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© 1999 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid MalignanciesFrom the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio; The University of Texas Health Science Center at San Antonio, San Antonio; Division of Oncology, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX; and Schering-Plough Research Institute, Kenilworth, NJ. Address reprint requests to Lisa A. Hammond, MD, The Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 650, San Antonio, TX 78229; email lhammond@ saci.org.
PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m2/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (ClS/F) averaging 1.8 hours and 115 mL/min/m2, respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in ClS/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 µg/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 µg-h/mL, P = .0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.
TEMOZOLOMIDE (TMZ; Temodal; SCH 52365; Schering-Plough, Kenilworth, NJ), an oral imidazotetrazine alkylating agent, has demonstrated notable anticancer activity in patients with several types of drug-resistant malignancies, including high-grade glioma and metastatic melanoma.1-7 The discovery and development of TMZ emanated from efforts to identify imidazotetrazines with greater cytotoxic potencies, broader antitumor activities, and higher therapeutic indices than dacarbazine (DTIC), which is the prototypic compound of the series.8,9 TMZ is a 3-methyl analog of mitozolomide that has been evaluated in phase I and phase II investigations, albeit to a lesser extent than TMZ because of severe, unpredictable myelosuppression and negligible antitumor activity.8-13 Both TMZ and DTIC damage cells by generating the highly reactive metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which alkylates DNA, specifically the O6 position of guanine.14,15 From metabolic, pharmacologic, and clinical standpoints, TMZ is likely to be more advantageous than DTIC. To form MTIC from DTIC, DTIC must first undergo oxidative N-demethylation by cytochrome P450 mixed function oxidases in the liver. The rate of this P450-dependent process is likely to be associated with much greater interindividual variability than the spontaneous, nonenzymatic, and rapid degradation of TMZ to MTIC under physiologic conditions, potentially resulting in both unpredictable toxicity and antitumor activity.14-17 TMZ may be more advantageous than DTIC because of the requirement for DTIC to undergo hepatic enzymatic activation to MTIC, which may result in significant interindividual variability in DTIC pharmacokinetics and, therefore, a greater likelihood for both unpredictable toxicity and antitumor activity.15,16 In preclinical evaluations, in which a wide variety of murine and human tumor cell lines and xenografts were treated with TMZ, tumors derived from malignant astrocytomas and glioblastomas were clearly the most sensitive.18 The activities of TMZ were also clearly schedule-dependent, with greater antitumor activity and toxicity noted with more frequent or divided dosing schedules than single dosing schedules.15 In addition, tumor sensitivity was inversely related to the expression of O6-alkylguanine DNA alkyltransferase (ATase), which repairs DNA cross-linking induced by alkylating agents.19,20 The Cancer Research Campaign performed the earliest clinical evaluations of both oral and parenteral formulations of TMZ administered on single and divided dosing schedules.1 Because bioavailability and metabolism studies with 14C-TMZ demonstrated that oral bioavailability is nearly complete and not erratic, the oral formulation of TMZ has been primarily used in clinical evaluations.21 As predicted from preclinical evaluations, antitumor activity in patients with high-grade glioma and melanoma was noted consistently in phase I trials in Europe. The activity of TMZ in patients with these tumor types was confirmed in European phase II studies that primarily evaluated TMZ administered orally for 5 consecutive days.1,2,4,5 Myelosuppression has been the principal toxicity of TMZ on all schedules evaluated to date.1-7 In European studies evaluating TMZ 150 mg/m2/d for 5 days, the extent of prior myelosuppressive chemotherapy and/or radiation seemed to be a determinant of relevant hematologic toxicities; however, separate dosing recommendations for minimally pretreated (MP) and heavily pretreated (HP) patients have been formulated retrospectively, empirically, and inconsistently.1,4 The overall purpose of this study was to characterize the toxicity profile of TMZ administered orally as a single dose for 5 days every 4 weeks, and to prospectively formulate dosing recommendations based on the extent of prior myelosuppressive therapy for phase II and III evaluations of TMZ. The specific objectives of this study were to characterize the principal toxicities of TMZ on this schedule in patients with advanced solid malignancies; determine the maximum-tolerated dose (MTD) and recommend a dose for subsequent studies of TMZ for both MP and HP patients; characterize the PK behavior of TMZ and the relationships between the principal toxicities and the pertinent PK parameters in both MP and HP patients; and continue to acquire information about the antitumor activity of TMZ.
Eligibility Patients with histologically documented solid malignancies refractory to conventional therapy or for whom no effective therapy existed were candidates for this study. Eligibility criteria also included: (1) age  18 years; (2) a Southwestern Oncology Group performance status 2 (ambulatory and capable of self-care); (3) a life expectancy of at least 12 weeks; (4) no surgery, wide-field radiation therapy and/or chemotherapy within 4 weeks of treatment (6 weeks for those previously treated with a nitrosourea or mitomycin); (5) adequate hematopoietic (absolute neutrophil count [ANC] 1,500/µL, platelets 130,000/µL, and hemoglobin 9 gm/dL), hepatic (total bilirubin 1.0 mg/dL, AST and ALT 2.0 times the upper normal limit), and renal (serum creatinine 1.3 mg/dL or estimated creatinine clearance 60 mL/min according to the method of Cockcroft and Gault22) functions; (6) no prior resection of the stomach or small intestine; (7) no frequent vomiting or medical condition that could potentially interfere with oral drug administration; and (8) no coexisting medical problem of sufficient severity to limit full compliance with the study. All patients gave written informed consent according to federal and institutional guidelines before treatment.
Dosage and Drug Administration
At least three new MP and HP patients each were treated at every dose level. Phase I objectives in MP and HP patients were assessed independently. All patients at each dose level were to be treated and observed for a least 28 days before the next cohort of patients were treated at the next higher dose level. Intrapatient dose escalation to 150 mg/m2 was permitted in those patients treated at 100 mg/m2 if no dose-limiting toxicity (DLT) was experienced in the first cycle of treatment and if one new patient had completed treatment at the 150-mg/m2 dose level without DLT. Dose reductions by one level were permitted for patients experiencing DLT. If one of three new patients at any dose level experienced DLT, then a maximum of six new patients were treated at that dose level. The MTD or recommended phase II dose was defined as the highest dose level that induced DLT in less than one third of new patients (at least two out of a maximum of six new patients). DLT was defined as any one of the following events occurring during the first course of treatment: (a) ANC less than 500/µL lasting longer than 5 days; (b) ANC less than 500/µL associated with fever requiring hospitalization for parenteral antibiotics; (c) hemoglobin less than 6.5 mg/dL; (d) platelets less than 25,000/µL; (e) serum creatinine elevation greater than twice the upper limit of normal; or (f) nonhematologic toxicity of grade 3 to 4 severity (except vomiting associated with suboptimal pharmacologic prophylaxis and/or management). Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria.23 Patients were considered HP with therapies that may affect long-term hematopoietic function if they received radiation to more than 15% of bone marrow–containing areas and/or if they had undergone three or more prior chemotherapeutic regimens (or
Pretreatment and Follow-Up Studies
Plasma Sampling and Assay
Pharmacokinetic Analysis TMZ PK parameters were summarized using descriptive statistics. PK parameters in MP and HP patients were compared using the Wilcoxon rank sum test. The Wilcoxon matched pair signed-rank test was used to compare PK parameters obtained on days 1 and 5. The Kruskal-Wallis exact test was used to determine whether TMZ PK parameters (Tmax, half-life [t1/2], Varea, Clr, and fe) were dose-independent. The relationship between dose and systemic exposure (AUC and Cmax) and body-surface area (BSA) and PK parameters was assessed by univariate linear regression analysis using the JMP version 3.1 statistical software program (SAS Institute, Cary, NC).
Pharmacodynamic Analysis
These relationships were described using either the simple or sigmoidal maximum effect (Emax) model of drug effect, ie, percent change in hematologic parameter = (Emax x AUC
Twenty-four patients, whose characteristics are listed in Table 1, received 85 courses of TMZ through three dose levels (Table 2). The most prevalent tumor types were colorectal carcinoma, non–small-cell lung carcinoma, and melanoma. The numbers of new and total patients and courses at each dose level, as well as the cumulative incidences of DLTs, are also listed in Table 2. The median number of courses administered per patient was two (range, one to 10). All courses were fully assessable for toxicity. One patient was inadvertently assigned to the HP group, instead of the MP group at the 200-mg/m2/d dose level, which did not affect the determination of the MTD. Two patients required dose reductions from the 200 to 150 mg/m2/d because of severe myelosuppression at the high dose. Doses were increased from 100 to 150 mg/m2/d in three subjects who experienced either minimal or no toxicity at the lower dose. Treatment delays of 1 week were required during two courses because of unresolved grade 2 neutropenia in an MP patient at the 200-mg/m2/d dose level and grade 1 thrombocytopenia in an HP patient at the 150-mg/m2/d dose level.
