• ER-, PR-, HER2- TNBC
• Clinical stage either
  • T2-T4, N0, M0 or
  • T1-T3, N1-2, M0
  • No T4/N+, any N3, or inflammatory breast cancer
• No prior systemic therapy for curative intent
• No previous ipsilateral surgery for current breast surgery
• ECOG PS 0-

• ER positive, HER2 negative breast cancer
  • Muticentric and multifocal also eligible if all tumors are ER+/HER2-
• Must have undergone definitive surgery of their primary breast tumor and axillary lymph nodes
• Must have finished adjuvant chemotherapy prior to randomization (if chemo was indicated)
• Resolution of all toxic effects of prior chemo
• Both node positive and node negative disease are eligible
• ECOG PS 0-2
• Not receiving and no plan to receive a CDF4/6 inhibitor as adjuvant therapy
• No prior malignancy within 3 years
• No prior endocrine treatment

• Premenopausal
  • Age 40 years or under with spontaneous menses within 12 months
  • Age 50-60 years with spontaneous menses within 12 months plus FSH and estrodiol measurements within premenopausal range
  • Amenorrhea due to IUD or uterine ablation or hysterectomy must have FSH and estrodiol ranges in premenopausal range
• ECOG PS 0-2
• Multicentric or multifocal breast cancer is allowed
• Must have had definitive breast surgery (+radiation if indicated)
• Primary tumor must be T1-3
• Nodes must be N0 or N1
• Oncotype score must be,
  • if node negative: 21-25 or high clinical risk (with oncotype 16-20)
  • If 1-3 nodes, must be <26
• Must be ER/PR positive
• Must be HER2 negative
• No metastatic disease

• Centrally confirmed TNBC
• No evidence of locregional or distant relapse
• Had neoadjuvant treatment based on the KEYNOTE-522 regimen (pembrolizumab with carboplatin/taxane and pembrolizumab with anthracycline-based chemotherapy) followed by surgery per NCCN guidelines for TNBC
• Had adequate excision and surgical removal of all clinically evident disease in the breast and/or lymph nodes and have adequately recovered from surgery
• Is able to continue on adjuvant pembrolizumab
• Has non-pathologic complete response at surgery
• Completed adjuvant radiation therapy if indicated and recovered before randomization
• Must be randomized within 16 weeks from surgery
• ECOG PS 0-1
• No known BRCA mutation
• Cannot have received anticancer therapy in adjuvant setting
• No additional malignancy that is progressing or has required active treatment within the last 5 years

• Women or men with breast carcinoma
• Documented ER-positive and/or PR positive
• PIK3CA mutation
• Documented HER2-negative
• De-novo HR+, HER2- ABC, or alternatively relapsed HR+, HER2- ABC after at least 2 years of standard neoadjuvant/adjuvant endocrine therapy without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment
• Bilateral breast cancer is allowed if both HR+/HER2-
• Measurable disease
• ECOG PS 0-1
• No metaplastic breast cancer
• No known or untreated CNS mets. History of treated CNS mets allowed
• No active lung disease
• No history of IBD

• Clinical Stage IV invasive mammary carcinoma or unresectable locoregional recurrnce of invasive mammary carcinoma
• ER or PR positive (> or = 1%) and HER2 negative
• Previously exposed to an AI or SERM plus a CDK4/6 inhibitor
• No unstable brain mets
• ECOG PS 0-1
• Evaluable disease (measurable or unmeasurable)
• Adequate organ function
• For randomized patients must be diagnosed as non-Luminal A using Blueprint and Mammaprint tests
• No prior chemo in metastatic setting
• No previous malignant disease other than breast cancer within the last 2 years (except non-melanoma skin, cervical CIS, or low risk cancers considered curateively treated)

Key Inclusion Criteria:

