A Phase I and Pharmacokinetic Study of Temozolomide and Cisplatin in Patients with Advanced Solid Malignancies1

Vol. 5, 1629–1637, July 1999 Clinical Cancer Research 1629

Carolyn D. Britten, Eric K. Rowinsky, bination with CDDP. Fifteen patients received a total of 44 Sharyn D. Baker, Sanjiv S. Agarwala, courses of TMZ/CDDP. The principal toxicities of the regi- John R. Eckardt, Rebecca Barrington, men consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new Sami G. Diab, Lisa A. Hammond, Tom Johnson, patients treated at the 200/100 mg/m2 dose level. Of five Miguel Villalona-Calero, Uwe Fraass, patients receiving 17 courses at the next lower dose level Paul Statkevich, Daniel D. Von Hoff, and (200/75 mg/m2), none experienced dose-limiting toxicity. An- S. Gail Eckhardt2 titumor activity was observed in patients with non-small cell Cancer Therapy and Research Center, Institute for Drug lung cancer, squamous cell carcinoma of the tongue, and Development, and The University of Texas Health Science Center at leiomyosarcoma of the uterus. Pharmacokinetic studies of ؎ San Antonio, San Antonio, Texas 78229 [C. D. B, E. K. R., S. D. B., TMZ revealed the following pertinent parameters (mean ؎ ؍ J. R. E., R. B., S. G. D., L. A. H., M. V-C., D. D. V. H., S. G. E.]; The SD): time to maximum plasma concentration (Tmax) 1.1 University of Pittsburgh Medical Center, Montefiore Hospital, 0.6 h (day 1) and 1.7 ؎ 0.9 h (day 2); elimination half-life ؎ ؎ ؍ Division of Medical Oncology, Pittsburgh, Pennsylvania 15213 [S. S. A.]; Brooke Army Medical Center, Fort Sam Houston, Texas (t1/2) 1.74 0.22 h (day 1) and 2.35 0.70 h (day 2); and ؎ 2 ؎ ؍ 78234 [T. J.]; and Schering-Plough Research Institute, Kenilworth, clearance (Cls/F) 115 27 ml/min/m (day 1) and 141 New Jersey 07033 [U. F., P. S.] 109 ml/min/m2 (day 2). TMZ drug exposure, described by

(the area under the plasma concentration-time curve (AUCؕ

and the maximum plasma concentration (Cmax), was similar ABSTRACT on days 1 and 2. Temozolomide (TMZ) is an oral imidazotetrazinone On the basis of these results, the recommended doses that is spontaneously converted to 5-(3-methyltriazen-1- for Phase II clinical trials are TMZ 200 mg/m2/day for 5 yl)imidazole-4-carboxamide (MTIC) at physiological pH. days with 75 mg/m2 CDDP on day 1, every 4 weeks. The 6 MTIC methylates DNA at the O position of guanine, al- addition of CDDP did not affect the tolerable dose of single- 6 -though this lesion may be repaired by the enzyme O -alkyl- agent TMZ (200 mg/m2/day ؋ 5 days), nor did it substan guanine-DNA alkyltransferase (AGAT). In this study, TMZ tially alter the pharmacokinetic behavior of TMZ. was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tu- INTRODUCTION mor types. Additionally, CDDP has been shown to inactivate 3 AGAT, and subtherapeutic concentrations of CDDP have The rationale for the development of TMZ (Fig. 1) is to been shown to increase the sensitivity of leukemic blasts to increase the therapeutic index of the imidazotetrazinone alky- TMZ. This Phase I study sought to determine the toxicities, lating agents (1). Like DTIC, the prototypical compound of this class, TMZ is a prodrug of MTIC (1–5), the putative active recommended dose, and pharmacological profile of the 6 TMZ/CDDP combination. species that methylates DNA at the O position of guanine Patients were treated with oral TMZ daily for 5 con- (6–13). DTIC requires hepatic p450-mediated metabolic acti- secutive days together with CDDP on day 1 (4 h after TMZ) vation to generate MTIC, which is associated with high inter- 2 individual variability (2, 14), whereas TMZ is converted to every 4 weeks at the following TMZ (mg/m /day)/CDDP 2 MTIC spontaneously, rapidly, and predictably at physiological (mg/m ) dose levels: 100/75, 150/75, 200/75, and 200/100. pH (1–3). This more consistent generation of the active moiety Plasma samples were obtained on days 1 and 2 to evaluate after TMZ administration may result in substantially less inter- the pharmacokinetic parameters of TMZ alone and in com- individual variability in the generation of MTIC and hence greater predictability with respect to the toxicity and efficacy of this imidazotetrazinone. In preclinical studies, TMZ has demonstrated antitumor Received 1/14/99; revised 3/31/99; accepted 4/1/99. activity against human lymphoblastoma, myeloid leukemia, The costs of publication of this article were defrayed in part by the Burkitt’s lymphoma, choriocarcinoma, astrocytoma, and lung, payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported in part by Schering-Plough Research Insti- tute. Some patients in the study were treated at the Frederic C. Bartter Clinical Research Unit of The Audie Murphy Veterans Administration 3 The abbreviations used are: TMZ, temozolomide; DTIC, dacarbazine; Hospital, supported in part by NIH Grant MO1 RR01346. MTIC, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; AGAT, O6- 2 To whom requests for reprints should be addressed, at Institute for alkylguanine-DNA alkyltransferase; DLT, dose-limiting toxicity; AUC, Drug Development, Cancer Therapy and Research Center, 8122 Data- area under the plasma concentration-versus-time curve; CDDP, cispla- point Drive, Suite 700, San Antonio, Texas 78229. Phone: (210) 616- tin; MTD, maximum tolerated dose; ECOG, Eastern Cooperative On- 5834; Fax: (210) 692-7502; E-mail: [email protected]. cology Group; ANC, absolute neutrophil count.

TMZ and CDDP at subtherapeutic concentrations (32). In addition, with nonoverlapping DLTs, the administration of TMZ and CDDP was anticipated to be feasible. Finally, even in the presence of CDDP-induced nephrotoxicity, the disposition of TMZ would not be expected to be affected, because TMZ is only minimally disposed of by renal mechanisms (5–7%; Refs. 4, 22, 23). The objectives of this Phase I and pharmacokinetic study were to: (a) describe the DLTs of TMZ administered as a Fig. 1 Chemical structure of TMZ. single oral dose daily for 5 days every 4 weeks combined with CDDP as a 60-min infusion on day 1; (b) determine the MTD and recommended Phase II doses of TMZ and CDDP on this schedule; (c) characterize the pharmacokinetic behavior of TMZ colorectal, and testicular carcinoma cell lines, with IC50 values in combination with CDDP; and (d) report any observed anti- ranging from 10 to 718 ␮M (6, 15, 16). The activity of TMZ in cancer activity in patients with advanced solid malignancies. vitro has been shown to be inversely proportional to the activity of the DNA repair enzyme AGAT (6–9), and certain cell lines are more sensitive to TMZ after AGAT inhibition (6, 7, 9–13). PATIENTS AND METHODS In the human tumor cloning assay, TMZ inhibits the growth of Patient Selection. Patients with histologically confirmed clonogenic cells from human tumors obtained from patients advanced solid malignancies refractory to standard therapy or with melanoma, sarcoma, and breast, ovarian, lung, renal cell, for whom no effective therapy existed were candidates for this colon, prostate, and pancreas carcinomas (17). In vivo, both i.p. study. Other eligibility criteria included: (a) age Ն18 years; (b) and oral administration of TMZ prolong the survival of nude ECOG performance status of Յ2 (ambulatory and capable of mice bearing murine TLX5 lymphoma (1). The effects on sur- self care); (c) life expectancy Ͼ12 weeks; (d) no known brain vival are schedule dependent, with greater efficacy noted with metastases or primary central nervous system tumor; (e)no repetitive divided dose administration (e.g., daily for 5 days) chemotherapy, radiotherapy, or biological therapy in the previ- compared with a single bolus administration (1). Additional ous 4 weeks; (f) no prior therapy with mitomycin C or nitro- studies have demonstrated appreciable cytoreduction in glioma, soureas; (g) no cumulative prior radiotherapy to fields contain- ependymoma, melanoma, ovarian, and colon cancer xenografts ing Ͼ15% of the bone marrow reserve; (h) adequate (18–20). hematopoietic (ANC Ն1500/␮l and platelet count Ն100,000/ In Phase I clinical trials, the principal DLT of TMZ has ␮l), hepatic (total serum bilirubin within the upper limit of been myelosuppression (21–25). Although nausea and vomiting normal and transaminases Յ2 times upper limit of normal), and were initially reported to be common, these effects have been renal (serum creatinine concentration Յ 1.5 mg/dl) functions; (i) mitigated by antiemetic medications, particularly serotonin an- no frequent vomiting or medical condition that could interfere tagonists (21–25). When administered daily for 5 days every 4 with the absorption of oral medications; and (j) no other coex- weeks, the recommended Phase II dose of TMZ has ranged from isting medical problems of sufficient severity to prevent full 125 to 225 mg/m2/day (21–24). Drug exposure, measured as the compliance with the study. In addition, patients were ineligible AUC, has increased linearly with dose, and drug clearance has for this study if they had received prior DTIC or more than three been dose independent, with mean values ranging from 102 to prior courses of platinum-based chemotherapy. Written in- 115 ml/min/m2 (4, 21–24). Oral TMZ has also been reported to formed consent was obtained according to federal and institu- be nearly completely bioavailable (Ͼ99%; Refs. 4, 21). In the tional guidelines. initial Phase I trial, there were no objective responses noted in Drug Dosage and Escalation. The starting doses were 51 patients treated with a single dose of TMZ (21). In view of 100 mg/m2 TMZ as a single oral dose daily on days 1–5 and 75 the schedule-dependent antitumor activity in preclinical studies, mg/m2 CDDP i.v. over1honday1,4hafter the administration an additional 42 patients were treated with TMZ daily for 5 days of TMZ. Courses were administered at a minimum interval of 28 every 4 weeks (21). On this schedule, there were five responses, days. The dose of TMZ in this combination was escalated in including two complete responses in patients with melanoma each successive group of new patients until the previously (21). Additional studies have confirmed the promising activity determined MTD for single-agent TMZ (200 mg/m2/day) was of TMZ on the daily ϫ 5 schedule in both melanoma (26) and reached (21). CDDP was then escalated from 75 to 100 mg/m2. high-grade astrocytoma (27–29), with response rates of 24 and The following dose levels of TMZ (mg/m2/day)/CDDP (mg/m2) 27–42%, respectively. were planned: 100/75, 150/75, 200/75, and 200/100. It was In this Phase I trial, oral TMZ was administered as a single planned to enroll one patient at the first dose level to ensure that oral dose daily for 5 days every 4 weeks with CDDP adminis- myelosuppression was not more severe than anticipated from tered i.v. on day 1. The rationale for evaluating this regimen studies of single-agent TMZ. Thereafter, it was planned to enroll was, in part, the single-agent activity of both TMZ (21–23, 26) at least three patients at each dose level until DLT was reached. and CDDP (30) against melanoma, a relatively refractory tumor DLT was defined as any one of the following: (a) ANC type. Furthermore, CDDP had been shown to reduce AGAT Ͻ500/␮l lasting for longer than 5 days or associated with fever; activity in vitro (31), suggesting that CDDP might enhance the (b) platelet count Ͻ50,000/␮l; (c) hemoglobin Ͻ6.5 g/dl; (d) antitumor activity of TMZ. This was supported by the demon- serum creatinine Ͼ2.2 mg/dl, persisting for Ͼ2 weeks after the stration of enhanced cytotoxicity in leukemic blasts treated with scheduled date of retreatment; and (e) nonhematological toxicity

that was at least National Cancer Institute grade 3 in severity the sum of the bidimensional measurements of all known dis- (excluding grade 3 nausea or vomiting and grade 3 fever in the ease by at least 25% or the appearance of new lesions. absence of infection). If one DLT occurred, a maximum of six Plasma Sampling and Assay. The effect of cisplatin on patients were treated at that dose level. The MTD level was the pharmacokinetic behavior of temozolomide was evaluated defined as the highest dose level in which fewer than two of six by sampling blood before (on day 1) and after (on day 2) new patients experienced DLT. Toxicities were graded accord- cisplatin administration. Blood was collected before treatment ing to the National Cancer Institute common toxicity criteria and at 0.5, 1, 2, 3, 4, 6, and 8 h after the administration of TMZ (33). on days 1 and 2 of course 1. The samples were collected in Patients who had not developed progressive disease at the prechilled syringes, placed in prechilled heparinized tubes, and time of reassessment and who had not experienced DLT were immediately transferred to an ice-water bath. Within 30 min of permitted to continue treatment with TMZ and CDDP at the sample collection, plasma was separated by centrifugation at same dose level. Patients who had experienced DLT were eli- 3000 ϫ g for 10 min at 4°C. After centrifugation, 2 ml of plasma gible for continuation of treatment with the combination after a were transferred to a plastic tube containing 100 ␮l of 8.5% reduction in the dose of TMZ by one dose level. No dose phosphoric acid, vortexed briefly, and then separated into two reduction was allowed for CDDP. CDDP was to be discontinued equal portions. These specimens were frozen immediately and in patients who experienced nephrotoxicity manifested by a stored at Ϫ20°C. persistently elevated serum creatinine of Ͼ1.8 mg/dl for 2 Plasma samples were assayed for TMZ by high-perfor- weeks after the scheduled day of dosing. Discontinuation of mance liquid chromatography as described previously (34). The CDDP in patients exhibiting severe (grade 3 or 4) neurotoxicity lower limit of quantification of TMZ was 0.1 ␮g/ml. Over the or ototoxicity was at the discretion of the investigator. concentration range of 0.1–20 ␮g/ml, the intra- and interday Drug Administration. TMZ was supplied by Schering- precision was Յ15%. As well, the accuracy demonstrated Plough Research Institute (Kenilworth, NJ) as white opaque, Յ15% deviation from nominal values. preservative-free, two-piece, hard gelatin capsules in strengths Pharmacokinetic Analysis. Individual TMZ plasma of 5, 20, 100, and 250 mg. The calculated doses of TMZ were concentrations on days 1 and 2 were analyzed using model- rounded to the nearest 5 mg to accommodate capsule strength. independent methods (35). The maximum plasma concentration

