title: A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours.
abstract: In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level (80 mg x m(-2) week(-1)), no dose-limiting toxicities occurred during the first cycle (n=3). Subsequently, three patients were enrolled at the second dose level (120 mg x m(-2) week(-1)). Two of three patients at the 80 mg x m(-2) week(-1) cohort developed haemorrhagic cystitis (grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg x m(-2) week(-1) cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg x m(-2) week(-1), grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg x m(-2) week(-1). Cumulative bladder toxicity was dose-limiting toxicity at 80 mg x m(-2) week(-1). Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours.
authors.affiliation: Department of Pulmonary Diseases, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Wachters
authors.forename: H J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: J G
authors.initials: JG
authors.lastname: Maring
authors.forename: J A
authors.initials: JA
authors.lastname: Gietema
authors.forename: M
authors.initials: M
authors.lastname: Porro
authors.forename: H
authors.initials: H
authors.lastname: Dumez
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: A T
authors.initials: AT
authors.lastname: van Oosterom
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003556:Cystitis / Q000139:chemically induced; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011145:Polyvinyls / Q000008:administration & dosage
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C023836:MAG (polymeric gel); D011145:Polyvinyls; D002166:Camptothecin