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Phase 2 study of dose-intense temozolomide in recurrent glioblastoma


Posted on: 07/03/2013

for full text.
 
Oxford JournalsLife Sciences & Medicine Neuro-Oncology Volume 15, Issue 7Pp. 930-935.
 
Phase 2 study of dose-intense temozolomide in recurrent glioblastoma
 
Andrew D. Norden, Glenn J. Lesser, Jan Drappatz, Keith L. Ligon, Samantha N. Hammond, Eudocia Q. Lee, David R. Reardon, Camilo E. Fadul, Scott R. Plotkin, Tracy T. Batchelor, Jay-Jiguang Zhu, Rameen Beroukhim, Alona Muzikansky, Lisa Doherty, Debra Lafrankie, Katrina Smith, Vida Tafoya, Rosina Lis, Edward C. Stack, Myrna R. Rosenfeld and Patrick Y. Wen
+ Author Affiliations
 
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (A.D.N., S.N.H., E.Q.L., L.D., D.L., K.S., V.T., P.Y.W.); Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts (A.D.N., E.Q.L., P.Y.W.); Section of Hematology and Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina (G.J.L.); Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (J.D.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L., R.B.); Neuro-oncology Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (C.E.F.); Massachusetts General Hospital Cancer Center, Pappas Center for Neuro-Oncology, Boston, Massachusetts (S.R.P., T.T.B.); The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Mischer Neuroscience Institute, Memorial Hermann Hospital, Houston, Texas (J-J.Z.); Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts (A.M.), Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (R.L., E.C.S., K.L.L.), Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (R.L., E.C.S., K.L.L.); Division of Neuro-Oncology, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania (M.R.R.)
Corresponding Author: Patrick Y. Wen, MD, Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Ave., Boston, MA 02215 (pwen@partners.org).
Received December 17, 2012.
Accepted February 20, 2013.
Abstract
 
Background Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O6-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.
 
Methods This was a multicenter, phase 2, single-arm study of temozolomide (75–100 mg/m2/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).
 
Results Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25–79 years) and a median Karnofsky performance score of 90 (range, 60–100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).
 
Conclusions Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.

 


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