TMZ was administered p.o. on days 1–5 to patients who fasted (Cmax) and time of maximum plasma concentration (Tmax) were for at least 4 h before and 2 h after dosing. CDDP (Platinol-AQ; determined by inspection of the plasma concentration-versus- Bristol-Myers Squibb, Princeton, NJ) was supplied in vials of time curves. The terminal rate constant, k (elimination phase 100 mg/ml. The calculated dose of CDDP was diluted in 500 ml rate constant), was calculated as the negative of the slope of the of normal saline containing 12.5 g of mannitol and was admin- log-linear terminal portion of the plasma concentration-versus- istered on the first day of each course, 4 h after TMZ. One liter time curve using linear regression. The terminal half-life, t1/2, of normal saline with 20 mEq KCl/liter, and1gofmagnesium was calculated as 0.693/k. The AUC from time zero to the time sulfate was administered both before and after the CDDP infu- of the final quantifiable sample, AUC(tf), was calculated using sion. the linear trapezoidal method and was extrapolated to infinity The following antiemetic medications were administered according to the following equation: prophylactically on day 1 of each course: 8 mg of ondansetron ϭ ͑ ͒ ϩ ͑ ͒ p.o. 30 min prior to TMZ, and both 32 mg of ondansetron i.v. AUCϱ AUC tf C tf /k and 10 mg of dexamethasone i.v. 30 min before CDDP. On day where C(tf) was the estimated concentration at time tf. Cls/F 2, all patients received 8 mg of ondansetron p.o. before treat- (systemic clearance) was calculated by dividing the dose by ment with TMZ. The prophylactic use of ondansetron before AUCϱ. Varea/F (volume of distribution) was calculated by di- treatment with TMZ on days 3–5 was optional. viding Cls/F by k. Pretreatment and Follow-Up Studies. Before each TMZ pharmacokinetic parameters were summarized using course of treatment, histories and physical examinations were descriptive statistics. A paired t test was used to compare phar- performed, and the following evaluations were obtained: com- macokinetic parameters between days 1 and 2. Statistical anal- plete blood counts, differential WBC counts, routine chemistry ysis was performed using the JMP version 3.1.6.2 statistical and electrolyte tests, clotting studies, urinalyses, electrocardio- software program (SAS Institute, Cary, NC). grams, and chest radiographs. Weekly evaluations included his- Pharmacodynamic Analysis. The relationships between tories, physical examinations, complete blood counts, routine TMZ systemic exposure and toxicity were explored. Day 1 Cmax chemistry and electrolyte tests, and toxicity assessments. Au- and AUCϱ values were used as measures of systemic exposure. diometric testing was conducted only in patients with symptoms Relevant parameters of myelosuppression that were evaluated of hearing loss or tinnitus. included percentage decrements in the ANC and platelet count, Appropriate radiological studies for documentation of which were calculated as: measurable disease were performed before enrollment and after every two courses of therapy. A complete response was scored Percentage decrement in blood cell count if there was disappearance of all known disease on two meas- Pretreatment count Ϫ nadir count urements, separated by a minimum of 4 weeks. A partial re- ϭ ϫ 100 Pretreatment count sponse required at least a 50% reduction in the sum of the products of the bidimensional measurements, separated by at Both simple and sigmoidal maximum effect (Emax) models of least 4 weeks. Progressive disease was defined as an increase in drug effect (36) were applied to these relationships using non-

Table 1 Patient characteristics Table 2 Dose escalations Characteristic No. of patients Dose level No. of patients Total number of patients 15 TMZ (mg/m2/day CDDP Reduced to Total Sex (male:female) 7:8 ϫ 5 days) (mg/m2) New this dose Total courses Median age, years (range) 54 (36–75) ECOG performance status 100 75 1 0 1 1 a 03150 75 4 0412 112200 75 4 1 5 17 Previous treatment 200 100 6 0 6 12 None 6 150 100 0 2 2 2 Radiation therapy only 3 Total 15 44 Chemotherapy and radiation therapy 3 Chemotherapy only 2 a One patient was replaced because of incomplete follow-up labo- Biological therapy only 1 ratory tests during the first course. Tumor type Non-small cell lung cancer 4 Melanoma 3 Primary unknown 3 though the original design of the study did not permit CDDP Adenocystic carcinoma (cerumen gland) 1 dose reduction, this modification enabled the patient to receive Endometrial cancer 1 2 Leiomyosarcoma (uterus) 1 seven additional courses of TMZ/CDDP at the 200/75 mg/m Mesothelioma 1 dose level. Squamous cell carcinoma (tongue) 1 Hematological Toxicity. Myelosuppression, particularly neutropenia, was a common toxicity of the TMZ/CDDP regimen. Table 3 displays the median values and ranges of ANC and platelet count nadirs, as well as the pertinent grades of neutro- linear least-squares regression (WINNONLIN version 1.1; Sta- penia and thrombocytopenia, as a function of dose level. The tistical Consultants, Apex, NC). Linear regression models were median time to ANC nadir was 22 days (range, 8–36), with also applied to the data. Discrimination between pharmacody- resolution of neutropenia (ANC Ն1.5) by day 28 in 30 of 41 namic models was guided by minimization of the weighted sum (73%) courses. Unresolved neutropenia that resulted in treat- of squares and standard errors for the pharmacokinetic param- ment delays as long as 2 weeks occurred in nine courses at the eters, examination of the dispersion of the residuals, and use of following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 2 the coefficient of determination (r ). 150/75 (two courses), 200/75 (four courses), and 200/100 (three courses). Platelet count nadirs were also typically experienced RESULTS on day 22, with recovery to pretreatment levels by day 28 in 35 General. Fifteen patients, whose characteristics are de- of 41 (85%) courses. Thrombocytopenia (platelets Ͻ100,000/ tailed in Table 1, received 44 courses of TMZ and CDDP. All ␮l) contributed to treatment delays as long as 2 weeks in three patients had an ECOG performance status of either 0 or 1. Six courses at the 150/75 dose level. patients had received no prior therapy. Three patients had re- The first two TMZ/CDDP dose levels, 100/75 and 150/75 ceived prior CDDP, and one patient had received prior carbo- mg/m2, were well tolerated, with no evidence of grade 3 or 4 platin. Three courses were not completely evaluable for toxicity neutropenia or thrombocytopenia. At the 200/75 mg/m2 dose because of failure of three patients to return for follow-up level, 5 of 16 (31%) fully assessable courses were associated investigations. One patient who received one course at the with brief (Ͻ5 days) grade 3 or 4 neutropenia. In addition, 2 of 150/75 mg/m2 dose level was noncompliant with follow-up 16 (13%) courses were associated with grade 3 or 4 thrombo- laboratory studies, was taken off study, and was replaced. Two cytopenia, and one platelet transfusion was administered. How- other patients, at the 150/75 and 200/75 mg/m2 dose levels, were ever, none of the hematological toxicities at the 200/75 dose fully evaluable during their first courses but were noncompliant level were dose limiting. At the highest dose level, 200/100 with follow-up laboratory studies during their second courses. mg/m2, 5 of 12 (42%) courses were associated with grade 3 or The total numbers of patients and courses as a function of 4 neutropenia. One previously untreated patient with melanoma TMZ/CDDP dose level and the overall dose escalation scheme developed dose-limiting hematological toxicity characterized by are depicted in Table 2. The median number of courses received grade 4 neutropenia accompanied by fever and grade 4 throm- by each patient was 2 (range, 1–8). Treatment with CDDP was bocytopenia. She was hospitalized for treatment with parenteral discontinued in a 69-year-old female after seven courses of antibiotics, granulocyte-colony stimulating factor, and platelet TMZ/CDDP at the 150/75 mg/m2 dose level due to the devel- transfusions. After a dose reduction, this patient again development of ototoxicity. Additionally, three patients who were oped grade 4 thrombocytopenia and neutropenia, for which she initially assigned to treatment at the 200/100 mg/m2 dose level received granulocyte-colony stimulating factor and platelet required dose reductions for severe toxicity. In the first and transfusions. Neither the neutropenia nor the thrombocytopenia second of these patients, the TMZ dose was reduced to 150 induced by the TMZ/CDDP regimen was cumulative, as dem- mg/m2/day after the development of dose-limiting grade 4 my- onstrated by Fig. 2, which depicts the mean percentage decre- elosuppression and protracted grade 3 nausea and vomiting, ment in ANC and platelet count as a function of the number of respectively. In the third patient, the dose of CDDP was reduced administered courses. to 75 mg/m2 after the development of grade 4 vomiting. Al- Anemia was also a common side effect of the TMZ/CDDP

