title: A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML).
abstract: Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML.
  
  
  
  MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID).
  
  
  
  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 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7μM·h,Cmax 1.5μM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L.
  
  
  
  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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: fravandi@mdanderson.org.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Johns Hopkins University, Baltimore, MD, United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.affiliation: Mayo Clinic, Rochester, MN, United States.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Patnaik
authors.affiliation: Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Fancourt
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lam
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Jones
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Clayton D
authors.initials: CD
authors.lastname: Knox
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Shelonitda
authors.initials: S
authors.lastname: Rose
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Payal Shah
authors.initials: PS
authors.lastname: Patel
authors.affiliation: MAYO Clinic Arizona, Scottsdale, AZ, United States.
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003561:Cytarabine / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D003561:Cytarabine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Acute myelogenous leukemia; Human double minute 2 inhibitor; MK-8242; Phase I; p53