Phase I clinical and pharmacokinetic study of combination chemotherapy with topotecan and ifosfamide in patients with progressive or relapsed solid tumors.
OBJECTIVE
Topotecan and ifosfamide are effective in the treatment of various solid tumors. Up to the time of this study, the two drugs have been combined just once (Smith et al. 1998). Due to its hematotoxicity, topotecan has been used predominantly within monochemotherapy protocols. However, the combination of topotecan and alkylating agents is supra-additive in many preclinical models. This phase-I trial was primarily performed to evaluate the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of a combination chemotherapy with topotecan and ifosfamide using a 5-day schedule. A secondary goal was to estimate the response rate in a group of heavily pretreated patients with advanced solid tumors.


METHODS
The pharmacokinetics of topotecan were preliminarily determined in some of the patients. A total of 12 patients (three female/nine male), median age 49 years (range 19-69), 11 with prior chemotherapy, received a total of 24 courses of chemotherapy at three dose-levels of topotecan. Ifosfamide was administered by intravenous infusion over 3 h immediately followed by a 30-min infusion of topotecan. Mesna (3 x 300 mg x m(2) x day) was given routinely during chemotherapy as a uroprotector. G-CSF (filgrastim) was permitted only in cases of febrile neutropenia (FN).


RESULTS
The major toxicity was non-hematologic; severe liver and renal toxicity were observed in three out of 11 patients. Two treatment-related deaths occurred. No clinical remissions occurred in 11 evaluable patients. The pharmacokinetics of topotecan were relatively similar in our patients and supported findings in recent literature. The MTD of this combination was defined at dose-level 2 (1.0 mg/m(2) of topotecan and 750 mg/m(2) of ifosfamide).


CONCLUSIONS
Further trials should not exceed this dose. The pharmacological causes for the pronounced toxicity have to be clarified.
Schneider
C-P
CP
Department of Internal Medicine II (Hematology, Oncology, Endocrinology and Metabolic Diseases), Friedrich-Schiller University Jena, Erlanger Allee 101, 07740 Jena, Germany. claus-peter.schneider@med.uni-jena.de
Merkel
U
U
Grübner
U
U
Kath
R
R
Höffken
K
K
Hoffmann
A
A
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012008:Recurrence; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D019772:Topotecan; D007069:Ifosfamide