A phase 1 study of MDM2 inhibitor DS-3032b in patients with well/de-differentiated liposarcoma (WD/DD LPS), solid tumors (ST) and lymphomas (L).

Abstract

11514 Background: Inactivation of p53 is the most frequent event in cancer driven by mutations in TP53 or overexpression of MDM2, a negative regulator of p53. DS-3032b is an oral small molecule that disrupts the MDM2-p53 interaction, resulting in reactivation of wild type p53 and causing growth arrest/apoptosis. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) and preliminary efficacy of DS-3032b. Methods: Patients (pts) received DS-3032b orally in 28 days cycle as per Table. TP53 status was confirmed post-enrollment. Results: 94 pts were enrolled with ST (50, 53%), WD/DD LPS (40, 43%), L (4, 4%). Doses, schedules (Sch), MTDs and responses are tabulated below. Median age was 60.5 years, 50% male, 63% had ≥ 3 prior therapies. 73/84 (87%) pts tested had WT TP53. The most common ( > 10%) TEAEs were nausea 71%, vomiting 31%, diarrhea 40%, decreased appetite 37%, abdominal pain 16%, dry mouth 11%, thrombocytopenia 61%, neutropenia 28%, anemia 43%, fatigue 55%, dysgeusia 18%, headache 19%, cough 19% and peripheral edema 14%. There were 8 dose limiting toxicities (DLT): six Gr 2-4 thrombocytopenia +/- neutropenia; 3 events resolved, 3 unresolved. One Gr 3 nausea, vomiting and anorexia and another Gr 2 fatigue. Sch D (3/14 days) had the best safety profile. In 79 efficacy-evaluable pts, 47 (60 %) achieved stable disease (SD). Median duration of SD was 6.7 (1.6 to 36.4) months. Partial responses (PR) were seen in DDLPS, synovial sarcoma and lung ca (SC).PK parameters AUC0-24h and Cmax were dose proportional with median Tmax 3 hours. PD biomarker MIC-1 correlated with drug exposure. In paired biopsies, MDM2 inhibition resulted in increase of nuclear p53 levels (IHC) in 5/6 pts (83%). Conclusions: DS-3032b has acceptable safety profile with intermittent dosing. Objective responses and durable SD were seen in MDM2 amplified ST and DDLPS warranting further studies Clinical trial information: NCT01877382.Schedule, days Doses, mg N = 94 pts Histology MTD, mg Best Response A – 21/28 15 – 240 40 ST/L 120 SD A – 21/28 120 20 120 B – 28/28 90 9 90 C – 7/28 120, 200 9 Progressing WD/DD LPS and MDM2 amp ST Not achieved 1 PR DDLPS D – 3/14 – 3/14 120, 200, 260, 340 16 260 2 PR: synovial sarcoma & SCLC