title: Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia.
abstract: BACKGROUND
  This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy.
  
  
  METHODS
  Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR.
  
  
  RESULTS
  Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m(2)) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m(2) DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive.
  
  
  CONCLUSIONS
  Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m(2). This regimen is being further evaluated in phase III trials.
authors.affiliation: Department of Hematology, Cancer Center, University Hospital Rotterdam Dijkzigt Room L407, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. sonneveld@haed.azr.nl
authors.forename: P
authors.initials: P
authors.lastname: Sonneveld
authors.forename: A
authors.initials: A
authors.lastname: Burnett
authors.forename: P
authors.initials: P
authors.lastname: Vossebeld
authors.forename: M
authors.initials: M
authors.lastname: Ben-Am
authors.forename: G
authors.initials: G
authors.lastname: Rosenkranz
authors.forename: C
authors.initials: C
authors.lastname: Pfister
authors.forename: G
authors.initials: G
authors.lastname: Verhoef
authors.forename: A
authors.initials: A
authors.lastname: Dekker
authors.forename: G
authors.initials: G
authors.lastname: Ossenkoppele
authors.forename: C
authors.initials: C
authors.lastname: Ferrant
authors.forename: L
authors.initials: L
authors.lastname: Yin
authors.forename: A
authors.initials: A
authors.lastname: Gratwohl
authors.forename: T
authors.initials: T
authors.lastname: Kovacsovics
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.forename: R
authors.initials: R
authors.lastname: Capdeville
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D003524:Cyclosporins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004487:Edema / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D012074:Remission Induction; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D009363:Neoplasm Proteins; D003561:Cytarabine; C070272:valspodar; D003630:Daunorubicin