Hematologic Toxicity
The next lower TMZ dose level, 150 mg/m2/d, was well tolerated by MP and HP patients. In addition, there was adequate cumulative experience at this dose level, with five new MP and three new HP patients receiving at least three courses of treatment. A total of 16 patients received 56 courses of TMZ at the 150-mg/m2/d dose level, with 26 and 30 courses administered to nine MP and seven HP patients, respectively. Two patients experienced grade 3 or 4 thrombocytopenia, during cycle 1 for one patient and during cycles 8, 9, and 10 for a second patient. Grade 3 or 4 neutropenia and neutropenic fever were not experienced by any of the 16 patients at the 150-mg/m2/d dose level. Anemia was never dose limiting (hemoglobin < 6.5 mg/dL). However, grade 3 anemia (hemoglobin 6.5 to 7.9 mg/dL) occurred during two courses involving two HP patients treated with TMZ at the 200-mg/m2/d dose level and during a single course in an HP patient treated with TMZ 150 mg/m2/d.
Nonhematologic Toxicity Other common complaints that were mild to moderate (grade 1 to 2) in severity included anorexia (12 patients, 50%), fever (12 patients, 50%), constipation (13 patients, 54%), fatigue (10 patients, 42%), and diarrhea (nine patients, 38%). However, the relative contributions of TMZ, progressive malignancy, and/or concurrent medications in the etiology of these complaints are not known. In addition, one patient developed a grade 2 rash, characterized by erythema, pruritus, and mild palmar and plantar desquamation on days 8 to 22 of course 2 of TMZ at 100 mg/m2/d. Another subject experienced grade 2 pruritus in the absence of an overt rash on days 2 to 7 of course 1 of TMZ at 150 mg/m2/d.
Antitumor Activity
Pharmacokinetic Studies
Within the narrow dose range studied, linear correlations were observed between TMZ dose and AUC values on day 1 (r2 = 0.78, P < .0001) and day 5 (r2 = 0.87, P < .0001) (Fig 2), whereas linear increases in Cmax as a function of dose were less evident on both day 1 (r2 = 0.28, P = .008) and day 5 (r2 = 0.56, P < .0001). Values for Tmax, t1/2, Cls, and Varea were not related to TMZ dose. Analysis of paired Cmax and AUC values on days 1 and 5 revealed that Cmax values were significantly higher on day 5 (P = .007) and AUC values were minimally (11%), albeit significantly (P = .001), higher on day 5 compared with day 1. Tmax and t1/2 values on days 1 and 5 were similar. The mean plasma concentration accumulation ratio was 1:1 (range, 0.88 to 1.64).
TMZ clearance values, in units of milliliters per minutes, and apparent volume of distribution values, in units of liters, increased with body size, with BSA as the size. TMZ Cls increased linearly with BSA on day 1 (r2 = 0.59, P < .0001) and day 5 (r2 = 0.61, P < .0001); similarly, relationships were observed for Varea on day 1 (r2 = 0.62, P < .0001) and day 5 (r2 = 0.52, P < .0001). Normalization of TMZ clearance to BSA decreased the interpatient variability (%CV) of this parameter from 20% to 13% on day 1, and from 16% to 10% on day 5. Renal clearance of the parent compound accounted for a negligible proportion of total drug disposition. Overall, 5% to 7% of TMZ systemic clearance was accounted for by renal clearance. The mean fe was 0.050 (range, 0.020 to 0.11) on day 1 and 0.069 (range, 0.010 to 0.13) on day 5 and Clr values averaged 5.7 mL/min/m2 (range, 2.4 to 115 mL/min/m2) and 6.9 mL/min/m2 (range, 0.77 to 17 mL/min/m2) on days 1 and 5, respectively.
Pharmacodynamic Studies
The favorable pharmacologic and clinical characteristics of the imidazotetrazine TMZ, including its predictable PK profile, penetration into the CNS, toxicity profile, and convenient oral dosing schedule, render the agent potentially useful in a variety of disease settings.1-7 TMZ has also demonstrated notable antitumor activity in patients with recurrent and refractory high-grade glioma and malignant melanoma, which are generally considered highly resistant malignancies.1-7 This phase I and PK study was performed to confirm the toxicities and dosing recommendations established in studies performed by the Cancer Research Campaign before phase II and III evaluations in North America and to determine whether the extent of prior myelosuppressive therapy influences the dosing recommendations. In this study, both untreated MP and HP patients were equally susceptible to the myelosuppressive effects of TMZ, experiencing unacceptable rates of DLT, which consisted of grade 4 neutropenia and thrombocytopenia, at the 200-mg/m2/d dose level. DLT was not observed in either MP or HP patients at the next lower TMZ dose level, 150 mg/m2/d for 5 consecutive days every 4 weeks, which was the MTD and dose recommended for further investigations. The conclusions of this present study were somewhat different than those of a concurrent phase I study reported by Dhodapkar et al,26 who stratified patients according to whether or not they had received prior treatment with nitrosourea. Dhodapkar et al demonstrated that prior treatment with nitrosourea affected the susceptibility to the myelosuppressive effects of TMZ. Thrombocytopenia was reported to be the principal DLT of TMZ on this administration schedule, with severe (grade 4) thrombocytopenia consistently noted at the 250- and 150-mg/m2/d dose levels in patients without and with prior nitrosourea exposure, respectively. In agreement with the results of this present study, these investigators also reported that the thrombocytopenia induced by TMZ was protracted, with complete recovery of platelet counts occasionally occurring 21 to 28 days after nadir counts were observed. The phase II doses that were recommended by Dhodapkar et al were 125 and 225 mg/m2/d for patients who were and were not previously treated with nitrosourea, respectively.26 The discrepancies between the two studies with regard to MTDs and doses recommended for phase II evaluations may be attributed to slight differences in study design, particularly differences in the definitions of DLT and the extensiveness of prior myelosuppressive therapy. First, with regard to the definitions of DLT, Dhodapkar et al defined DLT as a leukocyte count below 1,000/µL, which, in some cases, may be a lower threshold than the ANC count of 500/µL that was used in the present study. This may have accounted for the fact that neither neutropenia nor leukopenia was reported to be a principal DLT in that study. Dhodapkar et al considered a platelet count below 50,000/µL as a DLT, compared with 25,000/µL in the present study. This difference may have accounted for a lower recommended phase II dose for patients who had previously been treated with nitrosourea in the study performed by Dhodapkar et al.26 Therefore, these patients were possibly more susceptible to platelet toxicity compared with HP patients as defined in the present study. In addition, 100% of the HP patients who had received prior treatment with nitrosourea had also been treated with radiation, compared with only 19% of the patients without prior exposure to nitrosourea. Therefore, HP patients in the study reported by Dhodapkar et al were essentially patients who had previously been treated with both nitrosourea and radiation, which consists of a considerably high-risk group with regard to susceptibility to hematologic toxicity from any myelosuppressive therapy. In contrast, HP and MP patients were not as dissimilar in the present study because the definition of HP comprised patients who had received radiation to less than 15% of bone marrow–containing regions, which may have been too conservative. In the present study, HP patients also consisted of patients who had been treated with at least three prior regimens, which may not have been as relevant as the type of prior therapy. However, because the MTD for HP patients in the present study was principally defined by patients who would be considered HP with regard to myelosuppressive therapies by almost any criteria (eg, prior treatment with nitrosourea, carboplatin, multiple courses of alkylating agents, or wide-field radiation), it is likely that some HP patients as defined in the present study (ie, patients who had received more than three prior regimens of chemotherapy that do not contain alkylating agents and patients who had been treated with radiation therapy to < 25% of bone marrow–containing regions) could tolerate TMZ as well as the MP patients. There have been two other phase I studies of TMZ on this schedule in which patients were not stratified by the extent of prior therapy. The results of these other two studies are somewhat discrepant. Brada et al6 encountered severe thrombocytopenia at 250 mg/m2/d and the MTD was determined to be 200 mg/m2/d. In this study, the majority of patients were not previously exposed to chemotherapy, in contrast to the present study in which all but one patient was previously exposed to chemotherapy. In a similar study