• 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

• 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

• 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

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

• 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

• 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