Recombinant IL-21 in combination with sorafenib: Preliminary results from a phase I/II study in patients with metastatic renal cell cancer

A60 Introduction The development of multi-targeted tyrosine kinase inhibitors has changed treatment paradigms in metastatic renal cell cancer (RCC). However, durable responses continue to be elusive, except in a small subset of patients treated with high dose interleukin-2 (IL-2). Interleukin-21 (IL-21), an immunomodulatory cytokine with close homology to IL-2, has promising anti-tumor activity. A phase I study of recombinant interleukin-21 (rIL-21) in patients with metastatic RCC or melanoma demonstrated its safety and tolerability and provided preliminary evidence of anti-tumor efficacy (Proc ASCO 2006; 24:2505). Based on encouraging pre-clinical evidence of an additive effect with rIL-21 and sorafenib, a phase I/II dose escalation study of this novel combination was launched in patients with metastatic RCC. We report the preliminary results of this multi-center study. Methods Patients with metastatic RCC of predominantly clear cell histology, ECOG status 0 or 1, and a maximum of one prior systemic therapy are being enrolled to receive a combination of sorafenib and rIL-21. Sorafenib is administered on a continuous basis at standard dose (400 mg PO bid) with standard dose reduction for toxicity. Recombinant IL-21 is administered as once daily outpatient IV infusion on days 1-5 and 15-19 of a 6-week treatment course. In phase I, cohorts of 3-6 patients are being enrolled to receive rIL-21 at escalating dose levels (10, 30, or 50 μg/kg/day) to estimate the maximum tolerated dose (MTD). In phase II, 30 patients will receive rIL-21 at the MTD. Patients with stable disease or better response after the first 6-week course are eligible to receive additional courses of rIL-21 plus sorafenib. Results To date, twelve patients have been enrolled in the 10 μg/kg/day (n=8) and 30 μg/kg/day (n=4) cohorts. Nine patients were evaluable for dose escalation. One patient in the 10 μg/kg/day cohort had a dose-limiting toxicity (DLT), which was grade 3 hand-foot syndrome. The majority of adverse events were grades 1 or 2 and consistent with the known toxicities of rIL-21 and sorafenib, including flu-like symptoms, diarrhea, nausea, hypophosphatemia, hoarseness, hand-foot syndrome, and skin rash. Non-DLT grade 3 events considered related to study drugs were hypophosphatemia, hyponatremia, skin rash, fever and fatigue. Four patients have required reduction in sorafenib dose at some time on study. Eight patients with measurable disease were evaluable for tumor response and all have gone on to receive multiple courses of rIL-21 (range, 2-4 courses). One patient achieved a partial response. All other patients have had tumor shrinkage, with median reduction of 24%. Two patients to date have had progressive disease. Enrollment is currently ongoing into the 50 μg/kg/day cohort. Conclusions Preliminary data from the phase I portion of this trial suggests that the combination of rIL-21 and sorafenib is well tolerated, with a toxicity profile similar to the known toxicities of each agent given alone. The combination therapy has also shown promising anti-tumor efficacy. Updated data from phases I/II will be available at the time of the meeting.