A phase 1 study of the MDM2 inhibitor DS-3032b in patients (pts) with advanced solid tumors and lymphomas.

Abstract

2581 Background: About 50% of tumors harbor inactivating mutations in TP53. Aberrant MDM2 signaling is an alternate mechanism to inactivate wild type (WT) p53. In preclinical studies, DS-3032b disrupted the MDM2-WTp53 interaction resulting in cell cycle arrest, senescence and/or apoptosis. We characterized the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetic and pharmacodynamic (PD) profiles and efficacy of DS-3032b in a phase 1 trial. Methods: Using accelerated and Bayesian design in the dose-escalation phase of this 2-part study (part 1), we escalated DS-3032b from 15 to 240 mg orally once daily (QD) on a continuous or interrupted (QD 21/28 days) schedule. Results: Thirty-one of 34 pts enrolled in part 1 were evaluable for dose-limiting toxicities (DLTs). Median age was 59.5 years, 44% male, and 62% had ≥ 3 prior therapies. The majority of pts (79%) had wt TP53 and the most frequent tumor type was well/de-differentiated liposarcoma (LPS; n = 15). MTD was 120 mg (interrupted) and 90 mg (continuous) schedule. The most common drug-related adverse events were hematologic and gastrointestinal. Six pts had DLTs, 5 were due to thrombocytopenia alone or with neutropenia. Of 26 pts evaluable for efficacy, none had an objective response but 77% had stable disease (SD); consistent with cell cycle arrest/senescence seen in preclinical studies. Tumor shrinkage was seen but did not meet RECIST criteria. Two pts with previously progressing LPS and carcinoid remain on study for 26+ mos and tumor sequencing showed MDM2 gene amplification. Exposures of DS-3032b were significantly higher in pts with lower body weight. Induction of MIC- 1 (PD biomarker of WT p53 reactivation) correlated with drug exposure. Conclusions: DS-3032b has an acceptable safety profile at the MTD of 120 mg (QD 21/28). Clinical benefit with durable SD was seen in tumors with aberrant MDM2 signaling and WT p53. MDM2 is universally amplified in LPS and TP53 is the most commonly mutated gene in cancer; warranting further investigation of DS-3032b. Pts with melanoma or diffuse large B-cell lymphoma (DLBCL) are being enrolled in 2 dose-expansion cohorts (part 2) at the tentative recommended phase 2 dose 120 mg QD 21/28. Enrollment is ongoing (NCT01877382). Clinical trial information: NCT01877382.