Results of the phase i trial of RG7112, a small-molecule MDM2 antagonist in leukemia

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 Gonzalez, Xuelin Huang, Gong Chen, Bradford Graves, Steven Blotner, Peter Bridge, Lori JukofskySteve Middleton, Monica Reckner, Ruediger Rueger, Jianguo Zhi, Gwen Nichols, Kensuke Kojima

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

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 withhematologicmalignancieswas 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/refractoryAML and CLL/sCLL.MDM2inhibition 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.

Original languageEnglish (US)
Pages (from-to)868-876
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
StatePublished - Feb 15 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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