• 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

• Triple negative metastatic breast cancer
• 2nd line
• ECOG PS 0-2
• No prior treatment with any study agents
• No history of autoimmune disease
• Presence of measurable disease
• No symptomatic or untreated CNS disease

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.

• Confirmed locally recurrent inoperable or metastatic TNBC
• 1st line or 2nd line. Can have received (neo)adjuvant therapy if >6 months have passed between end of therapy and development of recurrent/metastatic disease
• Measurable disease
• ECOG PS 0-1
• No symptomatic brain mets
• No active autoimmune disease
• No other cancer within 2 years
• No poorly controlled diabetes

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

• Metastatic CRC
• Documented KRAS or NRAS mutation
• No prior systemic therapy in metastatic setting
• ECOG PS 0-1
• No BRAF mutation, no MSI-h
• No prior treatment with VEG-F inhibitor
• No DPD dficiency
• No untreated or symptomatic CNS mets

• 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

• Pathological/histological confirmation of advanced or metastatic colon or rectal adenocarcinoma
• Must be resistant, refractory, or intolerant to at least 2 prior lines of tx, that must include all of the following agents:
  • Fluoropyrimidine
  • Irinotecan
  • Platinum agents (oxaliplatin)
  • Anti EGFR agent if clinically indicated (RAS/BRAF wt)
  • Anti-VEGF agent (bevacizumab) unless contraindicated
  • IO therapy if clinically indicated (MSI-h)
• MEasurable disease
• ECOG PS 0-1
• No history of interstitial lung disease
• No severe pulmonary compromise
• No steroids at >10mg prednisone daily or equivalent
• No clinically active CNS disease
• No prior treatment with anti-HER3 antibody or ADC containing topoisomerase I inhibitor
• No other cancers within 3 years unless curatively treated
• No known HBV/HCV

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

• Histologically confirmed WHO Grade IV glioblastoma
• Failed initial systemic tx
• At least 3 weeks from prior surgical resection
• At least 6 months from previous radiation unless new area of enhancement outside the 80% isodose line of originial radiation field
• At least 6 weeks from prior mAbs
• Has not required escalting doses of steroids or had progression of neurologic symptoms in last 2 weeks
• No carcinomatous meningitis
• No extracranial disease
• No multifocal tumor
• No recurrent tumor greater than 6cm
• No intra- or pertumoral hemorrhage greater than grade 1
• Measurable Disease per RECIST and RANO
• Archival tissue or newly obtained tissue available
• ECOG PS 0-1
• BP < or = 150/90 at screening without change in antihypertensives within 1 week before C1D1
• No evidence of malabsorption syndrome
• No evidence of major blood vessel involvement
• No clinically significant hemoptysis or tumor bleeding
• No arterial thromboembolism within 12 months
• No significant CAD within 12 months
• No prior lenvatinib or checkpoint inhibitor therapy
• Prior bevacizumab is allowed
• No proteinuria defined as Uprotein >1g/24 hours
• LVEF must be 55% or greater
• No diagnosis of immunodeficiency
• No active CNS metastases
• No tumor involving the brain stem
• No active autoimmune disease that has required treatment within last 2 years
• No known HIV/HBV/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

• Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma per pre-treatment biopsies (laparoscopic or percutaneous)
• Histologic documentation of the original primary tumor is required
• FIGO Stage III-IV
• Following histologic subtypes eligible: high grade serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma NOS.
• ECOG PS 0-2
• No need for treatment with immunosuppressive medication
• No patients receiving treatment for active autoimmune disease
• No known CNS involvement
• No prior abdominal radiation or chemotherapy for abdominal or pelvic tumor

• 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

Inclusion Criteria:

• Patients with advanced or malignant solid cancers with RET-fusion positive tumors.
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

• 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

• Malignant solid tumor with pathogenic inactivating TSC1 or TSC2 alterations. GEnetic alterations should be identified using NGS in tumor tissue or liquid biopsy
• Metastatic or locally advanced solid tumors
• Must have received all standard therapies appropriate for their tumor type and stage of disease or, in the opinion of the investigator, the patient would b e unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy
• Measurable disease
• ECOG PS 0-1
• Fasting tryglecerid must be < or = 300; fast serus cholesterol must be < or = to 350
• No prior treatment with MTOR inhibitor
• No primary brain tumors
• No known HIV

• Diagnosis of relpased or regractory diffuse large B-Cell lymphoma or R/R follicular lymphoma with documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or 2008
  • Can include pts with double-hit or triple-hit DLBCL
  • Must have been previously treated wioth at least 2 prior systemic antineoplastic therapies including at least 1 anti-CD20 monoclonal antibody-containing therapy
  • Measurable disease
  • ECOG PS 0-2
  • No CNS involvement 

• Pathologically or cytologically confirmed metastatic pancreatic cancer
• Previously untreated with systemic agents in recurrent/metastatic setting
• Measurable disease
• May have received adjuvant therapy if given at least 6 months before study enrollment
• No significant cardiovascular impairment
• No other malignancy
•  

• Must have one of the following
  • Disease progression after platinum based chemotherapy (with or without PD-1 therapy) for recurrent or metastatic disease
  • Refractory disease defined as progression or recurrence within six months after the last dose of platinum based chemoradiation for locally advanced disease
• No more than two prior lines of treatment
• ECOG PS 0-1
• Able to swallow and retain oral medications
• No prior taxane
• No symptomatic CNS disease
• No known HIV
• No symptomatic CHF or LVEF <50%
• No active psychiatric illness

• Extensive stage small-cell lung cancer
• Has progressed within 6 months of receiving platinum based therapy or intolerant of platinum based therapy
• ECOG PS 0-1
• No more than 2 platinum-based regimens for SCLC
• No prior receipt of PD-1/L-1 agents or CTLA-4 inhibitors
• No active CNS mets
  • If history of CNS mets, must be stable for at least 4 weeks, and off steroids for at least 7 days
• No active autoimmune disease requiring treatment in previous 2 years
• Cannot be receiving more than 3 anti-hypertensive agents
• No known HIV/HBV/HCV

• Stage T1-3 N1 M0 at diagnosis (prior to start of neoadjuvant chemotherapy)
• No inflammatory breast cancer
• No other malignancy within 5 years
• Must have received axillary ultrasound with bx or axillary lymph nodes prior to or within 14 days of starting neoadjuvant therapy
• Must have documented ER/PR/HER2 status before neoadjuvant therapy
• Must have completed all planned chemotherapy prior to trial (ie. no planned adjuvant therapy)
• Must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane based regimen
• HER2 positive patients must have received anti-HER2 therapy as part of neoadjuvant regimen
• Must have clinically negative axilla documented on physical exam at the completion of neoadjuvant chemotherapy (no imaging needed)
• No neoadjuvant endocrine or radiation therapy
• No history of prior breast cancer
• ECOG PS 0-1
• Must complete surgery within 56 days of finish of neoadjuvant therapy
• At least 1 sentinel lymph node identified intra-operatively with at least micromets

• Histologically or cytologically confirmed urothelial carcinoma with predominantly transitional-cell features
• Locally advanced or metastatic disease before starting ICI therapy
• Must be receiving current active treatment with SOC FDA approved PD-1/L1 ICI containing therapy
• Tumor decrease (either in target or non-target lesions) after 12-15 months on ICI.  Does not need to be formal PR/CR. Any decrease confirmed by repeat scan 4 weeks later is OK
• ECOG PS 0-2
• Adequately treated CNS disease is eligible
• No current immunosuppresive drugs

• Invasive breast cancer (ductal, lobular, tubular, mammary, medullary)
• If received neoadjuvant therapy, pre treatment staging must have N1 or N2 disease pre-chemo or are T3N0
• If did not receive neoadjuvant, must be T0N1-2a, T1N1-2a, T2N1-2a, or T3N0-2a.
• No prior therapeutic radiation to the chest, neck, or axilla
• No prior history of ipsilateral breast cancer
  • DCIS or LCIS are allowed
• Negative margins following mastectomy
• No significant post mastectomy complications in the ipsilateral breast requiring unplanned re-operation or admission for IV antibiotics.
  • Reoperation for margins or lymph node dissection is allowed
• Radiation oncologist is NOT planning to use a chest wall/scar boost
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements
• No co-existing medical conditions with a life expectancy <5 years
• ECOG PS 0-1

• Histologically confirmed unresectable locally advanced or metastatic urothelial carcinoma. Subjects with urothelial carcinoma with squamous differentiation or mixed cell types are eligible provided that urothelial is the dominant histology.  Any element of neuroendocrine or small cell histology are excluded
• Must have received prior treatment with a immune checkpoint inhibitor in the locally advanced or metastatic setting
• Must have received prior treatment with platinum containing chemotherapy defined as received in the adjuvant/neoadjuvant setting with recurrent or progressive disease within 12 months of completion OR received treatment with platinum in the locally advanced or metastatic setting
• Must have had progression or recurrence during or following recept of most recent therapy
• ECOG PS 0-1
• Dose escalation cohorts must have available archival or fresh biopsy sample prior to study entry.  Others must have tumor accfessible for sequential biopsy and be willing to provide fresh pre-treatment and on-study tumor tissue biopsies
• No pre-existing sensory or motor neuropathy Grade >/= 2
• No symptomatic or unctrolled CNS metastases
• No prior treatment with enfortumab vedotin
• No prior treatment with any anti-CD47 or anti-SIRPa agent
• No known uncontrolled HBV/HCV/HIV
• No other malignancy within 3 years
• No active autoimmune disease requiring treatment in last year

• Unresected Stage IIIB, IIIC, or IV melanoma
• No prior therapy for metastatic disease
• At least 6 months from adjuvant therapy
• No clinically active CNS disease
• ECOG PS 0-1
• Measurable (at least 1 lesion >1cm)
• Injectable (total cutaneous/subcut/nodal lesions >1cm in aggregate)
• No prior ipilimumab, PD-1 inhibitors, T-VEC or tumor vaccines
• Previous BRAF or MEK inhibitors allowed if BRAF mutated
• No primary uveal or mucosal melanoma
• No prior intrathoracic XRT

-Histologically confirmed diagnosis of stage IIB, IIIC, or IVM1a melanoma elgible for complete surgical resection

- Measurable disease

- Injectable disease (cutaneous, subcutanous, or nodal lesions) measuring in aggregate > 10mm in diameter

- ECOG PS 0-1

- No ocular or mucosal melanoma

- No history of autoimmune disease

- No known HBV/HCV/HIV

• Unresectable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma
• Fibroblast growth factor receptor 2b (FGFR2b) overexpression positive by centrally performed IHC testing
• No prior therapy for metastatic or unresectable disease except for up to 1 dose FOLFOX with or withouy nivolumab. Prior adjuvant therapy allowed as long as completed longer than 6 months prior
• ECOG PS 0-1
• Measurable or non-measurable disease allowed
• No symptomatic CNS mets
• No corneal abnormalities
• No known HER2 positive status
• No peripheral sensory neuropathy grade 2 or higher

• Metastatic castration resistant prostate cancer
• Progression on abiraterone or enzalutamide but not both
• Prior anti-cancer therapy (e.g. docetaxel) permitted but not required
• Ongoing therapy with LHRH analog or orchiectomy
• Qualifying HRR mutation in tumor tissue (see path tab for full complement of qualifying mutations)
• No prior treatment with PARP inhibitor
• No prior treatment with platimum or mitoxantrone
• No known brain metastases
• No other malignancy within 5 years

• Histologically diagnosed relapsed high-grade serous ovarian cancer (including primary peritoneal and/or fallopian tube)
• Must have received at least 2 prior platinum-based lines of chemotherapy for ovarian cancer
• Must be partially platinum sensitive (progression 6-12 months after last platinum therapy) or platinum sensitive (progression >12 months after last platinum therapy)
• ECOG PS 0-1
• Available archived tissue for central testing
• No prior PARP inhibitor therapy
• No other malignancy within last 5 years
• No pneumonitis
• No symptomatic uncontrolled brain metastases
• No known active HBV or HCV
• No immunocompromised subjects

• Unresectable Stage IV transitional cell carcinoma of the urothelium
• No previous treatment in metastatic setting
• PD-L1 status to be determined centrally prior to randomization
• No prior anti-CTLA or anti PD-1 agents
• No CNS involvement
• No active or prior autoimmune disease
• No HIV, HBV, HCV

Histologically confirmed recurrent or metastatic SCCHN
Either progression after 1 line of chemo (must have contained platinum) or within 6 months of definitive multimodality therapy (containing platinum).
Tissue available for central PD-L1 testing
ECOG PS 0-1
At least one lesion that was not previously irradiated
No prior exposure to immune-mediated therapy
No history of CNS involvement
No history of primary immunodeficiency

• Confirmed pathologic diagnosis of HCC (from tumor tissue)
• Must not be eligible for locoregional therapy for unresectable HCC. Patients who progressed on local regional therapy are eligible if therapy was >28 days prior
• Barcelona Clinic Liver Cancer (BCLC) stage B or stage C
• Child-Pugh Score class A
• ECOG PS 0-1
• HBV or HCV may be allowed depending on activity (may not have both together)
• Measurable disease
• No prior receipt of durvalumab, tremelimumab, or sorafenib
• No prior receipt of any PD-1, PD-L1, or CTLA-4 antibody
• No autoimmune disease within the last 5 years
• No CNS mets
• No fibrolamellar or sarcomatoid HCC or mixed cholagiocarcinoma with HCC
• No recent steroid use (>10 mg prednisone/day)

• Metastatic Triple-Negative Breast Cancer

• Failed at least one line of therapy in metastatic setting

• No more than 3 previous lines of therapy in the metastatic setting

• Measurable disease

• No prior autoimmune or inflammatory disorders

• No CNS involvement or history of spinal cord compression

• Metastatic urothelial bladder cancer
• Failed (or intolerant to) exactly one line of prior therapy for metastatic disease, which must have contained platinum
• Prior surgery, radiation,and neoadj/adj chemo are permitted
• Measurable disease
• No active CNS disease
• No history of leptomeningeal disease
• No documented autoimmune or inflammatory disorders

• Metastatic Pancreatic Ductal Carcinoma

• Failed exactly 1 line of prior therapy for metastatic disease

• No active CNS disease

• No history of leptomeningeal disease

• No history of autoimmune disease

• NSCLC with locally advanced, unresectable, Stage III disease
• Must have completed, without progression, definitive chemoradiation within 28 days of randomization
• ECOG PS 0-1
• Must have at least one previously irradiated tumor lesion that is measurable at time of study entry
• No pneumonitis Grade 2 or higher from chemoXRT
• No tuberculosis, HBV, HCV, or HIV
• No mixed histology (small-cell and non-small cell)
• No recent severe cardiac disease
  • No history of other primary malignancy

• Female age 18 or greater
• Histologicall confirmed diagnosis of epithelial endometrial carcinoma. All histologies, including carcinosarcoma, are allowed
• Disease in one of the following categories
  • Newly diagnosed Stage III disease (with measurable disease following surgery or biopsy)
  • Newly diagnosed Stage IV disease (with or without disease following surgery or diagnostic biopsy)
  • Recurrence of disease where the potential for cure by surgery alone or in combination is poor
• Naive to first line systemic anti-cancer treatment.  For patients with recurrent disease only, prior chemo is allowed only if administered in the adjuvant setting and there is at least 12 months from the date of the last dose of chemo to the date of subsequent relapse
• ECOG PS 0-1
• No CNS disease
• No prior treatment with PARP inhibitors or immunotherapy

• Histologically confirmed TNBC, Stage I-III
• Residual invasive disease in the breasat and/or axillary lymph node(s) at surgical resection following neoadjuvant therapy
• Completed at least 6 cycles of neoadjuvant therapy containing an anthracycline and/or a taxane with or without carboplatin, with or without pembrolizumab
• No evidence of locoregional or distant relapse
• Surgical removal of all clinically evident disease
• ECOG PS 0-1
• No adjuvant systemic therapy
• LVEF > 50%
• No known germline BRCA mutation
• No Stage IV disease
• No history of prior invasive breast cancer
• No persistent toxicities from prior anticancer therapies
• No prior autoimmune or inflammatory disorders
• No known HIV

• Unresectable or metastatic transitional cell carcinoma or the urothelium (renal pelvis, ureters, urinary bladder, or urethra)
  • Both transitional cell and mixed transitional/non-transitional cell histologies are permitted
• No prior 1st line therapy for metastatic disease
  • Prior adjuvant therapy allowed if it has been >12 months since last therapy
  • Prior local intervesical chemo or immune therapy is allowed if at least 28 days before study treatment
• Either cisplatin-eligible or cisplatin-ineligible but carboplatin eligible patients are allowed
• Measurable disease
• ECOG PS 0-1
• No prior immunotherapy with exception of BCG or antitumor vaccines
• No autoimmune disease requiring immunosuppression
• No untreated CNS disease
• No contraindications to platinum-based doublet chemotherapy

• Breast cancer with history of HER2-low expression, defined as IHC2+/ISH negative or IHC1+ with a validated assay
• May be either hormone receptor positive or negative
• ECOG PS 0-1
• If hormone receptor positive disease
  • Part 1: Must have had at least 1 prior treatment line of endocrine therapy with or without a targeted therapy (CDK4/6, mTOR, or PI3K) and at least one prior line of chemotherapy, all for metastatic disease
  • Part 2: Only 1 prior treatment line of ET with or without a targeted therapy. No prior chemothearpy for MBC
• If hormone receptor negative disease
  • Part 1: At least 1 prior line of chemotherapy for MBC
  • Part 2: For Module 2, no prior lines of thearpy for MBC. For Modules 1 and 3, only 1 prior line fo chemotherapy for MBC
• No significant cardiovascular disease
• No history of pneumonitis requiring steroids
  • No clinically active CNS metastatses or spinal cord compression

• Advanced or metastatic breast cancer that is locally assessed and prospectively centrally confirmed as HER2-positive (IHC3+ or ISH+) with known horme receptor status
• No prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer.
• No more than 1 previous line of endorcrine therapy in the metastatic setting
• Adjuvant/neo-adjuvant therapy allowed if >6 months from treatment to metastatic diagnosis
• ECOG PS 0-1
• No clinically active CNS disease
• No active ILD/pneumonitis

• Histologically documented HER2-positive early breast cancer (EBC) participants, including clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition

• ECOG PS 0-1
• Adequate organ and bone marrow function
• LVEF ≥ 50% within 28 days before randomization
• FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician
• No prior history of invasive breast cancer
• No stage IV breast cancer (determined by AJCC staging system)
• No primary malignancy within 3 years (except resected non-melanoma skin cancer, curatively treated in situ disease) Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer)
• No history of DCIS (except those treated with mastectomy >5 years prior to current diagnosis)
• No history of, or current, ILD/pneumonitis
• No prior systemic therapy for the treatment of breast cancer
• No previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy

• Prostate adenocarcinoma which is de novo or recurrent and castrate sensitive
• No small cell, neuroendocrine, sarcomatoid, spindle cell, or signet ring histology
• Metastatic disease with clear evidence of at least 1 bone lesion and/or at least 1 soft tissue lesion that is assesable via CT or MRI
• Receiving ADT with a GnRH analogue or has had bileteral orchiectomy
• ECOG PS 0-1
• Confirmed HRRm status by central tumor tissue and/or ctDNA test
• No history of another primary malignancy (with some exceptions per protocol)
• No spinal cord compression or brain mets unless asymptomatic and not requiring steroids

Locally advanced or metastatic breast CA
BRCA 1 or 2 germline mutation
Appropriate for single-agent cytotoxic chemotherapy
Prior receipt of anthracycline and/or taxane
No more than 2 prior chemo regimens for metastatic disease
ECOG 0-1
No prior platinum treatment for metastatic disease
No active CNS mets
Adequate organ function

