PHASE IB TRIAL OF PENTOXIFYLLINE AND CIPROFLOXACIN IN PATIENTS TREATED WITH INTERLEUKIN-2 AND LYMPHOKINE-ACTIVATED KILLER-CELL THERAPY FOR METASTATIC RENAL-CELL CARCINOMA

The dose of interleukin 2 (IL-2) which can be administered to cancer p atients is limited largely by a capillary leak syndrome. Pentoxifyllin e (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ci profloxacin (Cipro) modifies the metabolism of methylxanthines and, wh en coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Th trial in patients receiving IL-2 and lymphokine-activated killer cell LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX wh ich could be coadministered with Cipro in this setting. Eighteen patie nts received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m( 2)/day on days 1-5 and underwent Leukapheresis on days 7-9. Wt cells w ere infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m( 2)/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusi on every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical reg imen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro wer e well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dos e-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor , responses were observed. Patients treated with 3.9 mg/kg PTX receive d 95.0% of the planned dose of IL-2 as compared to 72.8% in the contro l patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK wit hout apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipi ents exhibited less toxicity than historical controls. Therefore, trea tment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.