A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer.

TPS5105 Background: Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in American men. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA) is highly expressed on malignant prostate tissue but shows limited expression on normal tissue. As such, PSMA is an excellent research target for treatment of mCRPC. REGN4336 is a PSMAxCD3 bispecific antibody designed to facilitate T-cell–mediated killing of PSMA-expressing tumor cells. In preclinical models, REGN4336 demonstrated strong PSMA-dependent antitumor activity that was dose-dependent. Preclinical data also support clinical research into the combination of REGN4336 with cemiplimab (anti–programmed cell death-1) for treating mCRPC. Methods: This is an open-label, Phase 1/2, first-in-human, multicenter dose-escalation study with dose expansion evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of REGN4336 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with mCRPC (NCT05125016). Patients must have received at least two prior lines of systemic therapy approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. In this study, REGN4336 as monotherapy is administered weekly but may be extended to once every 3 weeks following identification of the minimal pharmacologically active dose. REGN4336 in combination with cemiplimab (350 mg) will be administered once every 3 weeks after a 4-week REGN4336 monotherapy lead-in cycle. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of REGN4336 alone and in-combination with cemiplimab. Expansion cohort(s) will be enrolled once RP2DRs have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate with REGN4336 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. This study is currently open to enrollment. Clinical trial information: NCT03088540.