Optimal circadian time of vinorelbine (V) combined with chronomodulated 5-FU in pretreated metastatic breast cancer patients. EORTC 05971 randomized multicenter study

2066 Background: Chronotherapy is an aim to increase efficacy/toxicity ratio. Objectives: to define the dosing least toxic time (DLTT) of V (30 mg/m2/d at D1 and D6), combined with chrono 5-FU (10 pm-10 am) (850 mg/m2 D2-D5) over 3 courses q3w. Methods: A logistic regression model (LRM) estimated the DLTT assuming a sinusoidal distribution over time (i.e. over the 8 different arms) of the toxicity rate observed in each arm. The associated 90% confidence limits (CL) has been obtained by bootstrap method. Results: 90 patients were recruited. Toxicity in 46 pts led to the V dosage reduction to 25 mg/m2/d. 40 and 43 pts were assigned the V30 and the V25 regimen. 12% pts went off for toxicity, 5% for PD, 1% for refusal, 1% for unrelated death. 224 cycles were analyzed . V and 5FU relative dose intensities were 79.4% and 78.2% in the V30 while 88.1% and 87.4% in the V25 pts. Over the 3 cycles, toxicity by cycle was: Grade (G) 3 and G4 leucopenia in 47% and 29%, G3 and G4 neutropenia in 12% and 77%. G3 febrile neutropenia in 34%. G2 thrombopenia and anemia in 4% each. Other G3 and G 4 toxicity were stomatitis (12%), alopecia (7%), and less than 5%: cardiovascular, lethargy, diarrhea, constipation, other gastrointestinal, infection, sensory, pulmonary. LRM could not demonstrate a DLTT for the neutropenia G3–4 incidence, the primary endpoint. However, based on the stratified by dose analysis, a 90% CI of less than 6 hours width was observed: - around 17H17 [14H04–20H03] for the incidence of leucopenia G3–4. - around 8H16 [06H04–10H39] for tolerability (dose reduction, dose delay or treatment interruption for toxicity reason). This suggests that treatment tolerability was influenced by other factors beside leucopenia nadir. No other 90% CI of less than 6 hours width could be observed for other toxicity endpoints. Conclusions: Using a novel time finding study design with ad hoc statistics, this first randomized multicenter study has determined a DLTT for Vinorelbine in 90 women with MBC. Additional studies are ongoing to further assess the relevance of this trial design method that could prove useful for improving the safety of anticancer drugs during their clinical development. Support Pierre Fabre Oncology, Ligue Bourguignonne contre le Cancer No significant financial relationships to disclose.