title: A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.
  
  
  METHODS
  Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized.
  
  
  RESULTS
  Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days.
  
  
  CONCLUSIONS
  Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bldg 10/Room 5A01, 9000 Rockville Pike, Bethesda, MD, 20892, USA, figgw@helix.nih.gov.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Manish
authors.initials: M
authors.lastname: Monga
authors.forename: Donna
authors.initials: D
authors.lastname: Headlee
authors.forename: Avni
authors.initials: A
authors.lastname: Shah
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Chau
authors.forename: Cody
authors.initials: C
authors.lastname: Peer
authors.forename: Richard
authors.initials: R
authors.lastname: Messman
authors.forename: Yusri A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Melillo
authors.forename: Qin C
authors.initials: QC
authors.lastname: Ryan
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalnitskiy
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Susan G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000855:Anorexia / Q000139:chemically induced; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010767:Phosphorylcholine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010767:Phosphorylcholine; C105905:perifosine