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Title: Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

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,more » 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.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [2];  [9]
  1. Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States)
  2. Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona (United States)
  3. Arizona Oncology Services Foundation, Scottsdale, Arizona (United States)
  4. University of Florida College of Medicine, Gainesville, Florida (United States)
  5. St. Joseph Mercy Hospital, Ann Arbor, Michigan (United States)
  6. University of Wisconsin Hospital, Madison, Wisconsin (United States)
  7. Medical College of Wisconsin, Milwaukee, Wisconsin (United States)
  8. University of Washington Medical Center, Seattle, Washington (United States)
  9. Emory University, Atlanta, Georgia (United States)
Publication Date:
OSTI Identifier:
22458669
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 91; Journal Issue: 5; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; COMPARATIVE EVALUATIONS; CONTROL; DEATH; DIAGNOSIS; GADOLINIUM; GLIOMAS; PATIENTS; RADIATION DOSES; RADIOTHERAPY; SURVIVAL TIME; TOXICITY

Citation Formats

Brachman, David G., E-mail: david.brachman@dignityhealth.org, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, Pugh, Stephanie L., Ashby, Lynn S., Thomas, Theresa A., Dunbar, Erin M., Narayan, Samir, Robins, H. Ian, Bovi, Joseph A., Rockhill, Jason K., Won, Minhee, and Curran, Walter P. Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513. United States: N. p., 2015. Web. doi:10.1016/J.IJROBP.2014.12.050.
Brachman, David G., E-mail: david.brachman@dignityhealth.org, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, Pugh, Stephanie L., Ashby, Lynn S., Thomas, Theresa A., Dunbar, Erin M., Narayan, Samir, Robins, H. Ian, Bovi, Joseph A., Rockhill, Jason K., Won, Minhee, & Curran, Walter P. Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513. United States. https://doi.org/10.1016/J.IJROBP.2014.12.050
Brachman, David G., E-mail: david.brachman@dignityhealth.org, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, Pugh, Stephanie L., Ashby, Lynn S., Thomas, Theresa A., Dunbar, Erin M., Narayan, Samir, Robins, H. Ian, Bovi, Joseph A., Rockhill, Jason K., Won, Minhee, and Curran, Walter P. 2015. "Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513". United States. https://doi.org/10.1016/J.IJROBP.2014.12.050.
@article{osti_22458669,
title = {Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513},
author = {Brachman, David G., E-mail: david.brachman@dignityhealth.org and Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona and Pugh, Stephanie L. and Ashby, Lynn S. and Thomas, Theresa A. and Dunbar, Erin M. and Narayan, Samir and Robins, H. Ian and Bovi, Joseph A. and Rockhill, Jason K. and Won, Minhee and Curran, Walter P.},
abstractNote = {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.},
doi = {10.1016/J.IJROBP.2014.12.050},
url = {https://www.osti.gov/biblio/22458669}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 5,
volume = 91,
place = {United States},
year = {Wed Apr 01 00:00:00 EDT 2015},
month = {Wed Apr 01 00:00:00 EDT 2015}
}