title: A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.
abstract: BACKGROUND
  Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).
  
  
  METHODS
  A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.
  
  
  RESULTS
  We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.
  
  
  CONCLUSIONS
  Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Bitting
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC.
authors.forename: Patrick
authors.initials: P
authors.lastname: Healy
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Creel
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: James
authors.initials: J
authors.lastname: Turnbull
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Karla
authors.initials: K
authors.lastname: Morris
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Sarah Yenser
authors.initials: SY
authors.lastname: Wood
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Starr
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC; Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC. Electronic address: daniel.george@duke.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D010793:Phthalazines / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D000068338:Everolimus; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Clinical trial; Renal cell carcinoma; VEGFR inhibitor; mTOR inhibitor