Table 3 Hematological toxicities of TMZ and CDDP No. of Dose levela (evaluable) Neutropenia Thrombocytopenia Median TMZ nadir Patients with (mg/m2/day CDDP Median nadir Grade Grade Grade 4 Ͼ Grade 4 platelets/␮l Grade Grade hematological ϫ 5 days) (mg/m2) Patients Courses ANC/␮l (range) 3 4 5 days ϩ fever (range) 3 4 DLT/Total 100 75 1 (1) 1 (1) 5740 0 0 0 0 255 0 0 0/1 150 75 4 (3) 12 (11) 2000 (1270–5560) 0 0 0 0 125 (69–433) 0 0 0/4 200 75 5 (5) 17 (16) 2555 (100–4180) 3 2 0 0 110 (11–335) 1 1 0/5 200 100 6 (6) 12 (12) 1165 (0–4500) 4 1 1 1 112.5 (22–356) 0 1 1/6 150 100 2 (1) 2 (1) 160 0 1 0 0 23 0 1 0/2 a Oral TMZ was administered in the fasting state on days 1 through 5. CDDP was administered i.v. on the first day of each course, 4 h after the administration of TMZ. Courses were repeated every 28 days.

the 200/100 dose level, this was an anticipated toxicity of CDDP and was not considered to be dose limiting. At the discretion of the investigator, CDDP was discontinued in one patient at the 150/75 dose level who exhibited grade 3 ototoxicity during the seventh course of combination chemotherapy. This patient received one course of single-agent TMZ before disease progres- sion. Transient elevations in serum creatinine concentrations (grade 1 to 2) attributable to the administration of TMZ and CDDP were noted in 10 of 41 (24%) courses involving six patients across all dose levels. The serum creatinine typically increased on days 5 to 10 and returned to pretreatment levels by day 28, without clinical sequelae. In addition, grade 1 to 2 hypomagnesemia and hypokalemia occurred in 8 of 41 (20%) Fig. 2 Mean percentage decrement in ANC (F) and platelet count (E) and 13 of 41 (32%) courses, respectively. These electrolyte 2 versus the number of courses received at the TMZ (mg/m /day)/CDDP abnormalities were readily correctable. (mg/m2) dose levels of 200/75 and 200/100. Bars, SD. Two patients developed transient grade 2 to 3 hyperbilirubinemia, which was possibly related to study medication. One patient with malignant melanoma experienced isolated grade 3 regimen. Decrements in the hematocrit by at least 5% were hyperbilirubinemia (bilirubin, 2 mg/dl) on day 8 of course 2 at experienced by 14 of 15 (93%) patients during 35 of 43 (81%) the 150/75 dose level, which resolved by day 22. This patient evaluable courses. RBC transfusions were required in 6 of 15 did not have liver metastases and was taken off study after the (40%) patients on at least one occasion. diagnosis of brain metastases on day 22 of course 2. A second Nonhematological Toxicity. The principal nonhemato- patient with malignant melanoma involving the liver developed logical toxicities of TMZ/CDDP were nausea and vomiting. grade 2 hyperbilirubinemia (bilirubin, 1.8 mg/dl) and concom- Despite premedication with ondansetron on days 1 and 2, nausea itant grade 1 elevation of serum aspartate aminotransferase on and/or vomiting (Ն grade 2) occurred in 28 of 44 (64%) courses, day 8 course 3 at the 150/100 dose level. This patient’s bilirubin and these symptoms persisted beyond the first week in 18 of 44 and transaminase returned to normal by day 10 course 3. Tran- (41%) courses. At the 200/100 dose level, one patient experi- sient grade 1 elevations in serum transaminases were associated enced dose-limiting grade 4 vomiting, despite treatment with with 5 of 41 (12%) courses. serotonin antagonists. After a dose reduction in CDDP to 75 Other mild to moderate (grades 1 to 2) adverse effects that mg/m2, the patient tolerated seven additional courses. In another were possibly related to chemotherapy included fatigue in 18 of patient at the 200/100 dose level, protracted grade 3 nausea and 44 (42%) courses, constipation in 14 of 44 (32%) courses, and vomiting were responsible for a reduction in TMZ to 150 anorexia in 13 of 44 (30%) courses. Mild to moderate peripheral mg/m2/day. neuropathy, diarrhea, malaise, fever, and stomatitis were each A total of six patients experienced symptoms indicative of noted in Ͻ20% of courses. One patient developed mild alopecia. ototoxicity, including two patients at the 150/75 dose level, one Antitumor Activity. Of the 14 patients who were evalu- patient at the 200/75 dose level, and three patients at the 200/100 able for antitumor activity, 2 patients developed major objective dose level. In three individuals, symptoms began during the first responses after treatment with TMZ and CDDP. The first pa- course. The ototoxicity was characterized by hearing loss (grade tient, a 69-year-old female with previously untreated non-small 3) in three patients, whereas the other three subjects experienced cell lung cancer, developed a partial response after two courses tinnitus (grade 2) without subjective hearing loss. Although one at the 150/75 dose level. The partial response was maintained patient developed grade 3 ototoxicity during her first course at for 6 months, during which time she received six additional

