Phase I trial of the addition of oral topotecan to standard 5-day temozolomide for malignant gliomas.

Abstract

2073 Background: Temozolomide is one of the most active agents to treat malignant gliomas. As an alkylating agent, the majority of tumors develop resistance. There are many mechanisms of resistance, including methyl guanine methyl transferase (MGMT), mismatched repair and single base excision repair. The addition of a topoisomerase 1 inhibitor may be synergistic with temozolomide and overcome resistance. Methods: We completed a phase I trial of oral topotecan and temozolomide, which was dosed at the standard 200 mg/m2/day for days 1-5. Topotecan was given days 2-6 of a 28 day cycle. The dose levels of topotecan are listed in the table. Dose limiting toxicity (DLT) was defined as ≥ grade 3 non-hematopoietic toxicity attributable to the treatment or ≥ grade 4 hematopoietic toxicity. The maximal tolerated dose (MTD) was the level in which ≤ 1 of 6 patients had DLT. There were 2 cohorts, one for patients on enzyme inducing anti-epileptic drugs (EIAED) and another cohort for patients not on EIAED (non-EIAED). Pharmacokinetic sampling was done for topotecan levels. Results: Sixty-two patients were enrolled, 33 on the EIAED cohort and 29 on the non-EIAED cohort. The major toxicities were hematologic, and every patient that had dose-limiting hematologic toxicity had both grade 4 thrombocytopenia and neutropenia. In the EIAED cohort, 2/6 patients at dose level 7 had dose-limiting hematologic toxicity, and 1/6 at dose level 6 had dose- limiting hematologic toxicity. In the non-EIAED cohort, 2/6 patients at dose level 5 had dose-limiting hematologic toxicity, and 1/6 at dose level 4 had dose- limiting hematologic toxicity. Interestingly, the pharmacokinetics of topotecan was similar in the two cohorts. The regimen was active, with many patients remaining stable over many cycles. Conclusions: The combination of standard 5-day temozolomide and oral topotecan was well tolerated and had clinical activity. The MTD of oral topotecan was 2.0 mg/M2/d in the EIAED cohort and 1.5 mg/M2/d in the non-EIAED cohort. A phase II trial for newly diagnosed GBM patients in combination with bevacizumab is planned. Dose level Dose topotecan mg/m2/d 1 0.75 2 1.0 3 1.25 4 1.5 5 1.75 6 2.0 7 2.3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough