Inclusion Criteria:

• Histopathological confirmation of locally advanced unresectable or metastatic urothelial carcinoma (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra.
• Measurable disease by investigator assessment per RECIST v1.1.
• Participant must not have received prior systemic therapy for LA/mUC. Exception will be made for neoadjuvant or adjuvant therapy, if disease recurrence/progression occurred more than 12 months after the last dose of therapy.
• Eligible to receive cisplatin- or carboplatin-containing chemotherapy.
• Able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks from a muscle-invasive or metastatic UC lesion or biopsy of metastatic UC prior to treatment initiation. If archival tissue is not available a newly obtained baseline biopsy of an accessible tumor lesion is required within 28 days of cycle 1 day 1.
• HER2 expression of 1+ or greater on immunohistochemistry (IHC).
• Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 within 7 days prior to randomization.

Exclusion Criteria:

• Known hypersensitivity to disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab or any of their components.
• History of severe/life threatening immune-related adverse event (irAE) with PD-(L)1 inhibitors are excluded.

• Central nervous system (CNS) and/or leptomeningeal metastasis. Participants with treated CNS metastases are permitted if all of the following are met.

  • CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastasis.
  • Participant is on a stable dose of ≤ 10 mg/day of prednisone or equivalent for at least 2 weeks.
• History of or active autoimmune disease that has required systemic treatment in the past 2 years.
• Prior treatment with an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists).
• Prior solid organ or bone marrow transplantation.
• Pleural effusion or ascites with symptoms or requiring symptomatic treatment.
• Estimated life expectancy <12 week
• Prior treatment with an MMAE agent or anti-HER2 therapy

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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, 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

• 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

• 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

Metastatic solid tumor_
No known RAS mutation
No melanoma, papillary thyroid, colorectal, or hematologic malignancies2nd line or greater
ECOG PS 0-2
No prior treatment with any BRAF inhibitor (sorafenib is allowed)
No prior treatment with a MEK inhibitor
No active or untreated CNS metastastasis

Metastatic cancer
EFGR activatingmutation (not exon 20)
NSCLC or pancreatic must not haveexon 19 deletions or exon 21 L858R substitution2nd line or greater
ECOG PS 0-2
No prior treatment with any EGFR inhibitor
No active or untreated CNS metastastasis

• One of the following malignancies
  • Biliary cancer
  • Salivary gland cancer
  • Bladder cancer
• HER2 overexpression or amplification
• ECOG PS 0-2
• No prior treatment with any HER-2 directed therapy
• No active or untreated CNS metastastasis
• LVEF must be > or = 50%

• 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)

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• ROS1 gene fusion positivity
• No non-small lung cancer (NSCLC)
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No primary CNS malignancy
• One of the following PIK3CA mutations:
  • R88Q
  • ​G106A/D/R/S/V
  • K111N/R/E
  • G118D
  • N345D/H/I/K/S/T/Y
  • C420R
  • E453A/D/G/K/Q/R/V
  • E542A/D/G/K/Q/R/V
  • E545A/D/G/K/L/Q/R/V
  • Q546E/H/L/P/R
  • M1043I/T/V
  • H1047D/I/L/M/P/Q/R/T/Y
  • G1049A/C/D/R/S
  • Others only with study medical monitor approval
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No anti-hyperglycemic medication (no treated T2DM or T1DM)

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No breast cancer (breast cancer is excluded)
• Either ERBB2 (HER2) amplification defined as a copy number of 6 or higher via FISH, CISH or DNA NGS assay OR
• Any of the following ERBB2 mutations:
  • 222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; C311R/S; E321G; C334S; S418T; A440T; P551L; R552S; S653C; V659E; G660D; R678Q; T733I; L755P/S_T759del; I767M; L768S; D769H/N/Y; Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); G776delins(VC/VV/LC); V777L; G778_P780dup; V779A/L; T798M; L841V; V842I; N857S; T862A; L869R; H878Y; R896C​​G
• ​TMB must be <10 mutations/megabase
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No breast cancer (breast cancer is excluded)
• Either ERBB2 (HER2) amplification defined as a copy number of 6 or higher via FISH, CISH or DNA NGS assay OR
• Any of the following ERBB2 mutations:
  • 222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; C311R/S; E321G; C334S; S418T; A440T; P551L; R552S; S653C; V659E; G660D; R678Q; T733I; L755P/S_T759del; I767M; L768S; D769H/N/Y; Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); G776delins(VC/VV/LC); V777L; G778_P780dup; V779A/L; T798M; L841V; V842I; N857S; T862A; L869R; H878Y; R896C​​G
• Must ALSO have one of the following alterations
  • ​TMB > or =10 mutations/megabase
  • MSI-h
  • dMMR (negative IHC for MLH1, MSH2, MSH6, or PMS2_
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Not Non-small cell lung cancer (NO NSCLC)
• ALK gene fusion positivety defined as a 3' AALK fusion with a protein coding 5' gene fusion partner, predicted to be in frame with an intact kinase domain
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Either PTEN protein loss as determined by a CLIA or equivalently certified immunohistochemistry assay OR
• PTEN loss of function defined as PTEN dominant negative missense mutations or deleterious in-frame and missense mutations affecting protein function
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No insuline dependent diabetes

