A PILOT-STUDY OF GAMMA-1B-INTERFERON IN COMBINATION WITH FLUOROURACIL, LEUCOVORIN, AND INTERFERON-ALPHA-2A

The combination of IFN-alpha-2a (IFN-alpha) and IFN-gamma-1b (IFN-gamm a) has been found to produce more than additive cytotoxicity with fluo rouracil (5-FU) in HT 29 colon cancer cells due to enhanced DNA-direct ed effects. We therefore studied the combination of IFN-gamma with IFN -alpha, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three pat ients received an initial cycle of 5 million units (MU)/m(2) IFN-alpha s.c. on days 1-7 with 500 mg/m(2) LV and 370 mg/m(2) 5 FU i.v. on day s 2-6. IFN-gamma was then added once tolerable doses of 5-FU and IFN-a lpha were established for each patient. IFN-gamma was administered at one of six dose levels between 0.3-4.8 MU/m(2) s.c. on days 1-7. This design permitted comparison of the clinical toxicity and pharmacokinet ics of 5-FU in two consecutive cycles in an individual treated with th e same doses of 5-FU/LV/IFN-alpha in the absence and presence of IFN-g amma. In 43 matched patient cycles, the addition of IFN-gamma did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder, 5-FU clearance was higher in 14 cycles with IFN-gamma compa red to the patient's prior cycle with the same doses of 5-FU/LV/IFN-ga mma: 798 +/- 309 versus 601 +/- 250 ml/min/m(2) (mean a SD; P = 0.04). In these 28 cycles, the median 5-FU clearance was significantly lower in 11 cycles that were complicated by more severe diarrhea: 524 versu s 798 ml/min/m(2) (grade 2 versus 0-1; P = 0.0032). Overall, 38% and 2 6% of patients had grade 3-4 diarrhea and mucositis. Dose reductions o f IFN-gamma for chronic fatigue, malaise, or anorexia were ultimately required more frequently with greater than or equal to 2.4 MU/m(2) (P = 0.018), and the maximum tolerated dose of IFN-gamma was considered t o be 1.2 MU/m(2)/day. Objective responses were seen in 41% of 29 measu rable colorectal cancer patients. Compared to our previous experience with 5-FU/LV/IFN-alpha, IFN-gamma and IFN-alpha appeared to have oppos ite effects on 5-FU clearance. These results suggest that any potentia l benefit of adding IFN-alpha to 5-FU/LV on this schedule may not depe nd solely on alterations in 5-FU clearance.