STARGLO; NCT04408638), or Study GO44900 (NCT06624085)
• Participant has failed only one prior line of therapy and is a candidate for stem cell transplantation
• History of transformation of indolent disease to DLBCL
• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma NOS, as defined by 2016 WHO guidelines
• Primary mediastinal B-cell lymphoma
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
• Contraindication to obinutuzumab, gemcitabine or oxaliplatin, or tocilizumab
• Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3
• Prior treatment with gemcitabine or oxaliplatin
• Peripheral neuropathy or paresthesia assessed to be Grade >/= 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 at enrollment
• Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to first study treatment
• Treatment with monoclonal antibodies for the purposes of treating cancer within 4 weeks prior to first study treatment
• Primary or secondary CNS lymphoma at the time of recruitment or history of central nervous system (CNS) lymphoma
• Prior CNS involvement that has been definitively treated and confirmed via magnetic resonance imaging (MRI) or cerebrospinal fluid analysis to be in complete remission is permissible
• Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
• History of other primary malignancy, with exceptions defined by the protocol
• Significant or extensive cardiovascular disease
• Significant pulmonary disease (including moderate or severe obstructive pulmonary disease)
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to the first study treatment
• Positive for: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); tuberculosis; hepatitis B virus (HBV); hepatitis C virus (HCV); chronic active Epstein-Barr viral infection
• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) or progressive multifocal leukoencephalopathy
• Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better (with the exception of alopecia and anorexia)
• Administration of a live, attenuated vaccine within 4 weeks before first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study
• Prior solid organ transplantation or prior allogenic stem cell transplant
• Active autoimmune disease requiring treatment
• Prior treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents), within 4 weeks prior to first dose of study treatment
• Ongoing systemic corticosteroid use which, in the opinion of the investigator, puts the participant at increased risk of steroid-related iatrogenic adrenal insufficiency
• Recent major surgery (within 4 weeks before the first study treatment) other than for diagnosis
• Clinically significant history of cirrhotic liver disease
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the participant at high-risk from treatment complications
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 18 months after the final dose of study treatment

Eligibility

Eligibility

Eligibility

Inclusion Criteria:

• Histologically or cytologically documented non-squamous NSCLC.
• Stage IIIB or IIIC or Stage IV metastatic NSCLC (according to Edition 8 of the AJCC staging manual) not amenable to curative surgery or definitive chemoradiation.
• Absence of sensitising EGFR mutations, and ALK and ROS1 rearrangements, and absence of documented local test result for any other known genomic alteration for which there are locally approved and available targeted first-line therapies.
• Must provide tumor sample to determine PD-L1 status, TROP2 status and other biomarkers.
• Known tumour PD-L1 expression status defined as TC ? 50%
• At least one lesion, not previously irradiated that qualifies as a RECIST 1.1 target lesion at baseline
• ECOG performance status of 0 or 1
• Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention

Exclusion Criteria:

• Prior systemic therapy for advanced/metastatic NSCLC.
• Squamous cell histology, or predominantly squamous cell histology NSCLC; mixed small cell lung cancer; NSCLC histology, sarcomatoid variant.
• History of another primary malignancy within 3 years
• Active or prior documented autoimmune or inflammatory disorders (with exceptions)
• Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
• Has clinically significant third-space fluid retention (for example pleural effusion) and is not amenable for repeated drainage.
• History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Has significant pulmonary function compromise, as determined by the investigator
• Spinal cord compression, or brain metastases unless participant treated and no longer symptomatic, radiologically stable, and who require no treatment with corticosteroids or anticonvulsants.
• History of leptomeningeal carcinomatosis
• Known clinically significant corneal disease
• Active infection with TB, HBV, HCV, Hepatitis A, or known HIV infection that is not well controlled
• History of active primary immunodeficiency

Eligibility

Inclusion Criteria:

• Have a full understanding of the study content, process, and possible adverse reactions before the study, and sign the informed consent form (ICF); voluntarily participate in the study; be able to complete the study as per protocol requirements;
• Aged ? 18 years at the time of signing the ICF, male or female;

• Histologically or cytologically confirmed, locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC not suitable for radical treatment (complete surgical resection, concurrent/sequential radio-chemotherapy) according to the Union for International Cancer Control and the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition), and should meet the following criteria:

  1. Subjects without actionable genomic alterations (AGAs):

     • Subjects with non-squamous NSCLC must have documented negative test results for EGFR and ALK alterations. If no prior test results for EGFR and ALK are available, subjects must undergo EGFR and ALK testing at the study site. For subjects with squamous NSCLC, EGFR and/or ALK testing is not required prior to enrollment if their status is unknown;
     • No other known actionable genomic alterations, such as ROS1, NTRK, BRAF, MET exon 14 skipping, and RET;
     • Prior standard treatment failure of ? 1 line, including at least anti-PD-(L)1 antibody and platinum-based chemotherapy;

  2. Subjects with AGAs:

     • Previous test results confirming the presence of one or more actionable genomic alterations;
     • Prior standard treatment failure of ? 1 line, including at least targeted therapy for driver gene alterations (patients with EGFR mutations must be previously treated with EGFR inhibitors) and platinum-based chemotherapy;
• At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to randomization;
• Subjects who agree to provide archived tumor tissue specimens that meets the testing requirements (either from the most recent surgery or biopsy, preferably within 2 years) or agree to undergo a biopsy to collect tumor tissue for PD-L1 expression testing;
• The following conditions must be met in terms of the time of the first administration of the investigational product: at least 3 weeks (or 5 half-lives of the drug, whichever is shorter) from the previous major surgery, medical device treatment, locoregional radiotherapy (except for palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; at least 2 weeks from the previous hormone therapy or small molecular targeted therapy; at least 1 week from the administration of the traditional Chinese medicine for anti-cancer indications or minor surgery; and recovery of treatment-induced AEs to Grade ? 1 (CTCAE v5.0, except for Grade 2 peripheral neurotoxicity and alopecia);
• ECOG PS score of 0-1 within 1 week prior to randomization;
• Life expectancy > 3 months;
• Adequate organ functions as confirmed by laboratory tests within 1 week prior to randomization (no blood transfusions or treatment with granulocyte colony-stimulating factor is allowed within 14 days prior to the first dose)
• Male and female subjects with child-bearing potential must agree to use at least one highly effective contraception method during the study and within at least 6 months after the last dose of the investigational product; female subjects of childbearing age must be negative for pregnancy test within 7 days prior to enrollment.

Exclusion Criteria:

