Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients.

OBJECTIVES: To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC). METHODS: Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome). RESULTS: Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3-4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose. CONCLUSION: This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.

Phase I-II study of pegylated liposomal doxorubicin combined with weekly paclitaxel as first-line treatment in patients with metastatic breast cancer.

OBJECTIVES: Pegylated liposomal doxorubicin (PLD) appears to be as active as doxorubicin in first-line metastatic breast cancer (MBC) patients, with lower cardiac toxicity. This phase I-II trial aimed to determine the dose limiting toxicity (DLT) and recommended dose (RD) of a first-line combination of PLD and weekly paclitaxel. METHODS: MBC patients received PLD on day 1, administered over 60 minutes IV. (starting dose 30 mg/m2, escalation by 5 mg/m2 increments), and paclitaxel on days 1, 8, and 15. Initially (schedule A), paclitaxel was administered over 60 minutes (starting dose 80 mg/m2, 10 mg/m2 increments), then (schedule B) over 24 hours on day 1 (at a dose of 70 mg/m2, 10 mg/m2 increments), and in a 60 minute IV infusion at a fixed dose of 90 mg/m2 on days 8 and 15. Pharmacokinetics were assessed during cycle 1 in schedule B. RESULTS: Thirty patients were treated (schedules A = 9; B = 21). Because of cutaneomucous toxicities in all patients in schedule A with discontinuation in 5 patients, schedule B was explored. Two DLTs (febrile neutropenia) occurred, with PLD 35 mg/m2 with paclitaxel 80 mg/m2 day 1 and 90 mg/m2 days 8 and 15 identified as recommended dose. Pharmacokinetic evaluation revealed an interaction, with increased levels of free doxorubicin and PLD during the paclitaxel infusion. CONCLUSIONS: This combination according to schedule and dosages results in cutaneomucous and hematological toxicity, probably because of a pharmacokinetic interaction, which is poorly compatible with a good quality of life for MBC patients.

Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma.

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.