AUCϱ values were similar on days 1 and 2 (P ϭ 0.45). There was no statistically significant difference between the TMZ clearance of 115 Ϯ 27 ml/min/m2 on day 1 and 141 Ϯ 109 2 ϭ ml/min/m on day 2 (P 0.34). The t1/2, however, increased slightly but significantly from 1.74 Ϯ 0.22 h on day 1 to 2.35 Ϯ 0.70honday2(P ϭ 0.005). Pharmacodynamic Studies. Fourteen patients were evaluable for pharmacodynamic studies. The relationships be-

tween TMZ AUCϱ and the percentage decrements in either ANC or platelet count were not well described by either simple 2 Յ 2 Յ or sigmoidal Emax models (r 0.12) or by linear models (r 0.14). Cmax was more predictive of the percentage decrements in platelet count (r2 ϭ 0.39) than ANC (r2 ϭ 0.15) using linear regression analysis (Fig. 4, A and C). The increase in myelo- Fig. 3 Representative TMZ plasma concentration-versus-time profiles suppression with increasing doses of TMZ is demonstrated in E F after treatment on days 1 ( )and2( ) at the recommended TMZ Fig. 4, B and D. (mg/m2/day)/CDDP (mg/m2) dose level of 200/75.

DISCUSSION courses of therapy. The second patient, a 54-year-old male with The rationale for combining TMZ on a daily schedule for squamous cell carcinoma involving the tongue, cervical lymph 5 days every 4 weeks, with CDDP on day 1, was based, in part, nodes, and lungs, experienced a partial response after one course on the potential for improved antitumor activity compared with at the 200/100 dose level and one course at the reduced level of single-agent TMZ. Although both TMZ and CDDP target DNA, 150/100. This patient, however, declined further treatment be- these agents have widely disparate mechanisms of cytotoxic cause of the protracted grade 3 nausea and vomiting that he action and induce different cytotoxic lesions. TMZ produces experienced while on study. methyl adducts at the O6 position of guanine via the MTIC In addition to the two patients with partial responses, one intermediate (1–13), whereas CDDP produces DNA cross-links patient developed a significant reduction in disease that was not preferentially at the N7 positions of guanine and adenine (37). maintained. This patient was a 62-year-old female with meta- The methyl adducts produced by TMZ are removed by the DNA static leiomyosarcoma of the uterus, involving the lungs, bones, repair enzyme AGAT (6–13), and TMZ activity correlates in- and peritoneum, who had previously been treated with doxoru- versely with AGAT activity (6–9). Depletion of AGAT by the bicin and radiation therapy to the lumbar spine. After six courses alkyltransferase inhibitors O6-methylguanine (6, 11) and O6- of TMZ/CDDP (one course at the 200/100 dose level and five benzylguanine (7, 9, 10, 12, 13) potentiates TMZ activity in courses at the 200/75 dose level), she developed a 61% reduc- vitro and in vivo. Moreover, murine hematopoietic stem cells tion in her disease. This antitumor activity did not meet the transfected with the human AGAT gene are protected from TMZ criteria for a partial response, because it was not confirmed by cytotoxicity (38), suggesting that AGAT activity confers resist- a repeat radiological study. Two months later, the patient was ance to TMZ. Conversely, the antitumor activity of single-agent found to have progressive disease after a total of eight courses CDDP is not related to AGAT activity (39). of therapy. Although AGAT does not influence the activity of CDDP, Pharmacokinetic Studies. All 15 patients had complete CDDP may affect AGAT activity. H4 rat hepatoma cells have blood sampling performed for pharmacokinetic studies of TMZ an almost 4-fold increase in AGAT activity after incubation on days 1 and 2. Plasma concentration data from one patient with CDDP (0.5 ␮M) for 1 h (40). In contrast, HeLa human 2 who was treated at the 200/100 mg/m dose level was not cervical carcinoma cells exposed to CDDP (0–14 ␮M) for up to analyzed because undigested capsule fragments were observed 6 days demonstrate a dose-dependent inactivation of AGAT in emesis on day 2. In one patient at each of the 150/75 and activity (31). This inactivation may be secondary to platinated 2 7 6 200/75 mg/m dose levels, AUCϱ, Cls/F, and Varea/F estimates DNA adducts at the N and O positions of guanine (31), on day 2 could not be reliably determined because the extrap- although platinated RNA and protein adducts may also be olated portion of the concentration-versus-time curve repre- implicated (32). The ability of CDDP to down-regulate AGAT sented Ͼ25% of the total AUC(tf). Representative plasma con- is supported by the increased sensitivity of leukemic blasts to centration-versus-time profiles on days 1 and 2 are shown in TMZ with concurrent CDDP administration (32). Simultaneous Fig. 3. The mean (Ϯ SD) TMZ pharmacokinetic parameters treatment of leukemic blasts with TMZ (125 ␮M) and noncyto- determined using noncompartmental methods are listed in Table 4. toxic concentrations of CDDP (0–5 ␮M) produces significantly The effect of CDDP on the pharmacokinetic behavior of greater growth inhibition than treatment with TMZ alone (32). TMZ was evaluated by determining the pharmacokinetic param- This preclinical evidence suggests that CDDP may enhance the eters of TMZ both before (day 1) and after (day 2) cisplatin antitumor activity of TMZ. administration. Oral TMZ was rapidly absorbed with a mean (Ϯ Other factors also contributed to the rationale for the com- Ϯ Ϯ SD) Tmax value of 1.1 0.6 h on day 1 and a mean ( SD) Tmax bination of TMZ and CDDP. Both TMZ (21–23, 26) and CDDP Ϯ ϭ value of 1.7 0.9honday2(P 0.03). Cmax values decreased (30) are active against melanoma, a tumor type with limited by an average of 22% from day 1 to day 2 (P ϭ 0.03), although therapeutic options for advanced disease. In addition, TMZ and

