A Phase I Trial of Tipifarnib With Radiation Therapy, With and Without Temozolomide, for Patients With Newly Diagnosed Glioblastoma

Journal Article · Thu Dec 01 00:00:00 EST 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2010.07.1997· OSTI ID:22054500

Wen, Patrick Y ^[1]; Lamborn, Kathleen R ^[2]; Drappatz, Jan ^[1]; Robins, H Ian ^[3]; Fink, Karen ^[4]; Malkin, Mark G ^[5]; Lieberman, Frank S ^[6]; DeAngelis, Lisa M ^[5]; Torres-Trejo, Alejandro ^[6]; Chang, Susan M ^[2]; Abrey, Lauren ^[5]; Fine, Howard A ^[7]; Demopoulos, Alexis; Lassman, Andrew B ^[5]; Kesari, Santosh ^[1]; Mehta, Minesh P ^[3]; Prados, Michael D ^[2]; Cloughesy, Timothy F ^[8]

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1. Dana -Farber/Brigham and Women's Cancer Center, Boston, MA (United States)
2. University of California, San Francisco, CA (United States)
3. University of Wisconsin, Madison, WI (United States)
4. University of Texas, Southwestern, Dallas, TX (United States)
5. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
6. University of Pittsburgh, Pittsburgh, PA (United States)
7. Neuro-Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD (United States)
8. University of California, Los Angeles, CA (United States)

Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Conclusion: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

• OSTI ID: 22054500
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 81, Issue 5; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
BIOPSY
DRUGS
ENZYMES
FATIGUE
GLIOMAS
HEMORRHAGE
PATIENTS
RADIATION DOSES
RADIOTHERAPY
SURGERY
TOXICITY