JAVELIN PARP medley: A phase Ib/II study of avelumab (anti–PD-L1) plus talazoparib in locally advanced or metastatic solid tumors

Abstract

Background: Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, is approved for the treatment of metastatic Merkel cell carcinoma in various countries and advanced urothelial carcinoma after progression on platinum therapy in the United States and Canada. Talazoparib is a potent, orally bioavailable PARP inhibitor with a dual mechanism (PARP enzyme inhibition and PARP trapping). Preclinical studies suggest that the combination of an immune checkpoint inhibitor and PARP inhibitor may have additive antitumor activity, and initial clinical studies support evaluation of this combination. Trial design: JAVELIN PARP Medley (NCT03330405) is an open-label, multicohort, phase 1b/2 trial investigating avelumab plus talazoparib in ≥316 patients with selected solid tumors. Eligible adult patients have locally advanced (primary/recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent, including non-small cell lung cancer with no EGFR mutations, triple-negative breast cancer, hormone receptor-positive and HER2-negative breast cancer, recurrent platinum- sensitive ovarian cancer, urothelial carcinoma, castration-resistant prostate cancer (CRPC), or advanced solid tumors with BRCA/ATM defects. Requirements for prior anticancer therapy and platinum exposure vary between phases 1b and 2 and between tumor types. Prior treatment with a PARP inhibitor or immunotherapy is not permitted. Different daily oral doses of talazoparib plus avelumab 800 mg IV Q2W will be administered in phase 1b to define the recommended phase 2 dose for the combination before enrolling patients in phase 2. The primary endpoint in phase 1b is first-cycle dose-limiting toxicity, and in phase 2, it is objective response according to RECIST 1.1 (also according to Prostate Cancer Working Group 3 [PCWG3] for patients with CRPC). Other endpoints include duration of response and progression-free survival according to RECIST 1.1 (plus PCWG3 for CRPC), overall survival, adverse events, laboratory abnormalities, pharmacokinetic parameters, and tumor tissue biomarkers.