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Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia
Michael Andreeff1, Kevin R Kelly2, Karen Yee3
1The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org.
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.
Insights
RG7112, an MDM2 antagonist, showed clinical activity in patients with relapsed/refractory leukemias. This study provides proof-of-concept for MDM2 inhibition restoring p53 function and generating responses in hematologic malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MDM2 is a negative regulator of the tumor suppressor p53.
- MDM2 is frequently overexpressed in leukemias.
- RG7112 is a small-molecule antagonist targeting MDM2.
Purpose of the Study:
- To determine the dose and safety profile of RG7112 in a Phase I study.
- To evaluate pharmacokinetics, pharmacodynamics, and preliminary clinical activity of RG7112.
- To assess RG7112 in patients with hematologic malignancies, including AML and CLL/sCLL.
Main Methods:
- Phase I study with two patient cohorts: Stratum A (AML, ALL, CML) and Stratum B (CLL/sCLL).
- Patients received RG7112, with some treated at the Maximum Tolerated Dose (MTD).
- Evaluated safety, pharmacokinetics, TP53 mutation status, MDM2 expression, and clinical response.
Main Results:
- 116 patients treated; all experienced adverse events, with 3 dose-limiting toxicities.
- Twice-daily RG7112 dosing enhanced exposure; antileukemia activity observed in AML patients at MTD.
- TP53 mutations present in 14% (Stratum A) and 40% (Stratum B); MDM2 expression correlated with response.
Conclusions:
- RG7112 demonstrated clinical activity in relapsed/refractory AML and CLL/sCLL.
- MDM2 inhibition stabilized p53 and activated p53-target genes.
- Proof-of-concept for MDM2 inhibition restoring p53 function and clinical responses in hematologic malignancies.