• Histologically or cytologically confirmed tumor containing components of small cell lung cancer, neuroendocrine carcinoma, or sarcomatoid carcinoma;
• Prior treatment with any medication targeting topoisomerase I, including chemotherapy or ADCs;
• Radical radiation therapy within 3 months prior to the first dose;
• History of any second malignancy within 2 years prior to randomization, except for early-stage malignancies (carcinoma in situ or stage I tumors) that have received radical treatment, such as non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma;
• History of adverse events leading to permanent discontinuation of immunotherapy, or occurrence of ? Grade 2 immune-related pneumonitis or myocarditis during prior immunotherapy;
• Presence of uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Presence of spinal cord compression or clinically active metastases to central nervous system (referring to untreated or symptomatic metastases, or metastases requiring corticosteroids or anticonvulsants to control associated symptoms), carcinomatous meningitis. Subjects who have previously received treatment for brain metastases (such as whole brain radiotherapy or stereotactic brain radiotherapy) may be eligible, provided that they are clinically stable for at least 4 weeks with no imaging evidence of brain metastasis progression;
• Subjects with current or prior history of clinically significant pulmonary impairment due to pulmonary comorbidities, including but not limited to any underlying lung disease (e.g., pulmonary embolism within 3 months prior to the first dose, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, interstitial pneumonia, pneumoconiosis, drug-related pneumonitis, and pleural effusion within 3 months prior to the first dose), any autoimmune, connective tissue, or inflammatory disease that may involve the lungs (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis), prior pneumonectomy that may interfere with the detection and management of suspected drug-related pulmonary toxicity, or history of with radiation pneumonitis within 6 months;
• Patients with any poorly-controlled cardiovascular and cerebrovascular clinical symptoms or diseases, including but not limited to: (1) NYHA Class II or greater heart failure or left ventricular ejection fraction (LVEF) < 50%; (2) unstable angina pectoris; (3) myocardial infarction or cerebrovascular accident within 6 months (except lacunar infarction, slight cerebral ischemia, or transient ischemic attack); (4) poorly controlled arrhythmia (including QTc intervals ? 470 ms) (QTc intervals are calculated by Fridericia's formula); (5) poorly-controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg after active treatment);
• Patients with active systemic infectious diseases requiring intravenous antibiotics within 2 weeks prior to randomization;
• Patients who have used moderate or potent CYP2D6 or CYP3A inhibitors or inducers within 2 weeks prior to randomization;
• Patients who have received systemic corticosteroids (prednisone > 10 mg/d or equivalent dose of similar drug) or other immunosuppressants within 2 weeks prior to randomization; Except: patients treated with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids; short-term prophylactic use of corticosteroids for contrast agents, etc.;
• Patients with known active or suspected autoimmune diseases. Patients with autoimmune-related hypothyroidism and receiving thyroid hormone replacement therapy and those with type 1 diabetes mellitus controlled with insulin therapy are eligible to be enrolled;
• Patients who have received live vaccine or live attenuated vaccine within 4 weeks prior to randomization;
• Patients who are known to have anaphylaxis to macromolecular protein preparations/monoclonal antibodies or are allergic to any component in the formulation of the investigational product;
• Patients with active tuberculosis;
• Patients with a history of immunodeficiency, including human immunodeficiency virus (HIV)-positive or other acquired or congenital immunodeficiencies, or history of organ transplantation;
• Patients with active HBV or HCV infection or HBV/HCV co-infection;
• Pregnant or lactating women;
• Patients who are not suitable for participating in this clinical study due to any clinical or laboratory abnormalities or other reasons as assessed by the investigator.

Eligibility

Inclusion Criteria:

• Has histological or cytological confirmation of squamous or nonsquamous non-small cell lung cancer (NSCLC), resectable clinical Stage II, IIIA or IIIB (with nodal involvement [N2]) per AJCC eighth edition guidelines.
• Has confirmation that epidermal growth factor receptor (EGFR)-directed therapy is not indicated as primary therapy.
• Is able to undergo surgery based on opinion of investigator after consultation with surgeon.
• Is able to receive neoadjuvant pembrolizumab and platinum-based doublet chemotherapy.
• Applies to screening for the adjuvant period only, before randomization: Has not achieved pathological complete response (pCR) at surgery by local review of pathology.
• Applies to screening for the adjuvant period only, before randomization: Tumor tissue sample from surgical resection has been provided for determination of programmed cell death ligand 1 (PD-L1) and trophoblast cell surface antigen 2 (TROP2) status by central vendor before randomization into the adjuvant period.
• Applies to screening for the adjuvant period only, before randomization: Confirmed to be disease-free based on re-baseline radiological assessment as documented by contrast enhanced chest/abdomen/pelvis computed tomography (CT) (or magnetic resonance imaging (MRI)) within 28 days before randomization.
• Participants who have AEs due to previous anticancer therapies must have recovered to ?Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load at screening.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at least 4 weeks before the start of study intervention.

