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

被引：306

作者：

Andreeff, Michael ^{[1
]}

Kelly, Kevin R. ^{[2
]}

Yee, Karen ^{[3
]}

Assouline, Sarit ^{[4
]}

Strair, Roger ^{[5
]}

Popplewell, Leslie ^{[6
]}

Bowen, David ^{[7
]}

Martinelli, Giovanni ^{[8
]}

Drummond, Mark W. ^{[9
]}

Vyas, Paresh ^{[10
]}

Kirschbaum, Mark ^{[6
]}

Iyer, Swaminathan Padmanabhan ^{[2
]}

Ruvolo, Vivian ^{[1
]}

Gonzalez, Graciela M. Nogueras ^{[1
]}

Huang, Xuelin ^{[1
]}

Chen, Gong ^{[11
]}

Graves, Bradford ^{[12
]}

Blotner, Steven ^{[11
]}

Bridge, Peter ^{[11
]}

Jukofsky, Lori ^{[11
]}

Middleton, Steve ^{[11
]}

Reckner, Monica ^{[11
]}

Rueger, Ruediger ^{[13
]}

Zhi, Jianguo ^{[11
]}

Nichols, Gwen ^{[11
]}

Kojima, Kensuke ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 448, Houston, TX 77030 USA

[2] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA

[3] Princess Margaret Canc Ctr, Toronto, ON, Canada

[4] McGill Univ, Montreal, PQ, Canada

[5] UMDNJ Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA

[6] City Hope Natl Med Ctr, Los Angeles, CA USA

[7] St Jamess Inst Oncol, Leeds, W Yorkshire, England

[8] Univ Bologna, Bologna, Italy

[9] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland

[10] Univ Oxford, Oxford, England

[11] Roche Innovat Ctr New York, New York, NY USA

[12] FORMA Therapeut, Boston, MA USA

[13] Roche Innovat Ctr Penzberg, Penzberg, Germany

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 04期

关键词：

ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; P53-MEDIATED MITOCHONDRIAL APOPTOSIS; ACUTE MYELOGENOUS LEUKEMIA; MANTLE CELL LYMPHOMA; CONCOMITANT INHIBITION; MEDIATED RESISTANCE; WORKING GROUP; P53; PATHWAY; ACTIVATION;

D O I：

10.1158/1078-0432.CCR-15-0481

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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/refractoryAML 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. (C) 2015 AACR.

引用

页码：868 / 876

页数：9

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