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

Clinical Cancer Research

Volumn 22, Issue 4, 2016, Pages 868-876

  Andreeff, Michael ^a   Kelly, Kevin R ^b   Yee, Karen ^c   Assouline, Sarit ^d   Strair, Roger ^e   Popplewell, Leslie ^f   Bowen, David ^g   Martinelli, Giovanni ^h   Drummond, Mark W ⁱ   Vyas, Paresh ^j   Kirschbaum, Mark ^f   Iyer, Swaminathan Padmanabhan ^b   Ruvolo, Vivian ^a   Gonzalez, Graciela M Nogueras ^a   Huang, Xuelin ^a   Chen, Gong ^k   Graves, Bradford ^l   Blotner, Steven ^k   Bridge, Peter ^k   Jukofsky, Lori ^k   Middleton, Steve ^k   Reckner, Monica ^k   Rueger, Ruediger ^m   Zhi, Jianguo ^k   Nichols, Gwen ^k   Kojima, Kensuke ^a   more..

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^c PRINCESS MARGARET HOSPITAL   (Canada)

^d MCGILL UNIVERSITY   (Canada)

^e ROBERT WOOD JOHNSON MEDICAL SCHOOL   (United States)

^f CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

^g ST JAMES S INSTITUTE OF ONCOLOGY   (United Kingdom)

^h UNIVERSITY OF BOLOGNA   (Italy)

ⁱ BEATSON WEST OF SCOTLAND CANCER CENTRE   (United Kingdom)

^j UNIVERSITY OF OXFORD   (United Kingdom)

^k Pharmaceutical Research and Early Development   (United States)

^l Forma Therapeutics   (United States)

^m ROCHE DIAGNOSTICS GMBH   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN P53; [2 (4 TERT BUTYL 2 ETHOXYPHENYL) 4,5 BIS(4 CHLOROPHENYL) 4,5 DIHYDRO 4,5 DIMETHYL 1H IMIDAZOL 1 YL][4 [3 (METHYLSULFONYL)PROPYL] 1 PIPERAZINYL]METHANONE; ANTINEOPLASTIC AGENT; IMIDAZOLINE DERIVATIVE; MDM2 PROTEIN, HUMAN; PROTEIN MDM2; TP53 PROTEIN, HUMAN;

ABDOMINAL PAIN; ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; ANEMIA; APOPTOSIS; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; ATRIOVENTRICULAR BLOCK; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; COHORT ANALYSIS; CONSTIPATION; CONTROLLED STUDY; DECREASED APPETITE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG WITHDRAWAL; EPISTAXIS; FATIGUE; FEVER; GENE MUTATION; HEADACHE; HEMATOLOGIC MALIGNANCY; HUMAN; HYPOCALCEMIA; HYPOKALEMIA; HYPOMAGNESEMIA; HYPOTENSION; MAJOR CLINICAL STUDY; MAXIMUM PLASMA CONCENTRATION; MULTIPLE CYCLE TREATMENT; MUTATIONAL ANALYSIS; NAUSEA; PHARMACOKINETICS; PHASE 1 CLINICAL TRIAL; PNEUMONIA; PRIORITY JOURNAL; SINGLE DRUG DOSE; THROMBOCYTOPENIA; TUMOR SUPPRESSOR GENE; VOMITING; WILD TYPE; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DNA MUTATIONAL ANALYSIS; DRUG ADMINISTRATION; GENE EXPRESSION; GENETICS; LEUKEMIA, LYMPHOID; MAXIMUM TOLERATED DOSE; METABOLISM;

ANTINEOPLASTIC AGENTS; APOPTOSIS; DNA MUTATIONAL ANALYSIS; DRUG ADMINISTRATION SCHEDULE; GENE EXPRESSION; HUMANS; IMIDAZOLINES; LEUKEMIA, LYMPHOID; MAXIMUM TOLERATED DOSE; PROTO-ONCOGENE PROTEINS C-MDM2; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84962677007     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-15-0481     Document Type: Article

References (35)

1. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408:307-10.
2. Xu-Monette ZY,Medeiros LJ, Li Y, Orlowski RZ, Andreeff M, Bueso-Ramos CE, et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood 2012;119:3668-83.
3. Marine JC, Lozano G. Mdm2-mediated ubiquitylation: P53 and beyond. Cell Death Differ 2010;17:93-102.
4. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992;69:1237-45.
5. Chene P. Inhibiting the p53-MDM2 interaction: An important target for cancer therapy. Nat Rev Cancer 2003;3:102-9.
6. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancermodels. Cancer Res 2013;73:2587-97.
7. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303:844-8.
8. Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, JiangN, et al. Discovery of RG7112: A small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 2013;4:466-9.
9. Fry DC, Wartchow C, Graves B, Janson C, Lukacs C, Kammlott U, et al. Deconstruction of a nutlin: Dissecting the binding determinants of a potent protein-protein interaction inhibitor. ACS Med Chem Lett 2013;4:660-5.
10. Bueso-Ramos CE, Yang Y, deLeon E, McCown P, Stass SA, Albitar M. The human MDM-2 oncogene is overexpressed in leukemias. Blood 1993; 82:2617-23.
11. Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: Implications for leukemia therapy. Blood 2005;106:3150-9.
12. Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 2006;108:993-1000.
13. Patnaik A, Tocher A, BeeramM, Nemunaitis J, Weiss G, Nichols G. Clinical pharmacology of RG7112, an MDM2 antagonist, in patients with advanced solid tumors [abstract]. In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. Abstract nr LB-201.
14. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81.
15. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F,DighieroG, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-56.
16. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in AcuteMyeloid Leukemia. J Clin Oncol 2003;21:4642-9.
17. Dicker F, Herholz H, Schnittger S, Nakao A, Patten N, Wu L, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia 2009;23:117-24.
18. Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: A NOVEL BIOMARKer for p53 pathway activation. Mol Cancer Ther 2003;2:1023-9.
19. Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition ofMDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 2006;5:2778-86.
20. Zhong H, Chen G, Jukofsky L, Geho D, Han SW, Birzele F, et al. MDM2 antagonist clinical response associationwith a gene expression signature in acute myeloid leukaemia. Br J Haematol 2015;171:432-5.
21. Drakos E, Thomaides A, Medeiros LJ, Li J, Leventaki V, Konopleva M, et al. Inhibition of p53-murine double minute 2 interaction by nutlin-3A stabilizes p53 and induces cell cycle arrest and apoptosis in Hodgkin lymphoma. Clin Cancer Res 2007;13:3380-7.
22. Kobayashi T, Consoli U, Andreeff M, Shiku H, Deisseroth AB, Zhang W. Activation of p21WAF1/Cip1 expression by a temperature-sensitive mutant of human p53 does not lead to apoptosis. Oncogene 1995;11: 2311-6.
23. Yee K, Martinelli G, Assouline S, Kasner M, Vey N, Kelly KB. Phase 1b study of the MDM2 antagonist RG7112 in combination with 2 doses/schedules of cytobarine. Blood 2013;122:498.
24. Carter BZ, Mak DH, Schober WD, Koller E, Pinilla C, Vassilev LT, et al. Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML. Blood 2010;115: 306-14.
25. Drakos E, Atsaves V, Li J, Leventaki V, Andreeff M, Medeiros LJ, et al. Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. Leukemia 2009;23:784-90.
26. Kojima K, Konopleva M, Samudio IJ, Ruvolo V, Andreeff M. Mitogenactivated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acutemyelogenous leukemia cells. Cancer Res 2007;67: 3210-9.
27. Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, et al. Selective FLT3 inhibitor FI-700 neutralizesMcl-1 and enhances p53-mediated apoptosis inAMLcells with activating mutations of FLT3 through Mcl-1/Noxa axis. Leukemia 2010;24:33-43.
28. Kojima K, Konopleva M, Tsao T, Nakakuma H, Andreeff M. Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia. Blood 2008;112:2886-95.
29. Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE, et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 2013;121:4166-74.
30. Kojima K, McQueen T, Chen Y, Jacamo R, KonoplevaM, Shinojima N, et al. p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1alpha-mediated down-regulation of CXCL12. Blood 2011;118:4431-9.
31. Kojima K, Shimanuki M, Shikami M, Andreeff M, Nakakuma H. Cyclindependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML. Cancer Sci 2009;100:1128-36.
32. Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 2008;22:1728-36.
33. Thompson T, Andreeff M, Studzinski GP, Vassilev LT. 1,25-dihydroxyvitamin D3 enhances the apoptotic activity ofMDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. Mol Cancer Ther 2010;9:1158-68.
34. Yoshimura M, Ishizawa J, Ruvolo V, Dilip A, Quintas-Cardama A, McDonnell TJ, et al. Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. Cancer Sci 2014;105:795-801.
35. Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 2013;56:5979-83.