Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy

PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose of the combination of CA-4948 plus pembrolizumab in patients with immune checkpoint blockade (ICB)-resistant metastatic urothelial cancer (Dose Escalation Cohort). II. To determine the safety of the combination of CA-4948 plus pembrolizumab in patients with ICB-resistant metastatic urothelial cancer (Dose Escalation Cohort and Dose Expansion Cohort). SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To measure the objective response (complete response \[CR\] or partial response \[PR\]) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 9 weeks and the best overall response (CR or PR) as defined by RECIST 1.1 at any time while on study. III. To determine progression-free survival, overall survival, and duration of response. IV. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in 2IR scores (as defined by ribonucleic acid \[RNA\] sequencing) in paired tumor biopsies. EXPLORATORY OBJECTIVES: I. To assess the clinical benefit rate with pembrolizumab plus CA-4948 therapy. II. To assess the "C-reactive protein (CRP) response rate" as defined by the proportion of patients achieving a ≥ 1.5 fold reduction in CRP at 9 weeks. III. To explore the association between the 2IR score as defined by bulk-ribonucleic acid (RNA) sequencing of pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. IV. To explore whether CA-4948 plus pembrolizumab leads to on-treatment changes in the cellular and/or molecular composition of the tumor microenvironment (TME). V. To explore the association between the quantity and spatial localization of SPP1+ monocytes-macrophages (MoMacs) defined by multiplex immunohistochemistry on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. VI. To explore the association between the cellular and molecular composition of the TME defined by spatial RNA sequencing on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. VII. To explore on-treatment changes in high-sensitivity (hs) CRP and cytokines and chemokines in peripheral blood and their association with objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. VIII. To explore the association between PD-L1 expression on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. IX. To explore the association between the CXCL9:SPP1 ratio as defined by bulk-RNA sequencing of pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival. X. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in the CXCL9:SPP1 ratio (as defined by RNA sequencing) in paired tumor biopsies. OUTLINE: This is a dose-escalation study of CA-4948 in combination with pembrolizumab followed by a dose-expansion study. Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) throughout the study. Additionally, patients may undergo a tumor biopsy on study. After completion of study treatment, patients are followed up every 3 months for 2 years.