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