A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients

The topoisomerase I inhibitor topotecan (T) and the topoisomerase II inhibitor etoposide (E) are active drugs in lung cancer. The complementary functions of their targets may suggest benefit from the combined use of these agents but drug scheduling has been shown to play a critical role in preclinical models. To establish the optimal schedule and assess the impact of sequential administration of the combination of T and E, we conducted a dose finding study of sequential intravenous T and E in a four-weekly-schedule in relapsed lung cancer patients.

The importance of drug sequence was assessed in consecutive patients throughout all dose levels; patients received in the first course either T followed by E (the TE group: T on days 1-3 and E on days 4-6) or E before T (the ET group: F on days 1-3 and Ton days 4-6). The sequence of Tand E was alternated in the successive courses. In this crossover design, each patient served as his own control for analysis of hematological toxicity in which TE sequence was compared to that of the ET sequence. Moreover, hematological toxicity after the first course was compared between the TE and the ET groups. The starting dose was T/E 0.75/75 mg/m2 at dose level 1and dose escalation was planned to T/E 1.00/75 mg/nm2 at dose level 2, T/E 1.00/100 mg/m2 at dose level 3, T/E 1.25/100 mg/m2 at dose level 4 and T/E 1.50/100 mg/m2 at dose level 5. Nineteen patients (small-cell lung cancer 7, non-small-cell lung cancer 11, mesothelioma 1 patient) were included.

The principal toxicity was myelosuppression, primarily neutropenia and thrombocytopenia. At dose level 3 several grade 4 toxicities were observed. DLT (febrile neutropenia) occurred in two patients, one in the TE and one in the ET group and precluded further dose escalation. There was no significant difference in WBC and platelet nadirs during the first course between the TE and the ET group. The influence of the sequence of administration of topotecan and etoposide was calculated by comparing the nadir values of cycles I and II for each patient. For none of the dose levels, a significant sequence-dependent effect could be detected. The MTD was reached at the doses of 100 mg/m2 topotecan and 75 mg/m2 etoposide. No objective responses were seen.

Although the combined use of topoisomerase I and II inhibitors is attractive on theoretical grounds, excessive myelosuppression prevents substantial dose escalation.