• 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)
• 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
• 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
• No evidence of residual cancer or metastasis after cystectomy

• 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).

  • (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
• ECOG PS 0-2
• No adjuvant systemic threapy after cystectomy
• No prior PD-1/L1 inhibitor or LAG-3 blockade
•  

• 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

Inclusion Criteria:

• Have a diagnosis of ER+, HER2- early-stage, resected, invasive breast cancer without evidence of distant metastasis.
• Participants must have received at least 24 months but not more than 60 months of any adjuvant ET, from time of adjuvant ET initiation.
• Participants may have received (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor.
• Must have an increased risk of disease recurrence based on clinical-pathological risk features.
• Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale.
• Have adequate organ function.

Exclusion Criteria:

• Have any evidence of metastatic disease (including contralateral ALN) or inflammatory breast cancer at primary breast cancer diagnosis.
• Participants with more than a 6-month consecutive gap in therapy during the course of prior adjuvant ET.
• Participants who have completed or discontinued prior adjuvant ET >6 months prior to screening.
• Participants with a history of previous breast cancer are excluded, with the exception of ipsilateral DCIS treated by locoregional therapy alone ≥5 years ago.
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study intervention.
• Participant has previously received ET of any duration for breast cancer prevention (tamoxifen or AIs) or raloxifene.
• Participants with a history of any other cancer.
• Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study.

• 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

• ER+, Her2 negative breast cancer
• Endocrine therapy recommended, cytotoxic chemotherapy not recommended
• Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease (note: at least one line of therapy must have contained a CDK4/6i administered for a minimum of 8 weeks prior to disease progression.)
• Postmenopausal status 
• ECOG 0-1
• Available tumor specimen
• Prior fulvestrant therapy is allowed
• Measurable disease
• No prior cytotoxic chemotherapy for metastatic disease
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

• Locally advanced or metastatic adenocarcinoma of the breast
• Documented ER positive, HER2 negative
• Confirmed ESR mutation status through central lab testing
• Resistance to prior adjuvant endocrine therapy
• No prior systemic anti-cancer therapy for advanced disease
• Prior use of adjuvant CDK4/6 inhibitor is allowed
• No prior treatment with another SERD (e.g. fulvestrant)
• No active cardiac disease

• 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

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.

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.

• Patients must have histologically/pathologically confirmed colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria. NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera™ ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.
• No radiographic evidence of overt metastatic disease
• Distal extent of tumor must be greater than or equal to 12cm from the anal verge
• Must have had curative resection (en bloc)
• Resected tumor specimen and blood must have central testing for ctDNA useing the Signatera assay
• Must be microsatellite stable or have intact mismatch proteins
• No more than 60 days post surgery to study entry
• No other invasive malignancy within 5 years
• No known active cardiac disease

• Locally confirmed microsatellite instability-high/ deficient mismatch repair (MSI-H/dMMR) stage IV colorectal carcinoma
• Locally confirmed BRAF V600E mutation in tumor tissue or blood
• ECOG PS 0 or 1
• Have not received prior systemic regimens for metastatic disease.
• Measurable disease
• RAS wt
• No known active central nervous system metastases and/or carcinomatous meningitis; leptomeningeal disease
• No immunodeficiency or active autoimmune disease requiring systemic treatment in the past 2 years
• No presence of acute or chronic pancreatitis
• No previous treatment with any selective BRAF inhibitor (eg, encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) or any epidermal growth factor receptor (EGFR) inhibitor (eg, cetuximab, panitumumab).
• No previous treatment with an immune checkpoint inhibitor (eg, anti-programmed cell death [PD-1], anti-PD-L1 or anti-PD-L2 agent); or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).

• Histologically or cytologically confirmed unresectable metastatic adenocarcinoma of the colon or recturm
• Has already received the following regimens for advanced colorectal cancer and has demonstrated PD or intolerance to their last regimen
  • Must have included a fluoropyrimidine, irinotecan, oxaliplatin, and an anti-VEGF monoclonal antibody, as well as an anti-EGFR antibody if indicated
  • Patients who received adjuvant therapy and had recurrence within 12 months can count the therapy as one regimen of therapy for advanced disease
  • No prior lonsurf
  • Patients with MSI-h/dMMR or BRAF mt should have received appropriate therapy
• Measurable disease
• ECOG PS 0-1
• EF >50%
• No untreated CNS disease
• No bevacizumab bleeding risks

Inclusion Criteria:

• Has a histologically-confirmed diagnosis of endometrial carcinoma or carcinosarcoma.
• Has radiographically evaluable disease, either measurable or nonmeasurable per response evaluation criteria in solid tumors (RECIST 1.1), as assessed by blinded independent central review (BICR).
• Has received prior platinum-based chemotherapy and anti-programmed cell death 1 protein (PD-1)/anti- programmed cell death ligand 1 (PD-L1) therapy, either separately or in combination.

Exclusion Criteria:

• Has neuroendocrine tumors or endometrial sarcoma, including stromal sarcoma, leiomyosarcoma, adenosarcoma, or other types of pure sarcomas.
• 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 had a recurrence of endometrial carcinoma or carcinosarcoma more than 180 days after completing platinum-based therapy administered in the curative-intent or adjuvant setting without any additional platinum-based therapy received in the metastatic or recurrent setting.
• Has received more than 3 prior lines of therapy for endometrial carcinoma or carcinosarcoma.

• Histogically or cytologicall confirmed diagnosis of advanced, unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma
• Has received, and progressed on, at least 2 prior chemotherapy and/or immunotherapy regimens
• Eligible regardless of HER2 status. However, if patients are HER2+, must have previously received trastuzumab
• Must provide tissue for measurement of TROP2 status before randomization (elgible regardless of TROP2 status)
• Measurable disease
• ECOG PS 0-1
• No severe weight loss in prior 3 months
• No grade 2 or higher peripheral neuropathy
• No prior TROP-2 ADC
• No known active CNS disease
• No history of HIV, active HBV, or active HCV

• Has newly diagnosed unresected LA histologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx or larynx and completed cisplatin plus radiotherapy (termed "CRT" in this protocol) with curative intent and has no evidence of distant metastatic disease.
• ECOG PS 0-1
• PD-L1 positive
• Must not have received prior XRT, systemic therapy, targeted thyerapy, or radical surgery for management of head and neck cancer not considered part of CRT
• No cirrhosis
• No prior PD-1/PD-L1 or other immunotherapy

• Locally advanced or unresectable HCC with diagnosis confirmed by histology/cytology by AASLD criteria in cirrhotic patients
• Not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for locally advanced or metastatic and/or unresectable HCC
• Measurable disease
• ECOG PS 0-2
• Child-Pugh B7 or B8 cirrhosis at screening and within 7 days prior to study treatment
• Life expectancy of at least 12 wks
• No prior tx with CD137 agonists or immunotherapy
• No known fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC
• No symptomatic or progressing CNS dz
• No co-infection with HBV or HCV
• No TIPS
• No ascites requring therapeutic paracentisis over past 3 months
• No history of spontaneous bacterial peritonitis over last 12 months

• Locally advanced unresectable, recurrent, and/or metastatic HCC
• Must have progressed on 1st line therapy that contained anti-PD-1 or anti-PD-L1 therapy as their immediate prior treatment regimen
• Child-Pugh A determined withint 14 days of first treatment
• All patients must undergo EGD with esophageal varices assessment
• Measurable and injectable disease
• Must be willing to undergo biopsy
• ECOG PS 0-1
• No significant bleeding event in last 12 months
• No macroscopic vascular invastion into major blood vessels
• No rare HCC variants
• No liver tumors that are estimated to invade more than one-third of the liver
• No known acute or chronic HBV/HCV unless PCR below lower limits of detection
• No known HIV
• No known CNS metastatses

• Histologically confirmed diagnosis of metastatic or unresectable NSCLC (squamous or nonsquamous) not a candidate for definitive therapy
• KRAS G12C mutation
• Known PD-L1 status (can enroll regardless of level)
• 1st line- no prior treatment for metastatic NSCLC
  • OK to have had radiosensitizing chemo >1 year prior
• ECOG PS 0-1
• Measurable disease
• No active CNS mets
• No XRT to the lungs within 6 months prior to first dose of study treatment
• No known autimmune disease

• Measurable disease by RECIST 1.1 criteria.
• Adequate bone marrow or organ function.
• Life expectancy of ≥ 3 months.
• Sufficient performance status.
• Confirmed NSCLC, without small cell lung cancer transformation with or without brain metastases.

