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Title: Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies

Abstract

Purpose: To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies. Patients and Methods: This open-label, dose-escalation, Phase I clinical study evaluated the safety of three dose levels of intravenously administered bortezomib (0.7, 1.0, and 1.3 mg/m{sup 2}/dose) on Days 1, 4, 8, and 11 of a 21-day cycle, in addition to concurrent radiotherapy and temozolomide at a daily dose of 75 mg/m{sup 2} starting on Day 1. The primary endpoint was dose-limiting toxicity, defined as any Grade 4-5 toxicity or Grade 3 toxicity directly attributable to protocol treatment, requiring hospitalization and/or radiotherapy interruption. The secondary endpoints included feasibility, non-dose-limiting toxicity, and treatment response. Results: A total of 27 patients were enrolled, 23 of whom had high-grade glioma (10 recurrent and 13 newly diagnosed). No dose-limiting toxicities were noted in any dose group, including the highest (1.3 mg/m{sup 2}/dose). The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia. All 27 patients were evaluable for response. At a median follow-up of 15.0 months, 9 patients were still alive, with a median survival of 17.4 months for all patients and 15.0 months for patientsmore » with high-grade glioma. Conclusion: Bortezomib administered at its typical 'systemic' dose (1.3 mg/m{sup 2}) is well tolerated and safe combined with temozolomide and radiotherapy when used in the treatment of central nervous system malignancies. A Phase II study to characterize efficacy is warranted.« less

Authors:
; ; ;  [1];  [2];  [3];  [4];  [1]
  1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA (United States)
  2. Genzyme Inc., Cambridge, MA (United States)
  3. Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA (United States)
  4. Department of Neurosurgery, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA (United States)
Publication Date:
OSTI Identifier:
21276819
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 74; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2008.08.050; PII: S0360-3016(08)03512-8; Copyright (c) 2009 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; CENTRAL NERVOUS SYSTEM; ERYTHEMA; GLIOMAS; PATIENTS; RADIATION DOSES; RADIOTHERAPY; TOXICITY

Citation Formats

Kubicek, Gregory J, Werner-Wasik, Maria, Machtay, Mitchell, Mallon, Gayle, Myers, Thomas, Ramirez, Michael, Andrews, David, Curran, Walter J, and Dicker, Adam P. Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies. United States: N. p., 2009. Web. doi:10.1016/j.ijrobp.2008.08.050.
Kubicek, Gregory J, Werner-Wasik, Maria, Machtay, Mitchell, Mallon, Gayle, Myers, Thomas, Ramirez, Michael, Andrews, David, Curran, Walter J, & Dicker, Adam P. Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies. United States. https://doi.org/10.1016/j.ijrobp.2008.08.050
Kubicek, Gregory J, Werner-Wasik, Maria, Machtay, Mitchell, Mallon, Gayle, Myers, Thomas, Ramirez, Michael, Andrews, David, Curran, Walter J, and Dicker, Adam P. 2009. "Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies". United States. https://doi.org/10.1016/j.ijrobp.2008.08.050.
@article{osti_21276819,
title = {Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies},
author = {Kubicek, Gregory J and Werner-Wasik, Maria and Machtay, Mitchell and Mallon, Gayle and Myers, Thomas and Ramirez, Michael and Andrews, David and Curran, Walter J and Dicker, Adam P.},
abstractNote = {Purpose: To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies. Patients and Methods: This open-label, dose-escalation, Phase I clinical study evaluated the safety of three dose levels of intravenously administered bortezomib (0.7, 1.0, and 1.3 mg/m{sup 2}/dose) on Days 1, 4, 8, and 11 of a 21-day cycle, in addition to concurrent radiotherapy and temozolomide at a daily dose of 75 mg/m{sup 2} starting on Day 1. The primary endpoint was dose-limiting toxicity, defined as any Grade 4-5 toxicity or Grade 3 toxicity directly attributable to protocol treatment, requiring hospitalization and/or radiotherapy interruption. The secondary endpoints included feasibility, non-dose-limiting toxicity, and treatment response. Results: A total of 27 patients were enrolled, 23 of whom had high-grade glioma (10 recurrent and 13 newly diagnosed). No dose-limiting toxicities were noted in any dose group, including the highest (1.3 mg/m{sup 2}/dose). The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia. All 27 patients were evaluable for response. At a median follow-up of 15.0 months, 9 patients were still alive, with a median survival of 17.4 months for all patients and 15.0 months for patients with high-grade glioma. Conclusion: Bortezomib administered at its typical 'systemic' dose (1.3 mg/m{sup 2}) is well tolerated and safe combined with temozolomide and radiotherapy when used in the treatment of central nervous system malignancies. A Phase II study to characterize efficacy is warranted.},
doi = {10.1016/j.ijrobp.2008.08.050},
url = {https://www.osti.gov/biblio/21276819}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 2,
volume = 74,
place = {United States},
year = {Mon Jun 01 00:00:00 EDT 2009},
month = {Mon Jun 01 00:00:00 EDT 2009}
}