Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Abstract

Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I -II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel -ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70 -100 mg m À2 over 1 h on day 1 followed by ifosfamide 5 -6 g m À2 divided over days 1 and 2 (2.5 -3.0 g m À2 day À1 over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32 -72) years and performance status (WHO) of 1 (range, 0 -2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3 -68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3 -24 months), median time to progression 6.5 month (0.1 -26 month), and median overall survival 13 months (0.1 -33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients -with 63% developing grade 4 neutropenia (p7 days) and in 12% of these FN, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 12%, grade 1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle. In conclusion, the present phase I -II study determined the feasibility of the docetaxel -ifosfamide combination, defined the MTD and demonstrated the encouraging activity of the regimen in phase II, thus warranting further randomised phase III comparisons to singleagent docetaxel or combinations of the latter with other active agents. ) has demonstrated a broad spectrum of activity against a variety of advanced solid tumours, and breast cancer represents the first in which docetaxel has been successfully tested (Salminen et al, 1999). In particular, for patients with prior anthracycline-based therapy, taxanes represent the treatment of choice in the salvage setting, since previously applied agents have demonstrated infe...

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

“…However, these data should be deemed rather premature and the schedule and doses administered were largely suboptimal; docetaxel 50 mg/m 2 on day 1 and ifosfamide 1.2 g/m 2 /day× 3days [31], compared to those defined in the study of Pronk et al [12], as well as in our phase I-II study [13]. In the aforementioned phase I-II study of Pagani et al [28], evaluating the paclitaxel/cyclophosphamide doublet, a dose-response effect was suggested for pretreated patients, with a lower RR reported for those receiving <1,500 mg/m 2 of cyclophosphamide [28].…”

“…The study was approved by the Ethical and Scientific Committees of the participating institutions and informed consent was obtained from each patient before study entry. A number of patients included in the present study (41 out of 71) has been reported previously as a part of a phase I/II study of the docetaxel+ifosfamide combination that defined the MTD and demonstrated a preliminary activity of the regimen [13].…”

“…was administered 1-h before chemotherapy (on day 1 as docetaxel pre-medication as well) on days 1, 2 and post-chemotherapy 4 mg t.i.d. or methylprednisolone 16 mg b.i.d per os on days 3-5 [13]. Hematopoietic growth factors included G-CSF: lenograstim at 150 μg/m 2 /day or filgrastim 5 μg/kg s.c. from day 4-until day 10 or until WBC≥10.000/μl.…”

“…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]. Given the feasibility and the acceptable toxicity profile, with a 12% incidence of febrile neutropenia (in phase II), as well as the encouraging clinical activity (RR: 64%) of the docetaxel-ifosfamide combination in the previous phase I/II study of our group [13], we elected to extend our phase II experience with the above regimen in HER2-non-overexpressing, anthracyclinepretreated metastatic breast cancer patients.…”

Phase II Study of Vinorelbine Plus Ifosfamide in Patients with Taxane-resistant Metastatic Breast Cancer

“…phase I/II studies that have combined ifosfamide with other agents for treating advanced breast cancer patients, such as doxorubicin, (13) paclitaxel (14) and docetaxel (15,16) and these studies have demonstrated the feasibility of considerably high ifosfamide doses as well as the substantial activity of the employed combinations.…”