Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma

Pre-Screening Eligibility

• Male or female subject aged ≥ 18 years.
• Clinically, subject is a candidate for urothelial diagnostic procedure (fresh soft-tissue biopsy or TURBT).
• Subject meets general medical criteria for consideration of treatment with immunotherapy using a checkpoint inhibitor.

Treatment Inclusion Criteria:

• Histologically proven transitional cell or urothelial carcinoma.
• Patients with locally advanced or metastatic urothelial carcinoma must meet one of the following:
• Patients who are not eligible for cisplatin-containing chemotherapy AND whose tumors express PD-L1 (Combined Positive Score (CPS) ≥ 10 as determined by an FDA-approved test; OR
• Patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
• Metastatic (any N+ or M1) or locally advanced, unresectable (T4bN0) disease.
• Measurable disease is required as determined by RECIST v1.1.
• Performance Status ECOG 0-2
• Cisplatin-ineligibility based on ≥1 of the following:
• Estimated creatinine clearance between ≥30 and 1
• Hearing loss
• Baseline neuropathy > grade 1.
• Patient refusal
• Be greater to or equal to 18 years of age on day of signing informed consent.
• Serum albumin ≥ 2.8 g/dl
• Alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN with documented bone metastases.
• Negative serum or urine pregnancy test at screening for women of childbearing potential.
• Highly effective contraception for both male and female subjects throughout the study and for at least 120 days after last pembrolizumab treatment administration if the risk of conception exists.
• Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy to grade ≤ 2. If notrecovered to grade ≤ 2, these must be deemed to be irreversible adverse events related to prior surgery and/or radiation therapy (such as incontinence or sexual dysfunction) per investigator clinical judgment.
• Recovery to baseline or ≤ Grade 2 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
• Last dose of any radiation therapy > 2 weeks before first dose of study treatment.
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
• Adequate organ function as defined in the protocol

Exclusion Criteria

• Prior chemotherapy for metastatic urothelial carcinoma.
• Prior chemotherapy for localized urothelial carcinoma that has been completed less than 6 months before registration.
• Variant histologies other than urothelial carcinoma will not be allowed. Patients with a component of variant histologies will be allowed to enroll, if urothelial carcinoma is the predominant histology per investigator judgement. Patients with any component of small cell will be excluded.
• Has received prior treatment with cabozantinib.
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or other checkpoint inhibitors previously.
• Radiation therapy for bone metastasis ≤ 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated br