xidases is an importantrate and also, in certain subgroups, in terms of survival, without a significant increase in severe toxicity. CHIR-258 Dovitinib The activity and tolerability of third generation agents led many investigators to evaluate platinum free doublets in the hope that platinum analogues could be spared for the treatment of advanced NSCLC. Addition of a third agent to platinum based doublet may be an option to improve outcomes in NSCLC. This strategy has been shown to be associated with superior outcomes in other malignancies. This led to the conduct of multiple trials comparing a two drug regimen with a three drug regimen in advanced NSCLC patients. Our group, in particular, developed two different triplets including ifosfamide, an alkylating agent with activity against NSCLC commonly used in old regimens.
Gemcitabine, ifosfamide and cisplatin and gemcitabine, ifosfamide and vinorelbine evidenced very interesting results in phase II first line studies, with a RRs of 54% and 52% and a median overall survival of 12 and 11 months, respectively, with acceptable toxicity profiles. The results of these studies suggested further investigations within prospective randomised study assessing the role of these triplets, with or without platinum. Considering this background, a randomised 2 2 factorial phase III trial addressing two questions: the role of replacing cisplatin with a non platinum agent, vinorelbine, and the role of adding a third agent, ifosfamide, in a chemotherapy doublet based on gemcitabine was performed. Here, the results of this multicenter Italian trial are reported.
PATIENTS AND METHODS Study population Patients with histologically or cytologically confirmed locally advanced stage IIIB or metastatic stage IV NSCLC were eligible for the study. Patients were required to be chemotherapy naive for advanced disease. Eligibility criteria included: age X18 years, ECOG performance status p2, adequate haematological, hepatic and renal function. Patients with active infection, severe co morbidity and a history of previous or concomitant neoplasm, other than epithelial tumours of the skin or in situ carcinoma of the uterine cervix, were ineligible. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study was approved by the ethics committee of each participating institution and written informed consent was obtained from each patient before inclusion.
Study design and treatment plan This was a randomised factorial study with the following two primary aims: to compare the effectiveness of two different treatment strategies, one containing cisplatin and one containing vinorelbine instead of cisplatin, to compare the effectiveness of two different treatment strategies, one with two and one with three drugs for the addition of ifosfamide, both in terms of OS. The factorial design was chosen to improve study efficiency, assuming no interaction between the two factors under investigation. After stratification by centre, eligible patients were randomly assigned to one of four treatment arms in a 1 : 1 : 1 : 1 ratio: gemcitabine cisplatin, gemcitabine vinorelbine, GIP and GIN. Random assignment was centrally performed by fax at the Trial Unit of the National Institute for Cancer Research o