title: Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of cancer and leukemia group B study 9420.
abstract: OBJECTIVE
  The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein-mediated multidrug resistance.
  
  
  METHODS
  One hundred ten newly diagnosed patients > or = 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m(2)/d. The starting dose of daunorubicin was 30 mg/m(2)/d for 3 days. Etoposide was administered at a dose of 100 mg/m(2)/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m(2). PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide.
  
  
  RESULTS
  There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m(2)/d for 3 days with etoposide 60 mg/m(2) for 3 days in the ADEP group and daunorubicin 60 mg/m(2)/d for 3 days and etoposide 100 mg/m(2)/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP.
  
  
  CONCLUSIONS
  It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.
authors.affiliation: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lee
authors.forename: S L
authors.initials: SL
authors.lastname: George
authors.forename: M
authors.initials: M
authors.lastname: Caligiuri
authors.forename: T P
authors.initials: TP
authors.lastname: Szatrowski
authors.forename: B L
authors.initials: BL
authors.lastname: Powell
authors.forename: S
authors.initials: S
authors.lastname: Lemke
authors.forename: R K
authors.initials: RK
authors.lastname: Dodge
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Baer
authors.forename: C A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003524:Cyclosporins / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D003524:Cyclosporins; D003561:Cytarabine; D005047:Etoposide; C070272:valspodar; D003630:Daunorubicin