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• One of the following mutations in AKT:
  • ​AKT 1 : E17K, L52R, or Q79K
  • AKT 2 : E17K
  • AKT 3: E17K, L51R, or Q78K
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No insulin dependent diabetes

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Tumor mutational burden-high (TMB-H) determined by CLIA opr quivalently certified assay, via tissue or blood
• No prior treatment with anti-PD1 or anti-PD-L1 agents
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Microsatellite instability high (MSI-h) or deficient mismatch repair dMMR
• No prior treatment with anti-PD1 or anti-PD-L1 agents
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• ECOG PS 0-2
• Histological or cytological evidence of urothelial (transitional cell) carcinoma of the renal pelvis, ureter, bladder or urethra
• Locally advanced/unresectable disease as determined by site attending urologic oncologist or metastatic disease
• Evaluable untreated tumor tissue for biomarker analysis.
• Willing to undergo a core needle or excisional biopsy on-treatment.
• Measurable disease
• No prior chemotherapy for locally advanced or metastatic urothelial cancer
  • Perioperative chemotherapy previously administered in the neoadjuvant and/or adjuvant setting is permitted
• Ineligible for cisplatin as defined by presence of one or more of the following:
  • Impaired renal function [GFR ≥ 30 but ≤ 60 cc/min].
  • Grade ≥ 2 Hearing Loss (hearing loss measured by audiometry of 25 dB at two contiguous frequencies)
  • Grade ≥ 2 peripheral neuropathy
  • ECOG Performance Status of 2
  • Solitary Kidney
• No Active or untreated central nervous system (CNS) metastases. Patients with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
  • Evaluable or measurable disease outside the CNS
  • No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
  • No history of intracranial or spinal cord hemorrhage
  • No evidence of significant vasogenic edema
  • No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose allowed
  • No stereotactic radiation, whole-brain radiation within 4 weeks prior to Cycle 1 Day 1
  • Patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy within 3 months prior to Cycle 1 Day 1 will be excluded
• No malignancies other than urothelial cancer within 5 years prior
• No history of autoimmune disease
• Known HIV, HBV, or HCV
• No inadequately controlled hypertension (defined as persistent systolic blood pressure (SBP) > 150 and/or diastolic blood pressure (DBP) > 100 mmHg)

• Naïve to cytotoxic chemotherapy (endocrine or targeted therapy allowed)
• Scheduled to receive at least 4 repeated consecutive cycles with one of the following reference HEC (alone or in combination with other chemo agents) on Day 1
  • Cisplatin as single IV dose >70mg/m2
  • Cyclophosphamide >1500mg/m2
  • Carmustine (BCNU) >250 mg/m2
  • Dacarbazine (DTIC)
  • Mechloretamine (nitrogen mustard)
• ECOG PS 0-2
• Adequate laboratory values
• Cannot be scheduled to receive MEC or HEC on Day 2-5 of a cycle
• No active nausea of vomiting in 24 hours prior to chemo
• No symptomatic CNS disease
• No systemic steroids within 3 days of HEC
• No anti-emetic medicine within 24 hours of HEC

• Advanced solid malignancies with PIK3CA mutations (see "malignancies" tab for current eligible disease states)
• No  untreated or active CNS mets
• No diabetes requiring active treatment
• No active CHF or ventricular arryhtmias requiring treatment
• Measurable disease via RECIST 1.1
• ECOG PS 0-1
• No O2 requirements
• No XRT within previous 2 weeks (for bony mets) or 4 weeks for all other reasons
• No requirements for immunosuppression

• Metastatic or surgically unresectable solid tumor
• Measurable disease
• Documentation of an FGFR1-3 gene mutation or translocation
• At least 1 prior line of therapy with progression
• No other therapy available likely to provide clinical benefit
• ECOG PS 0-2
• No other FGFR inhibitors within last 6 months
• No clinically significant corneal or retinal disorder
• No untreated CNS disease (except primary brain cancer)
• No additional malignancy at current time requiring active treatment
• No history of calcium or phosphate disorder or systemic mineral imbalance
• No clinically significant cardiac disease
• No active HBV/HCV
• No known HIV

• 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
•  

Predominantly transitional cell urothelial carcinoma of bladder, renal pelvis, ureter, or urethra
Recurred or progressed following platinum-based chemotherapy

