Phase i trial of the human double minute 2 inhibitor MK-8242 in patients with advanced solid tumors

Journal of Clinical Oncology

Volumn 35, Issue 12, 2017, Pages 1304-1311

  Wagner, Andrew J ^a   Banerji, Udai ^b   Mahipal, Amit ^c   Somaiah, Neeta ^d   Hirsch, Heather ^e   Fancourt, Craig ^e   Johnson Levonas, Amy O ^e   Lam, Raymond ^e   Meister, Amy K ^e   Russo, Giuseppe ^e   Knox, Clayton D ^e   Rose, Shelonitda ^e   Hong, David S ^d  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^c H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

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

^e MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; DEXAMETHASONE; MESSENGER RNA; MK 8242; PLECKSTRIN; PLECKSTRIN HOMOLOGY DOMAIN FAMILY A MEMBER 3; PROTEIN P53; UNCLASSIFIED DRUG; CYTARABINE; MDM2 PROTEIN, HUMAN; PROTEIN MDM2; TP53 PROTEIN, HUMAN;

ACCUMULATION INDEX; ADULT; ADVANCED CANCER; ANEMIA; ANOREXIA; AREA UNDER THE CURVE; CANCER CHEMOTHERAPY; CANCER PATIENT; CANCER SURVIVAL; CLINICAL ARTICLE; CONFERENCE PAPER; DECREASED APPETITE; DIARRHEA; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG FATALITY; DRUG HALF LIFE; DRUG TOLERANCE; FATIGUE; FEMALE; GENE EXPRESSION; HUMAN; HYPERBILIRUBINEMIA; HYPOPHOSPHATEMIA; LEUKOPENIA; LIPOSARCOMA; MALE; MAXIMUM PLASMA CONCENTRATION; MULTICENTER STUDY; NAUSEA; NEUTROPENIA; OPEN STUDY; PANCYTOPENIA; PATIENT SAFETY; PHASE 1 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN BLOOD LEVEL; SOLID TUMOR; THROMBOCYTOPENIA; TREATMENT RESPONSE; VOMITING; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DOSE RESPONSE; GENETICS; METABOLISM; MIDDLE AGED; NEOPLASMS;

CYTARABINE; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; MALE; MIDDLE AGED; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-MDM2; TUMOR SUPPRESSOR PROTEIN P53;

EID: 85017610538     PISSN: 0732183X     EISSN: 15277755     Source Type: Journal    
DOI: 10.1200/JCO.2016.70.7117     Document Type: Conference Paper

References (18)

1. Duffy MJ, Synnott NC, McGowan PM, et al: p53 as a target for the treatment of cancer. Cancer Treat Rev 40:1153-1160, 2014
2. Rayburn E, Zhang R, He J, et al: MDM2 and human malignancies: Expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 5:27-41, 2005
3. Zhang R, Wang H: MDM2 oncogene as a novel target for human cancer therapy. Curr Pharm Des 6:393-416, 2000
4. Saiki AY, Caenepeel S, Yu D, et al: MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways. Oncotarget 5:2030-2043, 2014
5. Ray-Coquard I, Blay JY, Italiano A, et al: Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, welldifferentiated or dedifferentiated liposarcoma: An exploratory proof-of-mechanism study. Lancet Oncol 13:1133-1140, 2012
6. Ravandi F, Gojo I, Patnaik MM, et al: A phase I trial of the human double minute 2 inhibitor (MK- 8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res 48:92-100, 2016
7. Simon R, Freidlin B, Rubinstein L, et al: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138-1147, 1997
8. Ji Y, Li Y, Nebiyou Bekele B: Dose-finding in phase I clinical trials based on toxicity probability intervals. Clin Trials 4:235-244, 2007
9. Dicker F, Herholz H, Schnittger S, 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 23:117-124, 2009
10. Chiaretti S, Tavolaro S, Marinelli M, et al: Evaluation of TP53 mutations with the AmpliChip p53 research test in chronic lymphocytic leukemia: Correlation with clinical outcome and gene expression profiling. Genes Chromosomes Cancer 50:263-274, 2011
11. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009
12. Kibukawa M, Zhang S, Marton MJ: Demonstration of p21 (CDKN1A) and PHLDA3 assay as pharmacodynamic biomarker for MK-8242, a small molecule inhibitor of the Hdm2-p53 interaction. J Molecular Diagnostics 17:815, 2015 (Abstract ST11)
13. Kubbutat MH, Jones SN, Vousden KH: Regulation of p53 stability by Mdm2. Nature 387: 299-303, 1997
14. Bond GL, Hu W, Bond EE, et al: A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119: 591-602, 2004
15. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol 34:786-793, 2016
16. Schöffski P, Chawla S, Maki RG, et al: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, multicentre, phase 3 trial. Lancet 387:1629-1637, 2016
17. DicksonMA, TapWD, Keohan ML, et al: Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31:2024-2028, 2013
18. Dickson MA, Schwartz GK, Keohan ML, et al: Progression-free survival among patients with welldifferentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: A phase 2 clinical trial. JAMA Oncol 2:937-940, 2016