Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas

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1 Journal of Neuro-Oncology 70: 91 95, Ó 2004 Kluwer Academic Publishers. Printed in the Netherlands. Clinical Study Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas Alexander M. Spence, Richard A. Peterson, Jeffrey D. Scharnhorst, Daniel L. Silbergeld and Robert C. Rostomily Departments of Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA Key words: anaplastic astrocytoma, glioblastoma multiforme, phase II, Tamoxifen, Temozolomide Summary Purpose and background: The aim of this study was to assess the frequency of response and toxicity in adults with recurrent anaplastic astrocytoma (AA) or glioblastoma multiforme (GM) treated with concurrent continuous TMZ and TMX. Methods: In addition to histology, eligibility included age >18 years, Karnovsky score 60, normal laboratory parameters, no radiotherapy (RT) for 4 weeks, measurable disease and normal EKG. The chief exclusions were: previous TMZ, TMX or dacarbazine (DTIC); nitrosourea within 6 weeks; history of deep venous thrombosis or pulmonary emboli. All patients (pts) had received prior RT. TMZ was given at 75 mg/m 2 /day for 6 weeks, repeated every 10 weeks, maximum 5 cycles. Four pts received 60 mg/m 2 /day for 6 weeks due to extensive prior chemotherapy exposure. TMX was started at 40 mg twice daily (b.i.d.) for 1 week and then was increased in three successive weeks to 60, then 80, then 100 mg b.i.d. Response was assessed before every cycle with MRI ± gadolinium (Gd). Results: Sixteen pts enrolled: GM 10, AA 6; female 6, male 10; median age 48 (21 58); prior chemotherapy 7. There was one partial response and one stable disease. Eleven pts progressed by the end of cycle 1; three pts failed due to toxicity before completing cycle 1. Median time to treatment failure was 10 weeks. The main toxicities were: transaminitis, pancytopenia, 1st division herpes zoster, deep vein thrombosis and fatigue. The study was closed due to the low response rate and frequency of toxicity. Introduction Temozolomide was developed and tested in the early 1990s by Newlands and coworkers who established the schedule of mg/m 2 /day for 5 days repeated every 28 days [1 3]. The chief mechanisms of action include alkylation of N-7 guanine and depletion of alkyl transferase [4 7]. The drug has now been widely tested for treatment of gliomas of several types in both phase II and phase III settings [8 15]. Additional phase I work reported in established the feasibility and safety of continuous TMZ at 75 mg/m 2 /day for 6 weeks [6,16,17]. This schedule permits a 2.1-fold greater drug exposure per 4 weeks in comparison with the 5 day schedule of 200 mg/ M 2 /day repeated every 28 days. The most frequent toxicities were gastrointestinal, namely, nausea and vomiting, and hematologic. There were 17 glioma patients, a mix of low and high grade, from which seven demonstrated objective responses and six maintained stable disease. These results have encouraged additional trials with this schedule [12,16,18]. Experience with high-dose TMX alone for recurrent high grade gliomas suggests a 20 40% response plus stabilization rate [19,20]. Distinct from TMZ, the mechanism of action of high-dose TMX in gliomas is thought to be mainly protein kinase C inhibition and interference with downstream signal transduction [21 26].

