Abstract LB-201: Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.
Authors: Patnaik Amita , Tolcher Anthony , Beeram Muralidhar , Nemunaitis John , Weiss Glen , Nichols Gwen , Middleton Steven , Sarapa Nenad , Beryozkina Anna , Zhi Jianguo 
Published: August 2014

MDM2 is overproduced as a mechanism to impair p53 function in many cancers. By reactivating p53, antagonists of p53-MDM2 interaction could offer a novel approach to treatment of solid tumors and leukemias. RG7112, the first potent and selective small-molecule MDM2 antagonist in clinical testing, is an oral p53 activator and is currently in phase I. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multi-center trial in patients (pts) with advanced solid tumors. In Part I, the impact of high-energy/high-fat meal and formulation (crystalline versus amorphous) was examined in cross-over design. In Part II, schedule optimization (4 schedules of drug adm under fasting condition and 1 cohort with liquid supplementation) was investigated in parallel, dose escalation design. Clinical endpoints were PK/PD and safety/tolerability including platelet reduction (a potential target-mediated hematological toxicity indicator).

A total of 76 pts (42F and 34M, mean age 60 yr) participated in the study. In their first-cycle treatment, 36 pts received weekly x3 (26 with food/formulation evaluation), 15 pts daily x5, 6 pts daily x20, and 19 pts daily x3 (3 with food evaluation) doses; daily doses ranged from 500-4500 mg. The most commonly reported AEs (&gt; 20%) were GI-related. Twelve pts have reported 21 SAEs, of which, 4 events in 2 pts (1 pt with G4 thrombocytopenia, anemia, and neutropenia; 1 pt with G3 delirium) were related to study treatment.

A high-energy (∼1000 kcal)/high-fat (∼60 g) meal and a reduced energy (∼500 kcal)/fat (∼30 g) liquid supplementation both enhanced overall bioavailability (BA) of tested formulations by 2-fold, with inter-pt variability reduced by half. At steady-state, amorphous formulation also reduced PK variability by half from the crystalline formulation. High-dose consecutive daily dosing for 5 and 3 d yielded highest drug concentrations on the last day of treatment. On the other hand, both weekly and low-dose/long-duration (20-day) schedules yielded lower peak concentrations (note that the per-cycle exposure was comparable to, or higher than, high-dose 5x and 3x daily schedules).

Serum profiles of MIC-1, a secreted protein that is strongly induced by activated p53, showed similar patterns to the PK when the clinical pharmacology conditions were varied.

The first-cycle platelet profiles indicate that the weekly schedule didn't cause platelet reduction, while the daily schedules showed a trend of dose- and length-dependent platelet reduction with daily x 5 at high doses being the most pronounced (1 pt resulted in G-4 thrombocytopenia).

In conclusion, RG7112 is well tolerated with or without food in the therapeutically relevant dose range, food enhanced BA with reduced variability, and high-dose consecutive daily for 3-5 d is superior in yielding sufficiently high PK exposure and PD effects potentially required for cancer treatment efficacy.

Citation Format: Amita Patnaik, Anthony Tolcher, Muralidhar Beeram, John Nemunaitis, Glen Weiss, Gwen Nichols, Steven Middleton, Nenad Sarapa, Anna Beryozkina, Jianguo Zhi. Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2013-LB-201