A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML)

Farhad Ravandi, Ivana Gojo, Mrinal M. Patnaik, Mark D. Minden, Hagop Kantarjian, Amy O. Johnson-Levonas, Craig Fancourt, Raymond Lam, Mary Beth Jones, Clayton D. Knox, Shelonitda Rose, Payal Shah Patel, Raoul Tibes

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Objective Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML. Methods MK-8242 was dosed p.o. QD (30–250 mg) or BID (120–250 mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300 mg BID). Results 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250 mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210 mg BID or 300 mg BID (doses >300 mg not tested). Best responses were: 1/24 PR (11 weeks;120 mg QD, 7on/7off); 1/24 CRi (2 weeks;210 mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250 mg BID, 7on/7off). PK on Day7 at 210 mg BID revealed AUC0–12 h 8.7 μM·h, Cmax 1.5 μM (n = 5, Tmax, 2–6 h), T1/2 7.9 h, CLss/F 28.8 L/h, and Vss/F 317 L. Conclusions The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.

Original languageEnglish (US)
Pages (from-to)92-100
Number of pages9
JournalLeukemia Research
Volume48
DOIs
StatePublished - Sep 1 2016

Keywords

  • Acute myelogenous leukemia
  • Human double minute 2 inhibitor
  • MK-8242
  • p53
  • Phase I

ASJC Scopus subject areas

  • Medicine(all)
  • Hematology
  • Oncology
  • Cancer Research

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  • Cite this

    Ravandi, F., Gojo, I., Patnaik, M. M., Minden, M. D., Kantarjian, H., Johnson-Levonas, A. O., Fancourt, C., Lam, R., Jones, M. B., Knox, C. D., Rose, S., Patel, P. S., & Tibes, R. (2016). A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leukemia Research, 48, 92-100. https://doi.org/10.1016/j.leukres.2016.07.004