Inclusion Criteria:

1. Patient must have histologically confirmed adenocarcinoma (usual/classic/NOS), squamous cell carcinoma, adenosquamous carcinoma (Including glassy cell)
2. Patient must be FIGO Stage IA2, IBI, IB2 (2018 staging) without evidence of definitive parametrial, vaginal, nodal or distant metastases on exam or imaging. Patients with tumor size less than or equal to 4 cm confirmed on MRI prior to randomization are eligible.
3. Patient must have uterine size <12 cm AND felt to be appropriate for vaginal delivery of the specimen per investigator.
4. Patient must be suitable surgical candidate with preoperative assessments such as labs and EKG performed per institutional standard.
5. Patient must be age 18 years or older.
6. Patient must have ECOG performance status 0-1.
7. Patient must have a negative urine pregnancy test within 30 days of surgery in pre-menopausal women.
8. Patient must have signed an approved informed consent and authorization permitting the release of personal health information.

Exclusion Criteria:

1. Patients with any tumor histology other than those listed above, specifically excluding the following histologies: neuroendocrine, other adenocarcinoma (gastric type, endometrioid, clear cell, serous, signet ring, minimal deviation)
2. Patients with FIGO stage 1A1, IB3, II-IV (2018 staging).
3. Patient with inability to receive an MRI.
4. Patients with a tumor size greater than 4cm or on MRI confirmed prior to randomization are excluded. Patients with definite evidence of vaginal/parametrial involvement on MRI are excluded; if MRI findings are not definitive, then clinical examination must also not reveal parametrial or vaginal extension).
5. Patients with evidence of metastatic disease (imaging or histologically positive lymph nodes).
6. Patients with a history of prior pelvic or abdominal radiotherapy.
7. Patients with a prior malignancy < 5 years from enrollment with the exception of non-melanoma skin cancer.
8. Patients who are unable to withstand prolonged lithotomy or steep trendelenberg.
9. Patient compliance and geographic proximity that do not allow adequate follow-up.
10. Patients with poorly controlled HIV with CD4 counts <500.

• 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

• 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.

• 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