title: Phase I trial of intoplicine (RP 60475) administered as a 72 h infusion every 3 weeks in patients with solid tumors.
abstract: Intoplicine (RP 60475) was selected for a phase I evaluation because it inhibits topoisomerase I and II, and has exhibited antitumor activity against a variety of preclinical solid tumor models. Intoplicine is a 7H-benzo[e]pyrido[4,3-b]indole that inhibits DNA nicking and closing reactions by stabilizing the cleavable complex, a transient intermediate in the religation reaction involving topoisomerase I and II and DNA. Twenty-eight patients with refractory advanced malignancies who met standard phase I eligibility criteria were enrolled in a dose-escalation study of intoplicine, ranging from 7 to 420 mg/m2/day administered as a continuous 72 h i.v. infusion. Fifty-three courses were administered and evaluated. Myelosuppression (four patients, grade 3; two patients, grade 4) and hepatic toxicity (one patient, grade 3) were dose limiting at 336 mg/m2/day. No objective antitumor responses were observed. The pharmacokinetic parameters of intoplicine were investigated in 11 patients at dose levels of 112 (n=1), 224 (n=3), 336 (n=6) and 420 (n=1) mg/m2/day. Both the area under the plasma concentration versus time curves and the maximum plasma concentrations increased linearly within the dose range studied. Intoplicine content measured in whole blood exceeded that found in plasma by 3- to 7-fold, indicating that red blood cells may serve as a drug reservoir. Preclinical cytotoxic concentrations were not achieved at the dose levels studied.
authors.affiliation: Division of Medicine, The University of Texas MD Anderson Cancer Center, Houston 77030, USA. rnewman@mdanderson.org
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: B M
authors.initials: BM
authors.lastname: Newman
authors.forename: R
authors.initials: R
authors.lastname: Bruno
authors.forename: M
authors.initials: M
authors.lastname: Bayssas
authors.forename: M
authors.initials: M
authors.lastname: Klink-Alaki
authors.forename: R
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; C081834:intoplicine