Cabozantinib plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma (PemCab)
Primary Objective: To evaluate measurable disease overall response rate (ORR).
Secondary Objectives and Endpoints:
- To evaluate progression-free survival (PFS) at 6 months (PFS6).
- To evaluate Overall Survival (OS).
- To evaluate toxicities associate with the combination treatment.
Exploratory Objectives and Endpoints:
- To evaluate molecular markers for pharmacodynamic pathways associated with response.
- To evaluate ORR and PFS6 using immune specific disease assessment criteria
Participant is a candidate for urothelial diagnostic procedure (fresh soft-tissue biopsy or TURBT).
Meets standard of care eligibility criteria for consideration of treatment with immunotherapy using a checkpoint inhibitor following surgical resection.
Treatment Inclusion Criteria:
Histologically proven transitional cell or urothelial carcinoma.
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.
Adequate organ function as defined in the protocol
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 Participants 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 not recovered 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.
Prior chemotherapy for metastatic urothelial carcinoma, and 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 in the adjuvant setting.
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. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
Concomitant anticoagulation with oral anticoagulants except for those specified in the protocol.
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