• Individuals assigned male or female at birth, 18 years of age or older, able to understand and give written informed consent.
• Histologically or cytologically locally confirmed TNBC.
• Phase 1: Individuals with unresectable, locally advanced or metastatic TNBC who are refractory to or relapsed after at least one prior standard-of-care chemotherapy regimen or systemic therapy given for locally advanced or metastatic disease.
• Phase 2: Individuals with unresectable, locally advanced or metastatic TNBC who have not received previous systemic therapy for advanced disease.
• Phase 2: Tumors must be PD-L1 negative, defined as tumor PD-L1 combined positive score (CPS) < 10 using the PD-L1 immunohistochemistry (IHC) 22C3 assay. Alternatively, individuals with tumor CPS ≥ 10 will be eligible if they received an anti-PD-(L)1 agent (ie, checkpoint inhibitor) in the adjuvant or neoadjuvant setting or if they cannot be treated with an anti-PD-(L)1 agent. due to a comorbidity.
• Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype status.

During Phase 1 safety run-in, individuals must be UGT1A1 wild-type.

After Phase 1 safety run-in, individuals with any UGT1A1 genotype may be eligible.

• Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST Version 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Adequate hematologic counts within 2 weeks prior to enrollment.
• Adequate hepatic and renal function.

Key Exclusion Criteria:

• Prior treatment with a topoisomerase 1 inhibitor or antibody-drug conjugate (ADC) containing a topoisomerase inhibitor.
• Prior treatment with a trophoblast cell-surface antigen 2 (Trop-2)-directed ADC.

• Measurable disease
• Progression on or afer the previous standard-of-care regimen in the advanced/metastatic setting
• ECOG PS 0-1
• No clinically active CNS mets
• If Endometrial carcinoma:
  • Pathologically or cytologically documented EC of any histological carcinoma subtype or endometrial carcinoma sarcoma, irrespective of MSI or MMR status
  • Relapse or progression after a platinum containing treatment and ICI containing regimen as well as targeted therapies when appropriate
• If Head and Neck Cancer:
  • Documented unresectable or metastatic squamous cell carcinoma of the oral cavity oropharynx, hypopharynx, or larynx, excluding nasopharynx, nasal cavity and paranasal sinuses
  • Disease progression after platinum-based and ICI tx, wiht targeted therapy where appropriate.
  • Maximum of 2 prior lines of therapy
• If pancreatic cancer
  • Unresectable or metastatic pancreatic adenocarcinoma that has relapsed or progressed after 1 prior line of gemcitabine-based systemic therapy in the metastatic setting or after 2 lines of therapy if treated with targeted therapy if appropriate
• If colorectal cancer
  • Unresectable or metastatic CRC with known microsatellite status
  • Relapse or progression after 1 prior line of tx including FOLFOX +/- bev or EFGR mAb tx, or relapse or progression after 2 lines of therapy if received targeted therapy.
  • No prior irinotecan
• If hepatocellular carcinoma
  • Documented unresectable or metastatic HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
  • Relapse or progression after 1 prior line of ICI tx (combo or mono) in metastatic setting.
  • Maximum of 2 prior lines
  • BCLC Stage B or C
  • Child-Pugh Class A
  • ALBI Grade 1 within 7 days
• If esophageal, gastric, or GE junction cancer
  • Documented unresectable or metastatic esophageal adenoCA/GE junction/Gastric carcinoma that has relapsed or progressed after 1 prior line of tx. If PD-L1+ or MSI-H should have received ICI treatment.
  • Must have been treated with HER2 targeted tx if HER2 positive
• If urothelial carcinoma
  • Documented unresectable or metastatic UC of the bladder, renal pelvis, ureter, or urethra. Participants with histological variants are allowed if urothelial histology is predominant. Small cell/neuroendocrine tumors are not allowed even if mixed histology
  • Relapse or progression after at least 1 prior line of ICI-containing tx and 1 prior line or chemo, with maximum of 3 prior lines
    • At least 1 line must include enfortumab vedotin
    • Perioperative systemic therapy will be counted as 1 line
    • If targeted therapy is appropriate should have been txed with targeted therapy
• If cervical cancer
  • Unresectable or metastatic cervical cancer previously treated with at least 1 line of systemic therapy in the locally advanced or metastatic setting
  • Should have received PD-1/PD-L1 tx and tisotumab vedotin
• If ovarian cancer
  • High-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer previously treated with at least 1 line of platinum based tx + bevacizumab
  • No longer eligible for platinum-based tx or has progressed less than 180 days after the last dose of platinum therapy
• If biliary tract cancer
  • Unresectable or metastatic biliary tract cancer (intra- or extrahepatic cholangiocarcinoma or gallbladder carcinoma). Ampullary cancer, small cell cancer, lymphoma, sarcoma, neuroendocrine cancer, mixed tumor histology, and/or mucinous cystic neoplasms are NOT allowed.
  • Relapse or progression after at least 1 prior line of systemic therapy. If appropriate, should have received a targeted therapy
• If HER-2 low breast cancer
  • Unresectable or metastatic breast cancer with low HER2 expression defined as IHC2+/ISH- or IHC 1+ (ISH- or untested) accordoing to ASCO-CAP 2018 HER2 testing guidelines, regardless of hormonal status
  • Progression on or after tx with T-DXd
  • Relapse or progression after at least 2 and less than 3 lines of systmic therapy. Endocrine therapy doesn't count as line of tx.
• If HER-2 negative breast cancer
  • Unresectable or metastatic breast cancer negative for HER2 expression, defined as IHC 0 (ISH negative or untested) according to ASCO-CAP 2018 HER2 testing guidelines
  • Relapse or progression after at least 2 and less than 3 prior systmic therapies.  Endocrine tx doesn't count as line of therapy.
• If melanoma
  • Confirmed cutaneous (acral or non-acral) melanoma
  • Disease progression while on or after having received treatment with at least 1 prior line of ICI based therapy.  If BRAF mt, must have also progressed after targeted therapy

