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

Acta Oncol. 2011 Jan;50(1):121-6. doi: 10.3109/0284186X.2010.509104.

Abstract

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 microg/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 microg/kg two dose-limiting toxicities (DLT) occurred in four patients, consisting of grade 4 neutropenia and grade 3 thrombocytopenia. The MTD was 3 microg/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 microg/kg IL-21 was not tolerated due to hematological DLTs. The dose level of 3 microg/kg rIL-21 was considered too low to be therapeutically relevant for further evaluation and therefore the study was discontinued.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / secondary
  • Drug Administration Schedule
  • Female
  • Hematologic Diseases / chemically induced
  • Humans
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Interleukins / administration & dosage
  • Interleukins / adverse effects
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / pathology
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects
  • Recombinant Proteins / administration & dosage
  • Sunitinib
  • Treatment Failure

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Interleukins
  • Protein Kinase Inhibitors
  • Pyrroles
  • Recombinant Proteins
  • Protein-Tyrosine Kinases
  • interleukin-21
  • Sunitinib