A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.

e13600^ Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration depen...