Measurable disease
No more than 2 prior lines of systemic�therapy (including adjuvant)
Willing to provide tissue (archived if available, new bx otherwise)
ECOG PS 0-2
No CNS mets
No active autoimmune disease
No active cardiac disease
No interstitial lung dz or non-infectious PNA
No HIV, HBV, or HCV

• Biliary Tract Cancer with 1 prior line of therapy
• Adjuvant therapy only counts as prior line if recurrence within 6 months of completing tx
• 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

• Histologically confirmed locally advanced or metastatic urothelial carcinoma
• ECOG PS 0-1
• Measurable disease per RECIST 1.1
• No prior receipt of immunotherapy with immunomodulators (eg. PD-1 inhibitors, CTLA-4 inhibitors, IDO inhibitors)
• Either;
  • No more than 1 prior line of platinum-containing therapy with disease progression on or following this therapy OR
  • Patient refuses standard of care therapy in the 1st line
•  No history of or active autoimmune disease (exceptions include Hashimoto's thyroiditis, Graves' disease, TIDDM, or Med Monitor approval)

• Histologically or cytologically confirmed non-small cell lung cancer lacking EGFR sensitizing mutations and lacking ALK translocation
• ECOG PS 0-1
• Measurable disease per RECIST 1.1
• No prior receipt of immunotherapy with immunomodulators (eg. PD-1 inhibitors, CTLA-4 inhibitors, IDO inhibitors)
• Either;
  • No more than 1 prior line of platinum-containing therapy with disease progression on or following this therapy OR
  • Patient refuses standard of care therapy in the 1st line
•  No history of or active autoimmune disease (exceptions include Hashimoto's thyroiditis, Graves' disease, TIDDM, or Med Monitor approval)

FGFR1�or FGFR2 amplification positive (+)
� � � � �or FGFR3 mutation positive__ (+)
No CNS involvement.�
No current corneal disorder/keratophathy.�
Normal calcium/phosphate homeostasis
Normal cardiac function (by echo/MUGA)__

Must have FGFR gene alteration as measured in CLIA-certified lab
None of the following malignancies:
Bladder cancer (urothelial)
Cholangiocarcinoma
Endometrial cancer
Glioblastoma multiforme (GBM)
Received at least 1 prior line of therapy
No standard therapy expected to result in durable remission
ECOG PS 0-1
No CNS disease
No acute/chronic pancreatitis
No impared cardiac function
No corneal or retinal disorder
No other cancer within 3 years
_

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

• Have histologically confirmed locally advanced (on TNM staging: T4b and any N, or any T and N2-3) or metastatic transitional cell carcinoma of the urothelium, including of the urinary bladder, urethra, ureter, and/or renal pelvis.
• Have progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
• Have measurable disease according to RECIST v1.1.
• Has available archival tumor or is willing to undergo diagnostic biopsy at screening
• ECOG PS 0-1
• No history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on the Screening chest CT scan
• No CNS disease or any history of brain metastases
• No autoimmune disease
• No history of significant coagulation or platelet disorder in last 12 months

• Unresectable locally advanced or metastatic urothelial carcinoma
• Measurable disease
• No prior systemic therapy for metastatic urothelial carcinoma with following exceptions
  • May have received neoadjuvant chemo with recurrence >12 months from completion of therapy
  • May have received adjuvant chemo with recurrence >12 months from completion of therapy
• Must be eligible to receive platinum based chemotherapy
• ECOG PS 0-2
• No CNS metastases
• No known HBV, HCV, or HIV
• No other malignancy within 3 years before study drug

• 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

• Histologically confirmed intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer
• Must have metastatic or unresectable disease and no prior therapy for metastatic disease
• Does not need to be measurable disease
• No ampullary cancer
• No adjuvant therapy within 6 months prior to registration
• ECOG PS 0-1
• No other prior malignancy within 2 years

• Advanced solid tumor or relapsed/refractory lymphoma OR
  • eligible to receive single agent pembrolizumab as standard-of-care OR
  • eligible to receive single-agent docetaxel as standard of care OR
    ​advanced pancreatic adenocarcinoma and eligible to receive gemcitabine plus nab-paclitaxel as standard of care
• Measurable disease
• ECOG PS 0-1
• No history of severe autoimmune disease
• Not receiving high-dose systemic steorid therapy or any other form of immunosuppressive therapy

Adenocarcinoma without neuroendocrine or small cell features
PSADT of < /=10 months (3 rising values during ADT, last >2ng/ml)
No evidence of metastasis (pelvic nodes up to 2cm allowed)
Castrate levels of testosterone x 4 weeks prior
Stable doses of bone resorptive agents x4 weeks prior
No anti-androgen x 4 weeks prior (ie. bicalutamide)
No surgery x 4 weeks prior
ECOG PS 0-1
No prior tx with 2nd gen anti-androgens
No hx of seizures
No prior malignancy (except skin and superficial bladder) within 5 years
No cardiac disease within 5years