1. Histologically documented locally advanced or metastatic, unresectable (i.e. surgery morbidity would outweigh potential benefits), progressive or recurrent Dedifferentiated liposarcoma (DDLPS), meeting the criteria for an open study cohort:

   • Cohort A: patient has not received prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative)
   • Cohort B: patient has received any prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative)
2. Written pathology report indicating the diagnosis of DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridisation (FISH) or next-generation sequencing (NGS)
3. Measureable disease
4. ECOG PS 0-1
5. No known mutation in TP53
6. No prior MDM2 inhibitor
7. No prior or concomittant cancers within 2 years except non-melanoma skin cancers, or other treatment curative by local therapy only

• Histologically confirmed advanced, relapsed, or refractory hematologic malignancies
• Have already received currently available standard of care therapies
• No know CNS involvement
• ECOG PS 0-2 (0-1 for dose escalation phase)
• May have received auto or allo SCT
• Not currently candidate for auto or allo SCT
• No acute GVHD, but chronic GVHD allowed if not requiring steroids and GI tract not affected such that absorption of oral drugs are impared.
• Must be able to take oral medication
• For Multiple Myeloma
  • Measurable disease with either serum M-protein ≥1 g/dl, urine M-protein ≥200mg/24h, or abnormal serum free light-chain ratio and abnormal light chain values
  • Must have received prior tx with both immunomodulatory agent and a proteasome inhibitor
• For Lymphoma
  • HL or NHL (B-cell or T-cell) relapsed or refractory to at least 1 line of prior therapy
• For AML/MDS
  • Relapsed or refractory disease after at least one prior line of standard therapy
  • M3 (APL) is allowed if potentially curative therapies are no longer an option
• For CML
  • Must have received at least 2 lines of prior therapy, and each line must have used a standard TKI alone or in combination
  • If T315I mutation is present must have received ponatinib if a candidate
• For CLL
  • Must have received at least 1 line of prior therapy

• Metastatic histologically confirmed CRC
• Must have failed treatment with one regimen containing a fluoropyrimidine and oxaliplatin for metastatic disease. All patients must have received a minimum of 6 weeks of the first line therapy. Treatment failure is defined as radiologic progression during or <6 months after the last dose of first-line therapy (including adjuvant)
• ECOG PS 0-1
• Must give access to either archived or new biopsy
• No more than 1 prior chemo regimen in metastatic setting
• No other cancers within 3 years 

Part 1:

• Locally advanced or metastatic NSCLC, or SCCHN
  • NSCLC and SCCHN must have received prior platinum-based therapy
  • Patients with targetable mutations (e.g. ALK, ROS, EGFR, etc.) must have had prior treatment with approved targeted therapy
• 1st line- no prior therapy for metastatic disease
• ECOG PS 0-1
• LVEF 50% or higher
• No known CNS mets
• No history of pneumonitis
• No prior cancer within 3 years (except locally curable cancers)
• No history of life-threatening toxicity to immunotherapy
• No known HBV/HCV/HIV

• Must have been diagnosed with either Stage IIIA (>1mm tumor in lymph node), Stage IIIB, Stage IIIC, Stage IIID, or Stage IV melanoma and have histologically confirmed melanoma that is completely surgically resected with negative margins
• ECOG PS 0-1
• Resection must have been performed within 12 weeks prior to randomization
• Tumor tissue available
• No history of uveal melanoma
• No untreated CNS metastases

• Measurable disease

• NSCLC

  • If EGFR mut or ALK positive must have received targeted therapy

  • Must have progressed on both platinum doublet and PD-1 therapy

• Cervical Cancer

  • Persistent, recurrent, or metastatic disease

  • Squamous, adenosquamous or adenocarcinoma histology

  • At least one prior platinum based regimen

  • Confirmation of HPV status

• Bladder cancer

  • Transitional cell carcinoma involving bladder, urethra, ureter, or renal pelvis

  • Minor histologic variants are acceptable

  • Must have progression or recurrence with platinum-containing regimen (in metastatic setting or within 12 months of peri-operative setting)

• SCCHN

  • Must have documented HPV status and subtype

  • Prior treatment with platinum containing regimen with progression or recurrence within 6 months of last dose

  • Cannot be amenable to local therapy with curative intent

• Ovarian

  • Can include epithelial ovarian, primary [peritoneal, or fallopian tube cancer

  • Must have received at least 1 standard systemic therapy for metastatic disease

• HCC

  • Progressive disease to at least one line of therapy or refuse treatment with sorafenib

  • Child-Pugh score of 6 or less. No encephalopathy and Tbili must be <1.5x ULN

  • HBV and HCV must be tested. HBV viral load <100 IU/mL and must be on anti-viral therapy

  • No clinical ascites or variceal bleeding

• No more than 5 prior lines of treatment

• Acceptable lab parameters

• No active CNS metastatases (treated brain mets may be allowed)

• No prior malignancy within 2 years (except for in-situ or non-melanoma skin)

• No autoimmune disease, interstitial lung disease, or requiring immunosuppressive meds

• ECOG PS 0-1
• No active CNS disease (controlled brain mets are allowed)
• Must have one of the five malignancies below
  • Clear-cell RCC
  • Triple-negative Breast Cancer
  • Squamous cell carcinoma of the head and neck
  • Colorectal cancer
  • Non-small cell lung cancer
• No other malignancies within 2 years
• No active, known, or suspected autoimmune disease (except asthma, vitiligo, T1DM, hypothyroidism, Graves disease, or psoriasis not requiring treatment)
• No severe autoimmune reactions to immunotherapy
• No need for active steroid therapy
• No significant cardiac disease
• No chronic hepatitis
• No active interstitial lung disease
• RCC specific eligibility criteria
  • Previously received one or two anti-VEGFR therapies
  • No more than 3 total prior systemic tx in metastatic setting
  • Must have evidence of progression on or after last treatment received and within 6 months of starting study
• CRC specific eligibilty criteria
  • Must have received and progressed on at least 1 standard therapy for metastatic disease
  • Must have known MSI status
• NSCLC specific eligibility criteria
  • Must have progressed on or been refractory to platinum doublet
  • Must have known EGFR, ALK, ROS1 status.
    • Those with EGFR or ALK alterations must have previously received TKI therapy
• SCCHN specific eligibility criteria
  • Not amenable ot local therapy with curative intent
  • Must have progressed on or been intolerant of platinum containing regimen
• TNBC specific eligibility criteria
  • Must have received and progressed on or been intolerant to at least 1 standard chemotherapy with anthracycline and taxane

• Renal cell, NSCLC, or SCCHN
• Must have received prior PD-1 or PD-L1 inhibitor
• ECOG PS 0-1
• No known autoimmune disease
• No need for steroids or other immunsuppressive medicine
• No interstitual lung disease or pulmonary fibrosis

• SCCHN
• Must have received prior PD-1 or PD-L1 inhibitor
• ECOG PS 0-1
• No known autoimmune disease
• No need for steroids or other immunsuppressive medicine
• No interstitual lung disease or pulmonary fibrosis

• Metastatic Non-small cell lung cancer
• At least 1 prior line of therapy (2nd line or later)
  • Current arms require patients to be PD-1 naive (this will change)
• Patients with EGFR or ALK alterations must have received targeted therapy
• Measurable disease
• Palliative XRT must be completed at least 2 weeks prior to enrollment
• Biopsies required pre-treatment, on-treatment, and at progression
• No active CNS mets
• No prior malignancy unless CRR achieved at least 2 years prior and no active therapy required
• No systemic therapy within 4 weeks of enrollment
• No active autoimmune disease (except skin disorders, hypothyroidism, T1DM)
• No severe toxicity due to prior immune therapy
• No symptomatic interstitial lung disease
• No known HIV/HBV/HCV

• Resected Stage IIB or IIC cutaneous melanoma (>4 mm deep, or >2mm deep with ulceration)
• Negative sentinel lymph node biopsy
• No prior systemic therapy for melanoma
• ECOG PS 0-1
• No ocular or mucosal melanoma
• No known or suspected autoimmune disease

IIIB or IV non-small cell lung cancer
Progression during or after at least one�prior systemic therapies
� �Progression within 6 months of adjuvant tx counts as 1st line
EGFR or ALK mutations are eligible if progressed on on anti-EGFR or anti-ALK
ECOG PS 0-2
No active CNS disease
No history of interstitial lung disease
No history of autoimmune disease
No prior PD-1 inhibitors
Willingness to undergo on-treatment biopsies

• Locally advanced or metastatic NSCLC
• For currently open cohort must have EGFR mutation
• ECOG PS 0-2
• Tumor tissue available for biomarker evaluation
• No active CNS involvement
• No known or active autoimmune disease
• No known HIV, HBV, HCV

• Advanced or metastatic RCC
• For Clear cell histology:
  • At least 1 but no more than 2 prior systemic anti-VEGF treatments
  • No more than 3 total prior systemic treatment regimens in the advanced/metastatic setting
  • No prior treatment with an mTOR inhibitor
• For Non-Clear Cell Histology
  • 0-2 prior therapies (1st line-3rd line)
  • Prior mTOR inhibitor is allowed
• CNS Disease is allowed if asymptomatic, no edema, and not on steroids
• KPS >70%
• No history of autoimmune disease
• No prior malignancy within 3 years except for curable cancers that are apparently cured
• No known HIV, HBV, or HCV

• Multiple myeloma
• Refractory (progressed on or within 60 days) to most recent treatment
• Must have received >2 lines of prior therapy which must have included at least 2 consecutive cycles of each immune modulatory drug (IMiD) and a proteasome inhibitor alone or in combination
• Measurable disease at screening defined as one or more of the following:
  • Serum IgG, IgA, or IgM M-protein >0.5 g/dL
  • Urine M-protein >200 mg excreted in 24-hour collection sample
  • Involved serum free light chain >100 mg/L provided the FLC ratio is abnormal
• ECOG PS <2
• No prior treatment with pomalidomide, elotuzumab, or any PD-1/PD-L1 inhibitor
• No MGUS, Smoldering myeloma, Waldenstrom’s, amyloidosis, POEMS syndrome, or active plasma cell leukemia (20% peripheral blood of plasma cells or absolute plasma cell count of 2 x10^9/L)
• No active autoimmune disease
• No active infection or uncontrolled severe CV or pulmonary disease
• No chronic steroid use within 14 days of enrollment
• No known HBV/HCV/HIV
• No Grade >2 peripheral neuropathy
• Auto transplant allowed as long as at least 12 weeks prior
• Allo transplant allowed as long as at least 1 year prior

• Measurable disease required
• ECOG PS <1
• Brain mets allowed but must not be active, cannot require steroids, have at least one measurable lesion outside of brain
• Excluded tumors:
  • No Pancreatic
  • No endometrial with ER>10%
  • No ovarian
  • No breast
  • No esophageal
  • No gastric
  • No glioma
  • No hepatocellular carcinoma
  • No lymphoma (except primary CNS lymphoma)
  • No leukemia
  • No melanoma
  • No MDS
  • No lung cancer
  • No renal cell
  • No bladder
• Must not have had other cancer within 2 years
• No prior PD-1/L-1 or CTLA-4 therapy
• No autoimmune disease
• No active steroids
• No known HIV, HBV, or HCV
• See "malignancy" list for accepted tumor types

• Histologic confirmation of adenocarcinoma of the prostate without small cell features
• Current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue lesions on CT/MRI
• ECOG PS 0-1
• Ongoing androgen deprivation therapy (ADT) with a GnRH analogue or bilateral orchiectomy
• Documented disease progression per PCWG3 criteria within 6 months prior to screening
• Only one prior 2nd generation hormonal therapy in the metastatic setting
  • Patients may have received two prior 2nd gen HT (abi + enza or apalutamide or darolutamide) if and only if the first drug had been used in the non-metastatic setting
• Chemotherapy naive for metastatic CRPC
• Must have progressed during or after 2nd gen hormonal therapy or have documented intolerance to 2nd gen HT
• No active brain mets
• No known or suspected autoimmune disease
• No condition requiring systemic corticosteroids (>10 mg prednisone or equivalent)
• No prior treatment with PD-1 or PD-L1 antibodies
•  

• Histologically confirmed incurable locally advanced, recurrent or metastatic SCCHN stage III/IV and not amenable to local therapy with curative intent (surgery or XRT with or without chemo)
• Confirmation of tumor HPV status
• Tumor progression or recurrence within 6 months of last dose of platinum therapy in either the adjuvant, primary, recurrent, or metastatic setting
• Measurable disease by RECIST
• ECOG PS 0-1
• No known CNS mets
• No prior or concurrent malignancies
• No history of autoimmune disorders
• No prior tx with PD-1, anti-KIR, or anti-CTLA4 therapy
• No RANK-L inhibitors within 10 weeks, no bisphosphonates within 4 weeks
• No known HIV/HBV/HCV

HER2+ adenocarcinoma (by FISH, regardless of IHC)
Unresectable or metastatic last line
ECOG PS 0-1
Limit of prior cumulative doxorubicin dose of 360mg/m2
No CNS disease
No history of prior cancer within last 3 years
No significant cardiac disease
No HIV, HBV, HCV

