Neuro-Oncology
A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study1 Michael D. Prados,2 Kathleen Lamborn, W.K.A. Yung, Kurt Jaeckle, H. Ian Robins, Minesh Mehta, Howard A. Fine, Patrick Y. Wen, Timothy Cloughesy, Susan Chang, M. Kelly Nicholas,3 David Schiff, Harry Greenberg, Larry Junck, Karen Fink,3 Ken Hess, and John Kuhn University of California, San Francisco (M.D.P., K.L., S.C., M.K.N.), San Francisco, CA 94143; University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 (W.K.A.Y., K.J., K.H.); University of Wisconsin Medical Center, Madison, WI 53792 (H.I.R., M.M.); National Institutes of Health, Bethesda, MD 20892 (H.F.); Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA 02115 (P.Y.W.); University of California, Los Angeles, Los Angeles, CA 90095 (T.C.); University of Virginia Health Science Center, Charlottesville, VA 22908 (D.S.); University of Michigan Medical Center, Ann Arbor, MI 48109 (H.G., L.J.); University of Texas Southwestern Medical Center, Dallas, TX 75390 (K.F.); and University of Texas Health Sciences Center, San Antonio, TX 78229 (J.K.); USA
The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with
Abbreviations used are as follows: AG, anaplastic glioma; AUC, area under the concentration–time curve; CI, confidence interval; CPT-11, irinotecan; EIAED, enzyme-inducing antiepileptic drug; GBM, glioblastoma multiforme; GCRC; General Clinical Research Center; MTD, maximum tolerated dose; NABTC, North American Brain Tumor Consortium; NABTT, New Approaches to Brain Tumor Treatment consortium; PFS-6, six-month progression-free survival; PR, partial response.
progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m2 i.v. every three weeks in patients not on EIAED and 750 mg/m2 in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42
Copyright © 2006 by the Society for Neuro-Oncology
Received September 26, 2005; accepted December 20, 2005. 1
This study was supported by NIH grant CA 62399 and by the GCRC and NABTC grants acknowledged at the end of this article. 2
Address correspondence to Michael Prados, University of California, San Francisco, 400 Parnassus Avenue, Room A808, San Francisco, California 94143-0372 (
[email protected]).
3
Karen Fink is currently with Baylor University Medical Center in Dallas. M. Kelly Nicholas is currently with the University of Chicago Brain Tumor Center. 4
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years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07– 0.31) for the GBM patients and 23% (95% CI, 0.07–0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population. Neuro-Oncology 8, 189–193, 2006 (Posted to Neuro-Oncology [serial online], Doc. D05-00009, March 13, 2006. URL www.dukeupress.edu/neuro-oncology; DOI: 10.1215/15228517-2005-010) Keywords: clinical trial, irinotecan, phase 2, recurrent malignant glioma
T
he treatment of recurrent malignant gliomas using available chemotherapy drugs is ineffective for the prolongation of life in the majority of patients. The median time to tumor progression after treatment for patients with recurrent glioblastoma multiforme (GBM)4 is only 8 to 12 weeks, and fewer than 20% of patients are progression free by six months (Hess et al., 1999). Patients with grade 3 anaplastic gliomas (AG) fare better, but fewer than half are progression free at six months. Irinotecan (CPT-11), a drug that is active against colon carcinoma, has been used to treat recurrent glioma. Preclinical activity of CPT-11 has been promising, with in vitro activity noted against a panel of xenografts derived from ependymoma, childhood and adult high-grade astrocytoma, and medulloblastoma (Hare et al., 1997). A phase 2 study of CPT-11 for malignant glioma was conducted at Duke University that used doses and schedules recommended for the treatment of colon cancer (Friedman et al., 1999). The results suggested clinical efficacy with less toxicity, particularly diarrhea, than has been seen in other cancer patient populations. This lack of toxicity in many cases may have been due to treatment of the glioma patients with enzymeinducing antiepileptic drug (EIAED) therapy, which could alter the exposure to CPT-11 in this population. Preclinical and clinical studies have demonstrated that EIAEDs can alter the metabolism and elimination of CPT-11 and its metabolites (Haaz et al. 1998). Pretreatment of rats with the