reported by Newlands et al,1 dose-limiting leukopenia and thrombocytopenia were noted at the 200-mg/m2/d dose level and 150 mg/m2/d was recommended as a starting dose for phase II evaluations, with subsequent dose escalation to 200 mg/m2/d in the absence of severe myelosuppression. Perhaps the best confirmation of the safety of the TMZ dose level established in phase I evaluations are the preliminary results of phase II studies of TMZ on a daily-for-5-days schedule, using a starting dose of 150 mg/m2/d with further dose escalation to 200 mg/m2/d if toxicity was acceptable. In these studies, severe (grade 3 to 4) thrombocytopenia was seen in approximately 5% of patients.2,4,7 The low interpatient variability in the clearance of TMZ (CV, 10% to 15%) and the lack of drug accumulation over 5 days of treatment may, in part, account for the predictable toxicologic profile of the agent, which has been noted in clinical evaluations to date.1,21,26 Such a low magnitude of interindividual variability in drug clearance is not generally noted with anticancer agents that are principally cleared by hepatic and renal mechanisms. This observation further supports the fact that TMZ clearance is not dependent on rate-limiting enzymatic mechanisms. Instead, the clearance of TMZ via formation of MTIC21,27 is rapid, spontaneous, pH-dependent, and occurs in all tissues to which TMZ distributes.14-17 The volume of distribution and clearance of TMZ increased in proportion with BSA, and interpatient variability in TMZ clearance was further reduced from 20% to 13% on day 1 and from 16% to 10% on day 5 when clearance was normalized to BSA. These results indicate that administering TMZ doses that are normalized according to BSA, instead of administering the same absolute TMZ dose in milligrams to all individuals, should result in less interpatient variability in TMZ exposure at any given dose level. Furthermore, these findings emphasize the importance of evaluating relationships between BSA, PK parameters, and drug effect in early clinical trials to determine the optimal appropriate dosing methods to minimize interpatient variability. The results of this present study, as well as other studies of TMZ on both single and multiple dosing schedules, indicate that the myelosuppressive effects of TMZ are related to drug exposure as assessed by AUC.28 Although drug dose and factors affecting absorption, distribution, and clearance are principal determinants of AUC, which, in the case of TMZ, was associated with low intersubject variability, the expression and activity of ATase has also been demonstrated to mediate the cytotoxicity of TMZ at the cellular level.29 A recent study of TMZ for 5 consecutive days demonstrated that progressive depletion of peripheral-blood mononuclear cell ATase, which facilitates the repair of DNA cross-linking induced by alkylating agents at the O6 position of guanine, may be responsible for the schedule-dependent activity of the agent.30 ATase depletion has also been demonstrated to correlate with sensitivity of hematopoietic progenitor cells to the cytotoxic effects of TMZ.31 In addition, intratumoral ATase activity has been shown to inversely correlate with tumor sensitivity to TMZ in preclinical studies. For example, Citron et al32 noted that 22% of primary brain tumors had no detectable levels of the DNA repair protein, which may help to explain the clinically relevant activity of TMZ against primary brain tumors. However, ATase has not been shown, as of yet, to be a principal determinant of tumor susceptibility to TMZ in the clinic. To perform population PD studies to address this issue, it will be important to establish whether ATase activity in peripheral-blood mononuclear cells is a surrogate for intratumoral ATase activity. In summary, this phase I and PK study of TMZ demonstrated that 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by both MP and HP patients alike, with higher doses resulting in unacceptably high rates of severe hematologic toxicity, particularly thrombocytopenia. To minimize nausea and vomiting, premedication with antiemetic medications is recommended. The results of PK studies indicate that the interindividual variability in clearance is low, which reflects the nature of TMZ's principal mechanism of elimination, and that intersubject variability can be minimized by individualized dosing based on BSA rather than use of a prespecified dose for all individuals. The low degree of toxicity of any type and general tolerability of TMZ at doses below 200 mg/m2/d on an oral daily dose schedule of 5 days every 4 weeks, the low degree of interindividual variability, and the spontaneous, nonenzymatic mechanism of drug elimination that is not likely to be affected by concurrent medications suggest that TMZ would be an optimal agent to develop in combination with other cytotoxic agents, as well as biologic and targeted therapeutics, for patients with melanoma, primary brain neoplasms, and other relevant malignancies.
Supported by a grant from Schering-Plough Research Institute, Kenilworth, NJ, and by the Frederic C. Bartter Clinical Research Unit of the Audie Murphy Veterans Administration Hospital through National Institutes of Health grant no. MO1 RR01346. We are grateful to Meredith Sterling for editorial assistance in the preparation of the manuscript.
Presented in part at the Thirty-First Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 20-23, 1995.
