A phase i trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma Journal Article

Authors: Nghiemphu, P. L.; Wen, P. Y.; Lamborn, K. R.; Drappatz, J.; Robins, H. I.; Fink, K.; Malkin, M. G.; Lieberman, F. S.; Deangelis, L. M.; Torres-Trejo, A.; Chang, S. M.; Abrey, L.; Fine, H. A.; Demopoulos, A.; Lassman, A. B.; Kesari, S.; Mehta, M. P.; Prados, M. D.; Cloughesy, T. F.
Article Title: A phase i trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma
Abstract: 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. © 2011 Elsevier Inc.
Keywords: adult; controlled study; aged; middle aged; surgical technique; unclassified drug; major clinical study; overall survival; drug tolerability; fatigue; intensity modulated radiation therapy; cancer combination chemotherapy; drug efficacy; drug safety; drug withdrawal; treatment duration; antineoplastic agents; cancer patient; temozolomide; brain neoplasms; dacarbazine; progression free survival; drug eruption; multiple cycle treatment; anemia; radiation; blood toxicity; leukopenia; thrombocytopenia; antineoplastic combined chemotherapy protocols; radiotherapy; cohort analysis; tumor biopsy; dizziness; drug dose escalation; dyspnea; lymphocytopenia; lung embolism; maculopapular rash; oxcarbazepine; phenobarbital; thrombosis; glioblastoma; tipifarnib; muscle weakness; erythema; maximum tolerated dose; phase 1 clinical trial; embolism; diagnostic test; anticonvulsive agent; corticosteroid; toxicity; phase ii; brain hemorrhage; phenytoin; granulocytopenia; chemoradiotherapy; antihistaminic agent; carbamazepine; phase i; farnesyltransferase; dose limiting toxicity; antiepileptic drugs; anticonvulsant therapy; intracranial hemorrhages; primidone; farnesyltransferase inhibitor; newly diagnosed glioblastoma; heat radiation; rating; enzyme inducing antiepileptic drug; fosphenytoin sodium; pleuritic pain; quinolones
Journal Title: International Journal of Radiation Oncology, Biology, Physics
Volume: 81
Issue: 5
ISSN: 0360-3016
Publisher: Elsevier Inc.  
Date Published: 2011-12-01
Start Page: 1422
End Page: 1427
Language: English
DOI: 10.1016/j.ijrobp.2010.07.1997
PROVIDER: scopus
PMCID: PMC3020272
PUBMED: 20934264
Notes: --- - "Export Date: 3 January 2012" - "CODEN: IOBPD" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Andrew Lassman
    111 Lassman
  2. Mark Malkin
    38 Malkin
  3. Lauren E Abrey
    276 Abrey