Originally published as JCO Early Release 10.1200/JCO.2005.23.622 on July 5 2005

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Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study

Evanthia Galanis, Jan C. Buckner, Matthew J. Maurer, Jeffrey I. Kreisberg, Karla Ballman, J. Boni, Josep M. Peralba, Robert B. Jenkins, Shaker R. Dakhil, Roscoe F. Morton, Kurt A. Jaeckle, Bernd W. Scheithauer, Janet Dancey, Manuel Hidalgo, Daniel J. Walsh

From the North Central Cancer Treatment Group; Mayo Clinic College of Medicine, Rochester, MN; The Johns Hopkins University, Baltimore, MD; The University of Texas Health Science Center at San Antonio, San Antonio, TX; Wyeth, Collegeville, PA; Cancer Therapy Evaluation Program, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Wichita Community Clinical Oncology Program, Wichita, KS; Iowa Oncology Research Association CCOP, Des Moines, IA; and the Mayo Clinic Jacksonville, Jacksonville, FL

Address reprint requests to Evanthia Galanis, MD, DSc, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905; e-mail: galanis.evanthia{at}mayo.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
BACKGROUND: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM).

METHODS: Recurrent GBM patients with 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly.

RESULTS: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (C_max), and sirolimus C_max and area under the concentration-time curve were decreased in patients receiving p450 enzyme–inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/– decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04).

CONCLUSION: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus–treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

	INTRODUCTION

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Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a dismal prognosis with 12- to 15-month median survival despite the use of surgery, chemotherapy, and radiation therapy. Treatment options are limited at recurrence. Although a variety of chemotherapy agents have been tried in this setting, response rates have been in the range of 0% to 20%,^1-5 and their impact on survival is in most cases questionable. There is an obvious need for the development of novel therapeutic agents for this disease.

Temsirolimus is an ester analog of sirolimus with improved aqueous solibility and pharmacokinetic properties (Fig 1).⁶ Sirolimus, a macrocyclic lactone and potent immunosuppressant, blocks growth factor–induced proliferation of T-cells by interacting with signal transduction systems that operate in both normal T cells and tumor cells.⁷ Rapamycin and temsirolimus bind to immunophilin FKBP-12 to form a complex that interacts with the mammalian target of rapamycin kinase (mTOR), blocking its activity. This in turn results in inhibition of key signal transduction pathways including those regulated by p70s6 kinase and the eukaryotic initiation factor 4E-binding protein (4E-BP1), resulting in cell cycle arrest at G1.^8-11

View larger version (15K): [in this window] [in a new window]   Fig 1. The structure of sirolimus ester temsirolimus (CCI-779) and its main metabolite sirolimus (rapamycin).

Temsirolimus and sirolimus are substrates for the cytochrome P450 3A4/5, which is primarily responsible for the oxidative biotransformation of temsirolimus in human liver microsomes.¹⁷ This is of particular importance in recurrent GBM patients given the fact that the majority of them are receiving P450-inducing anticonvulsant agents (EIACs), which could alter temsirolimus pharmacokinetics.

In in vitro experiments, glioma cell lines were among the most sensitive to the effect of temsirolimus (IC₅₀ < 10^–8).¹⁸ In vivo studies demonstrated activity of temsirolimus against subcutaneous and orthotopic glioblastoma models in nude mice.¹⁹ Temsirolimus phase I trials of temsirolimus in patients with solid tumors showed that weekly infusion of temsirolimus in doses of 7.5 to 220 mg/m² in patients with advanced cancer resulted in mild toxicity and evidence of antitumor activity.²⁰ Based on these data, a weekly dose of 250 mg temsirolimus was chosen for our trial of temsirolimus in recurrent GBM patients.²⁰

The goals of this study were to examine the efficacy of temsirolimus in the treatment of patients with recurrent glioblastoma multiforme, to further assess toxicity associated with the use of temsirolimus in this patient population, to evaluate the pharmacokinetics of temsirolimus in recurrent GBM patients receiving EIACs, to determine whether temsirolimus successfully interacts with the target pathway and correlate molecular characteristics of the patient's tumor with response to treatment.

