1079 Background: Aromatase inhibitors (AIs) have shown high activity in postmenopausal women. However, as AIs do not suppress ovarian oestrogen synthesis, they are not effective in premenopausal women. The aim of this trial was to assess the efficacy of the combination of anastrozole and goserelin (LHRH agonist) in premenopausal women with advanced or metastatic hormonal receptor positive breast cancer. Methods: Premenopausal women with advanced estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer were enrolled in this open, multicentre, non-comparative phase II trial and received anastrozole 1mg/day p.o. and gosereline 3.6 mg subcutaneously monthly until progression. The primary endpoint was objective response rate (ORR) assessed according to RECIST criteria. Results: Thirty-three patients (33), with a mean age of 44 (+ 5.9) years, PS 0–2, were enrolled from December 2001 to May 2005. All patients were ER positive and 75.8% PR positive and 6 patients (18.2%) received adjuvant treatment with anti estrogens. There were 4 (12.1%) complete responses (CR), 14 (42.4%) partial responses (PR), and 11 (33.3%) stable diseases (SD), giving an ORR of 54.6% (IC 95% [36.4; 71.9]). Twenty-one (63.6%) patients showed a clinical benefit (CR+PR+SD≥24 weeks) for a median duration of 13.7 (IC 95% [8.74; 22.97]) months. Median time to progression was 13 (6;33) months. The most commun AEs were hot flush in 29 (87.9%), arthralgia in 13 (39.4%) and nausea in 12 (36.4%) patients. Conclusions: The combination of anastrozole and gosereline is well tolerated and appears to be an effective treatment of premenopausal women with advanced breast cancer in this exploratory phase II trial. No significant financial relationships to disclose.

Purpose To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer. Patients and Methods Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks. Results Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m 2 . Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m 2 . No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m 2 and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m 2 . Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma. Conclusion Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m 2 without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

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.