Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia

Abstract

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted.

Experimental design: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity.

Results: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response.

Conclusions: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.

Figure 1

RG7112 pharmacokinetics and pharmacodynamics data. A, Correlation between RG7112 dose (mg/day) and exposure (AUC2 24 h [ng/h/mL]) for Stratum A and Stratum B on day 10. The diamonds represent individual patients. B, Correlation between RG7112 levels in bone marrow (ng/mL) and plasma concentration (ng/mL). The diamonds represent individual patients. C, Correlation between mean serum MIC-1 levels (% change) and RG1172 plasma levels (AUC24 [μg/h/mL] on day 10. The diamonds represent individual patients. MIC-1, macrophage inhibitory cytokine-1; AUC, area under curve; D, day.

Figure 2

Increased drug exposure to RG7112 correlates with increased MDM2 mRNA levels. A, Scatter plot of the absolute change from baseline of MDM2 relative gene expression levels at day 10 pre-dose of cycle 1 in the blood vs AUC_ss (hr/ng/mL) of Stratum A patients. The circles represent individual patients. AUC_ss,area under curve at steady state; MDM2,murine double minute 2. B, Scatter plot of the absolute change from baseline of MDM2 relative gene expression levels at day 2 24 h post-dose in the blood vs MIC-1 of Stratum A patients. The circles represent individual patients. MIC-1,macrophage inhibitory cytokine-1; MDM2,murine double minute 2.

Figure 3

RG7112 induces p53 target gene expression in circulating leukemia blasts. A, mRNA expression levels (peak relative to baseline expression) of p53-target genes significantly induced in leukemia samples. B, Expression of p53-target genes in p53 wild-type samples (left) and p53 mutant samples. Gene induction occurred in a wild-type p53 manner. No genes were significantly induced in p53-mutant samples.