title: Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome.
abstract: BACKGROUND
  The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation.
  
  
  METHODS
  The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1=40 mg/m(2); DL2=65 mg/m(2); DL3=90 mg/m(2)).
  
  
  RESULTS
  Thirteen patients were treated (DL1, n=6; DL2, n=4; DL3, n=3) according to a traditional "3+3" design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3-4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1-2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m(2) with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients' mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study.
  
  
  CONCLUSIONS
  UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.
authors: University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA, igojo1@jhmi.edu.
authors: Ivana
authors: I
authors: Gojo
authors: Alexander
authors: A
authors: Perl
authors: Selina
authors: S
authors: Luger
authors: Maria R
authors: MR
authors: Baer
authors: Kelly J
authors: KJ
authors: Norsworthy
authors: Kenneth S
authors: KS
authors: Bauer
authors: Michael
authors: M
authors: Tidwell
authors: Stephanie
authors: S
authors: Fleckinger
authors: Martin
authors: M
authors: Carroll
authors: Edward A
authors: EA
authors: Sausville
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; C054852:7-hydroxystaurosporine; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine