title: Two studies evaluating irinotecan treatment for recurrent malignant glioma using an every-3-week regimen.
abstract: Two studies were performed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. In the first study, CPT-11 was administered once every 3 weeks as a 90-minute intravenous infusion at a dose of 300 mg/m(2). After 2 treatments, doses were increased to 350 mg/m(2) in those patients without Grade 3/4 toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response (PR), and 2 patients (14%) had stable disease (SD). Median survival was 24 weeks; median time to tumor progression (TTP) was 6 weeks. The primary hematologic toxicity was Grade 3/4 neutropenia, which was observed in 14% of patients. Infrequent Grade 3/4 nonhematologic toxicity was observed, possibly due to the concomitant use of anticonvulsants that might have altered pharmacokinetics. The second study evaluated the potential underdosing observed in patients who did or did not receive enzyme-inducing antiepileptic drugs (EIAED) by implementing an intrapatient dose escalation design. In this open-label study, treatment of patients with recurrent malignant glioma (rMG) was started at 300-400 mg/m(2) of CPT-11 every 3 weeks and, depending on individual safety and efficacy evaluation, escalated by steps of 100 mg/m(2) in subsequent courses. Thirty-five patients (median age, 43 years; gender, 11F and 24M; histology, 26 glioblastoma multiforme and 9 anaplastic glioma) have completed at least two cycles of chemotherapy and are evaluable for toxicity and response. Dose-limiting toxicity (DLT) was reached in 12 patients at doses ranging from 400-1700 mg/m(2). Preliminary efficacy data show that 3 patients exhibited PR and 15 patients exhibited SD. Median TTP was 2.7 months, and median survival was 8.5 months. Patients who did not receive anticonvulsants achieved higher peak concentrations, relative to dose, of the active metabolite SN-38 than did patients in the EIAED group. This study confirmed the activity of CPT-11 in malignant glioma and indicated that the maximum tolerated dose (MTD) for patients with rMG was considerably higher than expected but still possessed significant variability. A higher level of efficacy for CPT-11 may be observed if an MTD can efficiently be established for each patient.
authors.affiliation: Henry Singleton Brain Cancer Research Program, UCLA School of Medicine, Los Angeles, California 90095, USA. tcloughesy@mednet.ucla.edu
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Emese
authors.initials: E
authors.lastname: Filka
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
authors.forename: Gillian
authors.initials: G
authors.lastname: Nelson
authors.forename: Fairooz
authors.initials: F
authors.lastname: Kabbinavar
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Langdon L
authors.initials: LL
authors.lastname: Miller
authors.forename: Gary L
authors.initials: GL
authors.lastname: Elfring
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012449:Safety; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin