• 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

• 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

• 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

• 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

• 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

• PD-L1 copy number gain/amplification (likely available on Foundation only)
• Patients with MSI-high
  • Using either Foundation 1 or other NGS defined by a shift in the size of 30% or more loci
• Patients with dMMR
  • Defined as loss of at least one of four markers (MLH1, MSH2, PMS2, MSH6)
• Patients with total mutational burden (TMB) high
  • 10 mut/Mb per any CLIA certified test
• Patients with alterations in DNA proofreading/repair genes
  • POLE mutations
  • POLD1 mutations
  • Mutations in genomic instability genes eg. MSH2, MLH1, MSH6
• If testing was not performed by Foundation Medicine, new pretreatment tissue sample is required. Tissue may be submitted within 4 weeks after enrollment
• No metastatic non-small cell lung cancer (no NSCLC)
• No metastatic urothelial carcinoma (no bladder cancer)
• No MSI-high colorectal cancer
• No history of autoimmune disease or immune deficiency
• No HIV/HBV/HCV
• No other malignancy within 5 years
• No need for immunosuppressive medications (including steroids)

Metastatic solid tumor
Loss of function mutation in PTCH or gain of function mutation in SMO
No basal cell CA, medulloblastoma, or SCLC2nd line or greater
ECOG PS 0-2
No prior treatment with any hedgehogdirected therapy
No active or untreated CNS metastastasis_

• ECOG PS 0-1
• Fresh baseline tumor biopsies are required unless med monitor approval
• No active ILD or pneumonitis
• No active receipt of steroids within 7 days or known immunodeficiency
• No prior anti-PD-1 or CTLA-4 treatment
• No known or active CNS mets
• No history of autoimmune disease
• For MSI-high CRC
  • MMR or MSI status is, respectively, determined by examining either CRC tumor: protein expression by IHC of 4 MMR enzymes (MLH1/MSH2/MSH6/PMS2) or 3 to 5 tumor microsatellite loci using PCR-based assay. Tumors are classified as MSI high when at least 2 allelic shifts among the 3 to 5 analyzed microsatellite markers are detected by PCR or absence of at least 1 of 4 MMR protein expression is detected by IHC
• For Gastric cancer (COHORT CLOSED)
  • Must have documentation of HER2 status. IF HER2+ must have progressed or been intolerant of HER2 directed therapy
  • No more than 2 prior lines of therapy
• For Hepatocellular carcinoma
  • Must be Child-Pugh Class A
  • Must be Barcelona Clinic Liver Cancer Stage C disease (or Stage B disease and either refractory to or not amenable to locoregional therapy
  • No more than 2 lines of prior therapy
  • Must have progressed on or intolerant to sorafenib
  • No history of liver transplant, clear invasion of bile duct or main portal branch, hepatorenal syndrome, or required esophageal variceal ablation within 28 days of study start
  • HBV/HCV only allowed if meet certain criteria
• For melanoma- (COHORT CLOSED)
  • Known BRAF status
  • No ocular melanoma
• For bladder/transitional cell (COHORT CLOSED)
  • TCC of bladder, ureter, or renal pelvis
  • 2nd line after progression on platinum (if no platinum received must have documented why unable to tolerate)
• For RCC (COHORT CLOSED)
  • Clear cell histology
  • Following progression on therapies with established clinical benefit
• For NSCLC (COHORT CLOSED)
  • 2nd line or later after platinum based therapy for metastatic disease
  • If EGFR or ALK positive, must have received targeted therapy
  • If progressed within 6 months of adjuvant therapy, OK to enroll 1st line
• For SCCHN (COHORT CLOSED)
  • No nasopharyngeal, salivary gland, or non-squamous histology
  • 2nd line or later after failure of platinum-based therapy
  • If progressed within 6 months of adjuvant therapy, OK to enroll 1st line
• For DLBCL
  • No prior allo transplants
  • 2nd line or later
  • Not a candidate for curative tx or SCT
•  