1. Newlands ES, Blackledge GRP, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer65:287-291, 1992[Medline] 2. O'Reilly SM, Newlands ES, Glaser MG, et al: Temozolomide: A new oral cytotoxic chemotherapy agent with promising activity against primary brain tumors. Eur J Cancer 29A:940-942, 1993 3. Nicholson HS, Krailo M, Seibel NL, et al: Phase I study of temozolomide (TEM) in children and adolescents: A report from the Children's Cancer Group (CCG). Proc Am Soc Clin Oncol16:214, 1997 (abstr 751) 4. Bleehan NM, Newlands ES, Lee SM, et al: Cancer research campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol13:910-913, 1995[Abstract] 5. Pearson ADJ, Estlin EJ, Lashford L, et al: Phase I study of temozolomide in pediatric patients with advanced cancer. Proc Am Soc Clin Oncol15:490, 1996 (abstr 1564) 6. Brada M, Moore S, Judson I, et al: A phase I study of SCH 52365 (temozolomide) in adult patients with advanced cancer. Proc Am Soc Clin Oncol14:470, 1995 (abstr 154) 7. Woll PJ, Crowther D, Johnson PWM, et al: Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma. Br J Cancer72:183-184, 1995[Medline]
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Gibson NW, Hickman JA, Erickson LD: DNA crosslinking and cytotoxicity in normal and transferred human cells treated in vitro with 8-carbamoyl-3-(2-chloroethyl)-imidazo (5-1-d),1, 2, 3, 5-tetrazin-4 (3 H)-one. Cancer Res44:1772-1775, 1985 10. Newlands ES, Blackledge G, Slack JA, et al: Phase I clinical trial of mitozolomide. Cancer Treat Rep69:7-8, 1985 11. Herait P, Rougier P, Oliviera J, et al: Phase II study of mitozolomide (M&B39565) in colorectal and breast cancer. Invest New Drugs6:323-325, 1988[Medline] 12. Harding M, Northcott D, Smyth J, et al: Short communication in: Phase II evaluation of mitozolomide in ovarian cancer. Br J Cancer57:113-114, 1988[Medline] 13. Stevens MFG, Hickman JA, Stone R, et al: Antitumor imidazotetrazines: I. Synthesis and chemistry of 8-carbamoyl-3(2-chloroethyl) imidazo (5, 1, d)-1, 2, 3, 5-tetrazin-4(3H)-one, a novel broad spectrum antitumour agent. J Med Chem27:196-201, 1984[Medline] 14. Denny BJ, Wheelhouse RT, Stevens MFG, et al: NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry33:9045-9051, 1994[Medline]
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Stevens MFG, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res47:5846, 1987 16. Mizuno NS, Decker RW: Alteration of DNA by 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (NSC-407347). Biochem Pharmacol25:2643-2647, 1976[Medline] 17. Wedge SR, Porteous SK, May BL, et al: Potentiation of temozolomide and BCNU cytotoxicity of O6-benzylguanine: A comparative study in vitro. Br J Cancer73:482-490, 1996[Medline]
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Baker SD, Wirth M, Statkevich P, et al: Absorption, metabolism and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res5:299-308, 1999 22. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron16:13, 1976 23. National Cancer Institute: Guidelines for Reporting of Adverse Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988 24. Shen F, Decosterd LA, Gander M: Determination of temozolomide in human plasma and urine by high-performance liquid chromatography after solid-phase extraction. J Chromatogr667:291-300, 1995[Medline] 25. Gibaldi M, Perrier D: Pharmacokinetics (ed 2). New York, NY, Marcel Dekker, 1982, pp 409-417 26. Dhodapkar M, Rubin J, Reid JM, et al: Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Clin Cancer Res3:1093-1100, 1997[Abstract]
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Liu L, Markowitz S, Gerson SL: Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis (2-chloroethyl) nitrosourea. Cancer Res56:5375-5379, 1996 30. Lee SM, Thatcher N, Crowther D, et al: Inactivation of O6 alkylguanine DNA transferase in human peripheral blood mononuclear cells by temozolomide. Br J Cancer69:452-456, 1994[Medline] 31. Fairbarn LJ, Watson AJ, Rafferty JA, et al: O6-benzylguanine increases the sensitivity of human primary bone cells to the cytotoxic effects of temozolomide. Exp Hematol23:112-116, 1995[Medline]
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Citron M, Decker R, Chen S, et al: O6 methyl-DNA methyl-transferase in human normal and tumour tissue from brain, lung, and ovary. Cancer Res51:4131-4134, 1991 Submitted September 15, 1998; accepted April 7, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
16% deviation from nominal values. 
)/(AUC50 + AUC
