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 language | English (US) |
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Pages (from-to) | 92-100 |
Number of pages | 9 |
Journal | Leukemia Research |
Volume | 48 |
DOIs | |
State | Published - Sep 1 2016 |
Keywords
- Acute myelogenous leukemia
- Human double minute 2 inhibitor
- MK-8242
- Phase I
- p53
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research