title: Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer.
abstract: BACKGROUND
  Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor).
  
  
  METHODS
  The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer.
  
  
  RESULTS
  Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months).
  
  
  CONCLUSIONS
  The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Thomas
authors.initials: T
authors.lastname: Abrams
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: McCleary
authors.forename: Deborah
authors.initials: D
authors.lastname: Schrag
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Jill N
authors.initials: JN
authors.lastname: Allen
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhargava
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Meaghan
authors.initials: M
authors.lastname: Elliot
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Eileen
authors.initials: E
authors.lastname: Regan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D000068338:Everolimus; D006801:Humans; D009367:Neoplasm Staging; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D000068338:Everolimus; D020123:Sirolimus