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.

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia / Andreeff, M; Kelly, Kr; Yee, Kw; Assouline, Se; Strair, R; Popplewell, L; Bowen, D; Martinelli, Giovanni; Drummond, Mw; Vyas, P; Kirschbaum, Mh; Padmanabhan Iyer, S; Ruvolo, Vr; Nogueras Gonzalez, Gm; Huang, X; Chen, Guodong; Graves, B; Blotner, S; Bridge, P; Jukofsky, L; Middleton, S; Reckner, M; Rueger, R; Zhi, J; Nichols, G; Kojima, K.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - ELETTRONICO. - 22:4(2016), pp. 868-876. [10.1158/1078-0432.CCR-15-0481]

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

MARTINELLI, GIOVANNI;CHEN, GUODONG;
2016

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.
2016
Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia / Andreeff, M; Kelly, Kr; Yee, Kw; Assouline, Se; Strair, R; Popplewell, L; Bowen, D; Martinelli, Giovanni; Drummond, Mw; Vyas, P; Kirschbaum, Mh; Padmanabhan Iyer, S; Ruvolo, Vr; Nogueras Gonzalez, Gm; Huang, X; Chen, Guodong; Graves, B; Blotner, S; Bridge, P; Jukofsky, L; Middleton, S; Reckner, M; Rueger, R; Zhi, J; Nichols, G; Kojima, K.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - ELETTRONICO. - 22:4(2016), pp. 868-876. [10.1158/1078-0432.CCR-15-0481]
Andreeff, M; Kelly, Kr; Yee, Kw; Assouline, Se; Strair, R; Popplewell, L; Bowen, D; Martinelli, Giovanni; Drummond, Mw; Vyas, P; Kirschbaum, Mh; Padmanabhan Iyer, S; Ruvolo, Vr; Nogueras Gonzalez, Gm; Huang, X; Chen, Guodong; Graves, B; Blotner, S; Bridge, P; Jukofsky, L; Middleton, S; Reckner, M; Rueger, R; Zhi, J; Nichols, G; Kojima, K.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/592949
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