Table 4 Mean TMZ pharmacokinetic parametersa

Varea/F Cls/F AUCϱ b 2 2 ␮ ⅐ Dose level Cmax (ng/ml) Tmax (h) t1/2 (h) (l/m ) (mL/min/m ) ( g h/ml) TMZ (mg/m2/day CDDP ϫ 5 days) (mg/m2) Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 100 75 3.94 4.99 2.0 1.0 1.93 2.52 17.2 20.1 103 92 16.4 18.3 150 75 6.50 6.10 1.1 1.5 1.90 2.01 20.2 18.1 122 103 22.6 25.9 (2.86) (3.82) (0.6) (1.0) (0.21) (0.12) (7.2) (4.1) (44) (21) (6.9) (6.8) 200 75 9.89 8.61 1.0 1.9 1.65 2.31 15.2 16.7 108 102 32.3 33.7 (1.86) (2.10) (0.7) (1.0) (0.10) (0.80) (2.2) (2.4) (21) (18) (7.2) (6.3) 200 100 9.10 4.73 1.1 1.8 1.65 2.56 16.7 45.3 117 212 29.3 22.4 (2.26) (3.26) (0.5) (0.8) (0.25) (0.90) (3.5) (45.1) (20) (169) (4.7) (11.8) Mean N/A N/A 1.1 1.7 1.74 2.35 17.3 27.8 115 141 N/A N/A (0.6) (0.9) (0.22) (0.70) (4.6) (28.4) (27) (109) a Ϯ Values represent mean ( SD). Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration; t1/2, elimination half-life; Varea/F, volume of distribution; Cls/F, clearance; AUCϱ, area under the plasma concentration versus time curve; NA, not applicable. b Oral TMZ was administered in the fasting state on days 1–5. CDDP was administered i.v. on the first day of each course, 4 h after the administration of TMZ. Courses were repeated every 28 days.

Fig. 4 Scatterplots A and C depict the relationship between day 1 TMZ Cmax and percentage decrement in the ANC (A) and platelet count (C). Shown are patients who received 75 mg/m2 CDDP (F) and 100 mg/m2 CDDP (E). Lines, fit of a linear model to the ANC (r2 ϭ 0.15) and platelet count (r2 ϭ 0.39) data. Scatterplots B and D depict the relationship between TMZ/CDDP dose level and percent decrement in ANC (B) and platelet counts (D).

CDDP have nonoverlapping DLTs, implying that the tolerable Interest in the DTIC/CDDP combination was generated after the doses of TMZ and CDDP in combination are similar to the demonstration of additive cytotoxic activity in the B16 human tolerable doses of single-agent TMZ and CDDP. Also, TMZ is melanoma model (41). In one study in which 30 patients with only minimally renally excreted (4, 22, 23), suggesting that even refractory metastatic melanoma were treated with 750 mg/m2 in the presence of CDDP-induced nephropathy, CDDP does not DTIC and 100 mg/m2 CDDP i.v. at 21-day intervals, objective alter the pharmacokinetic profile of TMZ. Given the potential responses lasting a median duration of 31 weeks were noted for a favorable therapeutic index, this study explored the MTD, (42). However, a multicenter Phase II Southwest Oncology toxicities, and pharmacokinetic parameters of TMZ in combi- Group study evaluating the same DTIC/CDDP regimen in pa- nation with CDDP. tients with stage IV or inoperable stage III melanoma failed to CDDP has previously been combined with another imida- confirm these results. In this study, significant renal and hema- zotetrazinone, DTIC, in the treatment of metastatic melanoma. topoietic toxicities were observed, and a much lower response

