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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3651-3656 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.2323 Phase II Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Either Receiving or Not Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study
From the University of California, Los Angeles, Los Angeles; Neuro-Oncology Service, University of California, San Francisco, CA; Dana-Farber/Brigham and Women's Cancer Center, Boston, MA; University of Wisconsin Hospital, Madison, WI; Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston; Department of Neurology, University of Texas, Southwestern Medical Center, Dallas; University of Texas, Health Science Center, San Antonio, San Antonio TX; Department of Neurology, University of Michigan Hospital, Ann Arbor, MI; University of Virginia Health System, Charlottesville, VA; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Northwestern University Feinberg School of Medicine, Chicago, IL; and Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD Address reprint requests to Timothy F. Cloughesy, MD, UCLA Neuro-Oncology Program, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Reed Bldg, Room 1-230, Los Angeles, CA 90095; e-mail: tcloughe{at}ucla.edu
PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG). PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety. RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups. CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.
Treatment of malignant glioma remains a major therapeutic challenge. The heterogeneity of molecular pathways and control steps in glioma pathology make the neoplasia difficult to treat.1,2 Chemotherapeutic treatment of glioma remains limited and novel agents that target aberrant signaling pathways need to be evaluated. RAS genes control normal cell growth and differentiation; however, overexpression of the ras oncogene is found in a large proportion of human cancers.3 Amplification of epidermal growth factor receptor (EGFR), platelet-derived growth factor, and the angiogenic factor, vascular endothelial growth factor, can lead to the downstream ras activation: these ras-dependent factors are implicated in the pathogenesis of malignant astrocytomas.3-5 Tipifarnib (R115777, Zarnestra; Johnson & Johnson Pharmaceutical Research & Development LLC, Titusville, NJ) is a potent and selective nonpeptidomimetic farnesyltransferase inhibitor (FTI). In pharmacokinetic studies, tipifarnib has demonstrated oral bioavailability with dose-proportional pharmacokinetics.6,7 In phase I studies, the maximum-tolerated dose (MTD) was established at 300 mg bid administered for 21 days every 4 weeks with myelosuppression as the dose-limiting toxicity (DLT). Given that glioma patients face limited therapeutic options and FTIs present a new therapeutic modality with a unique mechanism of action that affects multiple tumor-promoting pathways, the investigation of the clinical effectiveness of tipifarnib in patients with recurrent glioma was believed to be warranted. Commonly, glioma patients are treated with enzyme-inducing antiepileptic drugs (EIAEDs). Patients receiving EIAEDs show decreased plasma levels of several chemotherapeutic drugs when administered at conventional doses.8-10 Induction of hepatic enzymes by EIAEDs can alter the metabolism of concurrently administered chemotherapeutic agents, which might lead to ineffective dosing.11-13 Notably, EIAEDs reduced the area under the plasma concentration-time curve (AUC) of irinotecan by 1.5-fold in malignant glioma patients compared with those not receiving EIAEDs.14 It was therefore considered important to investigate any potential interaction between EIAEDs and tipifarnib in glioma patients. A phase I study using tipifarnib in recurrent glioma patients taking EIAEDs showed that both MTD and DLT were different from previous studies in patients not receiving EIAEDs15: MTD was 600 mg bid for 21 days every 4 weeks, which is double that for patients not receiving EIAEDs, and the DLT was rash rather than myelosuppression. Pharmacokinetic evaluation showed that the AUC0 to 12 hours at MTD was approximately halved in those receiving EIAEDs compared with those not receiving EIAEDs. However, a limited pharmacodynamic evaluation showed the MTD dosing scheme in the patients receiving EIAEDs was adequate to inhibit farnesylation in peripheral blood mononuclear cells. These results present uncertainty about whether the dosing scheme would be dose equivalent at MTD for patients receiving EIAEDs and not receiving EIAEDs. We therefore performed a phase II study of tipifarnib in patients with recurrent malignant glioma to determine efficacy in anaplastic glioma (AG) and glioblastoma multiforme (GBM). Although not planned prospectively, we also evaluated differences between those with recurrent glioblastoma multiforme either receiving or not receiving EIAED at MTD.
Patient Population Eligible patients were  18 years and had histologically confirmed diagnosis of progressive or recurrent malignant glioma with measurable disease confirmed by magnetic resonance imaging or computed tomography scan. For histologic stratification, GBM was defined as those patients with a primary or secondary GBM including gliosarcoma; AG was defined as patients with primary or secondary diagnosis of anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed gliomas. The baseline scan had to be performed within 14 days of entry and with the patient receiving a corticosteroid dose that was stable for more than 5 days. Patients may have had up to two prior relapses. All patients must have experienced treatment failure after radiation therapy; prior surgical resection was not a requirement. Prior irradiation or chemotherapy had to have been discontinued 4 weeks ( 6 weeks if prior therapy was with nitrosourea) before trial entry and patients had to have recovered from the toxic effects of all prior therapies. Patients had to have a Karnofsky performance score (KPS) 60, and acceptable hematology and biochemistry (WBC 3,000/µL, absolute neutrophil count 2,000/µL, platelet count 120,000/µL, hemoglobin 10 g/dL, AST and bilirubin < 2x the upper limit of normal, creatinine < 1.5 mg/dL, and creatinine clearance 60 mL/min).
Dosing was stratified according to EIAED use: group A was not taking EIAEDs and group B was taking EIAEDs. Phase I results for patients receiving EIAEDs have been reported previously in a separate publication.15 Patients needed to be taking an EIAED for
Patients were excluded from the study if they had a concurrent medical illness that, in the judgment of the investigator, would make the patient inappropriate for study entry. Patients were also excluded if they had active infection, were HIV positive, or were taking proton pump inhibitors. Pregnant patients and lactating mothers were ineligible. The protocol and informed consent were approved by the local institutional review board at each participating institution and all patients reviewed, signed, and provided written informed consent before enrollment.
Dosing
Patient Evaluation Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria, version 2 (http://ctep.info.nih.gov/reporting/index.html).
Statistical Considerations The sample size for the AG subgroups was intended to provide preliminary information on outcome for patients with grade 3 tumors, and was intended primarily to be descriptive. Accrual was stopped when the planned number of patients was enrolled based on institutional assessment of tumor histology. The final numbers differed somewhat from those planned because of changes in histology based on central pathology review. For the purpose of the primary planned evaluation of 6-month PFS for the two groups (A and B), all treated patients were included and the proportion known to have PFS more than 6 months was calculated separately for the GBM and AG subgroups. In addition, Kaplan-Meier curves were used to describe the results graphically. For these and other time-to-event analyses, patients not known to have progressed were censored at the time of the last known assessment before any nonprotocol therapy. For the unplanned comparisons between groups A and B, demographic comparisons used the Cochran-Mantel-Hanzel test for ordered or unordered categories, as appropriate for the measure being assessed. The comparison of PFS between groups used the log-rank test. In addition, a Cox proportional hazards model was used including KPS, age, and number of prior chemotherapies, as well as grouping based on anticonvulsant use, to determine if the difference in outcome between the groups remained when adjustment was made for these variables.
Patient Characteristics A total of 89 patients were enrolled between June 2000 and January 2003 at nine US centers. All patients were assessable for both efficacy and safety. Patient characteristics are summarized in Table 2. There were 46 patients in group A (36 GBM and 10 AG) and 43 patients in group B (31 GBM and 12 AG). All patients had experienced treatment failure after surgery and radiation therapy.
PFS Among the 46 non-EIAED patients, progression times are defined for all but five patients. Two patients, one with AG and one with GBM, were censored at 9 weeks because alternative therapy was started without documented progression. One GBM patient was without progression at 36 weeks, but was lost to follow-up for progression at that time. This patient subsequently died. Two GBM patients were alive without progression at last contact 147 and 187 weeks after start of study. None of the AG patients achieved the targeted goal of PFS more than 6 months. The median PFS was 8 weeks (95% CI, 4 to 14 weeks). Median PFS for the non-EIAED GBM patients was 9 weeks (95% CI, 7 to 14 weeks). Six of 36 GBM patients (16.7%; 95% CI, 7% to 32%) were alive and progression free at 6 months. None of these results met the prespecified definition of success.
Among the 43 EIAED patients, all patients have experienced disease progression. Among the 12 AG patients, median time to progression was 8 weeks (95% CI, 7 to 12 weeks). Two patients (16.7%; 95% CI, 3% to 45%) had PFS more than 6 months. Median PFS for the 31 GBM EIAED patients was 6 weeks (95% CI, 4 to 8 weeks). Two patients (6.5%; 95% CI, 1% to 20%) had PFS more than 6 months. There was a high frequency of early treatment failure in this group. Ten of the 31 patients experienced treatment failure in As an exploratory analysis, a comparison was made between the efficacy outcomes of GBM patients in groups A and B. The difference in PFS was statistically significant (P = .01; Fig 1). Ages were similar for the two groups (median, 49 and 52 years for group A and B, respectively; P = .24) as was KPS (median, 80 for both groups; P = .26). However, the EIAED group tended to have more prior chemotherapies (P < .001); 45% of the EIAED patients had two or three prior chemotherapy regimens compared with only 3% for the non-EIAED group. Although the two groups differed in number of prior chemotherapies, this difference did not seem to be a primary source of the observed difference in outcome. The estimated hazard ratio for the group difference (group B/group A) in a univariate Cox proportional hazards model was 1.9 (95% CI, 1.2 to 3.2). When number of prior chemotherapies was included in the model, the estimated hazard ratio was slightly smaller (1.8; P = .05), but there was no indication that the number of prior chemotherapies was predictive of 6-month PFS (P = .61). In a multivariate model adding age and KPS as well as number of prior therapies, the results were qualitatively the same, although the estimate was reduced further to 1.7 (P = .08). Again, of all the variables included, the group effect (group B/group A) was the strongest (most statistically significant) predictor and is the variable selected if a backward stepwise selection process is used.
Objective Response The only objective responses were seen in patients with GBM. Four GBM patients had a PR in group A and one patient had a PR in group B. The partial responses were not centrally reviewed. No patient achieved a CR.
Safety
In the total cohort of 89 patients with recurrent malignant glioma, 10 patients (11.2%) treated with tipifarnib showed 6-month PFS. In the main subgroup with GBM (grade 4 glioma), eight of 67 patients (11.9%) had 6-month PFS as compared with two of 22 patients (9.1%) in the exploratory subgroup with AG (grade 3 glioma). Among the eight GBM patients with PFS more than 6 months, six of 36 (16.7%) were not receiving EIAEDs, compared with two of 31 patients who were receiving EIAEDs. The difference in PFS was statistically significant. The majority of the difference between these subgroups was accounted for by the high frequency of early treatment failure in group B patients (ie, patients who were receiving EIAEDs). In addition, PRs were seen predominately in GBM group A patients. Tipifarnib was administered at the previously determined MTD doses of 300 and 600 mg bid on days 1 to 21 every 4 weeks in patients receiving and not receiving EIAEDs, respectively.15 Given that tipifarnib undergoes extensive hepatic metabolism,7,16,17 it had been anticipated that concomitant dosing with EIAEDs would substantially increase the hepatic clearance of tipifarnib. Our previous phase I study showed that even though the MTD of tipifarnib was doubled in patients receiving EIAEDs, the AUC0 to 12 hours at MTD was approximately halved in those receiving EIAEDs compared with those not receiving EIAEDs.15 At the MTD, tipifarnib was well tolerated in patients both receiving and not receiving EIAEDs. Hematologic adverse effects were more frequent and severe in group A (non-EIAED) as were grade 1/2 fatigue, nausea, and anorexia. Grade 1/2 alkaline phosphatase increase and constipation seemed to be more frequent in group B (EIAED). Rash/desquamation of any grade occurred at a similar frequency in groups A and B (15% v 16%, respectively) and grade 3 rash/desquamation was relatively rare in each group (one of 46 patients in group A and two of 43 patients in group B). These observations suggest an enhanced biologic