Abstract B27: A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas
Authors: Bauer Todd , Hong David , Somaiah Neeta , Cai Charles , Song Saeheum , Kumar Prasanna , Gajee Roohi , Rosen Michael , Kochan Jarema , Chen Shuquan , Hyman David , Masters Tyler , Meric-Bernstam Funda , Tse Archie , LoRusso Patricia , Weise Amy , Gounder Mrinal 
Published: May 2016

Abstract
Background: Reactivation of the tumor suppressor functions of p53 by targeting its negative regulator mdm2 represents an attractive approach to treat cancers expressing wildtype functional p53. DS-3032b disrupts the interaction between p53 and mdm2, and has demonstrated anti-tumor activity preclinically. Here, we report results from the Dose Escalation part (Part 1) of our Phase I Trial in solid tumors and lymphomas which aimed to determine a tentative recommended Phase 2 dose (tRP2D) and characterize the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of DS-3032b.
Methods: DS-3032b dose was escalated using an accelerated titration followed by modified Continuous Reassessment Method and Escalation with Overdose Control design, from 15 mg through 30, 60, 120, 160, and 240 mg in a PO QD schedule in 21 of 28 days per cycle (QD 21/28). A 90 mg dose schedule of everyday administration (QD 28/28) had also been tested.
Results: Thirty-one of 34 patients (pts) enrolled were evaluable for dose limiting toxicities (DLT). Of the 13 different tumors types enrolled, 77% were TP53 wildtype, with well-differentiated/de-differentiated (WD/DD) liposarcoma (LPS) being the most frequent (n = 13; 44%). The maximum tolerated dose (MTD) was determined to be 120 mg with 2/13 DLTs for the QD 21/28 schedule, which is currently being evaluated as the tRP2D in the Dose Expansion part (Part 2) of the study in more limited tumor types. The MTD was 90 mg with 1/9 DLT for the QD 28/28 schedule. The most common drug-related adverse events (AEs) were hematological (thrombocytopenia (Th) [68%], anemia [35%], neutropenia [29%] gastrointestinal (nausea [71%], vomiting [32%] and diarrhea [38%]), and fatigue [47%]. Prolonged Th resulting in &gt;4 weeks dose interruption was seen in 8 pts, 2 were treated at the tRP2D. Bone marrow examination performed in selected pts revealed no dysplastic changes. A total of 6 pts experienced DLTs, all treated at MTD or higher. The 3 MTD DLTs were caused by Th that resulted in &gt;1 week delay in starting Cycle 2. There was a moderate degree of inter-patient variability in PK exposure, with considerable overlap in exposures at the two MTDs (Cycle 1 Day 1 mean Cmax = 559.9 and 567.7 ng/mL, and mean AUC 0-24 = 8047.7 and 8629.3 ng*h/mL respectively for 120 and 90 mg doses). The steady state Cmin at MTDs exceeded the levels demonstrated as necessary for both disrupting MDM2-p53 interactions and showing antitumor activity preclinically. Induction of the PD biomarker MIC 1 in serum correlated with drug exposure. Twenty three pts were evaluable for tumor response. Most pts (20/26) experienced stable disease (SD) as the best tumor response though no pt had an objective response. The median progression free survival (mPFS) for all evaluable pts at 5.7 months, with 3 (1 carcinoid and 2 liposarcoma; all contain MDM2 amplification) still on study after receiving therapy for 12+, 20+, and 21+ cycles. The greatest tumor shrinkage and most durable SD were seen in pts with WD/DD LPS with mPFS of 6.3 months and 3-month PFS rate of 92%.
Conclusions: DS-3032b shows an acceptable safety profile at the tRP2D of 120mg QD x 21/28. Preliminary evidence of clinical activity with prolonged PFS was seen in WD/DD LPS in which MDM2 is universally amplified, warranting further investigation in this disease. ClinicalTrials.gov Identifier: NCT01877382
Citation Format: Todd Bauer, David Hong, Neeta Somaiah, Charles Cai, Saeheum Song, Prasanna Kumar, Roohi Gajee, Michael Rosen, Jarema Kochan, Shuquan Chen, David Hyman, Tyler Masters, Funda Meric-Bernstam, Archie Tse, Patricia LoRusso, Amy Weise, Mrinal Gounder. A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B27.