rate (14%) and a lower median survival (6.8 months) were noted REFERENCES (43). The differences between the two studies may have been 1. Stevens, M. F. G., Hickman, J. A., Langdon, S. P., Chubb, D., due to the variable generation of the active agent MTIC through Vickers, L., Stone, R., Baig, G., Goddard, C., Gibson, N. W., Slack, hepatic p450-mediated metabolism of DTIC (14). TMZ, unlike J. A., Newton, C., Lunt, E., Fizames, C., and Lavell, F. Antitumor DTIC, undergoes spontaneous biochemical decomposition to activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imi- dazo[5,1, d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045;M&B39831), MTIC at physiological pH (1–5). Thus, substituting TMZ for a novel drug with potential as an alternative to dacarbazine. Cancer Res., DTIC may result in more predictable toxicity and antitumor 47: 5846–5852, 1987. activity profiles. 2. Tsang, L. L. H., Quarterman, C. P., Gescher, A., and Slack, J. A. In this study, the combination of TMZ and CDDP was well Comparison of the cytotoxicity in vitro of temozolomide and dacarba- tolerated, with two patients developing DLT at the 200/100 zine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. mg/m2 dose level. At this dose level, one patient experienced Cancer Chemother. Pharmacol., 27: 342–346, 1991. both grade 4 thrombocytopenia and grade 4 neutropenia with 3. Denny, B. J., Wheelhouse, R. T., Stevens, M. F. G., Tsang, L. L. H., and Slack, J. A. NMR and molecular modeling investigation of the fever, requiring hospitalization. In addition, severe and persis- mechanism of activation of the antitumor drug temozolomide and its tent nausea and vomiting necessitated dose reductions in two interaction with DNA. Biochemistry, 33: 9045–9051, 1994. patients at this dose level, including one patient for whom 4. Baker, S. D., Wirth, M., Statkevich, P., Reidenberg, P., Alton, K., vomiting was dose limiting. Although treatment with single- Sartorius, S. E., Dugan, M., Cutler, D., Batra, V., Grochow, L. B., agent TMZ is associated with nausea and vomiting, which is Donehower, R. C., and Rowinsky, E. K. Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients typically brief and well controlled with serotonin antagonists with advanced cancer. Clin. Cancer Res., 5: 309–317, 1999. (21–25), the addition of 100 mg/m2 CDDP resulted in more 5. Reid, J. M., Stevens, D. C., Rubin, D. C., and Ames, M. M. Phar- severe nausea and vomiting, which was attributed to the inherent macokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide fol- emetogenic potential of CDDP (37). When 75 mg/m2 CDDP lowing administration of temozolomide to patients with advanced can- was combined with standard doses of TMZ, no DLTs were cer. Clin. Cancer Res., 3: 2393–2398, 1997. observed. Thus, the recommended Phase II doses are 200 mg/m2 6. Tisdale, M. J. Antitumour imidazotetrazines. XV. Role of guanine O6 TMZ daily on days 1–5 and 75 mg/m2 CDDP on day 1 every 4 alkylation in the mechanism of cytotoxicity of imidazotetrazinones. Biochem. Pharmacol., 36: 457–462, 1987. weeks. 7. Baer, J. C., Freeman, A. A., Newlands, E. S., Watson, A. J., Rafferty, The influence of CDDP on the pharmacokinetic behavior J. A., and Margison, G. P. Depletion of O6-alkylguanine-DNA alkyl- of TMZ was evaluated by sampling plasma before (day 1) and transferase correlates with potentiation of temozolomide and CCNU after (day 2) CDDP administration. With control of CDDP- toxicity in human tumour cells. Br. J. Cancer, 67: 1299–1302, 1993. induced emesis, TMZ absorption was expected to be constant 8. D’Atri, S., Piccioni, D., Castellano, A., Tuorto, V., Franchi, A., Lu, from day 1 to day 2. Although there were modest differences in K., Christiansen, N., Frankel, S., Rustum, Y. M., Papa, G., Mandelli, F., 6 T and C between days 1 and 2, these differences were not and Bonmassar, E. Chemosensitivity to triazene compounds and O - max max alkylguanine-DNA alkyltransferase levels: studies with blasts of leukae- clinically significant. Consistent with single-agent studies, TMZ mic patients. Ann. Oncol., 6: 389–393, 1995. was rapidly absorbed (4, 22, 24). At the recommended dose 9. Wedge, S. R., Porteous, J. K., May, B. L., and Newlands, E. S. 2 6 level of 200/75 mg/m , the Cmax values on days 1 and 2 were Potentiation of temozolomide and BCNU cytotoxicity by O -benzylgua- comparable with those reported previously (Cmax, 9.8–16 nine: a comparative study in vitro. Br. J. Cancer, 73: 482–490, 1996. ng/ml) for 200 mg/m2/day of single-agent TMZ daily for 5 10. Wedge, S. R., and Newlands, E. S. O6-Benzylguanine enhances the 6 days (22, 23). Likewise, TMZ AUCϱ and clearance were sensitivity of a glioma xenograft with low O -alkylguanine-DNA alkyl- unaffected by CDDP administration, with no significant transferase activity to temozolomide and BCNU. Br. J. Cancer, 73: 1049–1052, 1996. change from day 1 to day 2. At the recommended dose level, the mean AUC and clearance values on days 1 and 2 were 11. Taverna, P., Catapano, C. V., Citti, L., Bonfanti, M., and D’Incalci, ϱ M. Influence of O6 methylguanine on DNA damage and cytotoxicity of within the range of mean values that have been reported temozolomide in L1210 mouse leukemia sensitive and resistant to 2 previously for 200 mg/m /day of single-agent TMZ daily for chloroethyl nitrosoureas. Anti-Cancer Drugs, 3: 401–405, 1992. five days (AUC, 30–35 ␮g⅐h/ml, and clearance, 104–115 12. Fairbain, L. J., Watson, A. J., Rafferty, J. A., Elder, R. H., and ml/min/m2; Refs. 22, 23). The observation that TMZ clear- Margison, G. P. O6-Benzylguanine increases the sensitivity of human ance was not affected by the administration of CDDP is primary bone marrow cells to the cytotoxic effects of temozolomide. attributed to the fact that the disposition of TMZ is princi- Exp. Hematol., 23: 112–116, 1995. pally through chemical hydrolysis, with only minimal (5– 13. Chinnasamy, N., Rafferty, J. A., Hickson, I., Ashby, J., Tinwell, H., Margison, G. P., Dexter, T. M., and Fairbairn, L. J. O6-Benzylguanine 6%) excretion by renal mechanisms (4, 22, 23). potentiates the in vivo toxicity and clastogenicity of temozolomide and In conclusion, 75 mg/m2 CDDP did not alter the tolerable BCNU in mouse bone marrow. Blood, 89: 1566–1673, 1998. dose of TMZ on a daily for 5 days schedule, nor did it substan- 14. Mizuno, N. S., and Decker, R. W. Alteration of DNA by 5-(3- tially affect the pharmacokinetic profile of TMZ. There was methyl-1-triazeno)imidazole-4-carboxamide (NSC-407347). Biochem. minimal interindividual variability in toxicological profiles, as Pharmacol., 25: 2643–2647, 1976. expected from the ability of TMZ to spontaneously form the 15. Wedge, S. R., Porteous, J. K., Glaser, M. G., Marcus, K., and Newlands, E. S. In vitro evaluation of temozolomide combined with active moiety MTIC. This potential for more predictable toxicity X-irradiation. Anti-Cancer Drugs, 8: 92–97, 1997. and more reliable antitumor activity may lead to an improved 16. Pera, M. F., Koberle, B., and Masters, J. R. W. Exceptional sensi- therapeutic index when TMZ is substituted for DTIC in imida- tivity of testicular germ cell tumour cell lines to the new anti-cancer zotetrazinone/CDDP regimens. agent, temozolomide. Br. J. Cancer, 71: 904–906, 1995.

17. Raymond, E., Izbicka, E., Soda, H., Gerson, S. L., Dugan, M., and without mannitol diuresis in refractory disseminated malignant mela- Von Hoff, D. D. Activity of temozolomide against human tumor colony- noma: a Southwest Oncology Group study. Cancer Treat. Rep., 66: forming units. Clin. Cancer Res., 3: 1769–1774, 1997. 31–35, 1982. 18. Carter, C. A., Waud, W. R., and Plowman, J. Responses of human 31. Wang, L., and Setlow, R. B. Inactivation of O6-alkylguanine-DNA melanoma, ovarian, and colon tumor xenografts in nude mice to oral alkyltransferase in HeLa cells by cisplatin. Carcinogenesis (Lond.), 10: temozolomide. Proc. Am. Assoc. Cancer Res., 35: 297, 1994. 1681–1684, 1989. 19. Friedman, H. S., Dolan, M. E., Pegg, A. E., Marcelli, S., Deir, S., 32. Piccioni, D., D’Atri, S., Papa, G., Caravita, T., Franchi, A., Bon- Catino, J. J., Bigner, D. D., and Schold, S. C. Activity of temozolomide massar, E., and Graziani, G. Cisplatin increases sensitivity of human in the treatment of central nervous system tumor xenografts. Cancer leukemic blasts to triazene compounds. J. Chemother., 7: 224–228, Res., 55: 2853–2857, 1995. 1995. 20. Plowman, J., Waud, W. R., Koutsoukos, A. D., Rubinstein, L., Moore, T., and Grever, M. Preclinical antitumor activity of temozolo- 33. Guidelines for Reporting of Adverse Drug Reactions. Bethesda, mide in mice: efficacy against human brain tumor xenografts and MD, Division of Cancer Treatment, National Cancer Institute, 1988. synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res., 54: 34. Estlin, E. J., Lashford, L., Ablett, S., Price, L., Gowing, R., Gholkar, 3793–3799, 1994. A., Kohler, J., Lewis, I. J., Morland, B., Pinkerton, C. R., Stevens, 21. Newlands, E. S., Blackledge, G. R. P., Slack, J. A., Rustin, G., M. C. G., Mott, M., Stevens, R., Newell, D. R., Walker, D., Dicks- Smith, D., Stuart, N., Quarterman, C., Hoffman, R., Stevens, M., Mireaux, C., McDowell, H., Reidenberg, R., Statkevich, P., Marco, A., Brampton, M., and Gibson, A. Phase I trial of temozolomide (CCRG Batra, V., Dugan, M., and Pearson, A. D. J. Phase I study of temozo- 81045:M&B39831: NSC 362856). Br. J. Cancer, 65: 287–291, 1992. lomide in paediatric patients with advanced cancer. Br. J. Cancer, 78: 22. Dhodapkar, M., Rubin, J., Reid, J. M., Burch, P. A., Pitot, H. C., 652–661, 1998. Buckner, J. C., Ames, M., and Suman, V. Phase I trial of temozolomide 35. Gibaldi, M., Perrier, D. Pharmacokinetics, Ed. 2., pp. 409–417. (NSC 362856) in patients with advanced cancer. Clin. Cancer Res., 3: New York, NY: Marcel Dekker, 1982. 1093–1100, 1997. 36. Lalonde, R. L. Pharmacodynamics. In: W. E. Evans, J. J. Schentag, 23. Eckardt, J. R., Weiss, G. R., Burris, H. A., Rodriguez, G. I., Fields, and W. J. Jusko (eds.), Applied Pharmacokinetics: Principles of Ther- S. M., Rinaldi, D. A., Drengler, R. L., Dugan, M. H., Batra, V. J., and apeutic Drug Monitoring, Ed. 3, pp. 4-1 to 4-33. Vancouver, WA: Von Hoff, D. D. Phase I and pharmacokinetic trial of SCH52365 Applied Therapeutics, 1992. ϫ (temozolomide) given orally daily 5 days. Proc. Am. Soc. Clin. 37. O’Dwyer, P. J., Johnson, S. W., and Hamilton, T. C. Cisplatin and Oncol., 14: 484, 1995. its analogues. In: V. T. DeVita, Jr., S. Hellman, and S. A. Rosenberg 24. Brada, M., Moore, S., Judson, I., Batra, V. J., Quartey, P., and (eds.), Cancer: Principles and Practice of Oncology, Ed. 5, pp. 418–432. Dugan, M. A phase I study of SCH 52365 (temozolomide) in adult New York: Lippincott-Raven Publishers, 1997. patients with advanced cancer. Proc. Am. Soc. Clin. Oncol., 14: 470, 38. Wang, G., Weiss, C., Sheng, P., and Bresnick, E. Retrovirus- 1995. mediated transfer of the human O6-methylguanine-DNA methyltrans- 25. Brock, C. S., Newlands, E. S., Wedge, S. R., Bower, M., Evans, H., ferase gene into a murine hematopoietic stem cell line and resistance to Colquhoun, I., Roddie, M., Glaser, M., Brampton, M. H., and Rustin, the toxic effects of certain alkylating agents. Biochem. Pharmacol., 51: G. J. S. Phase I trial of temozolomide using an extended continuous oral 1221–1228, 1996. schedule. Cancer Res., 58: 4363–4367, 1998. 39. Damia, G., Imperatori, L., Citti, L., Mariani, L., and D’Incalci, M. 26. Bleehan, N. M., Newlands, E. S., Lee, S. M., Thatcher, N., Selby, 3-Methyladenine-DNA-glycosylase and O6-alkyl guanine-DNA-alkyl- P., Calvert, A. H., Rustin, G. J. S., Brampton, M., and Stevens, M. F. G. transferase activities and sensitivity to alkylating agents in human can- Cancer Research Campaign phase II trial of temozolomide in metastatic cer cell lines. Br. J. Cancer, 73: 861–865, 1996. melanoma. J. Clin. Oncol., 13: 910–913, 1995. 40. Lefebvre, F., and Laval, F. Enhancement of O6 27. O’Reilly, S. M., Newlands, E. S., Glaser, M. G., Brampton, M., -methylguanine- Rice-Edwards, J. M., Illingworth, R. D., Richards, P. G., Kennard, C., DNA-methyltransferase activity induced by various treatments in mam- Colquhoun, I. R., Lewis, P., and Stevens, M. F. G. Temozolomide. A malian cells. Cancer Res., 46: 5701–5705, 1986. new oral cytotoxic chemotherapeutic agent with promising activity 41. Friedman, M. A., Kaufman, D. A., Williams, J. E., Resser, K. J., against primary brain tumors. Eur. J. Cancer, 29A: 940–942, 1993. Rosenbaum, E. H., Cohen, R. J., Glassberg, A. B., Blume, M. R., 28. Newlands, E. S., O’Reilly, S. M., Glaser, M. G., Bower, M., Evans, Gershow, J., and Chan, E. Y. C. Combined DTIC and cis-dichlorodi- H., Brock, C., Brampton, M. H., Colquhoun, I., Lewis, P., Rice-Ed- ammineplatinum(II) therapy for patients with disseminated melanoma: a wards, J. M., Ilingworth, R. D., and Richards, P. G. The Charing Cross Northern California Oncology Group Study. Cancer Treat. Rep., 63: Hospital experience with temozolomide in patients with gliomas. Eur. J. 493–495, 1979. Cancer, 32A: 2236–2241, 1996. 42. Fletcher, W. S., Green, S., Fletcher, J. R., Dana, B., Jewell, W., and 29. Levin, V., Yung, A., Prados, M., Poisson, M., Rosenfeld, S., Brada, Townsend, R. A. Evaluation of cis-platinum and DTIC combination M., Friedman, H., Albright, R., Olson, J., Bruner, J., Yue, N., Dugan, chemotherapy in disseminated melanoma. Am. J. Clin. Oncol., 11: M., and Temodal Brain Tumor Group. Phase II study of Temodal 589–593, 1988. (temozolomide) at first relapse in anaplastic astrocytoma patients. Proc. 43. Fletcher, W. S., Daniels, D. S., Sondak, V. K., Dana, B., Townsend, Am. Soc. Clin. Oncol., 16: 384a, 1997. R., Hynes, H. E., Hutchins, L. F., and Pancoast, J. R. Evaluation of 30. Al-Sarraf, M., Fletcher, W., Oishi, N., Pugh, R., Hewlett, J. S., cisplatin and DTIC in inoperable stage III and IV melanoma. Am. J. Balducci, L., McCracken, J., and Padilla, F. Cisplatin hydration with and Clin. Oncol., 16: 359–362, 1993.

Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1999 American Association for Cancer Research. A Phase I and Pharmacokinetic Study of Temozolomide and Cisplatin in Patients with Advanced Solid Malignancies

Carolyn D. Britten, Eric K. Rowinsky, Sharyn D. Baker, et al.

Clin Cancer Res 1999;5:1629-1637.

Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/5/7/1629

Cited articles This article cites 37 articles, 11 of which you can access for free at: http://clincancerres.aacrjournals.org/content/5/7/1629.full#ref-list-1

Citing articles This article has been cited by 4 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/5/7/1629.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/5/7/1629. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.