antiepileptic drug phenobarbital, an inducer of UGT-1A1 and CYP3A4, has been shown to enhance the formation of SN-38G and decrease the area under the concentration–time curve (AUC) for both CPT-11 and SN-38. However, the non-enzyme-inducing antiepileptic drug valproic acid increased the AUC of SN-38, presumably by inhibiting the glucuronidation of SN-38 (Gupta et al., 1997). These results have been confirmed in clinical trials of CPT-11 in patients with glioma (Reid et al., 2001). Based on the aforementioned background, the North American Brain Tumor Consortium (NABTC) completed a phase 1 study of CPT-11 in patients on EIAED to determine the optimal phase 2 dose when given every three weeks, and to compare the pharmacokinetics with those in patients not on EIAED who are treated at the recommended phase 2 dose for other cancers (Prados et al., 2004). The recommended phase 2 dose was 750 mg/m 2 given every three weeks to patients on EIAED. A phase 2 study was then conducted based on the results
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of the phase 1 trial. Patients not on EIAED were treated at a dose of 350 mg/m 2 . This report details the results of the phase 2 study.
Patients and Methods Study Population and Patient Eligibility Patients 18 years or older with a histologically confirmed diagnosis of a progressive or recurrent malignant glioma were eligible to participate, provided they had measurable disease, a KPS of >60, and acceptable hematologic, liver, and renal function. The latter required an absolute neutrophil count of >1500/mm3 and platelet count of >100,000/mm3, serum creatinine level ,1.5 mg/dl, serum bilirubin level ,1.5 mg/dl, and aspartate aminotransferase level less than three times the institutional upper normal limits. Patients in this study had undergone no more than one prior chemotherapy regimen, including either one prior adjuvant therapy or one prior regimen for recurrent tumor. Patients not on EIAED (group A) received a dose of 350 mg/m 2 , and patients on EIAED (group B) were treated at a dose of 750 mg/m2. In both groups, the interval from prior irradiation or chemotherapy had to be at least four weeks, and six weeks if prior nitrosourea therapy had been used. All patients had a retrospective central neuropathology review. Patients previously treated with CPT-11, topotecan, or other topoisomerase 1 inhibitors were excluded. All patients were provided with and had to sign a written informed consent approved by the local Institutional Review Board at each institution before treatment, informing them of the investigational nature of this study. Treatment Patients who met eligibility requirements received an intravenous infusion of CPT-11 over a 90-min period every three weeks. Patients continued to receive this dose throughout treatment until tumor progression, unacceptable toxicity, or completion of 12 treatment cycles. A treatment cycle was considered one infusion and a three-week evaluation period. No dose escalation was allowed. Dose reduction was allowed if during the prior infusion there had been evidence of toxicity as defined by the NCI Common Toxicity Criteria version 2.0 scale. Patient Monitoring and Toxicity Assessment Complete physical and neurological examinations, including KPS, were performed every other cycle. Weekly complete blood counts with differential and platelets were obtained throughout treatment. Levels of creatinine, blood urea nitrogen, total bilirubin, aspartate aminotransferase, and serum electrolytes were measured before each cycle. Magnetic resonance imaging of the brain was done every other cycle to assess response. Patients with stable or responding disease received the same dose at the next cycle or a reduced dose if adverse events were observed in the current cycle. If a patient ex-
Prados et al.: Irinotecan in recurrent malignant glioma patients
perienced grade 3 or greater nonhematologic toxicity or grade 4 hematologic toxicity, the dose of the subsequent cycle was reduced by one level (50 mg/m 2). If the toxicity was thought to be directly related to CPT-11, subsequent doses were not reescalated, even if there was minimal or no toxicity at the reduced dose. A new course of treatment could begin if the absolute neutrophil count was >1500/mm 2 , the platelet count was >100,000/mm3, and any other treatment-related toxicities were