• Disease progression following or intolerance of standard of care (excluding patients in the treatment-naïve non-classical driver cohort):

  • Cohort 1 (Non-Classical driver cohort): Advanced/metastatic NSCLC with a non-classical driver EGFR mutation (eg, G719X) following up to 2 lines of therapy with only 1 prior EGFR TKI regimen (third-generation preferred; other approved EGFR TKI acceptable).
  • Cohort 2 (Acquired resistance C797S cohort): Advanced/metastatic NSCLC with the acquired resistance C797S EGFR mutation following up to 2 lines of therapy, including only one EGFR TKI, which must be a third generation EGFR TKI (eg, osimertinib).
  • Cohort 3 (First-line non-classical driver cohort): Treatment-naïve advanced/metastatic NSCLC with a non-classical driver EGFR mutation (1 cycle of chemotherapy or immune checkpoint inhibitor are permitted). Patients with co-occurring L858R mutations and a non-classical mutation are eligible for inclusion.

• Identification of one (or more) of the following EGFR mutations by Next Generation Sequencing (NGS) as determined by a local assay performed in a validated laboratory in the absence of other known resistance mutations (eg, T790M, MET):

  • Non-classical driver EGFR mutations (eg, L861R, S768I, G719X).
  • EGFR acquired resistance mutation (eg, C797S) to a 3rd generation EGFR TKI.
  • For Phase 2, dose expansion, patients in Cohort 1 who received 3rd generation EGFR TKI (eg, osimertinib), the NGS report within 6 months prior to the start of Screening is acceptable. For patients in Cohort 2, the NGS report must be from the last disease progression on the immediate prior therapy. For patients in Cohort 3, the NGS report must be at the time of diagnosis.
• No known resistant mutations in tumor tissue or by liquid biopsy (eg T790m, MET)
• No more than one line of EGFR TKI tx
• No symptomatic CBS dz

• Histologically or cytologically documented extensive-stage small cell lung cancer (ES-SCLC)
• Has received prior therapy with only one prior platinum-based line as systemic therapy for SCLC with at least 2 cycles of therapy and a chemotherapy free-interval of at least 30 days
• Measurable disease
• ECOG PS 0-1
• No brain or leptomeningeal disease
• No clinically significant corneal disease
• Cannot have received any of the comparators in the study or any topo-1 inhibitors

• Age ≥ 18 years.
• .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
• ECOG Performance Status grade 0-2

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

• Adequate renal function

• Adequate liver function

• Previously untreated participants with CD20-positive LBCL
• IPI score 2-5
• ECOG PS 0-2
• Measurable disease
• EF >50%
• HIV negative
• No contraindications to Pola-R-CHP
• No other history of lymphoma

• Histologically or cytologically confirmed melanoma
• Clinically detectable and resectable Stage IIIB, IIIC, or IIID melanoma
• Has been untreated for the melanoma with the exception that primary lesion may have been resected or irradiated
• No known CNS mets
• No ocular or mucosal melanoma
• No known HIV/HBV/HCV
• No active autoimmune disease requiring therapy in past 2 years
• Must not have received prior oncolytic viruses

• Has unresectable Stage III or Stage IV melanoma, not amenable to local therapy
• Has been untreated for advanced disease
• No ocular or mucosal melanoma
• No known additional malignancy that is progressing or requires active treatment within the past two years
• No known CNS metastatses
• No active autoimmune disease requiring systemic treatment in the past two years
• No known HIV/HBV/HCV
• Adequate organ function

• Has unresectable Stage III or Stage IV melanoma not amenable to curative therapy
• Has progressed on treatment with an anti-PD1/L1 monoclonal antibody administered either as monotherapy or in combination with other therapies
• Hsa not received more than 3 lines of therapy
• No known additional malignancy with past 2 years
• No known CNS metastases
• No active autoimmune disease requiring systemic treatment in the last 2 years
• No known HIV/HBV/HCV

• Histologically or cytologically confirmed unresectable or metastatic Stage IIIB through IV M1a through M1d cutaneous melanoma
• Confirmed disease progression on an approved anti-PD-1 and an anti-CTLA-4 treatment, administered either as a combination regimen or in sequence
• Documented BRAF mutation status. Those with BRAF mutation should have received BRAF/MEK therapy unless contraindicated
• Measurable and injectable disease (>1cm)
• ECOG PS 0-1
• No primary mucosal or uveal melanoma
• No more than 2 lines of prior systemic therapy for metastatic disease
• No known HIV
• No LDH .2x ULN
• No need for intermittend or chronic use of anti-viral therapy

• Stage IIIB-IV melanoma, following progression on PD-1 containing regimen
• ECOG PS 0-1
• At least one injectable tumor (visceral or deep nodal lesions may be injectable)
• Measruable disease by RECIST 1.1
• No prior oncolytic virus therapy (no prior T-VEC)
• No active CNS disease
• No history of major autoimmune disease
• No known HBV, HCV, or HIV
• No need for steroids >20mg prednisone daily or equivalent
• No need for chronic use of anti-virals (e.g. acyclovir)
• No prior malignancy in past 3 years except locally curable cancers such as non-melanoma skin cancer, or carcinoma in situ.

• Confirmed metastatic uveal melanoma not amenable to surgical resection
• At least 1 measurable and injectable tumor of > or = 1 cm in longest diameter (1.5 cm in short axis for a lymph node)
• LDH <2x ULH
• ECOG PS 0-1
• No prior exposure to PD-1 agents
• No known HBV/HCV/HIV
• No CNS involvement

• Subject has documented diagnosis of MM and measurable disease, defined as any of the following:
  • M-protein ≥ 0.5 g/dL by serum protein electrophoresis (sPEP) or 
  • M-protein ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or
  • For subjects without measurable disease in sPEP or uPEP: serum free light chain (sFLC) levels > 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda FLC ratio.
• Subject has received 1 to 3 prior lines of antimyeloma therapy. (Note: One line can contain several phases [eg, induction, (with or without) hematopoietic stem cell transplant, (with or without) consolidation, and/or (with or without) maintenance therapy
• Must have received prior treatment with a lenalidomide-containing regimen
• Must have achieved minimal response or better to at least 1 prior antimyeloma therapy
• Must have documented disease progression during or after their last antimyeloma therapy
• ECOG PS 0-2
• May not have had progression during treatment or within 60 days of the last dose of a proteasome inhibitor
• If prior treatment with a bortezomib containing regimen, must have had a best response of minimal response or better and the subject could not have discontinued bortezomib due to toxicity
• No prior allo transplant
• No plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or clinically significant light-chain amyloidosis
• No known CNS involvement of myeloma
• No grade 2 or higher peripheral neuropathy
• No other malignancy within 5 years
•  

• DIagnosis of relapsed/refractory multiple myeloma during of after the patient's last treatment
• ECOG PS 0-2
• Must have measruable disease with at least 1 of the following assessed within 28 days of enrollment
  • Serum M-protein >= 0.5g/dL
  • Urine M-protein >= 200/24 hrs
  • In patients without measurable serum or urine M protein, serum free light chain >= 100mg/L of the involved light chain and an abnormal serum kappa lambda ratio
• Must have received at least 2 or more lines of therapy, including a proteasome inhibitor, an immunomodulatory imide (IMiD), and an anti-CD38 mAb
• No clinically significant drug or alcohol abuse within last 6 months
• No CNS involvement
• No prior BCMA targeted therapy

• Confirmed diagnosis of symptomatic multiple myeloma
• ECOG PS 0-2
• Received 3 to 6 cycles of an induction therapy that includes a proteasome inhibitor (PI) and immunomodulatory (IMiD) [eg, bortezomib thalidomide and dexamethasone (VTd), lenalidomide, bortezomib and dexamethasone (RVd)] with or without a CD38 monoclonal antibody, or Velcade® (bortezomib), cyclophosphamide, dexamethasone (VCd), and followed by a single or tandem autologous stem cell transplantation (ASCT). Post-stem cell transplant consolidation is permitted.
• Participants within 12 months from initiation of induction therapy who achieved at least a partial response (PR) after autologous stem cell transplantation (ASCT) with or without consolidation, according to International Myeloma Working Group (IMWG 2016) criteria
• No PD or clinical replapse following ASCT or non-responsiveness to primary therapy
• No known CNS or meningeal involvement