2 92 The goals of the present study were to assess the frequency of response and toxicity of the combination of TMZ and TMX at high doses since both of these agents have shown activity against malignant gliomas and demonstrate non-overlapping mechanisms of action and toxicity. Methods Adult patients over 18 years with recurrences of either AA or GM following RT were sought for the study. Measurable disease on MRI T1 with Gd was required. The Karnovsky performance score requirement was 60. Adequate hematologic parameters, liver function and renal function along with normal electrocardiogram were required. No RT for 4 weeks was allowed. One prior chemotherapy was allowed including carmustine (BCNU) wafers, if progression was confirmed by positron emission tomography with [ 18 F]fluorodeoxyglucose. Patients were excluded if they had received previous chemotherapy with TMZ, TMX or DTIC or had received a nitrosourea within 6 weeks. History of deep venous thrombosis or pulmonary embolism were additional exclusions. The procedures followed were in accordance with ethical standards of the University of Washington Human Subjects Committee. Informed consent was obtained from the patient or a responsible relative. Temozolomide was prescribed at 75 mg/m 2 /day for 6 weeks, repeated every 10 weeks with a maximum of 5 cycles. For patients that had received extensive prior chemotherapy the starting dose was 60 mg/m 2 /day for 6 weeks. Tamoxifen was administered at 40 mg b.i.d. for 1 week, then escalated to 60 mg b.i.d. for 1 week, then 80 mg b.i.d. for 1 week, then 100 mg b.i.d. for the maintenance continuous dose. Patients were evaluated for response after every cycle of therapy by clinical and radiographic criteria. Complete response (CR) was disappearance of all disease on CT or MRI (with contrast) with stable or improving neurological examination without any increase in steroid dose persisting for at least 10 weeks (one cycle length). Partial response (PR) was a 50% or greater reduction in the sums of the products of the cross-sectional diameters of the lesion(s) persisting for at least 10 weeks with the same clinical and steroid requirements. Progressive disease (PD) was greater than 25% increase in the same measurements with stable or worsening neurological examination or appearance of new lesion(s). Stable disease (SD) was any other response. Results Sixteen patients enrolled in the study (Table 1). There were 10 GM and 6 AA; 6 female, 10 male. The median age was 48 years with a range of All patients had received prior RT. In three patients the RT included fast neutrons [27,28]. Seven patients had received prior chemotherapy. One patient completed 5 cycles (PR) and one completed 1 cycle plus a week (SD) before dying suddenly at home. Nine completed 1 cycle but progressed. Two progressed before completing 10 weeks of cycle 1 but had completed the 6 weeks of TMZ. Three came off study before completing 1 cycle and did not complete 6 weeks of TMZ in cycle 1 due to toxicity. Median time to treatment failure was 10 weeks (Figure 1). Median survival from time of initiation of protocol treatment was 26 weeks. The main toxicities were: transaminitis grade (gr) III, 2 pts; pancytopenia gr IV, 1 pt; 1st division herpes zoster gr III, 1 pt; deep vein Table 1. Patient data (n = 16) Age (years) Median 48 range No. % Sex Male Female 6 37 Histology GM AA 6 37 Karnovsky score Prior Radiotherapy Prior Chemotherapy 7 44 Cycle 1 dose TMZ 75 mg/m 2 /day mg/m 2 /day 4 25

3 93 Time to Treatment Failure Time (weeks) 1 Median 10 Median 26.8 Survival After TMZ/TMX Time (weeks) Figure 1. Kaplan Meier plots of the time to treatment failure (left) and survival after onset of treatment with TMZ and TMX (right). thrombosis gr IV, 2 pts; and fatigue gr III, 1 pt. Thus, from 16 patients there was 1 PR, 1 SD, 11 PD and 3 who failed in cycle 1 due to toxicity. Discussion The dose and schedule of continuous TMZ of 75 mg/m 2 /day was determined in Phase I work and the response and stable disease rates were encouraging [6,16,17]. Since this schedule permits a 2.1-fold greater drug exposure per 4 weeks in comparison to the standard 5-day schedule of 200 mg/m 2 /day repeated every 28 days, it was selected for testing in combination with high dose continuous TMX. However, Khan et al. reported a phase II study of 35 patients with recurrent malignant gliomas treated with TMZ alone at 75 mg/m 2 /day for 42 days in cycles of 70 days [18]. There were PRs in 2 patients with AA and marginal responses in 3 patients with GM. Median progression free survival and overall survival were 2.5 and 8.7 months, respectively. These authors felt that the results did not support an improved rate of response or survival. Prior experience with high-dose TMX alone for recurrent high grade gliomas, on the other hand, suggests a 20 40% response plus stabilization rate [19,20,29,30]. Other investigators have combined high-dose TMX with other agents for recurrent malignant astrocytic gliomas, e.g., procarbazine (PCB) [31] or alpha interferon [32]. The study of Brandes et al. included 53 pts treated with PCB at 100 mg/m 2 /day plus TMX 100 mg/day in repeated 30-day courses, with a 30- day interval between courses [31]. All cases had received prior chemotherapy with a nitrosoureabased regimen that included PCB in 21 or carboplatin plus teniposide. There were 2 CR, 13 PR and 17 SD but time to progression and median survival time were not increased. In the report of Chang et al. 18 pts with recurrent gliomas of all grades were treated with TMX at 240 mg/m 2 /day plus alpha interferon [32]. Because of side effects of moderate to severe reversible dizziness and unsteady gait, the dose of TMX was reduced to 120 mg/m 2 /day. Despite this dose reduction, the severity of these neurological toxicities lead the authors to close the investigation. In 16 evaluable pts there was 1 minor response, 3 SD and 12 PD. One small study of recurrent gliomas combined TMZ and TMX, but the pts had been previously treated with TMX. Therefore, these results are not comparable to ours [33]. From this brief review, it is apparent that there are no studies directly comparable to the present one. Our study was too small to determine whether the two drugs, TMZ and TMX, at some level, interfere with each other s mechanism of action. Nor did it determine whether TMZ at the conventional dose and schedule in combination with TMX might have done better or worse. In comparison to the major studies that initially evaluated TMZ, the results of the present study suggest no trend of improvement and discourage additional efforts with the doses and schedules reported here [14,15]. Acknowledgement This study was supported by Schering Plough Corporation.

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