A randomized phase II trial is designed to discover whether one treatment has more responses than another one. This means that historical controls do not need to be used, but it tells us nothing about how long the responses last or whether the overall survival differs between the two treatments.
Some years ago the idea that mitoxantrone might be a good drug for CLL was floated and the British group have conducted at trial comparing FCM with FCM-R. The patient group looked at were those who required treatment according to the NCI guidelines, who had had at least one previous course of treatment. 52 patients were randomized between the two arms. The median age was 68 (32-79) with 79% male. 23/37 had a beta-2M >4. The median number of prior therapies was 2 (1-6). 63% had had prior fludarabine. 21% were either refractory to fludarabine or had relapsed within 6 months of having fludarabine. 26/45 had unmutated IGHV genes, 11 had del 11q, and one del 17p. The two groups were well balanced. 69% received at least 4 cycles of treatment but 50% failed to receive all 6 prescribed cycles. reasons for early discontinuation were: death (1), toxicity (7), chest infection (2), patient choice (1) and the other unknown.
The treatment arms were Fludarabine 24mg/sq m/d for 5 days orally, Cyclophosphamide 150 mg/sq m/d for 5 days orally, Mitoxantrone 6 mg/sq m iv on day 1 plus or minus rituximab 375 mg/sq m on day 1 of the first course and 500 mg/sq m on day 1 of subsequent courses.
The overall response rate was 58% for FCM and 65% for FCM-R (not significantly different). The CR + CRi rate was 15% for FCM and 42% for FCM-R (not significantly different). Similarly the MRD negative rates were similar at 12% and 19%.
Forty-one serious adverse events were reported, equally distributed between the two arms. Thirty-one were thought to be treatment related. The safety profile for both arms was found to be similar.
The authors conclude that these regimens should be tested in larger studies and in fact this is being done in the ARCTIC and ADMIRE trials.