• 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

• 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
• ECOG PS 0-1
• 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 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)
• No presence of gastrointestinal condition
• No history of pituitary dysfunction
• No poorly controlled diabetes mellitus
• No active or unstable cardio/cerebro-vascular disease, including thromboembolic events
• Has not received a taxane-based chemotherapy and or NHA for metastatic castration-resistant prostate cancer (mCRPC)
• Has not received prior treatment with radium for prostate cancer
• Does not have 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
• No known active central nervous system (CNS) metastases

• Histologically confirmed CRPC
• Metastatic disease confirmed by bone scan or CT/MRI
• Any prior therapy but one must be contain docetaxel in the castrate-sensitive or castrate resistant setting
• Tumor specimens available
• Must have progressive disease from last therapy
• No prior receipt of carboplatin or cabazitaxel
• No untreated fractures
•  

• Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features
• Must provide a core or excisional biopsy from soft tissue or bone biopsy from soft tissue within 1 year of screening and after developing mCRPC
• Has prostate cancer progression within 6 months prior to screening by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on RECIST criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.
• Ongoing androgen deprivation with serum testoterone <50ng/dL
• Stable doses of bone resorptive therapy
• ECOG PS 0-1
• Has previously received docetaxel for mCRPC. Prior treatment with one other chemotherapy is allowed. Up to 2 second-generation hormonal agents (eg. abiraterone, enzalutimide, etc.) are allowed. Prior ketoconazole is allowed. Docetaxel used more than once is considered as 1 therapy.
• No diagnosis of immunodeficiency or systemic steroid therapy
• No autoimmune disease within last 2 years
• No known HBV/HCV/HIV
• No known active CNS mets
• No superscan bone scan
• No active cardiovascular disease
• No gastrointestinal malabsortion
• No active hemoptysis

• Has treated or de novo neuroendocrine  metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment
• Must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. Participants with bone metastasis only must provide an archival tumor tissue specimen.
• Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on RECIST criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL
• Patients receiving bone resorptive therapy must be on stable doses
• ECOG PS 0-1
• Participants must have received prior treatment with androgen deprivation therapy (ADT) for metastatic disease. Participants must also have received prior treatment with an NHA (eg, abiraterone acetate, apalutamide, etc.) or docetaxel for mHSPC or mCRPC. Prior treatment with up to a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2 second-generation hormonal manipulations for mCRPC. Participants who received prior ketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowed in addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. A limited number of de novo patients may enroll after consultation with the sponsor.
• No prior treatment with Radium or Lutitium
• No immunodeficiency or systemic steroids
• No autoimmune disease within the last 2 years
• No known HIV/HBV/HCV
• No known CNS mets
• No superscan bone scan
• No active cardiovascular disease
• No active hemoptysis

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
• Must provide a core or excisional biopsy from soft tissue or bone biopsy within 1 year of screening and after developing mCRPC. Participants with bone metastasis only must provide an archival tumor tissue specimen.
• Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on RECIST criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. 
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
• Patients receiving bone resorptive therapy must be on stable doses
• ECOG PS 0-1
• Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide or other next-generation hormonal agents [NHA]) are allowed. Participants who received prior ketoconazole for metastatic disease may be enrolled. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. Prior docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) is allowed if ≥4 weeks have elapsed from the last dose of docetaxel prior to Day 1 of Cycle 1
• No immunodeficiency or systemic steroid use
• No active autoimmune disease within 2 years
• No known HIV/HBV/HCV
• No known CNS mets
• No superscan bone scan
• No symptomatic ascites or pleural effusion

