Phase I/II Trial of Temozolomide (TMZ), Motexafin Gadolinium (MGd), and 60 Gy Fractionated Radiation (RT) for Newly Diagnosed Supratentorial Glioblastoma Multiforme (GBM): Final Results of RTOG 0513

• Type of Material: Article
• Authors: David G. Brachman, Arizona Oncology Services Foundation; Stephanie L Pugh, RTOG Statistical Center; Lynn S. Ashby, St. Joseph’s Hospital and Medical Center; Theresa A. Thomas, Arizona Oncology Services Foundation; Erin M. Dunbar, University of Florida; Samir Narayan, St. Joseph Mercy Hospital; H. Ian Robins, University of Wisconsin; Joseph A. Bovi, Medical College of Wisconsin; Jason K. Rockhill, University of Washington; Minhee Won, RTOG Statistical Center; Walter Curran, Emory University
• Language: English
• Date: 2015-01-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ijrobp.2014.12.050
• Title of Journal or Parent Work: International Journal of Radiation Oncology - Biology - Physics
• ISSN: 0360-3016
• Volume: 91
• Issue: 5
• Start Page: 961
• End Page: 967
• Grant/Funding Information: This trial was conducted by the Radiation Therapy Oncology Group (RTOG), and was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI).
• Keywords: Metalloporphyrins; Disease-Free Survival; Dacarbazine; Brain Neoplasms; Dose Fractionation; Multivariate Analysis; Antineoplastic Agents, Alkylating; Maximum Tolerated Dose; Male; Humans; Female; Supratentorial Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Glioblastoma
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of.1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.