Exclusion Criteria:

• Has one of the following tumor locations/types:

  • NSCLC involving the superior sulcus
  • Large cell neuro-endocrine cancer (LCNEC)
  • Sarcomatoid tumor
  • Diagnosis of SCLC or, for mixed tumors, presence of small cell elements
  • Documentation by local test report indicating presence of anaplastic lymphoma kinase (ALK) gene rearrangements
• Has Grade ?2 peripheral neuropathy.
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.
• Has received prior neoadjuvant therapy for their current NSCLC diagnosis.
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
• Has received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Is an HIV-infected participant with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has a concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV deoxyribonucleic acid (DNA)) and Hepatitis C virus (defined as anti-HCV antibody (Ab) positive and detectable HCV ribonucleic acid (RNA)) infection.
• Has a severe hypersensitivity (Grade ?3) to sacituzumab tirumotecan, any of its excipients and/or to another biologic therapy.
• Has a history of allogeneic tissue/solid organ transplant.
• Has not adequately recovered from major surgery or have ongoing surgical complications.

Eligibility

Inclusion Criteria:

• Adults aged 18 years or older at the time of the signing of the ICF.
• Life expectancy greater than 12 weeks.
• ECOG performance status score of 0 or 1.
• Disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available treatment to improve the disease outcome.
• Availability of a baseline archival tumor specimen or willingness to undergo a pretreatment and an on-treatment tumor biopsy.

For Part 1:

Participants in Part 1A (dose escalation): Histologically or cytologically confirmed advanced or metastatic solid tumors.

Participants in Part 1B (dose expansion):

• Disease Group 1: Ovarian/Fallopian/Primary Peritoneal Cancer
• Disease Group 2: Endometrial/Uterine Cancer
• Disease Group 3: Gastric, GEJ, and esophageal carcinomas
• Disease Group 4: TNBC
• Disease Group 5: HR+/HER2- breast cancer
• Disease Group 6: Other tumor indications excluding bone cancers

For Part 2:

Participants in Part 2A (dose escalation): Histologically or cytologically confirmed advanced or metastatic solid tumors.

• TGA, TGC, TGE, TGF, and TGG: Participants with HR+/HER2- breast cancer or participants with a different tumor.
• TGB and TGD: Participants with HR+/HER2- breast cancer.

Participants in Part 2b (dose expansion):

• TGH and TGJ:

  • Participants with HR+/HER2- breast cancer.
  • Participants with any other advanced or metastatic solid tumor.

• TGI and TGK:

  â?¢ Participants with HR+/HER2- breast cancer.

• TGL, TGM and TGN:

  â?¢ Participants with advanced or metastatic epithelial ovarian/fallopian/primary peritoneal carcinoma.

• Measurable lesions by CT or MRI based on RECIST v1.1 criteria.

Exclusion Criteria:

• History of clinically significant or uncontrolled cardiac disease.
• History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful.
• Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed.
• Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of the first dose of study drug.
• Specific laboratory values.
• Significant concurrent, uncontrolled medical conditions, including but not limited to Hepatic and Gastrointestinal.
• Has not recovered to ? Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study drug.
• Prior treatment with any CDK2 inhibitor.
• Any change in endocrine therapy within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug or any administration of targeted therapy, antibody, or hypomethylating agent to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
• Any major surgery within 28 days before the first dose of study drug.
• Any prior radiation therapy within 28 days before the first dose of study drug.
• Undergoing treatment with another investigational medication or having been treated with an investigational medication within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
• Active HBV or HCV infection that requires treatment.
• Known history of HIV.
• Known hypersensitivity or severe reaction to any component of study treatment or formulation components.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Eligibility

Eligibility

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Cohort A:

  • Has a diagnosis of hormone receptor positive/Human Epidermal Growth Factor Receptor 2 negative (HR+/HER2-) invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent.
  • Has experienced disease progression on or after at least 1 prior endocrine-based therapy in the metastatic setting.

• Cohort B:

  • Has histologically confirmed high-grade epithelial (including high-grade serous or predominantly serous, high-grade endometrioid, malignant mixed Müllerian tumors [carcinosarcoma], or clear cell) ovarian, fallopian tube, or primary peritoneal carcinoma.
  • Has received between 4 to 8 cycles of platinum-based doublet chemotherapy in third-line (3L) setting for ovarian cancer.

• Cohort C:

  • Histologically confirmed diagnosis of primary advanced or recurrent low-grade endometrioid carcinoma (eg, Federation of Gynecology and Obstetrics [FIGO] Grade 1/2, or well/moderately differentiated).
  • Treatment naïve or has received up to 1 prior line of platinum-based therapy in either the advanced/metastatic OR adjuvant/neoadjuvant setting.

• All Cohorts :

  • Participants who have AEs due to previous anticancer therapies must have recovered to ?Grade 1 or baseline.
  • Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy.
  • Participants who are Hepatitis B surface antigen positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load.
  • Participants with a history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable.

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Cohort A:

  • Breast cancer amenable to treatment with curative intent.
  • Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications, such as lymphangitic lung metastases, radiographic evidence of intratumoral cavitation or invasion/infiltration of a major blood vessel, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control.

• Cohort B:

  • Has nonepithelial cancers (germ cell tumors and sex cord-stromal tumors), borderline tumors (low malignant potential), mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor, low-grade serous, low-grade endometrioid, and undifferentiated carcinoma.
  • Has platinum-resistant ovarian cancer (defined as disease that has progressed per radiographic imaging within 180 days after the last dose of first-line [1L] platinum-based therapy) or platinum-refractory ovarian cancer (defined as disease that has progressed per radiographic imaging while receiving or within 28 days of the last dose of 1L platinum based therapy).
  • Is a candidate for curative-intent surgery or curative-intent radiotherapy for ovarian cancer.

• Cohort C:

  • Has high-grade (FIGO Grade 3 or poorly differentiated) endometroid carcinoma and nonendometrioid histologies of any type (including serous, clear cell, mixed, carcinosarcoma), and neuroendocrine tumors are not eligible. Uterine mesenchymal tumors such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas, and adenosarcomas are not eligible.
  • Is a candidate for curative-intent surgery or curative-intent radiotherapy.

• All Cohorts:

  • Has confirmed or suspected adrenal metastases.
  • Has known difficulty in tolerating oral medications, unable to swallow orally administered medication, or conditions which would impair absorption of oral medications.
  • Has any prior history or current condition of adrenal insufficiency.
  • HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Has known active central nervous system metastases and/or carcinomatous meningitis.
  • Has a history of stem cell/solid organ transplant.
  • Has not adequately recovered from major surgery or has ongoing surgical complications.

Eligibility

Eligibility

Inclusion Criteria:

1. ? 18 years of age at the time of signing the informed consent form (ICF).
2. Histologically or cytologically confirmed CCA/adenocarcinoma of biliary origin with radiological evidence of unresectable or metastatic disease.
3. Documentation of FGFR2 fusion/rearrangement gene status
4. Subjects must have received at least one line of prior chemotherapy and exactly one FDA approved FGFR inhibitor.

Exclusion Criteria:

1. Prior receipt of two or more FGFR inhibitors, either approved or investigational drugs.
2. Subjects with known brain or central nervous system (CNS) metastases that have radiologically or clinically progressed in the 28 days prior to initiation of therapy. Subjects with asymptomatic brain/CNS metastases or treated brain/CNS metastases that have been clinically stable for 14 days on steroids without escalation of steroids are eligible for enrollment.
3. Subjects with a known concurrent malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, including those that have previously undergone potentially curative therapy.
4. Subjects who have received prior systemic therapy or investigational study drug ? 5 half-lives or 14 days, whichever is shorter, prior to starting the study drug or who have not recovered (grade ? 1 or at pretreatment baseline except tolerable grade 2 alopecia, fatigue/asthenia, and neuropathy due to trauma) from adverse events (AEs) of prior therapy.
5. Concurrent anticancer therapy including chemo-, immune-, or radiotherapy. Hormone therapy may be allowed with Sponsor approval.
6. Subjects who have received wide field radiotherapy ? 4 weeks or limited field radiation for palliation ? 2 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.
7. Subjects with uncontrolled hypertension (defined as blood pressure of ? 150 mm Hg systolic and/or ? 90 mm Hg diastolic despite adequate treatment with antihypertensive medications at screening)