Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS).

Abstract

10514 Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3+3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m2 or 60 mg/m2on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m2and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526. [Table: see text]