• Gastric cancer
• Exactly 2 prior lines of therapy
• Neoadj or adjuvant tx not considered prior line unless recurrence within 12 months  
• Maintenance regimens are not considered lines of therapy
• Measurable Disease per RECIST 1.1
• 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 chronic systemic steroid or immunosuppressive therapy
• 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

• Patient planned to receive one of the following agents for Cancer with or without chemotherapy that has a risk of diarrhea in 50% of patients
  • CDK4/6 inhibitors (abemaciclib), 
  • PI3 kinase blockers (alpelisib),
  • anti-EGFR TKIs (afatinib, dacomitinib, erlotinib, gefitinib) 
  • anti VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, vendatinib)
  • anti ALK TKIs (ceritinib, crizotinib)
  • MEK inhibitor (cobimetinib) 
  • Anti HER2 TKIs (lapatinib, tucatinib)
• ECOG PS 0-2
• Not receiving immunotherapy (PD-1, CTLA-4, IL-2)
• No diarrhea before enrolling on the study (or starting TKI)
• No ongoing IBS or colitis
• Not planning on receiving an agent where anti-diarrheal prophylaxis is mandatory (e.g. neratinib, irinotecan, etc.)
• No laxative use within 7 days prior to randomization

ALK or ROS1 mutation, trnaslocation, rearrangement, or amplification by CLIA-certified laboratory (IHC or FISH allowed)

May not have ALK+ lung cancer (butROS1 positive lung CA allowed)
Relapsed or progressive disease
ECOG PS 0-1
2nd line or higher
No standard therapy withdurable remission expected
No CNS disease

• Histologically or cytologicall confirmed patients with advanced solid tumors
• Must have documented Globo H score of at least 100 from a qualified laboratory IHC assay
• Must have been treated with established standard-f-care therapy or physicians have determined that such established therapy is not sufficiently efficacious or patients have declined to received standard-of-care therapy
• ECOG PS 0-1
• Measurable disease
• Adequate organ function
• No known untreated CNS mets
• No significant clinical cardiac abnormality

• One of the following malignancies:
  • Cervical cancer
  • HR+/HER2- Breast cancer with prior CDK4/6 inhibitor
  • HR+/HER2 - Breast cancer without prior CDK4/6 inhibitor
  • TNBC
  • Salivary Gland tumor
  • NSCLC with EGFR exon-18 mutation
• Documented HER2 (ERBB2) mutation (or EGFR exon 18 mutation in NSCLC).
• At least one measurable or evaluable lesion
• LVEF >/=50%
• ECOG PS 0-2
• No prior treatment with ERBB2 (HER2) directed TKIs (eg lapatinib, afatinib, neratinib)
• No symptomatic or unstable brain mets (stable are allowed)
• No cumulative prior anthracycline dose >450mg/m2 doxorubicin or equivalent
• No uncontrolled cardiac disease
• No chronic diarrheal disorder

• Histologically confirmed metastatic cancer that is approved to be treated with nivolumab or pembrolizumab
• Must not be eligible for curative resection
• Must be positive for at least 1 of the following human leukocyte antigens:
  • HLA-A*02:01
  • HLA-A*02:06
  • HLA-A*24:02
  • HLA-A*03:01
  • HLA-B*15:01
• ECOG PS 0-1
• No known CNS mets
• No known HIV/HBV/HCV

• One of the following malignancies
  • Small cell lung cancer: locally recurrent or metastatic SCLC whose disease has progressed after at least 1 prior line of chemo
  • Gastric or GEJ adenoCA: Disease that has progressed after at least 1 prior line of chemo
  • SCC of genitalia (anus, cervix, vulva, or penis): disease that has progressed after at least 1 prior line (adjuvant counts as prior line)
  • Pancreatic CA: Disease that has progressed after at least 1 line of prior therapy (adjuvant tx counts as a line if recurrence is within 6 months)
  • Endometrial CA: Disease that has progressed after at least 1 line of prior therapy (adjuvant tx counts as a line if recurrence is within 6 months)
• ECOG PS 0-1
• Measurable disease
• No prior topoisomerase I inhibitor
• No symptomatic CNS involvement
• No known HIV/HBV/HCV