A phase i study of high-dose topotecan, ifosafamide/mesna and etoposide (Time) Followed by autologous stem cell rescue in refractory malignancies

Abstract

In this study, topotecan (TPT) has been dose-escalated from 10 mg/m2 to 85 mg/m2 (total dose over 3 days), with stem cell rescue, in combination with ifosfamide and etoposide at fixed total doses of 10 g/m2 and 1500 mg/m2, respectively. A two-hour infusion of ifosfamide is followed immediately by a 30-min. infusion of TPT on days -8, -7, and -6. On days, -5, -4, and -3 a CI of 500 mg/m2/d etoposide was administered. A total of 45 patients with refractory cancer were accrued (29- Breast CA, 8- NHL, 7- Ovarian CA, 1- Testicular CA) and the MTD of TPT was found to be 65 mg/m2. The DLT was mucositis/enteritis. The 100 day non-relapse mortality was 4.4%. One patient died on day +1- due to sepsis and cardiac failure and one on day +34 due to sepsis and CNS Aspergillus. The median day to engraftment is day +10 for ANC > 500/μL and day +17 for platelets > 50,0000/μL, untransfused. Pharmacokinetic analyses of total TPT and lactone show a harmonic mean t1/2 of 2.9 h and 2.6 h, median clearance of 14.0 L/h/m2 and 30.4 L/h/m2, and a median Vdss of 52.9 L/m2 and 88.3 L/m2, respectively. Median peak TPT concentrations (lactone) and AUC have ranged from 0.179 μM/0.24 μM·h (level 1) to 1.88 μM/2.44 μM·h (level 8). In this study we observed an overall response rate of 32%, with 5 and 9 of 44 evaluable patients achieving a CR or PR, respectively. In NHL, the overall responses rate was 57% (3- CR, 1- PR). The overall and event free survivals for all patients at 12 months were 55% ± 8% and 22% ± 6%, respectively.