Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours

Abstract

Summary Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase 11 studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m-2 and ifosfamide doses from 2.5 to 5.0 g m-2. Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m-2 of docetaxel combined with 5.0 g m-2 ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

“…The MTD occurred at docetaxel 85 mg/m 2 and ifosfamide 5000 mg/m 2 , and the authors recommended that docetaxel be given prior to ifosfamide. In contrast to our study, there were no episodes of ifosfamide encephalopathy noted, and greater than 50% incidence of mild peripheral neuropathy, possibly due to a higher cumulative dose of docetaxel delivered (Pronk et al, 1998). It is difficult to compare different schedules of ifosfamide for relative efficacy or toxicity.…”

“…In a previous phase I study of this combination, Pronk et al escalated the dose of both agents, and ifosfamide was infused over a 24-h period on day 1 only (Pronk et al, 1998). In addition they addressed the issue of scheduling, with docetaxel administered prior to ifosfamide in the first phase of the study, and reversal of the order of administration in the second part.…”

“…The major dose limiting toxicity (DLT) is myelosuppression, predominantly neutropenia, which is usually short lasting, dose dependent and non-cumulative (Extra et al, 1993;Tomiak et al, 1994;Pronk et al, 1998). Other toxicities are usually mild and easily managed or prevented.…”

Docetaxel–ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines

“…Moreover, as grade 4 neutropenia and febrile neutropenia represented the only significant toxicities in our study, the 10% incidence of the latter appears rather low and compares favorably to that of single agent docetaxel at 100 mg/m 2 with G-CSF support. The phase I study of Pronk et al [12], that has evaluated the feasibility of the docetaxel-ifosfamide combination without G-CSF in pretreated patients with a variety of advanced solid tumors determined the DLT of the combination being mainly neutropenia at docetaxel 85 mg/m 2 on day 1 followed by ifosfamide 5 g/m 2 administered as 24-h infusion, and the recommended phase II doses were docetaxel 75 mg/m 2 + ifosfamide 5 g/m 2 [12]. A subsequent pharmacokinetic analysis of the regimen by the same investigators found that the sequence of drug administration did not affect the clearance and the area under the curve (AUC) of docetaxel.…”

“…A single previous phase I study has evaluated the feasibility of the docetaxel-ifosfamide combination without G-CSF in pretreated patients with a variety of advanced solid tumors. Dose-limiting toxicity was reached at docetaxel 85 mg/m 2 on day 1 followed by ifosfamide 5 g/m 2 administered as 24-h infusion and the recommended phase II doses were docetaxel 75 mg/m 2 + ifosfamide 5 g/m 2 [12]. Similarly, our group conducted a phase I-II study of the docetaxel-ifosfamide combination with G-CSF support in patients with pre-treated metastatic breast cancer and defined an optimal dose of docetaxel 100 mg/m 2 (on day 1) and ifosfamide 5 g/m 2 (divided over days [1][2].…”