Pharmacokinetics (PK) and pharmacodynamics (PD) of RG7112, an oral murine double minute 2 (MDM2) antagonist, in patients with leukemias and solid tumors.

Abstract

3039 Background: RG7112 is a selective inhibitor of p53-MDM2 binding and frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. Results of clinical PK (plasma RG7112 concentrations) and PD (serum macrophage inhibitory cytokine-1, MIC-1, a potential indicator of p53 activation) are reported here from two phase 1 studies of RG7112 in patients (pts) with AML, ALL, CML in blast phase or refractory CLL/SCLL, and pts with advanced solid tumors and refractory lymphomas. Safety, tolerability, and clinical responses are reported separately. Methods: 49 leukemia pts and 76 solid tumor pts took RG7112 tablets once or twice daily in escalating oral doses (20 – 1920 mg/m2/day) for 10 days followed by 18 days of rest between cycles. Serial PK samples were drawn pre-dose and up to 120 hours post-dose on Days 1 and 10 and pre-dose on Day 5. MIC-1 samples were collected at the anticipated PK Cmax and up to 48-hr post- dose on Days 1 and 10. Limited confirmatory PK and PD samples were also taken in cycle 2. Results: Plasma RG7112 concentrations peaked ~ 4 hr post-dose at steady-state (SS) on Day 10 and then declined with a mean terminal elimination t1/2 ~ 1.5 days. The PK exposure (plasma Ctrough, Cmax, and AUC) was ~ dose-proportional without accumulation in the dose range studied. Inter-patient variability was ~70%; PK exposure tended to be higher in patients with solid tumors compared to those with leukemias at comparable dose levels. Serum MIC-1 levels were elevated from individual baseline starting from RG7112 doses > 320 mg/m2 and plasma concentrations > 1 µg/mL, suggesting a potential mechanistic PD relationship (p53 activation). The increase in MIC-1 (% of change from baseline) was highly associated with plasma RG7112 concentrations (R=0.60 and 0.80 in pts with leukemias and solid tumors, respectively). Conclusions: As expected from mechanism of action, RG7112 exhibited exposure-related PD response for the p53 biomarker MIC-1 within the dose range tested in pts with leukemias and solid tumors.