Inclusion Criteria:

• Participants with histologically/cytologically confirmed advanced recurrent or metastatic solid tumor malignancy
• Part 1 (dose escalation): Participants must have had disease progression on or following all available standard of care (SOC) therapies known to confer clinical benefit.
• Part 2 (dose expansion): Participants may be enrolled following disease progression that has progressed after at least 1 available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized SOC.
• Measurable Disease

Exclusion Criteria:

• History of another malignancy within 2 years prior to the first trial intervention administration (unless the malignancy was treated with curative intent with low risk of recurrence [e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar] which are allowed to enroll).
• Therapy with Immunosuppressive doses of systemic medications, such as steroids (doses >10 mg/day prednisone or equivalent daily) within 2 weeks before trial intervention administration
• Have known active central nervous system (CNS) metastases and/or leptomeningeal disease (LMD).
• Active and clinically relevant bacterial, fungal, or viral infection that is not controlled or requires systemic antibiotics, antifungals, or antivirals, respectively.
• Ascites or pleural effusion that is symptomatic and/or requiring drainage within 2 weeks prior to the first trial intervention administration.
• Have active hepatitis B virus (HBV) or hepatitis C virus (HCV), or participants with human immunodeficiency virus (HIV).
• Any medical condition that, in the investigator's or sponsor's opinion, poses an undue risk to the participant's participation in the trial.

• Histologically confirmed locally advanced, recurrent, or metastatic incurable solid tumors
• Must have tumor specimen available
• Measurable disease
• ECOG PS 0-1
• Life expectancy at least 12 weeks
• Phase 1a- must have exhausted all standard therapies for their disease
• Phase 1b- must have disease that has progressed after at least one available standard therapy
• Some cohorts are tumor-type specific- please contact study team to see if tumor type is eligible at any time during the study
• No active HBV/HCV or chronic or acute EBV
• No history of autoimmune disease
• No symptomatic or actively progressing CNS mets