	METHODS

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Eligibility Criteria
Patients were eligible for this phase II trial if they were 18 years of age or older and had histologic confirmation of a grade 4 astrocytoma at primary diagnosis or recurrence. Histologic diagnosis was confirmed by central pathology review. In addition, they were required to receive a fixed dose of corticosteroids or no corticosteroids for 1 week before baseline scan, could have received no more than one prior chemotherapy regimen for progressive or recurrent disease and had to have their last chemotherapy treatment 4 or more weeks before study start ( 6 weeks if nitrosourea was administered), and 12 weeks from completion of radiotherapy. They were also required to have an Eastern Cooperative Oncology Group performance score of 0 to 2; acceptable hematologic function defined as absolute neutrophil count (ANC) 1,500/µL, platelets 100,000/µL, and hemoglobin 9 g/dL; satisfactory hepatic and renal function, defined as total bilirubin 1.5 mg/dL, AST 3 x upper limit of normal, creatinine 2 mg/dL; and acceptable lipid levels defined as serum cholesterol 350 mg/dL and serum triglycerides 400 mg/dL.

Study Treatment
Temsirolimus at a dose of 250 mg was administered as a 30-minute intravenous (IV) infusion weekly. Patients were pretreated with diphenhydramine 25 to 50 mg IV 30 minutes before starting the temsirolimus infusion in order to prevent allergic reactions. Modifications of the temsirolimus dose were based on hematologic and nonhematologic toxicity at the time of weekly retreatment. Treatment delay was required for ANC count < 1,000/µL, platelet count < 100,000/µL, or for any nonhematologic toxicity grade 3 or higher. Upon recovery, a 25% decrease in temsirolimus dose was implemented for grade 3 interim toxicity and a 50% temsirolimus dose decrease was implemented for grade 4 toxicity. Patients requiring more than two dose reductions were taken off study and went into the event-monitoring phase.

A treatment cycle was defined as 4 weeks. Patients had CBCs performed weekly and chemistry groups performed at baseline and before each subsequent cycle. Patients receiving anticonvulsants had levels measured at baseline and before each subsequent cycle. In this study, EIACs included phenytoin, carbamazepine, phenobarbital, and valproic acid. Neuroimaging including head magnetic resonance imaging or computed tomography with contrast was performed at baseline, before the third cycle, and every second cycle thereafter. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0.

Definition of Response
The MacDonald criteria²¹ were employed for response assessment for patients with measurable disease. Complete response (CR) was defined as total disappearance of all tumor with patient no longer receiving corticosteroids. Partial response (PR) was defined as 50% reduction in the product of perpendicular diameters of contrast enhancing mass with no new lesions and the patient receiving stable or decreased corticosteroid dose. Stable disease was defined as failure to qualify for CR, PR, or progression. Progression was defined as 25% increase in the product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions.

For patients with evaluable disease, regression was defined as unequivocal reduction in size of contrast enhancement or decrease in mass effect as determined by primary physician and quality control physicians and no new lesion, with the patient receiving stable or decreased steroid dose. Progression was defined as unequivocal increase in size of contrast enhancement or increase in mass effect as assessed by primary physician and quality control physicians or appearance of new lesions. Patients with imaging findings not meeting criteria for complete response, regression or progression were determined to have stable disease. Responses were confirmed by central review by a neuroradiologist (B.J.E) and the principal investigator.

Statistical Considerations and Methodology
The primary end point of the trial was the percentage of patients alive and progression free at 6 months (PFS6). Secondary end points included the percentage of patients who were progression free at 3, 12, and 18 months, confirmed tumor response, overall survival (OS), and time to progression (TTP). The smallest success proportion, which would warrant subsequent studies with the proposed regimen in this patient population was defined as 30%, while the regimen would be considered ineffective if a success rate of less or equal to 10% was observed. Of note, in the North Central Cancer Treatment Group (NCCTG) database of recurrent GBM patients, the PFS6 is 10%. This design uses 33 patients and has an level of .04 and power of 0.89 for detecting a true success probability of 30%.

The original sample size of the trial was 37 (33 patients with four additional in case of drop-outs), and 41 patients were accrued initially. Based on antitumor activity observed in the first 41 patients, an additional 24 patients were enrolled to further evaluate the relationship, if any, between molecular characteristics of the patient's tumor and observed antitumor effect.

TTP was defined as time from study entry to disease progression. Patients who died were considered to have disease progression at time of death unless there was documented evidence that no progression occurred before death. OS was defined as time from study entry to death of any cause. Patients who had not died or progressed were censored at last known follow-up. For comparisons of time-to-event variables (ie, OS, TTP) with study outcomes (ie, hyperlipidemia, response, etc), patients with an event before the evaluation of the study outcome were not included in the analysis.²² Time to event was calculated from the study outcome until event or last known follow-up. Associations of categoric baseline, outcome, and translational data were tested using ² and Fisher's exact tests. Comparisons of continuous baseline, outcome, and translational data were tested using the Wilcoxon rank sum test. Survival and time-to-progression curves were compared via the log-rank test; Cox proportional hazards models were used to assess the relationship between time-to-event end points and baseline, outcome, and translational variables.

Pharmacokinetic Studies
The first six patients receiving P450-inducing anticonvulsants had pharmacokinetic analysis performed at the following time points to determine temsirolimus and sirolimus levels in whole blood. On treatment weeks 1 and 4, blood samples were obtained before treatment and at 0.5, 1, 2, 6, and 24 hours after treatment initiation. On treatment weeks 2 and 5, baseline blood samples for pharmacokinetic analysis were also obtained before drug administration.

Tesirolimus and sirolimus metabolite concentrations in whole blood were analyzed using separate validated methods for tesirolimus (0.25 to 100 ng/mL) and sirolimus (0.1 to 100 ng/mL) as previously described.^20,23 Analytes were detected and quantified by tandem mass spectrometry using atmospheric pressure chemical ionization.

The concentration-versus-time data for tesirolimus and sirolimus in whole blood were analyzed using a noncompartmental analysis technique.²⁴ Pharmacokinetic analysis was based on concentrations of tesirolimus and sirolimus measured in whole blood. Assay in plasma was also performed to examine the blood-to-plasma ratio. Calculated were peak concentration (C_max)_, area under the concentration-time curve (AUC), clearance (Cl), and steady-state volume of distribution (V_dss). In addition, the sum of tesirolimus plus sirolimus AUCs (AUC_sum) were calculated (unadjusted for modest differences in molecular weight).

Correlative Laboratory Analysis of Tissue Samples
p70s6 kinase activity was assessed in peripheral-blood mononuclear cells (PBMCs) before the first treatment, 24 hours after the first dose, and before the fourth temsirolimus dose. The p70s6 kinase was immunoprecipitated from protein extracts obtained from PBMCs and then assayed for kinase activity, as follows:

Whole blood was collected in a CPT vacutainer tube (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ), centrifuged at 1,500 g (2,860 rpm) for 30 minutes at room temperature, and PBMCs were collected after a second centrifugation of the pellet at 600 g (1,860 rpm) for 10 minutes at 4°C. PBMCs were homogenized in lysis buffer (50 mmol/L Tris; pH, 7.5, 120 mmol/L NaCl; 1 mmol/L ethylenediaminetetraacetic acid (EDTA); 50 mmol/L NaF; 40 mmol/L 2-glycerophosphate; 0.1 mmol/L sodium orthovanadate; 1 mmol/L benzamidine; 0.5 mmol/L phenylmethylsulfonyl fluoride, containing 1% Nonidet P-40 (Roche Applied Science, Indianapolis, IN), and 10 µg/ml aprotinin, pepstatin, leupeptin, and antipain). The protein concentration was determined, and equal amounts of lysate protein were incubated with antibody against p70s6 kinase (Santa Cruz Biotechnology, Santa Cruz, CA) overnight at 4°C, and then with 25 µL of protein G-agarose for 1 hour. The immune complex beads were washed twice with lysis buffer and with kinase buffer (50 mmol/L Tris; pH, 7.5; 10 mmol/L MgCl₂; 0.2 mmol/L ethyleneglycoltetracetic acid; 1 mmol/L dithiothreitol; 1 mmol/L benzamidine; and 0.5 mmol/L phenylmethylsulfonyl fluoride).

The washed immunocomplexes were resuspended in 30 µl of kinase assay buffer containing 40 µmol/L adenosine triphosphate (ATP), 2.5 µCi [³²P] ATP, 1 µmol/L protein kinase A inhibitor peptide, and 250 µmol/L p70s6 Rsk peptide substrate (Santa Cruz Biotechnology), and incubated at 37°C for 30 minutes. Samples (20 µl) were placed onto 0.25-mm p81 phosphocellulose paper circles, the papers were washed six times (5 minute each) in 75 mmol/L phosphoric acid, and radioactivity was counted by scintillation counting.

Fluorescence in Situ Hybridization Analysis of Tumor Samples for EGFR Amplification and PTEN Deletion in Baseline Tumor Samples
Dual-probe fluorescence in situ hybridization (FISH) analyses were performed on paraffin-embedded sections as described previously,²⁵ with locus-specific probes for EGFR and PTEN paired with centromere probes for chromosomes 7 (CEP7) and 10 (CEPT10), respectively (Vysis, Downders Grove, IL). Criteria for FISH anomalies were defined by use of histologically normal brain specimens as described previously.^25,26 Simple chromosome 7 or 10 gain required 30% or more of nuclei with three or more centromere probe signals. Loss of the q arm of chromosome 10 required 60% or more nuclei with one or fewer PTEN and CEP10 signals. PTEN deletion required an overall mean PTEN/CEP10 signal ratio of < 0.80. Amplification was applied for EGFR hybridizations only and required that the overall mean EGFR/CEP7 ratio be > 2.0.

Immunohistochemistry of Baseline Tumor Samples
PTEN immunohistochemistry (IHC) of baseline tumor samples was performed in paraffin slides that were incubated at 65°C for 30 minutes, deparaffinized through three changes of xylene for 5 minutes each, and dehydrated. The slides were subsequently placed in preheated EDTA buffer for 30 minutes, cooled in the buffer for 5 minutes, rinsed and stained by use of the DAKO Cytomation Autostainer (Carpenteria, CA) and the DAKO Mouse EnVision+, HRP/DAB+ Labeled Polymer detection kit (K4007). This includes a peroxidase blocking step and a 30-minute incubation of the primary PTEN antibody (A2B1 SC-77974, Santa Cruz Biotechnology). Slides were counterstained with a modified Schmidt's hematoxylin for 5 minutes and mounted with a permanent mounting media from DAKO. The following staining system was used: 0, negative or no staining; 1+, 1% to 24% of the cells stained; 2+, 25% to 64% of the cells stained; and 3+, 65% to 100% of cells stained.

IHC for p70s6 kinase, phosphorylated p70s6 kinase, Akt, and phosphorylated (phospho-) Akt in baseline tumor samples was performed using rabbit polyclonal antibodies to p70s6 kinase and Akt (Santa Cruz Biotechnology) and rabbit polyclonal antibodies to phospho-Akt (Ser 473) and phospho-70s6 kinase (Thr421/Ser424; Cell Signaling Technology, Beverly, MA). Sections were stained as reported previously,^27-29 heated to 60°C, and dehydrated in xylene and graded alcohols. Antigen retrieval was performed with 0.01 M citrate buffer at pH 6.0 at 95°C. Sections were incubated for 12 hours in primary antibody diluted in 50 mmol/L Tris HCl; pH, 7.6; 150 mmol/L NaCl; 0.1% Tween-20; 1% ovalbumin; and 1 mg/ml sodium azide, followed by incubations with biotinylated secondary antibody for 15 minutes, peroxidase-labeled streptavidin for 15 minutes (LSAB-2 System Dako Corp, Carpenteria, CA), and diaminobenzidine and hydrogen peroxide chromogen substrate (Dako Corp, Carpentaria, CA) and DAB enhancer (Signet, Dedham, MA) for 10 minutes. Slides were counter-stained with hematoxylin and mounted. The negative controls were incubated with immunoglobulin fraction (normal rabbit for polyclonal antibodies) in place of polyclonal primary antibody. The positive control for total and phospho-Akt antibodies was LNCaP prostate tumor cells while the positive control for total and phospho-p70s6 kinase was PC-3 cells.

The staining was scored as the product of the staining intensity (on a 0 to 3 scale) x the percentage of tumor cells stained, which is referred to as staining index (scale of 0 to 300). Staining intensity was scored as follows: 0 when none of the cells stained positively, 1 when there was weak staining, 2 when there was moderate staining intensity, and 3 when there was strong staining intensity.³⁰ Positive controls were also graded using the staining intensity scoring, and the staining considered acceptable only when the positive control displayed greater than a "2" staining intensity (on a scale of 0 to 3 reactivity). All assays demonstrating inferior reactivity on positive controls were repeated.

	RESULTS

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Patient Characteristics and Treatment
Sixty-five patients were accrued to the study; one patient was ruled ineligible for prior use of Gliadel wafers (Guilford Pharmaceuticals, Baltimore, MD) as per study eligibility criteria. Table 1 lists the characteristics of the patients in the study. The median age was 54 years (range, 19 to 79 years). Twenty-nine patients (44.6%) had received prior nitrosourea-based chemotherapy, and 35 patients (54%) were on p450 inducing anticonvulsants. The median number of cycles was two (range one to 10).

View larger version (16K): [in this window] [in a new window]   Fig 2. Most commonly observed treatment related toxicities for glioblastoma multiforme patients receiving temsirolimus (N = 65). The majority of the observed toxicity was mild (grade 1 and 2). The most common grade 3 and 4 toxicities included hypercholesterolemia (11%), hypertriglyceridemia (8%), hyperglycemia (8%) and thrombocytopenia (9%).

View larger version (166K): [in this window] [in a new window]   Fig 3. Magnetic resonance imaging scans in a study patient before (A,C) and after 8 weeks of temsirolimus treatment (B,D). There is significant improvement in T2 signal abnormality (B) with associated decrease in gadolinium enhancement (D), in T1 enhanced images, despite decrease in dexamethasone dose from 16 mg pretreatment to no dexamethasone at 8 weeks after initiation of treatment.

The first response assessment was scheduled, per protocol, before the ninth dose of temsirolimus. Only patients who underwent the scheduled scan after eight doses of temsirolimus were used for comparison of response and TTP/OS²² in order to avoid bias against the nonresponse group, which may have had a higher likelihood of early progression. The median TTP from study entry for the patients who had improvement in neuroimaging was 5.4 months (95% CI, 4.0 to 6.2), as compared with 1.9 months (95% CI, 1.9 to 3.0) for the nonresponse group (P = .007). The median OS was 5.8 months (95% CI, 4.6 to 8.7) for responders and 4.6 months (95% CI, 3.6 to 5.2) for nonresponders (P = .09). Of the patients who had a scan before the first scheduled assessment, median TTP was 4.8 months (95% CI, 3.1 to 5.5) for the responders and 1.8 months (95% CI, 1.4 to 1.9) for nonresponders. Of all patients assessed for response, median OS was 5.2 months (95% CI, 4.4 to 6.1) for responders and 4.1 months (95% CI, 3.3 to 4.8) for nonresponse group. Based on Cox proportional hazards models, response to treatment was the only variable associated with either TTP or OS (data not shown).

Pharmacokinetic Analysis
Pharmacokinetic analysis of temsirolimus and its main metabolite sirolimus was performed in whole blood from the first six patients on EIACs. As a comparison, data from six renal cell carcinoma patients not receiving EIACAs who were treated in the previously reported phase II study³¹ were examined. Table 3 summarizes these results. In patients from the GBM group receiving EIACs, temsirolimus C_max was decreased by approximately 73%, whereas Cl and V_dss were generally unchanged as compared to renal patients. For sirolimus, C_max, AUC and AUC_sum were decreased by approximately 47%, 50%, and 40%, respectively, in the GBM group receiving EIACs.

View larger version (56K): [in this window] [in a new window]   Fig 4. Immunohistochemistry staining for phosphorylated p70s6 kinase (Thr 421/Ser 424). (A) Pretreatment tumor sample in a study patient with a staining index of 300. (B) Pretreatment tumor sample in a different patient with a staining index of 0.

	DISCUSSION

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The majority of the observed toxicity was grade 1 and 2. The most common grade 3 or higher toxicity was nonhematologic and consisted of grade 3 or higher hypercholesterolemia observed in 11% of patients, hypertriglyceridemia in 8%, and hyperglycemia in 8%. Given the fact that mTOR is a component of the insulin signaling pathway,^32,33 its inhibition could be responsible for these metabolic abnormalities. Furthermore, these metabolic parameters could conceivably serve as correlates of temsirolimus target inhibition, and antitumor activity. Our observation that patients who developed grade 2 or higher hyperlipidemia had a higher likelihood of antitumor activity (71%) versus patients without this toxicity (31%; P = .04) supports this hypothesis. If this novel observation is confirmed in other trials of mTOR inhibitors, it could support the concept of intrapatient dose escalation to mild metabolic toxicity.

With a PFS6 of 7.8% for all patients, the primary efficacy end point of this trial was not met. In addition there were no objective responses, as defined by the MacDonald criteria. Nevertheless, 20 patients in our trial (36%) had evidence of radiographic improvement by neuroimaging, observed as early as 3 weeks from initiation of temsirolimus treatment and, in the majority of patients, was associated with improvement in symptom status. The predominant radiographic change consisted of improvement in T2 signal abnormality (with the patient receiving stable or decreased doses of steroids) and it was frequently associated with a decrease in gadolinium enhancement. These patients had a significantly longer TTP as compared with nonresponders (5.4 v 1.9 months; P = .007), indicating that the observed improvement in neuroimaging represents clinically meaningful activity of tesirolimus.

Furthermore, the neuroimaging changes observed in our study in response to treatment emphasize the challenges associated with glioma response assessment when cell cycle inhibitors or biologic agents, with different mechanisms of action as compared to conventional chemotherapy agents, are tested in clinical trials. There is therefore an ongoing need to validate alternative methodology for response assessment, either magnetic resonance imaging based³⁴ or functional imaging,³⁵ and correlate with outcomes.

Temsirolimus is metabolized in the liver through the CYP3A4/5.¹⁷ This is of particular importance in glioma trials because the majority of glioma patients in a community setting (54% in our series) were receiving EIACs, which have been shown to significantly affect pharmacokinetics and toxicity of other antitumor agents, such as topotecan and irinotecan. In contrast to other trials of temsirolimus in which different doses were administered to patients who were versus patients who were not on EIACs,⁵ all patients received the same temsirolimus dose in our trial. Pharmacokinetic analysis of temsirolimus and sirolimus levels from the first six GBM patients receiving EIACs and from six renal cell carcinoma patients not receiving EIACs appeared to demonstrate a decrease in peak exposure (temsirolimus and sirolimus), and in AUC (sirolimus). Nevertheless, the sirolimus AUC for the patients receiving EIACs was still above the level of 3,930 ng·h/mL, which has been found to be therapeutic in preclinical glioblastoma models (J. Boni, personal communication, April 2005). Consistent with this observation, there was no difference in antitumor activity in our study between patients who were and were not concomitantly receiving EIACs (P = .52). Furthermore, toxicity was comparable between the two groups of patients, with the exception of grade 3 hematologic toxicity, which was more common in patients who were not receiving EIACs than in those who were receiving EIACs (20% v 3%; P = .04). Dose reductions due to toxicity were similar between the two patient groups, however (32% v 43%; P = .37). It should be noted, however, that the tesirolimus dose of 250 mg used in our trial is higher than the tesirolimus dose of 25 mg weekly employed in phase II tesirolimus trials in other tumor types. The impact of EIACs on the tesirolimus/sirolimus pharmacokinetics, as demonstrated in our study could have clinical implications, and should be taken into consideration, if lower tesirolimus doses are to be employed in brain tumor patients.

In addition to addressing classic questions regarding safety, efficacy, and pharmacology in the clinical development of targeted antitumor agents, other key issues to be addressed include assessing the pharmacodynamic effect of the agent and identifying a patient population most likely to derive clinical benefit from the drug. The inhibition of mTOR blocks the signals of at least two separate downstream pathways. One involves the activity of the 40S ribosomal protein S6 kinase, p70s6k, and the other the function of eukaryotic initiation factor-4E (eIF-4E)-binding protein-1 (4E-BP1).^36,37 In order to identify possible predictive markers of antitumor activity to tesirolimus, we examined baseline tumor specimens for EGFR amplification (by FISH) and PTEN deletion/mutation (by FISH and IHC). In addition, we assessed activation of the PI3K pathway by examining baseline tumor specimens for Akt, phosphorylated Akt, p70s6 kinase and phosphorylated p70s6 kinase. Of these tissue biomarkers, only phosphorylation of P70s6 kinase in baseline tumor samples was associated with response, with p70s6 kinase staining indices 200 being significantly more frequent in responders versus nonresponders (P = .04). Because p70s6 kinase is downstream from mTOR, its activation can reflect the activation status of multiple upstream pathways. This may explain its higher sensitivity in predicting activity of tesirolimus as compared with the other tissue biomarkers tested. Although based on a small number of patients, this finding represents one of the first examples of a tissue biomarker possibly allowing the identification of a GBM patient population, for which a targeted therapeutic agent may have a higher likelihood of activity. Thus, levels of phospho-p70s6 kinase should be evaluated prospectively in other mTOR inhibitor studies. In contrast, inhibition of p70s6 kinase activity in PBMCs, a potentially very useful surrogate of target inhibition³⁸ was not associated with neuroimaging improvement.

Does temsirolimus have a role as palliative monotherapy in patients with recurrent GBM? With a median TTP of 5.4 months for responders, our study appears to indicate that tesirolimus may be a useful treatment for GBM patients with high baseline tumor levels of phosphorylated p70s6 kinase. Prospective validation of these findings is warranted. Furthermore, on the basis of data indicating synergy with other modalities such as radiation therapy³⁹ and small-molecule tyrosine kinase inhibitors such as EKI-785,⁴⁰ combination studies in gliomas are in development or ongoing. Characterization of molecular alterations in gliomas that may be predictive of response to treatment should represent an important component of these trials.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Author Name Employment Leadership Consultant Stock Honoraria Research Fund Testimony Other Joseph Boni Wyeth Wyeth (A)

Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported by North Central Cancer Treatment Group grant CA25224, R21 CA99209, and General Clinical Research Centers grant MO1 RR00585-34.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted April 12, 2005; accepted April 28, 2005.

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