North American Brain Tumor Consortium Research Articles

Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03

A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles. In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.

Surgery, a prognostic marker for progression-free survival?

Clarke and colleagues1 are to be congratulated for their recently reported retrospective analysis of whether surgery is a prognostic factor for progression-free survival (PFS) based upon 2 datasets of patients (1 each in the pre- and post-temozolomide eras) treated according to the North American Brain Tumor Consortium phase II trials in recurrent glioblastoma (GB). We would like to make several comments regarding the report and the role of resective (nonbiopsy) surgery in the management of patients with recurrent GB. Counterintuitive results were reported, as surgery preceding enrollment in a clinical trial for recurrent GB did not affect the primary outcome of the analysis, which was 6-month PFS or overall survival. It is generally believed as a tenet of neuro-oncology treatment that reoperation for patients with recurrent GB is of value and positively influences outcome both by decreasing mass and attendant side effects and by improving results of subsequent therapy (either radiotherapy or chemotherapy) by diminishing tumor burden. The analysis of Clarke et al, however, suggests no difference in outcome in patients undergoing surgery, and consequently patients with smaller tumor masses at time of enrollment (the postsurgery cohort) in a clinical trial fared no better than patients not otherwise undergoing reoperation and with presumably larger tumors at the time of salvage treatment. Not clear from the analysis is whether patients undergoing surgery did indeed have smaller tumors than patients not undergoing reoperation. There was no re-analysis of tumor volume as defined by magnetic resonance imaging prior to study entry, so the statement that patients undergoing re-resection had smaller tumors is conjectural. Also not clear from the analysis was how a decision to undertake repeat surgery was determined. At present there are no clear guidelines for reoperation in patients with GB aside from the belief that reoperation is of value (diminishing tumor burden as well as decreasing side effects related to intracranial mass) and favorably influences outcome as defined by PFS and overall survival, a view that appears to be at odds with the Clarke analysis. Park and colleagues, in a recent provocative study,2 suggested 3 criteria for determining best candidates for reoperation in patients with recurrent GB: location in the brain (eloquent or non-eloquent), performance status (independent or otherwise), and expected survival ( 3 months). In most neuro-oncology centers, reoperation is driven primarily by tumor location, resectability, and performance and secondarily by symptoms related to tumor mass and the age of the patient. These less codified criteria are similar to those reported by Park et al but lack outcome data such as those provided by the Park researchers suggesting that there are clear candidates for which reoperation may have limited value. Importantly, it is unclear what criteria were used to suggest re-resection in the study by Clarke et al. How then to interpret this retrospective analysis? And does it affect present management of recurrent GB? Clarke et al1 conclude that surgery continues to offer benefit by reducing tumor mass–related symptoms, although no data were provided suggesting how many of the repeat surgery cohort in fact underwent surgery due to symptomatic tumor. In addition, repeat surgery may pathologically distinguish recurrent GB from treatment-related side effects such as pseudoprogression and radiation necrosis. Again, there are no data provided in the analysis by Clarke et al to indicate how often repeat surgery was used to make this clinically relevant distinction. Currently, there are no formal neuropathological criteria for grading previously treated gliomas. Because glioma grading was based on the most recent surgery, tumors that were lower grade at the initial surgery may have been upgraded and included in the GB group for further analysis. Tumors in the group that did not undergo reoperation were GB at the initial surgery. This may be an additional source of bias. Lastly, Clarke et al1 opine that repeat surgery allowed patients to enter a clinical trial that may have not been possible due to size of tumor and performance status. However, there are no data to support that the surgical cohort underwent surgery and converted from ineligible to eligible for a clinical trial. Furthermore, there are no data about preoperative and postoperative tumor volumes, or any comparison of volumes in the surgical and nonsurgical cohorts. A more provocative, and perhaps counterintuitive, conclusion based on the available data would be that repeat surgery does not impact survival, and consequently the value of repeat surgery in patients with recurrent GB otherwise eligible for a salvage clinical trial is poorly defined and perhaps minimal. As this conclusion is supported by the data presented, perhaps a re-analysis of the database, with inclusion of omitted information, such as surgical criteria, tumor volumes, alterations of performance status by surgery, extent of resection, and change in initial tumor grade, would help to determine whether or not this conclusion is valid.

Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?

Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.

Multicenter phase II trial of temozolomide (TMZ) and rituximab (RIT) for recurrent primary CNS lymphoma (PCNSL): North American Brain Tumor Consortium (NABTC) study 05-01.

2039 Background: Salvage chemotherapy for PCNSL has been poorly characterized, with few, mostly retrospective studies reporting objective response rates (RR) of 26-53% and 1y overall survival (OS) ...

