title: Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.
abstract: GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.
authors.affiliation: Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78229, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: J R
authors.initials: JR
authors.lastname: Eckardt
authors.forename: T G
authors.initials: TG
authors.lastname: Burke
authors.forename: D L
authors.initials: DL
authors.lastname: Warner
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: G
authors.initials: G
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Fields
authors.forename: A
authors.initials: A
authors.lastname: Thurman
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: M L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: L
authors.initials: L
authors.lastname: White
authors.forename: P
authors.initials: P
authors.lastname: Wissel
authors.forename: R
authors.initials: R
authors.lastname: Kunka
authors.forename: S
authors.initials: S
authors.lastname: DePee
authors.forename: D
authors.initials: D
authors.lastname: Littlefield
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C091719:lurtotecan; D002166:Camptothecin