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.

• Authors: Michael Andreeff, Kevin R Kelly, Karen Yee, Sarit Assouline, Roger Strair, Leslie Popplewell, David Bowen, Giovanni Martinelli, Mark W Drummond, Paresh Vyas, Mark Kirschbaum, Swaminathan Padmanabhan Iyer, Vivian Ruvolo, Graciela M Nogueras González, Xuelin Huang, Gong Chen, Bradford Graves, Steven Blotner, Peter Bridge, Lori Jukofsky, Steve Middleton, Monica Reckner, Ruediger Rueger, Jianguo Zhi, Gwen Nichols, Kensuke Kojima
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 4 Pg. 868-76 (Feb 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26459177 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Imidazolines
• RG7112
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Antineoplastic Agents (pharmacokinetics, therapeutic use, toxicity)
• Apoptosis
• DNA Mutational Analysis
• Drug Administration Schedule
• Gene Expression
• Humans
• Imidazolines (pharmacokinetics, therapeutic use, toxicity)
• Leukemia, Lymphoid (drug therapy, genetics)
• Maximum Tolerated Dose
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)