A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03

Romidepsin, a potent histone deacetylase inhibitor, has shown activity in preclinical glioma models. The primary objectives of this trial were to determine the pharmacokinetics of romidepsin in patients with recurrent glioma on enzyme-inducing antiepileptic drugs (EIAEDs) and to evaluate the antitumor efficacy of romidepsin in patients with recurrent glioblastoma who were not receiving EIAEDs. Two dose cohorts were studied in the phase I component of the trial (13.3 and 17.7 mg/m(2)/d). Patients in the phase II component were treated with intravenous romidepsin at a dosage of 13.3 mg/m(2)/day on days 1, 8, and 15 of each 28-day cycle. Eight patients were treated on the phase I component. A similar romidepsin pharmacokinetic profile was demonstrated between patients receiving EIAEDs to those not receving EIAEDs. Thirty-five patients with glioblastoma were accrued to the phase II component. There was no objective radiographic response. The median progression-free survival (PFS) was 8 weeks and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). To date, 34 patients (97%) have died, with a median survival duration of 34 weeks. Despite in vitro studies showing that romidepsin is primarily metabolized by CYP3A4, no decrease in exposure to romidepsin was seen in patients receiving potent CYP3A4 inducers. Romidepsin, at its standard dose and schedule, was ineffective for patients with recurrent glioblastomas. ClinicalTrials.gov identifier: NCT00085540.

Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma

The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n = 469, 1980-2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n = 596, 1998-2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.

Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08)

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.

Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG) (NABTC 04–02)

2004 Background: Glioblastomas (GBM) frequently have EGFR amplification/mutations and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have limited activity, combinations of these agents may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor temsirolimus in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, >18 years old, KPS >60, adequate bone marrow and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. Patients must not be receiving enzyme-inducing antiepileptic drugs. The dose of erlotinib was 150 mg/d in phase I and titrated up to maximum of 200mg/d in phase II depending on tolerability. Patients initially received temsirolimus 50 mg i.v. once weekly and the dose adjusted based on toxicities. Escalation was performed in groups of three. MTD was defined as the dose with 1/6 or fewer patients with dose-limiting toxicities (DLTs). Primary endpoint for the phase II component was PFS6. Results: In phase I, 22 patients were enrolled (15 GBM; 7 AG). Median age was 54 years (26–74); median KPS 90 (70–100); median prior relapses 1 (0–3). The MTD was determined to be 150 mg of erlotinib daily combined with 15 mg of temsirolimus weekly. DLTs were rash, mucositis, and liver function abnormalities. Pharmacokinetic data were similar to that for single agent erlotinib and temsirolimus; there was no interaction between the two drugs. AUC accumulation ratios between cycle 1 and 2 for erlotinib and OSI-420 were 3.6 and 4.6, respectively. In phase II, there were 56 patients (including 12 phase I patients treated at the MTD): 40 GBM; 16 AG, median age 47 years (20–72); median KPS 90 (range 60–100), median prior relapses 1 (range 1–3). Six patients discontinued therapy as a result of toxicities. For GBM patients, there was no PR, 30% SD, and PFS6 was 12.5%. For AG patients there was 12.5% PR, 12.5% SD, and PFS6 was 6.25%. Conclusions: The combination of erlotinib and temsirolimus was associated with a higher than expected incidence of toxicities and had minimal activity in recurrent MG. [Table: see text]

Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.

A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas

This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.

A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05)

This phase II study was designed to determine the overall survival time of adults with supratentorial glioblastoma treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC), in combination with and following radiation therapy (RT). This was an open-label, single arm phase II study. Patients were treated with RT in combination with poly-ICLC followed by poly-ICLC as a single agent. Poly-ICLC was initiated 7-28 days after the surgical procedure that established the diagnosis; radiotherapy began within 7 days of the first dose of poly-ICLC and within 35 days of surgical diagnosis. Treatment with poly-ICLC continued following the completion of RT to a maximum of 1 year or until tumor progression. 31 patients were enrolled in this study. One patient did not have a Glioblastoma mutiforme and was deemed ineligible. For the 30 eligible patients, time to progression was known for 27 patients and 3 were censored. The estimated 6-month progression-free survival was 30% and the estimated 1-year progression-free survival was 5%. Median time to progression was as 18 weeks. The 1-year survival was 69% and the median survival was 65 weeks. The combined therapy was relatively well-tolerated. This study suggests a survival advantage compared to historical studies using RT without chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea or non-temozolomide chemotherapy. Our results suggest that poly-ICLC has activity against glioblastoma and may be worth further study in combination with agents such as temozolomide.

Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium

The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.

Progression-free survival: An important end point in evaluating therapy for recurrent high-grade gliomas

The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.

How the North American Brain Tumor Consortium Shaped Clinical Research in Neuro–oncology

How the North American Brain Tumor Consortium Shaped Clinical Research in Neuro–oncology

Phase I Study of Temozolomide and Irinotecan for Recurrent Malignant Gliomas in Patients Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study

To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m(2)) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m(2), which was escalated to 550 mg/m(2) in 50-mg/m(2) increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m(2). The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.

Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study

This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide. Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m(2)/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m(2)/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only. For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC(0-24hr) at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h. The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.

Phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with temozolomide (TMZ) in patients with malignant gliomas (NABTC 04–03)

2039 Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, &gt; 18 yrs old, life expectancy &gt; 8 weeks, KPS &gt; 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. PKs were determined on cycle 1 for TMZ, V and its metabolites. Results: To date, 19 eligible patients have been enrolled (15 GBM; 4 AG). Patients’ characteristics are 11 male, 8 female; median age 54 yrs (36–78); median KPS 90 (70–100). DLTs were encountered at 300 mg bid of vorinostat (1 grade 3 thrombocytopenia; 1 grade 3 fatigue in 3 patients), 200 mg tid (1 grade 3 nausea, 1 grade 4 thrombocytopenia in 3 patients) and 200 mg twice daily (grade 3 fatigue in 2/6 patients). No DLTs were encountered in 6 patients receiving 300 mg daily. TMZ PKs included [n=16: Cmax 5.2 (± 1.55) μg/ml; AUC 20.1 (±4.66) μg x hr/ml; t1/2 1.9 (±0.32)/hr]. Vorinostat PKs (300mg dose level) were [n=4; Cmax 267 (±174) ng/ml; AUC0–8 603 (±197) ng x hr/ml]. The t1/2 for V and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Conclusions: The MTD of vorinostat in combination with TMZ is 300 mg daily on days 1–14 every 28 days. Final PK results, and toxicities from an additional 10 patients enrolled at the MTD will be presented. [Table: see text]

Joint NABTC + NCCTG prognostic factors analysis for high grade recurrent glioma

2075 Background: Multiple variables may impact endpoints used to assess therapeutic efficacy for patients with recurrent gliomas. To identify prognostic factors for each of 3 outcome variables, a master analysis file was constructed by pooling datasets summarizing key baseline factors and outcomes obtained in 15 North Central Cancer Treatment Group (NCCTG) trials (n=583, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n=596, 1998–2002). Methods: In addition to traditional variables (gender, age, performance score (PS), race, extent of primary resection, year of study entry, last known histology, time since initial diagnosis, baseline steroid use, prior chemotherapy (Y/N), prior nitrosoureas, baseline anticonvulsant use), we investigated prior t (TMZ), number of relapses, academic vs. community site and low grade at initial diagnosis. Outcome variables were: (1) overall survival (OS), (2) progression free survival (PFS) and (3) PFS6 = proportion of patients alive and progression-free 6 months after start of treatment. For all 3 endpoints, Classification and Regression Tree (CART) models and bootstrap samples were used to identify prognostic variables and to look for evidence of interactions among the independent variables affecting outcome. Results: For all outcomes the initial CART analysis selected last known grade (4 vs. 3) as the most important variable. Additional factors selected as predicting poor prognosis differed with grade and outcome measure and included prior TMZ, longer time since primary diagnosis, older age and poor PS. Community vs. academic was not a strong predictor in any of the models nor was low grade at initial diagnosis. Additional analyses are planned to better describe the impact of all the variables on outcome, including use of Cox models and logistic models considering all baseline variables with backwards selection. Conclusions: The results from analyses to date are consistent with current thinking that last known histology (grade) is an important factor. Time since initial diagnosis is likely a surrogate for number of relapses. More definitive conclusions await the completion of ongoing analyses. No significant financial relationships to disclose.

Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02)

2057 Background: Glioblastomas (GBM) frequently have amplification/mutation of EGFR and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have only modest activity, there is a rationale for combinations of these agents. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor CCI-779 in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, &gt; 18 yrs old, KPS &gt; 60, adequate bone marrow reserve and organ function. Patients (pts) must not be receiving enzyme inducing antiepileptic drugs. The dose of erlotinib was fixed at 150 mg/d. Patients initially received CCI-779 50 mg intravenously once weekly and the dose was adjusted based on toxicities. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade (G) 4 hematologic toxicity except for G3 thrombocytopenia, and any G3 or unacceptable G2 non-hematologic toxicities. Escalation was performed in groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 pts. Results: To date 22 eligible pts have been enrolled (15 GBM; 7 AG). Patient characteristics were 12 male, 10 female; median age: 54 (26–74); median KPS 90 (70–100); median prior chemotherapy regimens 1 (0–3). Two of 3 pts receiving 50 mg of CCI-779 developed DLTs (intolerable G2 rash &amp; mucositis, &amp; G3 liver function abnormalities; G3 rash &amp; dehydration). Three of 6 pts receiving 25 mg of CCI-779 weekly experienced DLTs (G3 rash; G3 rash, diarrhea, dehydration; G3 mucositis &amp; infection). Two of 6 patients receiving weekly 15 mg of CCI-779 experienced G3 rash. The protocol was amended to define a DLT only if &gt; G3 toxicities persisted despite maximal therapy. Six additional pts were treated at 15 mg of CCI-779. One of 6 pts developed a G3 rash. Conclusions: The combination of erlotinib and CCI-779 was associated with a higher than expected incidence of rash and mucositis. The MTD for this combination is likely to be 150 mg/d of erlotinib and 15 mg/d of CCI-779. Final pharmacokinetics and response data will be presented. No significant financial relationships to disclose.

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

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 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. 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. 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.