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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7178-7187 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.502 Phase I Trial of Temozolomide Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant GliomaFrom the Departments of Surgery, Pathology, Radiology, and Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC; Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore; National Cancer Institute, Frederick Cancer Research and Development Center, Frederick; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD; Department of Medicine, Committee on Cancer Biology and Cancer Research Center, University of Chicago, Chicago, IL; Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Hershey, PA; Laboratory of Comparative Carcinogenesis, AOI Pharmaceuticals, Memphis, TN Address reprint requests to Jennifer A. Quinn, MD, Brain Tumor Center at Duke, Room 047 Baker House, Trent Dr, S Hospital, Durham, NC 27710; e-mail: quinn008{at}mc.duke.edu
PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
Resistance to chemotherapy remains the central reason for the failure to cure patients with a diverse spectrum of malignancies. Malignant glioma is a neoplasm with particularly dismal attributes in that virtually all tumors display marked de novo or acquired drug resistance and ultimate lethal growth. Conventional treatment with surgery, radiotherapy, and alkylnitrosourea-based chemotherapy cures a minority of patients with anaplastic astrocytoma (AA) and few patients with glioblastoma multiforme (GBM).1-3 temozolomide (Temodar; Schering-Plough, Kenilworth, NJ), a novel alkylating agent, has shown significant activity in recurrent malignant glioma.4-11 Unfortunately, the majority of patients with malignant glioma treated with alkylators, including temozolomide, demonstrate de novo or acquired resistance with subsequent tumor progression. A series of preclinical studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that resistance to temozolomide is mediated in part through the DNA repair protein AGT.12-15 AGT removes chlorethylation or methylation damage from the O6 position of DNA guanines before cell injury and cell death. Although it is clear that AGT is not the only mechanism of resistance to temozolomide in malignant glioma,13,16 it is certainly a highly important one. The high incidence of AGT activity in human CNS tumors,17 as well as recent clinical trials in malignant glioma using temozolomide that show an inverse relationship between response and AGT levels18 and survival and inactivation of the AGT gene by promoter methylation,19 provides the rationale for strategies designed to deplete tumor AGT levels during therapy with temozolomide. O6-benzylguanine (O6-BG) is an AGT substrate that inactivates AGT and enhances the cytotoxicity of temozolomide both in vitro14,15,20 and in vivo.12,21 The dose of O6-BG required to inactivate AGT and the duration of this inactivation in surgically removed tumor have proven to be controversial. Four clinical trials addressing this issue have been performed thus far. Spiro et al22 and Dolan et al23 found undetectable AGT levels in solid tumors, none of which were malignant gliomas, 18 hours and 16 ± 4 hours, respectively, after O6-BG administration. Friedman et al13 found a dose of 100 mg/m2 O6-BG to be adequate in depleting AGT activity to undetectable levels in malignant gliomas 18 hours after administration. On the other hand, Schold et al24 found 120 mg/m2 O6-BG effective in suppressing AGT 6 hours but not 18 hours after administration. We now report a two-phase clinical trial in patients with recurrent or progressive malignant glioma. The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete suppression of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the MTD of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine (8-oxoBG) were evaluated after O6-BG.
Objectives The primary objectives were three-fold: (1) to determine the dose of O6-BG administered as an intravenous bolus and subsequent 48-hour infusion effective in producing complete suppression of tumor AGT activity, (2) to determine the maximum tolerated dose (MTD) of temozolomide when administered after O6-BG and thus characterize any toxicity associated with this combination, and (3) to determine the plasma concentration of O6-BG and metabolites after this dose schedule of O6-BG. Our secondary objective was to observe patients for antitumor response.
Patient Eligibility Criteria The following patients were excluded from the study: pregnant women, nursing women, potentially fertile women or men who were not using an effective contraception method and patients recovering from surgery.
Treatment Design and Statistical Considerations O6-BG was supplied by the National Cancer Institute (Bethesda, Maryland) in a dual pack with diluent. The O6-BG was provided as a 100-mg vial of lyophilized powder with 670 mg of mannitol United States Pharmacopeia (USP) and sodium hydroxide. The diluent was provided as a 30-mL vial containing a sterile solution of 40% polyethylene glycol 400 in pH 8 phosphate buffer (106 mg of dibasic sodium phosphate and 102 mg of monobasic potassium phosphate in sterile water for injection USP). The 30-mL diluent was added to the O6-BG vial. Completely in solution, the O6-BG was further diluted to 0.04 mg/mL with 0.9% saline and given intravenously.
The prevalence of AGT at the time of craniotomy was used in this two-stage study to determine at each O6-BG dose level whether it was the optimal biologic dose. The null hypothesis used in this design anticipated that approximately 20% of tumors will have undetectable AGT in the absence of any treatment with O6-BG. In particular, the hypothesis tested at each dose level differentiated between an undesirable (20%) and desirable (90%) level of AGT prevalence. In the first stage, a maximum of 10 patients was accrued. During the first stage, if AGT levels at any time were detectable in three or more patients, the patient accrual in that cohort was terminated and the dose of O6-BG was escalated to the next dose level for subsequent patients. Otherwise, an additional four patients was added. If The decision rule concerning dose escalation satisfied the following criteria1: The chances of concluding that O6-BG inhibited AGT (ie, percentage of patients without AGT at craniotomy is 90%) when in reality O6-BG was not effective (ie, percentage of patients without AGT at craniotomy is 20%) was extremely small—much smaller than traditionally used error probabilities. A probability level of approximately 0.000004 was arbitrarily chosen.2 The chance of concluding that O6-BG inhibited AGT when in reality O6-BG did inhibit AGT was greater than 95%.
Second Phase: Determination of MTD for Temozolomide With Optimal Biologic Dose of O6-BG Temozolomide was commercially available from Schering-Plough Research Institute (Kenilworth, NJ). Temozolomide was supplied as a machine-filled, white opaque, preservative-free, two-piece, hard gelatin capsule available in 250-, 100-, 20-, and 5-mg strengths. Temozolomide was administered orally on an empty stomach with approximately 100% bioavailability. The dose was being rounded up to the nearest 5 mg. In establishing the optimal temozolomide dose when combined with O6-BG, a modified classic "3 + 3" dose escalation design was employed, which permitted up to three additional patients to be accrued at a given dose level as long as none of the first three patients enrolled at that dose level experienced a DLT. The dose level was escalated in successive cohorts of three patients as long as no DLT was observed. If one instance of DLT was observed among the initial three assessable patients, an additional three patients had to be treated at that dose level with no further DLT in order for dose escalation to proceed. If two instances of DLT were observed at a dose level, the MTD was determined to be surpassed, and a total of six patients were treated at the previous level to ensure its tolerability. The MTD was therefore the highest, causing DLT in no more than 1 of 6 patients at that dose level. Any patient who had stable or responding disease who developed DLT could continue to be treated at the next lowest dose level, provided the patient's toxicity resolved to grade 1 or lower and no more than 2 weeks were required for recovery. However, the patient was removed from study if DLT occurred on the lower dose. Dose-limiting toxicity was defined as grade 3 or greater nonhematopoietic toxicity or grade 4 hematologic toxicity if it occurred during the first cycle and was felt to be attributable to the study regimen. Furthermore, failure to recover from any non-DLT to no greater than grade 1 toxicity within 2 weeks of the end of the cycle (ie, 6 weeks from drug administration) was considered a DLT.
Pathologic Review
Toxicity Evaluation
AGT Activity
Plasma Sampling and Pharmacokinetic Studies
Response Criteria
As detailed in Table 1, 15 patients with malignant gliomas were enrolled into the first phase of the study, where the dose of O6-BG effective in producing complete depletion of tumor AGT activity was identified. Only one dose level of the 48-hour continuous infusion of O6-BG was evaluated before identifying a dose of 30 mg/m2/d as effective in depleting AGT at 48 hours when preceded by a fixed dose of O6-BG at 120 mg/m2 over 1 hour. Tumor AGT levels were not assessable in two of the 15 patients because of compromised tissue. These two samples were not analyzed because the pathologist found no viable tumor. One of the 13 assessable patients had AGT activity  10 fmol/mg of protein (11.6 ± 16.4 fmol/mg of protein). Twelve of the 13 assessable patients had AGT activity of less than 10 fmol/mg of protein, fulfilling our criterion for AGT depletion. Although statistically 14 assessable patients were recommended, only 13 assessable patients were enrolled once the AGT status of 12 of these patients was found to be undetectable. In other words, the AGT status of the fourteenth patient would not have changed the outcome, because only 11 patients with undetectable AGT levels were necessary to determine that the biologic modulatory dose of O6-BG was reached.
Patient Data Between February 7, 2001, and August 19, 2002, a total of 38 patients with recurrent or progressive high-grade gliomas (WHO stage III-IV) were enrolled into the study (Table 2) at one of six dose levels of temozolomide: 100, 200, 267, 355, 472, and 628 mg/m2. Consistent with the distribution of high-grade gliomas in adults, the majority of patients had a GBM (69%), whereas cases of AA were less frequent (26%), and AO was rare (5%). The median age was 43 years (range, 19 to 73 years), and there was a male predominance (76%). All patients underwent prior resection (82%), or biopsy (18%), radiotherapy, and chemotherapy (median of two different regimens [range, 1 to 5]). All patients but one (patient 21 in Table 4) had experienced prior chemotherapy treatment failure with temozolomide. In addition to radiotherapy, one patient received liquid brachytherapy with radioisotope-labeled monoclonal antibodies.
Toxicity Evaluation Of the 38 patients enrolled into the study, 34 were assessable for toxicity (Tables 3 and 4). At the first temozolomide dose level of 100 mg/m2, four of seven patients were assessable for toxicity. Of the three patients who were not assessable for toxicity, all failed to return for follow-up after study enrollment, one of whom died of cerebral herniation before completing the first cycle. Although no DLTs were noted at this dose level, one patient was hospitalized 3 days after initiation of the first cycle for signs of cerebral herniation (grade 3 nausea, vomiting, headache, and decreased level of consciousness) confirmed on MRI and deemed not related to study drug. At the second temozolomide dose level of 200 mg/m2, six of seven patients were assessable for toxicity. One patient was not assessable for toxicity because she died of cerebral herniation 18 days after enrollment. Although there were no DLTs at this dose level, one patient experienced a grade 3 leukopenia during the first cycle. At the third temozolomide dose level of 267 mg/m2, all six patients were assessable for toxicity with none experiencing any toxicities. At the fourth temozolomide dose level of 355 mg/m2, all six patients were assessable for toxicity. One of the six patients experienced a DLT of a grade 4 thrombocytopenia during the first cycle, followed by grade 3 anemia and vomiting after the first cycle. Two patients experienced an elevation in alanine aminotransferase (ALT) levels, both categorized as not dose limiting. One patient's ALT became elevated after the first cycle and the other patient's ALT remained elevated during the first cycle with the elevation proceeding study enrollment. At the fifth temozolomide dose level of 472 mg/m2, all seven patients were assessable for toxicity. One patient experienced a DLT of a grade 4 neutropenia. At the sixth temozolomide dose level of 628 mg/m2, all five patients were assessable for toxicity. Four of the five patients experienced DLTs consisting of grade 4 thrombocytopenia, grade 4 anemia, and grade 4 neutropenia along with grade 3 anemia and grade 3 thrombocytopenia, which were not dose limiting. Thus, after exceeding the MTD at a temozolomide dose of 628 mg/m2, the MTD was established at 472 mg/m2.
Antitumor Responses Of the 38 patients enrolled into the study, 36 were assessable for response. Two patients were not assessable for response because they failed to return for follow-up after enrollment. Twenty patients demonstrated progressive disease as their best response (Table 4). Thirteen patients demonstrated stable disease for one or two cycles. Seven patients with stable disease continued on treatment, having received a median of five cycles (range, three to 12). One patient (8) demonstrated a complete response (Fig 1) and remains free of disease after 12 cycles of temozolomide and 33 months off therapy.
Pharmacokinetic Analysis Plasma concentrations of O6-BG and metabolites during and up to 73 hours after the initial O6-BG infusion were collected on the initial 10 patients from the second phase of this trial; however, one patient was dropped from analysis because only a 25-hour post sample was collected (Fig 2). The number of patient samples collected for analysis at pre-O6-BG and at 25, 49, and 73 hours after were n = 9, 7, 9, and 4. Previous clinical studies13,27 demonstrated single bolus O6-BG (120 mg/m2) was rapidly oxidized to a longer-lived and equally effective alkyltransferase inactivator 8-oxoBG. Consistent with single bolus O6-BG, higher concentrations (19x to 24x) of mean plasma concentrations (± standard deviation) of 8-oxo-BG than O6-BG were observed at 25 and 49 hours after 120 and 30 mg/m2 continuous IV.