• Females >18 years old

• TNBC defined as ER/PR <1%, HER2 negative

• ECOG PS 0-1

• Labs within standard limits

• No known CNS disease unless adequately treated with XRT or surgery and stable by symptoms for at least 2 months prior

• No other malignancy within 3 years (except non-melanoma skin cancer or in situ cancers)

• No unstable cardiac disease

• No known sensitivity Cremaphor

• Cohort 1- 3rd+ line in African ancestry

  • Must have received prior taxane for metastatic disease but not in most recent treatment

  • Adjuvant therapy counts as therapy if time to recurrence <12 months

• Cohort 2- 1st line in African ancestry- no prior systemic tx for advanced disease

  • Adjuvant therapy only allowd if time to recurrence >12 mo

• Cohort 3- 3rd+ line in non-African ancestry

  • Similar to Cohort 1

• Cohort 4- 1st line in non-African ancestry

  • Similar to cohort 2

• Metastatic renal cell carcinoma with a clear cell component
• Karnofsky PS 70% or higher
• 1-2 lines of prior therapy for advanced or metastaic RCC including at least one antiangiogenic therapy or nivolumab+ipilimumab
• No prior treatment with cabozantinib or other MET inhibitor
• No active CNS malignancies
• No known HIV, HBV, HCV
• No need for Proton -pump inhibitors

• Histologically confirmed CRC
• Documentation of KRAS or NRAS mutation in exon 2, 3, or 4 in primary lesion or metastasis from CLIA certified lab

• Participants with tumors that have progressed on an oxaliplatin/fluoropyrimidine--based regimen with or without bevacizumab.

  • Participants must have had systemic therapy within 180 days of the screening visit.

  • Participants must have, at any time previously, received oxaliplatin-based chemotherapy with or without bevacizumab (≥ 6 weeks in duration).

  • Participants who received oxaliplatin/fluoropyrimidine-based neoadjuvant, adjuvant, and/or fluoropyrimidine maintenance or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of oxaliplatin will be required to have received oxaliplatin/fluoropyrimidine-based therapy with or without bevacizumab as first-line treatment for metastatic disease.

  • Participants who received an oxaliplatin-based regimen in the first-line setting and discontinued oxaliplatin because of toxicity or who received oxaliplatin for maintenance therapy are eligible as long as progression occurred < 6 months after the last dose of oxaliplatin therapy for advanced metastatic disease. It is recommended that these participants be re-challenged (if feasible) with oxaliplatin/fluoropyrimidine therapy and subsequently progress prior to eligibility. Participants with oxaliplatin-related neuropathy or oxaliplatin infusion-related hypersensitivity that cannot be rechallenged with oxaliplatin are eligible.

• No prior treatment with irinotecan

• No BRAF mutation or MSI-h/dMMR

• No more than 1 prior chemotherapy line in the metastatic setting

• No untreated or symptomatic CNS disease

• No contraindications for bevacizumab (heart disease, recent bleeding, etc.)

• Multiple myeloma either
  • 3rd line after failure of BOTH proteasome inhibitor and IMiD OR
  • 4th line regardless of prior therapies
• Measurable disease activity as indicated by serum or urine M-protein, serum free light chain, biopsy-proven plasmacytoma, >5% bone marrow plasma cells.
• No plasma cell leukemia
• No CNS disease
• No severe autoimmune diseas
• No chronic pulmonary disease
• ANC (>1000/uL), Pplatelet count (>50,000/uL), hemoglobin (>8 g/dL),
• ALT and AST (each <3.0 x upper limit of normal), total bilirubin (<2 mg/dL), creatinine clearance (>30 mL/min),
• Cardiac ejection fraction >45%

Biopsy proven DLBCL
Relapsed or refractory to standard treatment
ECOG PS 0-1
Measurable disease
ANC>1.5, plts>50
No CNS involvement
No impared cardiac function
No active tx for diabetes (if on CC-223 arm only)
No prior allo HCT
No auto HCT within 3 months
No systemic anti-cancer tx within 4 weeks_

• ECOG PS 0-1

• Age 18-80 years old

• Must have CLL/SLL requiring treatment per Hallek, 2008

• Must have at least one clinically measurable lesions defined as

  • Nodal lesion measuring >1.5cm in longest diameter and >1.0cm in longest perpendicular diameter OR

  • Spleen measuring >14cm in longest vertical dimension with a minimum of 2 cm enlargement OR

  • Liver measuring >20 cm in longest vertical dimenstion with a minimum of 2 cm of enlargement OR

  • Peripheral blood B lymphocyte count >5000/uL

• For single agent and obinutuzumab combo must have relapsed refractory disease as follows:

  • Must have received either prior chemoimmunotherapy or therapy with an approved BTK inhibitor unless significant co-morbidities or contraindications

• For ibrutinib combo arm, must have not received prior treatment with ibrutinib or BTK inhibitors and must have high-risk disease defined as follows:

  • 17p- and/or TP53 mutation positive in treatment naïve CLL OR

  • 17p- and/or TP53 mutation positive, and/or complex karyotype and/or progression <24 months after completion of 1st line chemoimmunotherapy in relapsed/refractory CLL

• Subjects with R/R SLL or CLL with bulky disease (LN>5.0cm) may only be enrolled after discussion with sponsor medical monitor

• Must have adequate lab values

• No prior allo or auto SCT within 12 months

• No known HIV/HBV/HCV

• No significant peripheral neuropathy

• No impaired cardiac function

• Histologically or cytologically confirmed, metastatic solid malignancy
• Has exhausted all available standard therapy or not a candidate for standard therapy
• ECOG PS 0-1
• Prior PD-1/PD-L1 allowed
• No other malignancy within 2 years prior
• No active autoimmune disease requiring systemic therapy within last 2 years
• No chronic steroids or immunosuppressants.

• Histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all available standard therapy or not a candidate for standard therapy
• ECOG PS 0-1
• Prior therapy with immune therapy are eligible (except in ovarian cohort)
• In Expansion cohorts patients must either have
  • Advanced epithelial cancer of the ovary, fallopian tube, or peritoneum
  • Advanced MSS endometrial cancer
  • A different malignancy that has high expression of PVRL2
• No active autoimmune disease
• No interstitial lung disease
• No active CNS metastases
• In ovaran cohort, no prior immunotherapy
• No prior therapy with PVRIG inhibitor or anti-TIGIT antibody

• High grade (grade 3) serous, epithelial ovarian, primary peritoneal, or fallopian tube carcinoma
• Platinum resistant disease (defined progression <6 monhths from completion of a platinum containing therapy)
• Measurable disease
• ECOG PS 0-1
• Received at least 1 but < or = 3 lines of prior systemic anticancer therapy.
• Prior treatment with bevacizumab is required
• No low-grade endometrioid, clear cell, mucinous, or sarcomatous histology, or mixed tumors containing any of these histologies
• No primary platinnum refractory disease
• No requirement of treatment with chronic or frequent use of oral steroids
• No concurrent treatment with mifepristone or other GR modulators
• No peripheral neuropathy
• No symptomatic CNS disease

• Metastatic or unresectable colorectal cancer.
• KRAS, NRAS, and BRAF wt
• Must have at least 1+ on HER2 testing by central vendor
• Able to provide archival tumor sample
• ECOG PS 0-1
• LVEF > or = 50%
• No surgery or radiation within 4 weeks prior to enrollment
• No MI within 6 months
• No symptomatic CHF or elevated troponins within 4 weeks
• No corneal disease
• No active CNS mets
• No other malignancy within 3 years (except solid tumors curatively treated, in situ dz, or non-melanoma skin cancer)
• No known HIV/HBV/HC

• Histologically confirmed unresectable or metastatic breast cancer
• HER-2 positive (HER2+) by ASCO-CAP guidelines and confirmed by central lab
• Previously treated with T-DM1
• Progression following last treatment (cannot go on after stopping treatment for toxicity alone)
• No prior capecitabine
• No history of insterstitial lung disease or pneumonitis requiring steroids
• No active CNS disease

• Intrahepatic cholangiocarcinoma diagnosed by histology
• Unresectable disease
• Less than 50% of liver involved
• No clinically significant extra-hepatic disease (regional nodes 2cm or less are acceptable)
• ECOG PS 0-1
• No history of liver transplantation
• Hepatic vasculature must be compatible with perfusion (prior Whipple is allowed only if anatomy is compatible)
• No prior radiation therapy to the liver (including Y-90, I-131, etc.)
• No prior treatment with percutanous trans-arterial treatment to liver (such as TAE or TACE)
• No Class II or higher CHF
• No prior malignancy within 5 years except in-situ disease or non-melanoma skin cancer
• No active HBV or HCV
• No CNS disease
• Plts >100, Hgb >10 (independent of transfusions), ANC >1500
• Bili <1.5x normal, ALT/AST <5x normal 

• Histologically or cytologically proven ocular melanoma to the liver
• No more than 50% liver parenchema involvement
• Evidence of limited extrahepatic disease allowed as long as life threatening component of disease is in liver
• ECOG PS 0-1
• No Child Class B or C cirrhosis
• No active HBV or HCV
• No active CNS mets

• Metastatic or unresectable BC histologically confirmed to be either HER2 positive (IHC 3+ or ISH positive) or HER2 low (IHC 1+ or 2+ and negative ISH). Must be documented before having received T-DXd treatment previously
• Must have previously received T-DXd
• Measurable disease
•  At leat 1 but no more than 3 prior chemo-based regimens in the metastatic /unresectable setting. If gotten in adjuvant setting but recurred within 6 months, this would count as a line of therapy
• ECOG PS 0-1
• If HR-positive HER2-low, must have received endocrine therapy in the past and not be expected to have further benefit
• No active CNS mets
• No prior eribulin treatment
• No active pneumonitis or ILD
• No CHF greater than NYHA Class II or LVEF <50%
• No known history of TB
• HIV allowed if CD4+ <350 and viral load <400
• HBV allowed if willing and able to take anti HBV therapy
• HCV only allowed if completed curative therapy

Treated for one course of platinum-based therapy
Recurrence at least 6 months after completing platinum therapy
ECOG PS 0-2
No prior tx with gemcitabine
No CNS involvement_

Stage IV NSCLC
ECOG PS 0-1
Off all anti-cancer tx for at least 21 days
No CNS mets
No serious cardiac history (except chronic afib)



Part D (abemaciclib + LY3023414)

At least 3rd line but no more than 4th line
No prior tx with a PI3K or mTOR inhibitor
No history of ILD

Part E (abemaciclib + pembrolizumab)

At least 2nd line but no more than 4th line.

• Confirmed HR+, HER2-, early stage resected invasive breast cancer without evidence of distant metastases.
• Must have undergone definitive surgery of the primary breast tumor.
• Must have tumor tissue from breast (preferred) or lymph node for exploratory biomarker analysis available prior to randomization.

• Pathologic lymph node involvement and at least one of the following indicating a higher risk of recurrence:

  • 4 or more positive axillary lymph nodes
  • Tumor size of at least 5 centimeters
  • Grade 3 defined as at least 8 points on the Bloom Richardson grading system
  • Ki-67 index by central analysis of ≥20% on untreated breast tissue
• Must be randomized within 16 months from the time of definitive breast cancer surgery.
• May receive up to 12 weeks of endocrine therapy until randomization following the last non-endocrine therapy (surgery, chemotherapy, or radiation) whichever is last.
• ECOG PS 0-1
• No metastatic disease (including contralateral axillary lymph nodes) or node-negative disease.
• No inflammatory breast cancer.
• No previous breast cancer, with the exception of ipsilateral ductal carcinoma in situ (DCIS) treated by locoregional therapy alone ≥5 years ago.
• No other malignancy within 5 years
• No concurrent exogenous reproductive hormone therapy (for example, birth control pills, hormone replacement therapy, or megestrol acetate).
• No prior endocrine therapy for breast cancer prevention (tamoxifen or raloxifene or aromatase inhibitors).
• No history of venous thromboembolism (VTE).

Postmenopausal adenocarcinoma of breast

Tumor >1cm in diameter

HR+, HER2-

Neoadjuvant endocrine monotherapy deemed to be suitable therapy

Suitability for baseline core biopsy

No bilateral breast cancer

No inflammatory breast cancer

No metastatic disease

No prior systemic therapy or XRT in same breast as being currently treated

No prior anti-estrogen therapy

• Advanced unresectable or metastatic soft tissue sarcoma
• Not amenable to cure with surgery or radiation
• ECOG PS 0-1
• No prior treatment with anthracyclines (doxorubicin, idarubicin, etc.)
• Any number of prior lines of therapy. Therapy must have stopped at least 28 days before randomization
• Available tumor tissue (FFPE)
• LVEF >50%
• No GIST or Kaposi's sarcoma
• No prior whole pelvis or mediastinal radiation

• Must have confirmed HR+, HER2+ lymph node positive early invasive breast cancer 
• Must have undergone definitive surgery of the primary breast tumor
• Must have receievd a minimum of 4 cycles of chemotherapy either in neoadjuvant or adjuvant setting
• Must have completed 9 months to 1 year of followingadjuvant HER2-targeted therapy
  • For those treated with neoadjuvant chemo/HER2, must have received T-DM1 in adjuvant setting 
  • For those not-treated with neoadjuvant chemo/HER2, must have received adjuvant pertuzumab + trastuzumab
• Must have completed adjuvant HER2 therapy within 12 weeks of randomization
• High risk disease defined as follows:
  • Neoadjuvant patients must have positive axillary node at time of surgery
  • Non-neoadjuvant patients must either have
    • 4 or more positive lymph nodes at surgery
    • 1-3 positive lymph nodes with either
      • Grade 3 disease or
      • Tumor size 5 cm or greater
• No inflammatory breast cancer
• No prior invasive breast cancer including most DCIS/LCIS
• No history of VTE
• No prior CDK4/6 agents
• No prior neratinib, tucatinib, trastuzumab deruxtecan, or investigational HER2 therapy
• No history of tamoxifen or AI for primary prevention

Currently open only for 1st line renal cell carcinoma

Available tissue (archival or fresh)
No prior therapy with immune checkpoint inhibitor_
No history of brain mets
No active cardiac disease
No flu-shot within 4 weeks of study

• Histologically or cytologically confirmed TNBC
• At least 1 line of systemic therapy for metastaic disease and have progressed on line of therapy immediately prior to study entry
• May screen for HMGA2 during preceding treatment, but should only occur if MD thinks progression will occur within 6 months
• Measurable disease
• Availability of archival tumor tissue, fresh core, or excisional biopsy to determine HMGA2 expression prior to enrollment
• ECOG PS 0-1
• HIV, HBV, HCV are eligible
• No active CNS metastases causing clinical symptoms
• No prior immunotherapy or checkpoint inhibitor therapy
• No active autoimmune disease

• Expansion Cohort A (ccRCC): Subjects with previously treated advanced RCC with clear cell histology (including those with a sarcomatoid component) who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts B and E (nccRCC): Subjects with previously treated advanced RCC with non-clear cell histology who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts C and F (HR+ BC): Subjects with breast cancer that is hormone receptor positive (ER+ and/or PR+) and negative for human epidermal growth factor receptor 2 (HER-2) and who have radiographically progressed during or following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts D and G (mCRPC): Subjects with metastatic CRPC (adenocarcinoma of the prostate). Neuroendocrine differentiation and other features permitted if adenocarcinoma is the primary histology.
• Expansion Cohort H (CRC): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum who received prior fluoropyrimidine-containing chemotherapy with oxaliplatin and irinotecan.
  • KRAS/NRAS wild type
  • Must have received all of the following: fluropyridmidine, irinotecan,  oxaliplatin,  EGFR monoclonal antibody, and, for those with BRAF mutation, BRAF inhibitor in combination with cetuximab
  • Must have progression during or within 3 months following the last dose of the most recent regimen
  • Prior therapy with regorafenib or TAS-102 are NOT allowed
• Expansion Cohort I (UC, Maintenance Therapy): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who received first-line chemotherapy of gemcitabine + cisplatin and/or gemcitabine + carboplatin.
• Expansion Cohort J (UC, ICI-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after PD-1/PD-L1 targeting ICI therapy.
• Expansion Cohort K (UC, platinum-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after first-line platinum-based combination therapy.
•  Locally advanced, recurrent, or metastatic
• No known untreated CNS mets
• ECOG PS 0-1

• Unresectable metastatic or locally advanced TNBC
• Pre- or post-menopausal
• ECOG PS 0-1
• Tumor specimen (FFPE) must be available prior to randomization
• Measurable disease per RECIST 1.1
• No prior systemic anti-breast cancer therapy in metastatic or inoperable setting
• No prior tx with AKT, PI3k, or mTOR inhibitors
• No CNS disease

• Men or women

• Metastatic or locally advanced or recurrent breast cancer

• If HER2 negative, no more than two prior chemotherapy lines in metastatic disease and no prior anthracycline

• Must have prior treatment with a taxane and trastuzumab in any setting

  • If treated in 2nd line or later, must have progressive disease since last regimen

  • If treated in 1st line metastatic, must have progression within 6 months of completing adjuvant therapy

• Tumor specimen must be obtained after the most recent breast cancer systemic therapy

• ECOG PS 0-2

• Measurable disease

• LVEF >50% by ECHO or MUGA

• Adequate labs

• No known CNS disease except for treated asymptomatic supratentorial mets with no need for active steroids

• No leptomeningeal disease

• No grade 2 or higher peripheral neuropathy
• No history of autoimmune disease or need for current immunosuppressants
• No HVB/HCV/HIV

• Men or women

• Primary tumor size >2cm

• Stage at presentation cT2-cT4, cN0-cN3, cM0

• HER2 positive disease (ISH positive and/or 3+ by IHC)

• HLA-A2 positive (by central laboratory)

• ECOG PS 0-2

• Adequate lab tests

• Baseline LVEF >50% by ECHO or MUGA

• No prior systemic therapy for treatment or prevention of breast cancer

• No history of DCIS unless >5 years prior to current diagnosis

• No Grade 2 or higher peripheral neuropathy

• No history of autoimmune disease, need for current immunosuppressants

• No HBV/HCV/HIV

• ER-positive and HER2-negative breast tumor as assessed locally on a primary disease specimen
• Participants who have multicentric (the presence of two of more tumor foci within different quadrants of the same breast) and/or multifocal (the presence of two or more tumor foci within a single quadrant of the breast) breast cancer are also eligible if all examined tumors meet pathologic criteria for ER positivity and HER2 negativity
• Participants must have undergone definitive surgery of their primary breast tumor(s) and axillary lymph nodes (axillary lymph node dissection [ALND] and/or sentinel lymph node biopsy [SLNB])
• Participants who received or will be receiving adjuvant chemotherapy must have completed adjuvant chemotherapy prior to randomization. Participants may also have received neoadjuvant chemotherapy. A washout period of at least 21 days is required between last adjuvant chemotherapy dose and randomization.
• Participants with node-positive and node-negative disease are eligible provided they meet additional risk criteria as defined in the protocol
• ECOG PS 0-2
• No pregnant or breastfeeding women
• No CDK4/6 inhibitor as neoadjuvant or adjuvant therapy
• No active cardiac disease
• No Stage IV disease
• No history of any prior invasitve breast cancer
• No other malignancies within 3 years
• No prior endocrine therap

• Metastatic solid tumor
• ALK alterations as follows
  • ALK gene rearrangements by NGS or FISH using Vysis ALK Break Apart FISH Probe Kit
  • Activating non-synonymous mutations in and around the ALK kinase domain by NGS
  • ALK copy number gains by NGS
  • Patients with melanoma and high ALK expression by IHC
• ECOG PS 0-2
• No prior treatment with any ALK inhibitor
• Following tumor types are not eligible
  • Non-small cell lung cancer (NSCLC)
  • Neuroblastoma
  • Childhood tumors