• Has  treated or de novo metastatic neuroendocrine prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment
• Must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. Participants with bone metastasis only must provide an archival tumor tissue specimen.
• Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on RECIST criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL 
• Patients receiving bone resorptive therapy must be on stable doses
• ECOG PS 0-1
• Participants must have received prior treatment with androgen deprivation therapy (ADT) for metastatic disease. Participants must also have received prior treatment with an NHA (eg, abiraterone acetate, apalutamide, darolutamide, enzalutamide, or other NHA) or docetaxel for mHSPC or mCRPC. Prior treatment with up to a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2 second-generation hormonal manipulations for mCRPC. Participants who received prior ketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowed in addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. A limited number of de novo patients will be allowed to enroll based on consultation with the study team.
• No immunodeficiency or systemic steroid use
• No autoimmune disease within last 2 years
• No known HIV/HBV/HCV
• No known active CNS mets
• No superscan bone scan
• No symptomatic ascited or pleural effusion
• No prior treatment with platinum containing compounds for prostate cancer

• Has treated or de novo neuroendocreine metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment
• Must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. Participants with bone metastasis only must provide an archival tumor tissue specimen.
• Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; radiographic disease progression in soft tissue based on Response Evaluation Criteria In Solid Tumors Version 1.1 criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL
• Patients receiving bone resorptive therapy must be on stable doses
• ECOG PS 0-1
• Participants must have received prior treatment with androgen deprivation therapy (ADT) for metastatic disease. Participants must also have received prior treatment with an NHA (eg, abiraterone acetate, apalutamide, darolutamide, enzalutamide, or other NHA) or docetaxel for mHSPC or mCRPC. Prior treatment with up to a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2 second-generation hormonal manipulations for mCRPC. Participants who received prior ketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowed in addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. A limited number of de novo neuroendrcine CRPC patients will be allowed to enroll with consultation with the study team.
• No immunodeficiency or systemic steroid use
• No autoimmune disease within last 2 years
• No known HIV/HBV/HCV
• No known CNS mets
• No superscan bone scan
• No symptomatic ascites or pleural effusion

• Clinical stage II or III rectal adenoCA defined as T4N0 or any T with node positive disease. T3N0 requiring APR or coloanal astamosis is also allowed
• No prior systemic non-surgical treatment for rectal cancer within last 5 years
• ECOG PS 0-2
• No upper rectal tumors (>12 cm above anal verge)
• No recurrent rectal cancer
• No known MMR deficient cancer

• Patients with recurrent cutaneous SCC histologically confirmed who have failed at least first line standard of care therapy who are not indicated for surgery and standard radiation therapy, or non alpha radiation brachytherapy technologies, and for whom no curative systemic treatment is available
• Histopathological confirmation following previous treatment
• Measurable disease
• One single lesion
• Tumor size </= 7cm
• Targeted lesion must be technically amenable for complete coverage (including margins) by the DaRT seeds.Targets will be deemed technically amenable for complete coverage if there are entry and exit vectors for placement that are not hindered by bone or major vessels or other vital organs (eg. eye)
• ECOG PS 0-2
• No distant or nodal metastatic disease
• No T4 disease or perineural spread
• No previously untreated disease indicated for surgery or radiation
• No mucosal, vulvar, anal, or penile SCC
• No systemic immunosuppresive therapy
• No keratoacanthoma histology
• No clinically significant cardiovascular disease

• Diagnosis of locally advanced or metastatic non-melanoma skin cancer not considered treatable by surgery. Could include;
  • Basal cell carcinoma,
  • Cutaneous squamous cell carcinoma,
  • Merkel cell carcinoma
  • Angiosarcoma of the skin
  • Eccrine carcinoma
  • high grade dermatofibroma protuberans
  • CTCL is NOT allowed
• Must have exhausted or refused currently available therapy
• ECOG PS 0-1
• At least one injectable tumor (visceral or deep nodal lesions may be injectable)
• Measurable disease by RECIST 1.1
• No prior oncolytic virus therapy (no prior T-VEC)
• No active CNS disease
• No history of major autoimmune disease
• No known HBV, HCV, or HIV
• No need for steroids >20mg prednisone daily or equivalent
• No need for chronic use of anti-virals (e.g. acyclovir)
• No prior malignancy in past 3 years except locally curable cancers such as non-melanoma skin cancer, or carcinoma in situ.

• 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.

• 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