Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx®) in combination with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcoma

This phase I study evaluated the toxicity of first-line combined pegylated liposomal doxorubicin (Caelyx®) and ifosfamide in patients with advanced and/or metastatic soft tissue sarcomas. Five dose levels (L) were studied: Caelyx® 30 mg/m2 (L1-4) or 40 mg/m2 (L5) 1-h infusion d 1 q 3 weeks + ifosfamide and mesna at X g/m2/4 h d 1-3 q 3 weeks at five doses: L1: X = 1.7 g; L2: X = 2 g; L3: X = 2.5 g; L4 and L5: X = 3 g. Cohorts of 3 patients were entered at each level unless a dose-limiting toxicity (DLT) occurred. In case of DLT in 1 of 3 patients a new cohort was added. Toxicity was evaluated by Common Toxicity Criteria (CTC). A total of 28 patients was included: 4 at dose L1, 8 at L2, 3 at L3, 6 at L4, and 7 at L5. Median age was 60 years (range 29-69 years). Male/female ratio was 12/16. Seventy-five percent of patients had a performance status of 1.0 and 36% had leiomyosarcomas. No DLT was observed at dose L1-4. Six patients developed a DLT at dose L5, and thus the recommended dose is level 4 (i.e. Caelyx® 30 mg/m2/1 h d 1 + ifosfamide at 3 g/m2/4 h d 1-3 q 3 weeks). Few haematological and biochemical events were observed and the principal toxicities were granulocytopaenia and leucopaenia. Five patients discontinued therapy because of toxicity, 4 of them at dose level 5. Non-haematological toxicities > grade 2 were also few. Palmar-plantar erythrodysesthesia (PPE) > grade 1 was not seen. Two patients obtained partial response (PR) and 13 stable disease (SD). Median overall survival (OS) was 333 d and median progression-free survival (PFS) 174 d. In conclusion, this seems to be a feasible combination in patients with advanced soft tissue sarcomas, allowing ifosfamide to be given in a dosage similar to that used when given alone. The recommended dose for future studies is Caelyx® 30 mg/m2/1 h d 1 + ifosfamide 3 g/m2/4 h d 1-3 q 3 weeks.