title: A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC).
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.
  
  
  METHODS
  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.
authors.affiliation: Medical School Hannover, Clinic for Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Desar
authors.forename: John
authors.initials: J
authors.lastname: Haanen
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Ulrik
authors.initials: U
authors.lastname: Mouritzen
authors.forename: M W Brændholt
authors.initials: MW
authors.lastname: Olsen
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007378:Interleukins / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage; D000077210:Sunitinib; D017211:Treatment Failure; D000098546:Interleukin-21
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D000098546:Interleukin-21; D000077210:Sunitinib