A phase I dose escalation and cohort expansion study of CB307, a trispecific Humabody® against PSMA, CD137, and albumin in patients with PSMA-positive solid tumors

Abstract Background:CB307 is a tri-specific variable heavy-chain antibody fragment against PSMA, CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in the PSMA-positive tumors and to increase drug half-life by albumin binding. This Phase I study investigated the safety and tolerability of CB307 as monotherapy or with pembrolizumab.Methods: Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. Additional safety and efficacy of CB307 were assessed in CB307 monotherapy expansion cohort and in combination with pembrolizumab.Results:CB307 was administered in 75 patients. CB307 was given Q1W as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (DLTs, grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with mCRPC enrolled in 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rate: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post-hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR 60% vs. ORR 0%, DCR 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression.