A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)

Background. Sunitinib induces partial responses in 47% of patients with metastatic renal cell carcinoma (mRCC). However, the achievement of complete responses remains scarce and all patients will eventually develop progressive disease. Recombinant interleukin-21 (rIL-21) is a novel cytokine, which is believed to deliver sustained cellular anti-tumor response and the combination of both agents may work synergistically. Material and method. From July 2007 to July 2008 in this phase I trial nine therapy-naive patients with metastatic RCC in five European centers were enrolled. Patients with either good or intermediate risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) were eligible without restrictions to histology subtype nor measurable disease. Patients were treated with increasing doses of rIL-21 administered subcutaneously (s.c.) in combination with sunitinib 50 mg once daily (OD) orally at the '4 weeks on/2 weeks off' schedule. Dose-escalation was applied by a conventional '3+3 design'. Planned dose levels (DL) for rIL-21 were 3, 10, 30 and 100 mu g/kg s.c. The primary endpoint was to determine the maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives included pharmacokinetics of sunitinib and rIL-21, and the induction of rIL-21 antibodies. Results. At 10 mu g/kg two dose-limiting toxicities (DLT) occurred in four patients, consisting of grade 4 neutropenia and grade 3 thrombocytopenia. The MTD was 3 mu g/kg rIL-21 combined with sunitinib 50 mg OD at the '4 weeks on/2 weeks off' schedule. Frequent occurring adverse events were injection site reaction, stomatitis, fatigue and dysgeusia. Conclusions. The combination of sunitinib 50 mg at the '4 weeks on/2 weeks off' schedule and 10 mu g/kg IL-21 was not tolerated due to hematological DLTs. The dose level of 3 mu g/kg rIL-21 was considered too low to be therapeutically relevant for further evaluation and therefore the study was discontinued.