Although considerable effort has gone into the creation of novel therapies for brain tumors, alkylating agents remain the mainstay of glioma therapy. Of the alkylating agents, temozolomide, an orally available DNA-methylating agent that readily crosses the blood-brain barrier, has shown efficacy against human gliomas in clinical trials.4-11,28,29 Although, there have been attempts to improve the efficacy of temozolomide in anaplastic gliomas by combining it with carmustine [BCNU], these attempts have failed.30,31 The cytotoxic action of temozolomide, like that of other DNA-methylating agents, is dependent on the creation of O6-methylguanine DNA adducts,32 which initiates a futile recycling of the mismatch repair pathway, causing DNA strand breaks and apoptotic cell death in mismatch repair-proficient cells.33,34 The DNA repair protein AGT repairs these adducts in a suicide manner and reduces the cytotoxic action of temozolomide.12-15 The high incidence of AGT activity in human CNS tumors,17 as well as the inverse relationship between procarbazine activity and alkyltransferase levels in human brain tumor xenografts,35 support a role for this protein in mediating resistance to nitrosoureas in patients with CNS tumors and provide an approach for reversal of drug resistance. Furthermore, recent clinical trials have suggested that AGT levels in patients receiving BCNU therapy correlate with outcome. Belanich et al36 reported that in 167 patients treated with BCNU for malignant glioma, low tumor AGT content correlated with enhanced survival and longer time to treatment failure, whereas patients with elevated tumor AGT had poorer outcomes. Likewise, Hotta et al37 showed the same relationship in 42 patients with malignant glioma. Jaeckle et al.38 have reported a Southwest Oncology Group trial also correlating survival of patients with malignant glioma with tumor AGT levels. Finally, Esteller et al39 have also confirmed the relationship, albeit using methylation of the AGT promoter gene in lieu of quantitation of tumor AGT levels. The Brain Tumor Center at Duke has demonstrated the relationship between high AGT levels in GBM and failure to respond to preradiation temozolomide.18 Furthermore, Hegi et al19 have shown a relationship between inactivation of the AGT gene by promoter methylation and survival in patients with newly diagnosed glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide. Therefore, depletion of tumor AGT might enhance subsequent BCNU or temozolomide therapy and patient survival. Depletion of AGT activity by a selective inhibitor, O6-BG, enhances the cytotoxicity of chloroethylators and methylators.12,14,18,20,21,40-42 However, the main limitation in the clinical use of alkylating agents in combination with O6-BG is their potential for dose-related acute toxicity to the hematopoietic system. In animal studies43-45 of the combination of O6-BG and BCNU, enhanced bone marrow toxicity has been noted. This may also be true in humans, because AGT activity in hematopoietic progenitor cells has been shown to be low.46,47 Furthermore, O6-BG pretreatment markedly sensitized hematopoietic progenitor colony-forming cells to BCNU.47 To further explore the effect of O6-BG on BCNU activity and toxicity we performed phase 148 and phase 249 clinical trials in which this drug combination was administered to patients with recurrent or progressive malignant gliomas resistant to nitrosoureas. Our phase 1 trial established the MTD of BCNU to be 40 mg/m2 when combined with a sufficient dose of O6-BG (1-hour IV bolus of 120 mg/m2) found to deplete AGT in gliomas 18 hours after administration. This trial demonstrated the need for a marked reduction in the dose of BCNU compared with the usual dose of 200 mg/m2 when BCNU is used alone. The myelosuppression seen in the phase 1 trial was also seen in the phase 2 trial. This profound reduction of BCNU may be the underlying factor in the failure of this drug combination to cause frank tumor regressions in our phase 2 trial. Given the fact that O6-BG seemed to enhance the toxicity of BCNU without a corresponding increase in activity, a clinical combination of temozolomide with O6-BG may be preferred to a regimen involving BCNU and O6-BG, simply because the chloroethylnitrosoureas are inherently more toxic, particularly to hematopoietic cells. Thus, we explored temozolomide in combination with O6-BG for treatment of patients with malignant gliomas. The results of this trial clearly indicate that a O6-BG bolus dose of 120 mg/m2 over 1 hour followed by a 48-hour continuous infusion of 30 mg/m2/d can maintain tumor AGT levels at less than 10 fmol/mg of protein at 48 hours. Once this dose of O6-BG was combined with a single dose of temozolomide, the MTD of temozolomide was established at 472 mg/m2. Dose-limiting toxicity was limited to myelosuppression. Severe but reversible neutropenia, leukopenia, and thrombocytopenia were observed at a temozolomide dose of 628 mg/m2, which required reduction to 472 mg/m2 as the suggested dose for our phase 2 trial. Despite prior temozolomide failure, one patient demonstrated a complete response and currently remains disease-free 33 months after therapy completion. The mean plasma concentrations of O6-BG and 8-oxoBG over time after administration of 120 mg/m2 O6-BG for 1 hour have been reported13,27; however, this is the first report of plasma concentrations of drug and metabolite after a bolus dose of O6-BG at 120 mg/m2 with 30 mg/m2 continuous infusion for 48 hours. Previous studies demonstrated the area under the concentration-time curve for 8-oxoBG were 12- to 29-fold greater than those of O6-BG.27 Our data are consistent with 8-oxoBG plasma concentrations higher than those of O6-BG.
