title: Combination phase I/II study of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or refractory non-Hodgkin's lymphoma. CPT-11/Lymphoma Study Group.
abstract: Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.
authors.affiliation: Department of Medical Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: K
authors.initials: K
authors.lastname: Tobinai
authors.forename: T
authors.initials: T
authors.lastname: Hotta
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Ohnishi
authors.forename: R
authors.initials: R
authors.lastname: Ohno
authors.forename: M
authors.initials: M
authors.lastname: Ogura
authors.forename: Y
authors.initials: Y
authors.lastname: Ariyoshi
authors.forename: K
authors.initials: K
authors.lastname: Takeyama
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohashi
authors.forename: S
authors.initials: S
authors.lastname: Shirakawa
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin