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Phase I Trial of Tipifarnib (R115777) Concurrent With Radiotherapy in Patients with Glioblastoma Multiforme
Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 5, pp. 1396–1401, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.02.043
CLINICAL INVESTIGATION
Brain
PHASE I TRIAL OF TIPIFARNIB (R115777) CONCURRENT WITH RADIOTHERAPY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME ELIZABETH COHEN-JONATHAN MOYAL, M.D., PH.D.,*y ANNE LAPRIE, M.D.,* MARTINE DELANNES, M.D.,* MURIEL POUBLANC,z ISABELLE CATALAA, M.D., PH.D.,x FLORENCE DALENC, M.D., PH.D.,k DELPHINE BERCHERY, M.D.,{ JEAN SABATIER, M.D., PH.D.,# PHILIPPE BOUSQUET, M.D.,# PETER DE PORRE, M.D.,** BE´ATRICE ALAUX, M.D.,z AND CHRISTINE TOULAS, PH.D.y Departments of *Radiation Oncology, z Clinical Trials, k Medical Oncology, and { Medical Information, Institut Claudius Regaud, Toulouse, France; y Department of Therapeutic Innovation and Molecular Oncology, INSERM U563, Toulouse, France; x Department of Neuroradiology, CHU Rangueil, Toulouse, France; # Department of Neurosurgery, CHU, Toulouse, France; and ** Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium Purpose: To conduct a Phase I trial to determine the maximally tolerated dose (MTD) of tipifarnib in combination with conventional three-dimensional conformal radiotherapy (RT) for patients with glioblastoma multiforme. Methods and Materials: After resection or biopsy, tipifarnib was given 1 week before and then continuously during RT (60 Gy), followed by adjuvant administration until progression. The tipifarnib dose during RT was escalated in cohorts of 3 starting at 200 mg/day. Results: Thirteen patients were enrolled, and 12 were evaluable for MTD. Of these patients, 7 had undergone biopsy, 4 had partial resection, and 1 had gross total resection. No dose-limiting toxicity (DLT) was observed during the concomitant treatment at 200 mg. All 3 patients at 300 mg experienced DLT during the concomitant treatment: 1 with sudden death and 2 with acute pneumonitis. The MTD was reached at 300 mg. The adjuvant treatment was suppressed from the protocol after a case of pneumonitis during this treatment. Six additional patients were included at 200 mg/day of the new protocol, confirming the safety of this treatment. Of the 9 evaluable patients, 1 had partial response, 4 had stable disease, and 3 had rapid progression; the patient with gross total resection was relapse-free after 21 months. Median survival of the evaluable patients was 12 months (range, 5.2–21 months). Conclusion: Tipifarnib (200 mg/day) concurrent with standard radiotherapy is well tolerated in patients with glioblastoma. Preliminary efficacy results are encouraging. Ó 2007 Elsevier Inc. Tipifarnib, Radiotherapy, Farnesyltransferase inhibitor, Glioblastoma, Phase I.
INTRODUCTION
more specifically to radiotherapy. Our laboratory has been involved for several years in analyzing the radioresistance mechanisms of glioblastoma, aiming to identify proteins implicated in this process and subsequently targeting these proteins with specific inhibitors to radiosensitize these tumors. We have shown that tipifarnib (R115777; Zarnestra; Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium), a potent and selective nonpeptidomimetic farnesyltransferase inhibitor (FTI), administered before radiotherapy, radiosensitized glioblastoma cell lines (4). Moreover, tipifarnib given orally for 4 days inhibited hypoxia and
Glioblastoma multiforme accounts for 25% of all primary central nervous system tumors in adults and is associated with a dismal prognosis (1) despite sequential treatment of resection, when possible, followed by radiotherapy. More recently, temozolomide has been co-administered with radiotherapy (2, 3), yielding a real but still modest benefit in terms of survival. These tumors are characterized by invasiveness, hypoxia, high expression of angiogenic factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), and resistance to all therapies,
Presented at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), November 5–9, 2006, Philadelphia, PA. Conflict of interest: none. Received Jan 16, 2007, and in revised form Feb 2, 2007. Accepted for publication Feb 5, 2007.
Reprint requests to: Elizabeth Cohen-Jonathan Moyal, M.D., Ph.D., Department of Radiation Oncology, Institut Claudius Regaud, and INSERM U563, 20-24 rue du Pont St Pierre, 31052 Toulouse, France. Tel: (+33) 5-61-42-41-78; Fax: (+33) 5-61-42-46-43; E-mail: [email protected] The Institut Claudius Regaud was supported by Johnson & Johnson Pharmaceutical Research and Development for conducting this trial. 1396
Tipifarnib and radiotherapy in glioblastoma d E. COHEN-JONATHAN MOYAL et al.
angiogenesis in part by controlling matrix metalloproteinase2 expression and activity in human glioblastoma xenografts (5). We then identified the small Guanosine tri phosphate hydrolase (GTPase) protein, RhoB, as a target of this FTI radiosensitizer effect (4). RhoB belongs to the Rho protein family (6) and is known to be inducible by different stresses, such as ultraviolet (7) or ionizing radiation (Cohen-Jonathan Moyal, unpublished data), and by hypoxia (8). Moreover, RhoB is inducible by growth factors such as epidermal growth factor (EGF) (9), whose receptor amplification, observed in up to 40% of glioblastoma multiforme, has been related to radioresistance in preclinical (10, 11) and clinical studies (12). RhoB, which is also induced by FGF-2 (Cohen-Jonathan Moyal, unpublished data), which has been recognized as a negative prognostic marker in glioblastoma (13, 14), also mediates the radioresistance induced by this factor (15, 16). We demonstrated that RhoB controls the radioresistance of human glioblastoma in vitro and in vivo, by regulating intracellular radioresistance, but also angiogenesis and hypoxia (4, 8, 17). Moreover, we have shown that the radioprotective effect of RhoB expression is only due to its farnesylated form (18). All these results clearly demonstrated that the farnesylated form of RhoB is an important target to inhibit for improving the radiotherapy efficiency in the treatment of glioblastoma and led us to hypothesize that FTI could be an interesting radiosensitizing agent in the treatment of glioblastoma. Moreover, FTIs have shown efficacy in in vivo animal models with human brain tumors implanted intracranially (19). Specifically, the FTI tipifarnib has been evaluated as a single agent in patients with recurrent glioblastoma for the determination of dose-limiting toxicity (DLT) in a phase I study (20) and more recently in a phase II study (21). Tipifarnib has generated a modest benefit and a better biologic effect for patients not receiving EIAEDs. On the basis of our previous in vitro and in vivo preclinical results, we conducted a phase I clinical trial associating, for the first time, a continuous administration of tipifarnib with radiotherapy in patients with newly diagnosed glioblastoma. Because we have previously demonstrated that the FTI radiosensitizer effect was obtained when the target was inhibited before radiotherapy (4, 22) and that FTI-induced inhibition of hypoxia (5, 17) was observed within 4 days of treatment, we designed this trial starting tipifarnib 1 week before the beginning of radiotherapy. The aims of this study were to identify the maximally tolerated dose (MTD), define the
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toxicities, and explore potential clinical activity of this association. METHODS AND MATERIALS Eligibility All patients provided written informed consent. The protocol was approved by the local ethics committee, the institutional review board, and the French drug administration. Patients with newly diagnosed, histologically confirmed glioblastoma multiforme (Grade IV astrocytoma) according to the World Health Organization criteria (23), previously untreated except for biopsy or surgery (subtotal or gross total resection), were eligible. Patients were enrolled at least 1 week but not more than 6 weeks after biopsy or surgery. No prior chemotherapy or prior cranial irradiation was allowed. Other inclusion criteria included age >18 years, Eastern Cooperative Oncology Group performance status 0, 1, or 2, and acceptable hematologic and biochemical profiles (absolute neutrophil count $1500/mL, platelet count $100,000 mL, aspartate aminotransferase #2.5 times the upper limit of normal, bilirubin #2 mg/dL, and creatinine #1.5 mg/ dL). Exclusion criteria included pregnancy, nursing, or refusal to use contraception if the patient or partner was of childbearing age. Patients with clinically apparent leptomeningeal metastases, known sensitivity to imidazole derivatives, or patients under law protection were also excluded.
Tipifarnib dose-escalation schedule Tipifarnib was supplied by Johnson & Johnson Pharmaceutical Research and Development in tablets of 100 mg and was to be taken with food. The drug was given twice daily, and doses were separated by intervals of 12 h. Tipifarnib was administered continuously from 1 week before start of radiotherapy until the last day of radiotherapy, followed for the first 6 patients of the study (Study 1), after 1 week of rest, by adjuvant tipifarnib given for 21 consecutive days, followed by a 7-day rest period for every 28-day treatment cycle (Fig. 1). The tipifarnib dose administrated during radiotherapy was escalated in cohorts of 3, with a starting dose of 100 mg b.i.d. and increments of 100 mg/day. Intrapatient dose escalation was not allowed. During adjuvant treatment, tipifarnib dosing was 300 mg b.i.d. No dose escalation was performed during the adjuvant treatment. The last patients of each cohort were assessed for 1 month after completion of radiation therapy before dose escalation to the next cohort could occur. If 0 of 3 patients developed DLT, dose escalation would occur. The MTD would be considered reached if 2 of 3 patients developed DLT. If 1 of 3 patients developed DLT, an additional 3 patients were to be enrolled, and MTD would be established if 3 or more of 6 patients developed DLT. In this case, 6 additional patients were enrolled in the previous cohort to confirm the recommended dose (RD) for phase II.
Fig. 1. Study design. Patients began tipifarnib 1 week before the start of radiotherapy and then continuously until the last day of radiotherapy. After 1 week of rest, tipifarnib was given for 21 consecutive days, followed by a 7-day rest period for every 28-day treatment cycle until relapse.
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Concomitant drug provision According to the results obtained in the phase I and II trials using tipifarnib in patients with recurrent malignant glioma (20, 21), the use of non–enzyme-inducing antiepileptic drugs (non-EIAEDs) was encouraged for patients who required anticonvulsant therapy. Corticosteroids were administered as needed.
Radiation therapy Radiation therapy was delivered once per day, 5 times per week, in standard fractions of 2 Gy. For patients undergoing biopsy, 60 Gy was delivered to the enhancing tumor on T1-weighted magnetic resonance images obtained after injection of a gadolinium contrast agent, with a 2-cm margin. For patients undergoing gross total resection or partial resection, the same dose was delivered to similar areas according to the preoperative imaging studies. Radiotherapy was planned with computed tomography and three-dimensional planning systems. Conformal radiotherapy was delivered with multileaf collimator linear accelerators at an energy level of 6 MV or more.
Patient evaluations Baseline evaluations were performed within 7 days from study entry and included a complete medical history, physical examination, determination of performance status, complete blood count, and serum chemistries. Patients were assessed for adverse events, and toxicity, complete blood count, and chemistry were checked weekly during radiotherapy and Cycle 1 of the adjuvant treatment, then every 2 weeks thereafter. Baseline tumor measurements were taken within 7 days from entry into the study by magnetic resonance imaging (MRI), and MRI was then performed every 2 months after the completion of radiotherapy for the first 6 months and every 3 months until relapse.
Assessment of response and toxicity Response was evaluated by MRI. Three-dimensional tumor measurement was performed on an Advantage Windows (version 3.1) workstation (GE Medical Systems, Milwaukee, WI). Complete response was defined as the disappearance of all visible tumor. Partial response was defined as a 50% decrease compared with baseline in the sum of products of all measurable disease. Progression was defined as a >25% increase in the volume of the contrast-enhancing mass, increase in the mass effect, or appearance of new lesions. National Cancer Institute Common Toxicity Criteria (version 3.0) were used throughout. Dose-limiting toxicity was defined as Grade 3 thrombocytopenia lasting >5 days, Grade 3 neutropenia lasting >7 days, Grade 4 neutropenia or thrombocytopenia of any duration, febrile neutropenia, or severe acute central nervous system deterioration attributable to radiation and tipifarnib, which could not be controlled with corticosteroid administration. Any Grade 3 or 4 nonhematologic toxicities, excluding nausea/vomiting responsive to symptomatic management or alopecia, also constituted DLT. In case of DLT, tipifarnib administration was withheld until any drug-related toxicity had diminished to Grade 1 or resolved. Failure to recover within 3 weeks caused the patient to be removed from the study. For concomitant administration of tipifarnib during irradiation, at restart after withholding tipifarnib, the dose of tipifarnib was reduced by 100 mg for the first DLT, and a second reduction by 100 mg of tipifarnib was allowed from the second dose level. Neither a second dose-reduction for the patients included at the 100-mg b.i.d. starting dose nor a third reduction for any patient were allowed. If DLT occurred during adjuvant treatment with tipifarnib, at restart after withholding the drug, the dose of tipifarnib was reduced by 100 mg b.i.d. for the first and second reductions.
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For other adverse events, such as Grade 3 hepatic toxicities, the same scheme of dose reduction was applied. No radiation dose modification was allowed.
Statistical considerations The primary endpoint was the determination of MTD. Secondary endpoints included efficacy outcomes: best objective response, time to progression, and overall survival. Best objective response was classified as complete response, partial response, stable disease, or immediate progression. Overall survival was calculated from time of histologic diagnosis until death. Patients who were alive (progression free) at the time of our analysis (November 2006) were censored for survival.
RESULTS Between April 2003 and March 2005, 13 patients were entered into the study. Baseline patient characteristics are detailed in Table 1. Twelve were treated according to the protocol, and 1 died before the start of radiotherapy. All patients but 1, who underwent a gross total resection, had evaluable targets on MRI at the beginning of the treatment. All patients were followed until death or for 21 months in the case of the surviving patient. Toxicity During the first part of the trial (Study 1), there was no DLT observed during the concomitant administration of tipifarnib and radiotherapy in the first 3 patients treated with Dose Level 1. All three patients at Dose Level 2 (300 mg daily) experienced DLT: one sudden death occurred during the sixth week of concomitant treatment, and two cases of Table 1. Patient demographic and clinical characteristics Characteristic
All patients
Study 1
Study 2
Total no. of patients Gender Male Female Age (y) Median Range ECOG performance status 0 1 2 Extent of resection Biopsy Incomplete resection Gross total resection Recursive partitioning analysis class III IV V Antiepileptic drugs used EIAED Non-EIAED No antiepileptic drug
13
7
6
8 5
4 3
4 2
55 28–74
62 53–74
46 28–71
6 3 4
1 2 4
5 1 0
8 4 1
4 3 0
4 1 1
3 4 6
0 3 4
3 1 2
2 6 5
2 4 1
0 2 4
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EIAED = enzyme-inducing antiepileptic drug.
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Table 2. Non–dose-limiting toxicities by dose level Dose level 1 Toxicities Anorexia Arthralgia Constipation Diarrhea Dry skin Dysgeusia Fatigue Glaucoma Hepatotoxicities Mouth dryness Myalgia Nausea Edema Rash Stomatitis
Dose level 2
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 1
1
1 2 1 1 1 2 1
1 1
1
1 1
1
2 1 1 1 1 2 1
2 2 1
1
1
acute pneumonitis occurred during the second and sixth weeks of concomitant treatment. The first case of pneumonitis was associated with Grade 4 neutropenia, Grade 2 thrombocytopenia, and Grade 3 phlebitis; this patient died 30 days later because of general deterioration not related to disease progression. The second case was associated with bilateral pulmonary embolism and Grade 3 diarrhea; this patient died 1 month later of respiratory failure, and biopsies of the lungs showed a diffuse fibrosis with hyalin membranes and pulmonary emboli. Moreover, 1 of the 3 patients included at Dose Level 1 experienced a nonfebrile interstitial pneumonitis compatible with a drug-induced pneumonitis, during the fourth cycle of adjuvant tipifarnib treatment. No germ, in particular no Pneumocystis carinii, was found to be responsible for this pneumonitis. Because of the toxicities observed at Dose Level 2, this dose level was considered the MTD. With the aim of confirming that Dose Level 1 was the RD, and considering the potential risk of pneumonitis and concurrent thromboembolic events in this patient population, the protocol was modified by deleting the adjuvant treatment. Six additional patients were included at Dose Level 1 (100 mg b.i.d.) of the new protocol (Study 2). Only minor toxicities were observed under these conditions (Table 2). No increase in the radiation-induced toxicities was observed for any patient. Response Although it was not the primary objective of this study, the response to the combination of tipifarnib and radiotherapy was determined. In Study 1 at Dose Level 1, 2 patients had stable disease with 26% and 39% decreases in tumor volume (time to progression from start of radiotherapy was 8 and 6 months), and 1 patient had progression at the first assessment 2 months after the end of the concomitant treatment. At Dose Level 2, all 3 Study 1 patients had a discontinuation of treatment for DLT before the end of the radiotherapy and, thus, were not evaluable for response. Of the 6 patients included in Study 2 at 100 mg b.i.d., 2 had progressive disease 2 months after radiotherapy and 2 had stable disease for 4.5
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months after the end of combination therapy, the patient with gross total resection was relapse free after 21 months, and 1 patient had a partial response. The patient with partial response showed a 54% decrease of irradiated tumor volume 2 months after the end of the combined treatment and progression 2 months later. Survival With the exception of the 3 patients who died of toxicity before completion of treatment, the median overall survival for the 9 evaluable patients was 12 months (range, 6–21 months). Of these 9 patients, the 8 who either underwent biopsy only (4 patients) or partial resection (4 patients) had local relapse within the radiotherapy fields. These relapses led to death at a median time of 10.8 months (range, 5–14 months). The other patient, who underwent gross total resection, was still alive after 21 months. Four of the relapsing patients belonged to Class V of the modified Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification (24) and had a median survival of 10.91 months. DISCUSSION We have shown that the MTD of the continuous administration of tipifarnib starting 1 week before radiotherapy was 300 mg. The main DLTs were pulmonary embolisms and pneumonitis, but no increase in radiation-induced toxicities due to this concomitant administration was observed. Moreover, at the dose of 100 mg b.i.d., considered to be the RD, partial responses and stabilizations were obtained. Compared with trials in which tipifarnib was used as a single agent or given discontinuously (20, 25, 26), we found DLTs at a lower dosage when given continuously during 7 weeks and combined with radiotherapy. The RD for singleagent tipifarnib in solid tumors is 300 mg b.i.d. for 21 of 28 days. Dose-limiting toxicity has been reported in studies using cytotoxic agents, at or near their standard dose, in combination with tipifarnib at either 300 mg b.i.d. or 200 mg b.i.d., using an intermittent dosing schedule of 14 out of 21 or 21 out of 28 days (27–32). Hence, the RD was the same or, at most, one level lower in the studies associating tipifarnib with other agents. It is worth noting that tipifarnib was given discontinuously in those combination studies, in contrast to the present study. Other FTIs, such as L-778,123 or SCH66336, when combined either with radiotherapy (33, 34) or with other drugs, such as paclitaxel (35, 36), showed lower MTD than the doses recommended for either agent alone. At the level of doses at which tipifarnib was administered in this study, in a population of patients known to be at high risk of thromboembolic events (37), pneumonitis and pulmonary embolisms were the main DLTs observed. A possible involvement of tipifarnib in the emergence of thromboembolism and pneumonitis can not be ruled out. Given continuously for 7 weeks in a population of patients known to be at risk of veinous thrombosis, tipifarnib may increase, under such conditions, the risk of thrombosis. Indeed, we have
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demonstrated in our laboratory that tipifarnib, by inhibiting RhoB, normalizes the vasculature, just as antiangiogenic therapies (e.g., anti-VEGF bevacizumab) do. The latter is known to increase the risk of thromboembolism (38, 39). Moreover, we have shown that inhibiting RhoB decreases VEGF expression (unpublished personal data). Pulmonary embolism has been recently reported in 1 patient in a Phase I trial combining tipifarnib and tamoxifen (40), a compound known to increase the risk of thrombosis. In this case, pulmonary embolism was considered as being possibly related to tamoxifen and not to tipifarnib. Moreover, one case of inferior vena cava clot, in a patient with metastatic colorectal cancer, has also been reported in another Phase I trial; this event was not considered related to tipifarnib (41). In a large, randomized study of pancreatic cancer patients treated with gemcitabine plus continuous tipifarnib or a placebo, the overall incidence of pneumonitis and pulmonary embolism was very low and similar in the two arms (42). Furthermore, in several studies assessing the use of tipifarnib in malignant glioma, pneumonitis was rarely or not reported (20, 21). Given continuously 1 week before and then during the total course of radiotherapy at a dose of 100 mg b.i.d., no thromboembolism or pneumonitis was observed, and tipifarnib was very well tolerated and was considered as the RD for the next, phase II trial. Although the primary objective of the study was not to assess clinical efficacy, we observed interesting findings in tumor response. Of the 9 evaluable patients, 1 experienced a partial response, 4 had stable disease, and 1 was diseasefree 21 months after the end of treatment, corresponding to a clinical benefit in 66% of the evaluable patients. Interestingly, 4 of these patients were treated in the modified protocol without the adjuvant treatment. Moreover, of the 6 patients who experienced a response, 2 received a non-EIAED, 2 re-
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ceived an EIAED, and 2 did not receive any antiepileptic drug. Notably, of the 9 patients treated at the RD of 100 mg b.i.d., 4 belonged to RPA Class V and had a median survival of 10.91 months. This value is close to the 10.3 months’ median survival recently reported by Mirimanoff et al. for the phase III trial combining temozolomide with radiotherapy, published after the beginning of our trial (2, 3). Our value of 10.91 months is higher than the 8.9 months’ median survival of the RPA Class V of the RTOG database (24, 43). Considering these encouraging results, which need to be confirmed in the ongoing Phase II, a next step would be to study the radiosensitizing effect of the association of tipifarnib with temozolomide and radiotherapy, first in preclinical studies and then in early-phase clinical trials. These results strongly suggest that continuous doses of tipifarnib 100 mg b.i.d. are able to access the brain of patients with glioblastoma and inhibit the farnesylation of a prenylated target involved in the radioresistance of this tumor. The nature of the molecular target of FTI that is involved in radiosensitization is still debated. Several proteins have been described as potential targets of the FTI radiosensitizing effect, such as Ras in bladder or lung carcinoma (44–47) and HDJ-2 and RhoB in glioblastoma (4, 8, 16, 17, 48). The inhibition of the farnesylation of RhoB, at the crossroads of different cellular pathways controlling radioresistance of these aggressive tumors, will probably offer new perspectives in the treatment of glioblastoma. On the basis of the encouraging experimental results obtained in our laboratory, the promising results of this phase I trial need to be confirmed in the phase II clinical trial currently underway. This trial includes additional studies of biologic and metabolic markers of clinical response to the combination of tipifarnib and radiotherapy.
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ase inhibitor (FTI) R115777 + docetaxel: A promising combination in patient (PTS) with solid tumors [Abstract]. Proc Am Soc Clin Oncol 2001;20(Suppl):318. Cohen SJ, Gallo J, Lewis NL, et al. Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer. Cancer Chemother Pharmacol 2004;53:513–518. Martin NE, Brunner TB, Kiel KD, et al. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res 2004;10:5447–5454. Hahn SM, Bernhard EJ, Regine W, et al. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 2002;8:1065–1072. Khuri FR, Glisson BS, Kim ES, et al. Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors. Clin Cancer Res 2004;10:2968–2976. Kim ES, Kies MS, Fossella FV, et al. Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. Cancer 2005;104:561–569. Streiff MB, Segal J, Grossman SA, et al. ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 2004;100:1717–1723. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/ leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–65. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: An NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 2006;24:3354–3360. Lebowitz PF, Eng-Wong J, Widemann BC, et al. A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. Clin Cancer Res 2005;11:1247–1252. Zujewski J, Horak ID, Bol CJ, et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2000;18:927–941. Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22: 1430–1438. Curran WJ Jr., Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85: 704–710. Bernhard EJ, McKenna WG, Hamilton AD, et al. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res 1998;58:1754–1761. Cohen-Jonathan E, Muschel RJ, Gillies McKenna W, et al. Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS. Radiat Res 2000;154:125–132. End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61: 131–137. Prevost GP, Pradines A, Brezak MC, et al. Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM-46228. Int J Cancer 2001;91: 718–722. Wang CC, Liao YP, Mischel PS, et al. HDJ-2 as a target for radiosensitization of glioblastoma multiforme cells by the farnesyltransferase inhibitor R115777 and the role of the p53/p21 pathway. Cancer Res 2006;66:6756–6762.
doi:10.1016/j.ijrobp.2007.02.043
CLINICAL INVESTIGATION
Brain
PHASE I TRIAL OF TIPIFARNIB (R115777) CONCURRENT WITH RADIOTHERAPY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME ELIZABETH COHEN-JONATHAN MOYAL, M.D., PH.D.,*y ANNE LAPRIE, M.D.,* MARTINE DELANNES, M.D.,* MURIEL POUBLANC,z ISABELLE CATALAA, M.D., PH.D.,x FLORENCE DALENC, M.D., PH.D.,k DELPHINE BERCHERY, M.D.,{ JEAN SABATIER, M.D., PH.D.,# PHILIPPE BOUSQUET, M.D.,# PETER DE PORRE, M.D.,** BE´ATRICE ALAUX, M.D.,z AND CHRISTINE TOULAS, PH.D.y Departments of *Radiation Oncology, z Clinical Trials, k Medical Oncology, and { Medical Information, Institut Claudius Regaud, Toulouse, France; y Department of Therapeutic Innovation and Molecular Oncology, INSERM U563, Toulouse, France; x Department of Neuroradiology, CHU Rangueil, Toulouse, France; # Department of Neurosurgery, CHU, Toulouse, France; and ** Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium Purpose: To conduct a Phase I trial to determine the maximally tolerated dose (MTD) of tipifarnib in combination with conventional three-dimensional conformal radiotherapy (RT) for patients with glioblastoma multiforme. Methods and Materials: After resection or biopsy, tipifarnib was given 1 week before and then continuously during RT (60 Gy), followed by adjuvant administration until progression. The tipifarnib dose during RT was escalated in cohorts of 3 starting at 200 mg/day. Results: Thirteen patients were enrolled, and 12 were evaluable for MTD. Of these patients, 7 had undergone biopsy, 4 had partial resection, and 1 had gross total resection. No dose-limiting toxicity (DLT) was observed during the concomitant treatment at 200 mg. All 3 patients at 300 mg experienced DLT during the concomitant treatment: 1 with sudden death and 2 with acute pneumonitis. The MTD was reached at 300 mg. The adjuvant treatment was suppressed from the protocol after a case of pneumonitis during this treatment. Six additional patients were included at 200 mg/day of the new protocol, confirming the safety of this treatment. Of the 9 evaluable patients, 1 had partial response, 4 had stable disease, and 3 had rapid progression; the patient with gross total resection was relapse-free after 21 months. Median survival of the evaluable patients was 12 months (range, 5.2–21 months). Conclusion: Tipifarnib (200 mg/day) concurrent with standard radiotherapy is well tolerated in patients with glioblastoma. Preliminary efficacy results are encouraging. Ó 2007 Elsevier Inc. Tipifarnib, Radiotherapy, Farnesyltransferase inhibitor, Glioblastoma, Phase I.
INTRODUCTION
more specifically to radiotherapy. Our laboratory has been involved for several years in analyzing the radioresistance mechanisms of glioblastoma, aiming to identify proteins implicated in this process and subsequently targeting these proteins with specific inhibitors to radiosensitize these tumors. We have shown that tipifarnib (R115777; Zarnestra; Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium), a potent and selective nonpeptidomimetic farnesyltransferase inhibitor (FTI), administered before radiotherapy, radiosensitized glioblastoma cell lines (4). Moreover, tipifarnib given orally for 4 days inhibited hypoxia and
Glioblastoma multiforme accounts for 25% of all primary central nervous system tumors in adults and is associated with a dismal prognosis (1) despite sequential treatment of resection, when possible, followed by radiotherapy. More recently, temozolomide has been co-administered with radiotherapy (2, 3), yielding a real but still modest benefit in terms of survival. These tumors are characterized by invasiveness, hypoxia, high expression of angiogenic factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), and resistance to all therapies,
Presented at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), November 5–9, 2006, Philadelphia, PA. Conflict of interest: none. Received Jan 16, 2007, and in revised form Feb 2, 2007. Accepted for publication Feb 5, 2007.
Reprint requests to: Elizabeth Cohen-Jonathan Moyal, M.D., Ph.D., Department of Radiation Oncology, Institut Claudius Regaud, and INSERM U563, 20-24 rue du Pont St Pierre, 31052 Toulouse, France. Tel: (+33) 5-61-42-41-78; Fax: (+33) 5-61-42-46-43; E-mail: [email protected] The Institut Claudius Regaud was supported by Johnson & Johnson Pharmaceutical Research and Development for conducting this trial. 1396
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angiogenesis in part by controlling matrix metalloproteinase2 expression and activity in human glioblastoma xenografts (5). We then identified the small Guanosine tri phosphate hydrolase (GTPase) protein, RhoB, as a target of this FTI radiosensitizer effect (4). RhoB belongs to the Rho protein family (6) and is known to be inducible by different stresses, such as ultraviolet (7) or ionizing radiation (Cohen-Jonathan Moyal, unpublished data), and by hypoxia (8). Moreover, RhoB is inducible by growth factors such as epidermal growth factor (EGF) (9), whose receptor amplification, observed in up to 40% of glioblastoma multiforme, has been related to radioresistance in preclinical (10, 11) and clinical studies (12). RhoB, which is also induced by FGF-2 (Cohen-Jonathan Moyal, unpublished data), which has been recognized as a negative prognostic marker in glioblastoma (13, 14), also mediates the radioresistance induced by this factor (15, 16). We demonstrated that RhoB controls the radioresistance of human glioblastoma in vitro and in vivo, by regulating intracellular radioresistance, but also angiogenesis and hypoxia (4, 8, 17). Moreover, we have shown that the radioprotective effect of RhoB expression is only due to its farnesylated form (18). All these results clearly demonstrated that the farnesylated form of RhoB is an important target to inhibit for improving the radiotherapy efficiency in the treatment of glioblastoma and led us to hypothesize that FTI could be an interesting radiosensitizing agent in the treatment of glioblastoma. Moreover, FTIs have shown efficacy in in vivo animal models with human brain tumors implanted intracranially (19). Specifically, the FTI tipifarnib has been evaluated as a single agent in patients with recurrent glioblastoma for the determination of dose-limiting toxicity (DLT) in a phase I study (20) and more recently in a phase II study (21). Tipifarnib has generated a modest benefit and a better biologic effect for patients not receiving EIAEDs. On the basis of our previous in vitro and in vivo preclinical results, we conducted a phase I clinical trial associating, for the first time, a continuous administration of tipifarnib with radiotherapy in patients with newly diagnosed glioblastoma. Because we have previously demonstrated that the FTI radiosensitizer effect was obtained when the target was inhibited before radiotherapy (4, 22) and that FTI-induced inhibition of hypoxia (5, 17) was observed within 4 days of treatment, we designed this trial starting tipifarnib 1 week before the beginning of radiotherapy. The aims of this study were to identify the maximally tolerated dose (MTD), define the
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toxicities, and explore potential clinical activity of this association. METHODS AND MATERIALS Eligibility All patients provided written informed consent. The protocol was approved by the local ethics committee, the institutional review board, and the French drug administration. Patients with newly diagnosed, histologically confirmed glioblastoma multiforme (Grade IV astrocytoma) according to the World Health Organization criteria (23), previously untreated except for biopsy or surgery (subtotal or gross total resection), were eligible. Patients were enrolled at least 1 week but not more than 6 weeks after biopsy or surgery. No prior chemotherapy or prior cranial irradiation was allowed. Other inclusion criteria included age >18 years, Eastern Cooperative Oncology Group performance status 0, 1, or 2, and acceptable hematologic and biochemical profiles (absolute neutrophil count $1500/mL, platelet count $100,000 mL, aspartate aminotransferase #2.5 times the upper limit of normal, bilirubin #2 mg/dL, and creatinine #1.5 mg/ dL). Exclusion criteria included pregnancy, nursing, or refusal to use contraception if the patient or partner was of childbearing age. Patients with clinically apparent leptomeningeal metastases, known sensitivity to imidazole derivatives, or patients under law protection were also excluded.
Tipifarnib dose-escalation schedule Tipifarnib was supplied by Johnson & Johnson Pharmaceutical Research and Development in tablets of 100 mg and was to be taken with food. The drug was given twice daily, and doses were separated by intervals of 12 h. Tipifarnib was administered continuously from 1 week before start of radiotherapy until the last day of radiotherapy, followed for the first 6 patients of the study (Study 1), after 1 week of rest, by adjuvant tipifarnib given for 21 consecutive days, followed by a 7-day rest period for every 28-day treatment cycle (Fig. 1). The tipifarnib dose administrated during radiotherapy was escalated in cohorts of 3, with a starting dose of 100 mg b.i.d. and increments of 100 mg/day. Intrapatient dose escalation was not allowed. During adjuvant treatment, tipifarnib dosing was 300 mg b.i.d. No dose escalation was performed during the adjuvant treatment. The last patients of each cohort were assessed for 1 month after completion of radiation therapy before dose escalation to the next cohort could occur. If 0 of 3 patients developed DLT, dose escalation would occur. The MTD would be considered reached if 2 of 3 patients developed DLT. If 1 of 3 patients developed DLT, an additional 3 patients were to be enrolled, and MTD would be established if 3 or more of 6 patients developed DLT. In this case, 6 additional patients were enrolled in the previous cohort to confirm the recommended dose (RD) for phase II.
Fig. 1. Study design. Patients began tipifarnib 1 week before the start of radiotherapy and then continuously until the last day of radiotherapy. After 1 week of rest, tipifarnib was given for 21 consecutive days, followed by a 7-day rest period for every 28-day treatment cycle until relapse.
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Concomitant drug provision According to the results obtained in the phase I and II trials using tipifarnib in patients with recurrent malignant glioma (20, 21), the use of non–enzyme-inducing antiepileptic drugs (non-EIAEDs) was encouraged for patients who required anticonvulsant therapy. Corticosteroids were administered as needed.
Radiation therapy Radiation therapy was delivered once per day, 5 times per week, in standard fractions of 2 Gy. For patients undergoing biopsy, 60 Gy was delivered to the enhancing tumor on T1-weighted magnetic resonance images obtained after injection of a gadolinium contrast agent, with a 2-cm margin. For patients undergoing gross total resection or partial resection, the same dose was delivered to similar areas according to the preoperative imaging studies. Radiotherapy was planned with computed tomography and three-dimensional planning systems. Conformal radiotherapy was delivered with multileaf collimator linear accelerators at an energy level of 6 MV or more.
Patient evaluations Baseline evaluations were performed within 7 days from study entry and included a complete medical history, physical examination, determination of performance status, complete blood count, and serum chemistries. Patients were assessed for adverse events, and toxicity, complete blood count, and chemistry were checked weekly during radiotherapy and Cycle 1 of the adjuvant treatment, then every 2 weeks thereafter. Baseline tumor measurements were taken within 7 days from entry into the study by magnetic resonance imaging (MRI), and MRI was then performed every 2 months after the completion of radiotherapy for the first 6 months and every 3 months until relapse.
Assessment of response and toxicity Response was evaluated by MRI. Three-dimensional tumor measurement was performed on an Advantage Windows (version 3.1) workstation (GE Medical Systems, Milwaukee, WI). Complete response was defined as the disappearance of all visible tumor. Partial response was defined as a 50% decrease compared with baseline in the sum of products of all measurable disease. Progression was defined as a >25% increase in the volume of the contrast-enhancing mass, increase in the mass effect, or appearance of new lesions. National Cancer Institute Common Toxicity Criteria (version 3.0) were used throughout. Dose-limiting toxicity was defined as Grade 3 thrombocytopenia lasting >5 days, Grade 3 neutropenia lasting >7 days, Grade 4 neutropenia or thrombocytopenia of any duration, febrile neutropenia, or severe acute central nervous system deterioration attributable to radiation and tipifarnib, which could not be controlled with corticosteroid administration. Any Grade 3 or 4 nonhematologic toxicities, excluding nausea/vomiting responsive to symptomatic management or alopecia, also constituted DLT. In case of DLT, tipifarnib administration was withheld until any drug-related toxicity had diminished to Grade 1 or resolved. Failure to recover within 3 weeks caused the patient to be removed from the study. For concomitant administration of tipifarnib during irradiation, at restart after withholding tipifarnib, the dose of tipifarnib was reduced by 100 mg for the first DLT, and a second reduction by 100 mg of tipifarnib was allowed from the second dose level. Neither a second dose-reduction for the patients included at the 100-mg b.i.d. starting dose nor a third reduction for any patient were allowed. If DLT occurred during adjuvant treatment with tipifarnib, at restart after withholding the drug, the dose of tipifarnib was reduced by 100 mg b.i.d. for the first and second reductions.
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For other adverse events, such as Grade 3 hepatic toxicities, the same scheme of dose reduction was applied. No radiation dose modification was allowed.
Statistical considerations The primary endpoint was the determination of MTD. Secondary endpoints included efficacy outcomes: best objective response, time to progression, and overall survival. Best objective response was classified as complete response, partial response, stable disease, or immediate progression. Overall survival was calculated from time of histologic diagnosis until death. Patients who were alive (progression free) at the time of our analysis (November 2006) were censored for survival.
RESULTS Between April 2003 and March 2005, 13 patients were entered into the study. Baseline patient characteristics are detailed in Table 1. Twelve were treated according to the protocol, and 1 died before the start of radiotherapy. All patients but 1, who underwent a gross total resection, had evaluable targets on MRI at the beginning of the treatment. All patients were followed until death or for 21 months in the case of the surviving patient. Toxicity During the first part of the trial (Study 1), there was no DLT observed during the concomitant administration of tipifarnib and radiotherapy in the first 3 patients treated with Dose Level 1. All three patients at Dose Level 2 (300 mg daily) experienced DLT: one sudden death occurred during the sixth week of concomitant treatment, and two cases of Table 1. Patient demographic and clinical characteristics Characteristic
All patients
Study 1
Study 2
Total no. of patients Gender Male Female Age (y) Median Range ECOG performance status 0 1 2 Extent of resection Biopsy Incomplete resection Gross total resection Recursive partitioning analysis class III IV V Antiepileptic drugs used EIAED Non-EIAED No antiepileptic drug
13
7
6
8 5
4 3
4 2
55 28–74
62 53–74
46 28–71
6 3 4
1 2 4
5 1 0
8 4 1
4 3 0
4 1 1
3 4 6
0 3 4
3 1 2
2 6 5
2 4 1
0 2 4
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EIAED = enzyme-inducing antiepileptic drug.
Tipifarnib and radiotherapy in glioblastoma d E. COHEN-JONATHAN MOYAL et al.
Table 2. Non–dose-limiting toxicities by dose level Dose level 1 Toxicities Anorexia Arthralgia Constipation Diarrhea Dry skin Dysgeusia Fatigue Glaucoma Hepatotoxicities Mouth dryness Myalgia Nausea Edema Rash Stomatitis
Dose level 2
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 1
1
1 2 1 1 1 2 1
1 1
1
1 1
1
2 1 1 1 1 2 1
2 2 1
1
1
acute pneumonitis occurred during the second and sixth weeks of concomitant treatment. The first case of pneumonitis was associated with Grade 4 neutropenia, Grade 2 thrombocytopenia, and Grade 3 phlebitis; this patient died 30 days later because of general deterioration not related to disease progression. The second case was associated with bilateral pulmonary embolism and Grade 3 diarrhea; this patient died 1 month later of respiratory failure, and biopsies of the lungs showed a diffuse fibrosis with hyalin membranes and pulmonary emboli. Moreover, 1 of the 3 patients included at Dose Level 1 experienced a nonfebrile interstitial pneumonitis compatible with a drug-induced pneumonitis, during the fourth cycle of adjuvant tipifarnib treatment. No germ, in particular no Pneumocystis carinii, was found to be responsible for this pneumonitis. Because of the toxicities observed at Dose Level 2, this dose level was considered the MTD. With the aim of confirming that Dose Level 1 was the RD, and considering the potential risk of pneumonitis and concurrent thromboembolic events in this patient population, the protocol was modified by deleting the adjuvant treatment. Six additional patients were included at Dose Level 1 (100 mg b.i.d.) of the new protocol (Study 2). Only minor toxicities were observed under these conditions (Table 2). No increase in the radiation-induced toxicities was observed for any patient. Response Although it was not the primary objective of this study, the response to the combination of tipifarnib and radiotherapy was determined. In Study 1 at Dose Level 1, 2 patients had stable disease with 26% and 39% decreases in tumor volume (time to progression from start of radiotherapy was 8 and 6 months), and 1 patient had progression at the first assessment 2 months after the end of the concomitant treatment. At Dose Level 2, all 3 Study 1 patients had a discontinuation of treatment for DLT before the end of the radiotherapy and, thus, were not evaluable for response. Of the 6 patients included in Study 2 at 100 mg b.i.d., 2 had progressive disease 2 months after radiotherapy and 2 had stable disease for 4.5
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months after the end of combination therapy, the patient with gross total resection was relapse free after 21 months, and 1 patient had a partial response. The patient with partial response showed a 54% decrease of irradiated tumor volume 2 months after the end of the combined treatment and progression 2 months later. Survival With the exception of the 3 patients who died of toxicity before completion of treatment, the median overall survival for the 9 evaluable patients was 12 months (range, 6–21 months). Of these 9 patients, the 8 who either underwent biopsy only (4 patients) or partial resection (4 patients) had local relapse within the radiotherapy fields. These relapses led to death at a median time of 10.8 months (range, 5–14 months). The other patient, who underwent gross total resection, was still alive after 21 months. Four of the relapsing patients belonged to Class V of the modified Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification (24) and had a median survival of 10.91 months. DISCUSSION We have shown that the MTD of the continuous administration of tipifarnib starting 1 week before radiotherapy was 300 mg. The main DLTs were pulmonary embolisms and pneumonitis, but no increase in radiation-induced toxicities due to this concomitant administration was observed. Moreover, at the dose of 100 mg b.i.d., considered to be the RD, partial responses and stabilizations were obtained. Compared with trials in which tipifarnib was used as a single agent or given discontinuously (20, 25, 26), we found DLTs at a lower dosage when given continuously during 7 weeks and combined with radiotherapy. The RD for singleagent tipifarnib in solid tumors is 300 mg b.i.d. for 21 of 28 days. Dose-limiting toxicity has been reported in studies using cytotoxic agents, at or near their standard dose, in combination with tipifarnib at either 300 mg b.i.d. or 200 mg b.i.d., using an intermittent dosing schedule of 14 out of 21 or 21 out of 28 days (27–32). Hence, the RD was the same or, at most, one level lower in the studies associating tipifarnib with other agents. It is worth noting that tipifarnib was given discontinuously in those combination studies, in contrast to the present study. Other FTIs, such as L-778,123 or SCH66336, when combined either with radiotherapy (33, 34) or with other drugs, such as paclitaxel (35, 36), showed lower MTD than the doses recommended for either agent alone. At the level of doses at which tipifarnib was administered in this study, in a population of patients known to be at high risk of thromboembolic events (37), pneumonitis and pulmonary embolisms were the main DLTs observed. A possible involvement of tipifarnib in the emergence of thromboembolism and pneumonitis can not be ruled out. Given continuously for 7 weeks in a population of patients known to be at risk of veinous thrombosis, tipifarnib may increase, under such conditions, the risk of thrombosis. Indeed, we have
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demonstrated in our laboratory that tipifarnib, by inhibiting RhoB, normalizes the vasculature, just as antiangiogenic therapies (e.g., anti-VEGF bevacizumab) do. The latter is known to increase the risk of thromboembolism (38, 39). Moreover, we have shown that inhibiting RhoB decreases VEGF expression (unpublished personal data). Pulmonary embolism has been recently reported in 1 patient in a Phase I trial combining tipifarnib and tamoxifen (40), a compound known to increase the risk of thrombosis. In this case, pulmonary embolism was considered as being possibly related to tamoxifen and not to tipifarnib. Moreover, one case of inferior vena cava clot, in a patient with metastatic colorectal cancer, has also been reported in another Phase I trial; this event was not considered related to tipifarnib (41). In a large, randomized study of pancreatic cancer patients treated with gemcitabine plus continuous tipifarnib or a placebo, the overall incidence of pneumonitis and pulmonary embolism was very low and similar in the two arms (42). Furthermore, in several studies assessing the use of tipifarnib in malignant glioma, pneumonitis was rarely or not reported (20, 21). Given continuously 1 week before and then during the total course of radiotherapy at a dose of 100 mg b.i.d., no thromboembolism or pneumonitis was observed, and tipifarnib was very well tolerated and was considered as the RD for the next, phase II trial. Although the primary objective of the study was not to assess clinical efficacy, we observed interesting findings in tumor response. Of the 9 evaluable patients, 1 experienced a partial response, 4 had stable disease, and 1 was diseasefree 21 months after the end of treatment, corresponding to a clinical benefit in 66% of the evaluable patients. Interestingly, 4 of these patients were treated in the modified protocol without the adjuvant treatment. Moreover, of the 6 patients who experienced a response, 2 received a non-EIAED, 2 re-
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ceived an EIAED, and 2 did not receive any antiepileptic drug. Notably, of the 9 patients treated at the RD of 100 mg b.i.d., 4 belonged to RPA Class V and had a median survival of 10.91 months. This value is close to the 10.3 months’ median survival recently reported by Mirimanoff et al. for the phase III trial combining temozolomide with radiotherapy, published after the beginning of our trial (2, 3). Our value of 10.91 months is higher than the 8.9 months’ median survival of the RPA Class V of the RTOG database (24, 43). Considering these encouraging results, which need to be confirmed in the ongoing Phase II, a next step would be to study the radiosensitizing effect of the association of tipifarnib with temozolomide and radiotherapy, first in preclinical studies and then in early-phase clinical trials. These results strongly suggest that continuous doses of tipifarnib 100 mg b.i.d. are able to access the brain of patients with glioblastoma and inhibit the farnesylation of a prenylated target involved in the radioresistance of this tumor. The nature of the molecular target of FTI that is involved in radiosensitization is still debated. Several proteins have been described as potential targets of the FTI radiosensitizing effect, such as Ras in bladder or lung carcinoma (44–47) and HDJ-2 and RhoB in glioblastoma (4, 8, 16, 17, 48). The inhibition of the farnesylation of RhoB, at the crossroads of different cellular pathways controlling radioresistance of these aggressive tumors, will probably offer new perspectives in the treatment of glioblastoma. On the basis of the encouraging experimental results obtained in our laboratory, the promising results of this phase I trial need to be confirmed in the phase II clinical trial currently underway. This trial includes additional studies of biologic and metabolic markers of clinical response to the combination of tipifarnib and radiotherapy.
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