effect in group A (no EIAED) compared with those in group B (EIAED). However, there are concerns regarding defining an enhanced biologic effect in group A from these results. These evaluations were not designed to take into consideration all important prognostic stratification factors that might provide for more definitive efficacy comparisons. For instance, group B patients were more heavily pretreated than were those in group A. In addition, one might question whether group B MTD was effectively defined since rash was an unexpected DLT in the phase I study. Moreover, failure to reach the predefined goal for success of 6 month PFS makes it difficult to consider the biologic effect as clinically significant. Nevertheless, these findings, in total, favor an enhancement in biologic effect at MTD for patients not receiving EIAED (group A). However, the therapeutic benefit from single-agent tipifarnib is modest. Given these data, two opportunities exist for the possible effective use of single-agent tipifarnib in recurrent malignant gliomas. Recently it was found that responsiveness to EGFR kinase inhibitors is increased in a subgroup of glioblastoma patients who coexpress EGFRvIII and phosphatase and tensin homologue deleted on chromosome.18 EGFR kinase inhibitors previously had been thought to have limited use as a single agent in recurrent glioblastoma, with 6-month PFS ranging from 0% to 17%.19-21 Similar tissue interrogations on tumor samples from patients treated with tipifarnib might be focused on farnesylated proteins22 as well as RAS-MAP kinase and PI3 kinase pathways23 to aid in identifying a subset of patients who are more likely to respond to this agent. Additional dosing strategies may allow for greater drug exposure, potentially leading to a greater clinical effect.24 In the absence of a defined effective use as a single agent, tipifarnib will likely need to be used in combination with conventional cytotoxic therapies or complementary targeted molecular agents to provide clinically significant benefit in patients with malignant gliomas. A number of glioblastoma trials are ongoing to evaluate the benefit of combining tipifarnib with other therapies in the newly diagnosed and recurrent setting. These trials currently are only evaluating patients not receiving EIAED. In conclusion, tipifarnib when dosed at MTD shows some evidence of enhanced biologic effect in patients with recurrent GBM (grade 4) who are not receiving EIAEDs, compared with those receiving EIAEDs. Future studies in glioblastoma with tipifarnib should be limited to those patients not receiving EIAEDs.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
The following North American Brain Tumor Consortium members enrolled patients onto this study and were involved in the collection and assembly of data: Dr Vinay Puduvalli and Dr Charles Conrad, M.D. Anderson Cancer Center; Dr Harry Greenberg, University of Michigan; and Dr Eric Burton and Dr M. Kelly Nicholas, University of California, San Francisco. Dr Ken Hess provided statistical involvement with the conception and design of the protocol and provided assistance during manuscript writing. We thank the study coordinators and data managers from each of the sites for their tireless effort.
Supported by grants to the following institutions: University of California, Los Angeles, Grants No. U01CA62399 and General Clinical Research Center M01-RR0865, and a grant from Art of the Brain; University of California, San Francisco, Grants No. U01CA62422 and GCRC M01-RR00079; The University of Texas M.D. Anderson Cancer Center, Grants No. CA62412 and CA16672; Dana-Farber Cancer Center, Grant No. U01CA62407-08; University of Texas, Southwestern Medical Center, Grants No. CA62455-08 and GCRC M01-RR00633; University of Pittsburgh, Grants No. U01CA62405 and GCRC M01-RR00056; University of Texas, San Antonio, Grant No. CA62426; University of Michigan, Grants No. U01CA62399 and GCRC M01-RR00042; Memorial Sloan-Kettering Cancer Center, Grant No. 5-U01CA62399-09; University of Wisconsin Hospital, Grants No. U01CA62421-08 and GCRC M01 RR03186. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Louis DN, Cavenee WK: Molecular biology of central nervous system neoplasms, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 2091-2100 2. Mischel PS, Cloughesy TF: Targeted molecular therapy of GBM. Brain Pathol 13:52-61, 2003[Medline] 3. Guha A: Ras activation in astrocytomas and neurofibromas. Can J Neurol Sci 25:267-281, 1998[Medline] 4. Feldkamp MM, Lala P, Lau N, et al: Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 45:1442-1453, 1999[CrossRef][Medline] 5. Feldkamp MM, Lau N, Rak J, et al: Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int J Cancer 81:118-124, 1999[CrossRef][Medline] 6. Hudes GR, Schol J, Baab J, et al: Phase I clinical and pharmacokinetic trial of the farnesyltransferase inhibitor R115777 in a 21-day dosing schedule. Proc Am Soc Clin Oncol 18:156a, 1999 (abstr 601) 7. Zujewski J, Horak ID, Bol CJ, et al: Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R11577 in advanced cancer. J Clin Oncol 18:927-941, 2000 8. Fetell MR, Grossman SA, Fisher JD, et al: Preirradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. J Clin Oncol 15:3121-3128, 1997[Abstract] 9. Grossman SA, Hochberg F, Fisher J, et al: Increased 9-aminocamptothecin (9-AC) dose requirements in patients on anticonvulsant. Proc Am Soc Clin Oncol 16:389a 1997 (abstr 1387) 10. Chang SM, Kuhn JG, Rizzo J, et al: Phase 1 study of paclitaxel in patients with recurrent malignant glioma: A North American Brain Tumor Consortium report. J Clin Oncol 16:2188-2194, 1998[Abstract] 11. Chang SM, Kuhn JG, Robins HI, et al: A phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: A North American Brain Tumor Consortium report. Cancer 91:417-422, 2001[CrossRef][Medline] 12. Kuhn JG: Influence of anticonvulsants on the metabolism and elimination of irinotecan: A North American Brain Tumor Consortium preliminary report. Oncology (Huntingt) 16:33-40, 2002 (suppl 7) 13. Kuhn JG, Prados M, Robins HI, et al: Phase I trial of R115777 (Zarnestra) in patients with recurrent malignant glioma taking enzyme inducting antiepileptic drugs (EIAED): A North American Brain Tumor Consortium (NABTC) report. Proc Am Soc Clin Oncol 21:86a, 2002 (abstr 342) 14. Prados M, Kuhn J, Yung WKA, et al: A phase-1 study of CPT-11 given every 3 weeks to patients with recurrent malignant glioma: A North American Brain Tumor Consortium (NABTC) study. Proc Am Soc Clin Oncol 19:162a, 2000 (abstr 627) 15. Cloughesy TF, Kuhn J, Robins HI, et al: Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: A North American Brain Tumor Consortium study. J Clin Oncol 23:6647-6656, 2005 16. Garner RC, Goris I, Laenen AAE, et al: Evaluation of accelerator mass spectrometry in human mass balance and pharmacokinetic study: Experience with 14C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolone (R1157777), a farnesyl transferase inhibitor. Drug Metab Dispos 30:823-830, 2002 17. Crul M, de Klerk GJ, Swart M, et al: Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 20:2726-2735, 2002 18. Mellinghoff IK, Wang MY, Vivanco I, et al: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012-2024, 2005 19. Cloughesy T, Yung A, Vrendenberg J, et al: Phase II study of erlotinib in recurrent GBM: Molecular predictors of outcome. J Clin Oncol 24:115s, 2005 (abstr 1507) 20. Lieberman FS, Cloughesy T, Fine H, et al: NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. J Clin Oncol 3:109s, 2004 (abstr 1510) 21. Raizer JJ, Abrey LE, Wen P, et al: A phase II trial of erlotinib (OSI-774) in patients (pts) with recurrent malignant gliomas (MG) not on EIAEDs. J Clin Oncol 24:107s, 2004 (abstr 1502) 22. Sebti S, Hamilton AD: Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: Lessons from mechanism and bench-to-bedside translational studies. Oncogene 19:6584-6593, 2000[CrossRef][Medline] 23. Choe G, Horvath S, Cloughesy TF, et al: Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63:2742-2746, 2003 24. Lara PN Jr., Law LY, Wright JJ, et al: Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: A phase I California Cancer Consortium Trial. Anticancer Drugs 16:317-321, 2005[CrossRef][Medline] Submitted February 23, 2006; accepted May 23, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
value of .1 in each of the GBM subgroups. 
4 weeks compared with five of 36 among the non-EIAED GBM patients. 
