TY - JOUR
T1 - Results of the phase i trial of RG7112, a small-molecule MDM2 antagonist in leukemia
AU - Andreeff, Michael
AU - Kelly, Kevin R.
AU - Yee, Karen
AU - Assouline, Sarit
AU - Strair, Roger
AU - Popplewell, Leslie
AU - Bowen, David
AU - Martinelli, Giovanni
AU - Drummond, Mark W.
AU - Vyas, Paresh
AU - Kirschbaum, Mark
AU - Iyer, Swaminathan Padmanabhan
AU - Ruvolo, Vivian
AU - Gonzalez, Graciela M.Nogueras
AU - Huang, Xuelin
AU - Chen, Gong
AU - Graves, Bradford
AU - Blotner, Steven
AU - Bridge, Peter
AU - Jukofsky, Lori
AU - Middleton, Steve
AU - Reckner, Monica
AU - Rueger, Ruediger
AU - Zhi, Jianguo
AU - Nichols, Gwen
AU - Kojima, Kensuke
N1 - Funding Information:
This work was supported in part by Hoffmann-La Roche, Inc. and by grants from the NIH (P01 CA49639 and CA16672; to M. Andreeff) and by the Paul and Mary Haas Chair in Genetics (to M. Andreeff). Support for third-party writing assistance for this article was provided by Hoffmann-La Roche, Inc.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-0481
DO - 10.1158/1078-0432.CCR-15-0481
M3 - Article
C2 - 26459177
AN - SCOPUS:84962677007
SN - 1078-0432
VL - 22
SP - 868
EP - 876
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -