• 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

• ECOG PS 0-1
• Confirmed diagnosis of high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer
• If patients are BRCA positive, must have received treatment with PARP inhibitors
• Must be folate receptor alpha positive as defined by FRa positivity of >75% of tumor membrane staining at 2+ intensity or higher.
• Disease must have relapsed after 1 line of platinum-based therapy and must be platinum-sensitive defined as progression greater than 6 months from last dose of primary platinum therapy
• Must be appropriate for, currently be on, or have completed platinum-based triplet therapy in the second line. Must have received no less than 4 and no greater than 8 cycles in the second line
• Must have receirved, be currently be receiving, or be planned to receive paclitaxel, gemcitabine, pegylated lipsomal doxorubicin as the partner drug to platinum based therapy
• After completion of platinum based triple therapy and before randomization, patient must have achieved a CR, pR, or SD
• Before randomization must have either a) measurable disease, b) persistently elevated CA-125 or c) no evidence of disease and normalization of CA-125
• No endometrioid, clear cell, mucinous, or sarcomatous histology
• No more than 1 line of prior chemotherapy before planned triplet therapy
• No PD while on triple therapy
• No cirrhotic liver disease
• No severe cardiac disease
• No history of bowel obstruction, abdominal fistula, or GI perforation
• No folate deficiency
• No other malignancy within 3 years

Key Inclusion criteria

• Participants with confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
• Participants must have platinum-resistant disease:
• Participants who have only had one prior line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date of the last dose of platinum.
• Participants who have received 2 or 3 lines of platinum therapy must have progressed ≤ 6 months after the date of the last dose of platinum.
• Participants must have radiologically progressed on or after their most recent line of therapy.
• Participants must have received at least one, but no more than 3, prior systemic lines of anti-cancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment
• Participants with documented BRCA mutation (germline and/or somatic) must have received prior PARPi if the participant is eligible per approved label and standard-of-care institutional guidelines, except in cases of documented contraindication, precaution or intolerance.
• Provision of an FFPE tumour tissue sample

Key Exclusion criteria

• Participants with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumours containing any of the above histologies, or low-grade or borderline ovarian tumour.
• Primary platinum-refractory disease, defined as disease that did not respond to or has progressed ≤ 3 months after the last dose of first line platinum-containing chemotherapy.
• Participants with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring
• Current signs, symptoms, or clinical investigations consistent with bowel obstruction, including sub-occlusive disease.
• Participant has non-infectious ILD/pneumonitis or has a history of non-infectious ILD/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Prior treatment with any FRα-targeted therapy, including MIRV, or any TOP1i ADC.
• Major surgical procedure within 4 weeks of the first dose of study intervention

• Histologically or cytologically confirmed diagnosis of advanced (unresectable) or metastatic high grade serous ovarian, primary peritoneal, or fallopian tube cancer.  High-grade endometrioid ovarian cancer is permitted, Carcinosarcoma is permitted
• Positive CLDN6 expression as per central lab
• Platinum resistant disease as per protocol
• Patients who are platinum refractory during front-line treatment are excluded
• Must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy and for whom single-agent therapy is appropriate as next line
  • Adjuvant or neoadjuvant therapy is counted as one line
• Measurable disease
• ECOG PS 0-1
• Must have recovered from acute effects of prior therapy
• No clear cell, mucinous, sarcomatous, mixed histology, or low grade, borderline ovarian tumors or non-epithelial ovarian cancers
• No prior cancer within 3 years

• 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

• ECOG PS 0-1
• Subjects who relapsed, progressed, or were intolerant to standard therapy, have a disease for which no therapy with a known overall survival benefit exists or are not a candidate for these therapies, and have one of the following cancers:

i. Histologically confirmed locally advanced/metastatic HER2-negative breast cancer, with deleterious or suspected deleterious BRCA1/2 mutation, that progressed on, was intolerant to, was refused, or ineligible for (PARPi).

ii. Histologically confirmed locally advanced/metastatic HGSOC (high-grade serous ovarian cancer), including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC), that progressed on, was intolerant to, refused, or ineligible to maintenance treatment with a PARPi.

iii. Histologically confirmed locally advanced/metastatic CRPC, with deleterious or suspected deleterious BRCA1/2 mutation, that progressed on, was intolerant to, refused, or ineligible for PARPi.

iv. Histologically confirmed locally advanced/metastatic pancreatic cancer with deleterious or suspected deleterious BRCA1/2 mutation that progressed on, was intolerant to, refused, or ineligible for maintenance treatment with a PARPi.

v. Locally advanced/metastatic tumors with deleterious or suspected deleterious germline or somatic HRR mutation or HRD phenotype.