Although the 5-day dosing regimen of temozolomide (150 to 200 mg/m2/d) is accepted as the most efficacious regimen for administration, it is far from clear that it is the most efficacious and least toxic regimen when combined with O6-BG. Thus, we explored the 1-day temozolomide dosing schedule before exploring the 5-day schedule when combined with O6-BG for the following four reasons. First, although experimentally temozolomide activity seems to be schedule-dependent,50 with improved efficacy on a 5-day dosing regimen compared with a 1-day dosing regimen, no classic phase 1 or 2 trials have been performed to evaluate a single-day dosing schedule of temozolomide. Newlands et al51 performed a dose escalation study using a single dose of temozolomide and reported that no clinical responses were seen on this regimen. However, most of the courses the patients received were at a dose When designing this clinical trial, no preclinical information existed to address the optimum dosing schedule of O6-BG when combined with temozolomide in glioma cells. However, it was theorized that suppression of AGT for 48 hours after temozolomide administration would provide the time required for temozolomide to push cells toward the apoptotic pathway through futile mismatch repair cycling. Since initiation of this clinical trial, a preclinical study was performed by Hirose et al54 that addresses this exact issue. They report that maximal temozolomide sensitization in gliomas through prolonged AGT depletion with continuous O6-BG exposure was achieved 2 to 3 days after temozolomide exposure. This would suggest that continuous depletion of O6-BG for at least 48 hours, as performed in this study, would be preferred to intermittent depletion, as inferred from an alternative O6-BG regimen used in a clinical trial in pediatric tumors.55 This competing regimen uses a daily 60-minute IV infusion of O6-BG at 120 mg/m2 in combination with daily temozolomide, both of which were administered for 5 days. Although research13 shows depletion of AGT at 18 hours after a 120 mg/m2 60-minute IV infusion of O6-BG, it is highly unlikely and has never been proven that this depletion is continuous from 18 to 24 hours. Thus, the daily O6-BG bolus regimen in which continuous AGT depletion is improbable becomes a less attractive alternative. Support of our O6-BG regimen in providing levels of AGT activation can be found in the study by Gerson,56 where patients who received a 1-hour infusion of 120 mg/m2 O6-BG followed by a 23-hour infusion of 40 mg/m2 had persistent AGT inactivation.
Given the ubiquitous presence of AGT in all human organs and tissues, it was not surprising to find that temozolomide toxicity was enhanced and the dose of temozolomide defined as the MTD in this trial was significantly less ( The current trial of O6-BG and temozolomide has defined the therapeutic approach for our current phase 2 trial of temozolomide plus O6-BG. Patients with recurrent temozolomide-resistant malignant glioma, defined as tumor growth within 8 weeks of receiving temozolomide, will be enrolled onto this trial. This will provide the evidence needed to determine whether temozolomide plus O6-BG can restore temozolomide sensitivity in patients for whom this agent has previously failed.
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' conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Supported by National Institutes of Health Grants No. U01-CA62474 and NS30245. Pharmacological studies by the Pharmacology Core Facility at the University of Chicago Cancer Research Center were supported by National Cancer Institute Grant No. CA14599 (M.E.D.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 mg/dL or creatinine clearance greater than 60 mL/dL and serum urea nitrogen 
exc = 295 nm and 
) of all patients evaluated (except patient 8) at various time periods after O6-BG. Plasma concentration of O6-BG (
) and 8-oxoBG (
) of patient 8 (complete responder) after O6-BG.
50%) than when temozolomide was administered on the standard 5-day dosing schedule. However, it is far from clear whether the temozolomide dose has been reduced to an insufficient level at which antitumor activity will not be seen. Despite the reduced dose of temozolomide, our results suggest that O6-BG was effective in restoring temozolomide sensitivity in one patient with a temozolomide resistant tumor who demonstrated a complete response and remains disease-free after 33 months off therapy. 