Cohort-Expansion Stage Single Agent and Combination:

b) HER2-negative BRCAm Breast cancer cohort: i. Histologically confirmed locally advanced/metastatic HER2-negative Breast cancer with deleterious or suspected deleterious BRCA1/2 mutation have documented radiographic disease progression during or following their last systemic anticancer therapy and that progressed on, was intolerant to, refused, or ineligible for treatment with a PARPi.

c) Platinum-resistant HGSOC cohort: i. Histologically confirmed locally advanced/metastatic HGSOC, including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC), that progressed on, was intolerant to, refused, or ineligible to maintenance treatment with a PARPi and who have platinum-resistant disease, defined by platinum free interval of less than 6 months ii. Platinum-refractory disease (progression on first-line treatment or within 4 weeks of completion) are excluded.

d) Platinum-sensitive HGSOC cohort - expansion combination only: i. Histologically confirmed locally advanced/metastatic HGSOC, including PPC and FTC, that progressed on, refused, or ineligible to maintenance treatment with a PARPi, and who have platinum-sensitive disease, defined by platinum free interval of more than 6 months e) mCRPC cohort: i. Subjects with metastatic, castration-resistant adenocarcinoma of the prostate with deleterious or suspected deleterious BRCA1/2 mutation, that progressed on, or was intolerant, refused, or ineligible to PARPi.

f) HRRm advanced solid tumors cohort: i. Locally advanced/metastatic tumors with deleterious or suspected deleterious germline or somatic HRR mutation or HRD phenotype.

• No known symtomatic brain mets

• Participants must meet all of the following criteria to be eligible for enrollment into the trial:

• Adults ≥18 years of age on the day of signing the ICF.
• Participants must have at least 1 lesion, not previously irradiated, amenable to biopsy, and must consent to provide a pre-treatment biopsy from a primary and/or metastatic lesion.
• Has at least 1 measurable lesion according to RECIST version 1.1 per investigator assessment.
• Participants must have progressed radiologically on or after their most recent line of systemic therapy.
• Eastern Cooperative Oncology Group performance status of 0 or 1.

• Additional inclusion criteria for endometrial cancer cohort

  1. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological subtype or carcinosarcoma), irrespective of MSI or mismatch repair status.
  2. Documented disease progression after having received ≥1 line of therapy (no more than 3), including PBC-containing systemic treatment and an anti-PD-1 therapy containing regimen (combined or sequential) in the advanced/metastatic setting.

• Additional inclusion criteria for cervical cancer cohort

  1. Pathologically or cytologically documented recurrent or persistent squamous, adenosquamous, or adenocarcinoma of the uterine cervix.
  2. Disease progression after having received ≥1 prior line of therapy that includes systemic therapy in the advanced or metastatic setting.

• Additional inclusion criterion for non-HGSOC cohort

  a. Pathologically or cytologically documented unresectable or metastatic CCOC, low grade endometrioid, low-grade serous, or mucinous OVC that was previously treated with at least 1 prior line of therapy.

• Additional inclusion criteria for urothelial cancer cohort

  1. Pathologically or cytologically documented unresectable or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Histological variants are allowed if urothelial histology is predominant.
  2. Relapsed or progressed after treatment with ≥1 prior line of therapy (maximum of 3) that contains anti-PD-(L)1 therapy in the perioperative or metastatic setting.
• Additional inclusion criterion for the ccRCC cohort a. Pathologically or cytologically documented unresectable or metastatic ccRCC that was previously treated with no more than 3 prior systemic regimens for locally advanced or metastatic RCC, including both a PD-(L)1 checkpoint inhibitor and a VEGF-TKI in sequence or in combination.

• Participants who meet any of the following criteria will be disqualified from entering the trial:

• Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis
• Any of the following within the past 6 months prior to enrollment: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.
• Uncontrolled or significant cardiovascular disease as specified in the protocol.
• 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
• Chronic steroid treatment (>10 mg/day) with exceptions as noted in the protocol.
• History of other active malignancy 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.
• 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.
• 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, datopotamab deruxtecan).
• Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
• Has active or uncontrolled HIV, HBV, or HCV infection.

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.