title: Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group Trial N0745 (Alliance).
abstract: Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis.
  
  
  
  To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC.
  
  
  
  Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID.
  
  
  
  Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively.
  
  
  
  The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.).
authors.affiliation: Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Joleen M
authors.initials: JM
authors.lastname: Hubbard
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.affiliation: Cancer Research Center of Hawaii, Honolulu, HI, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Loui
authors.affiliation: Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Creighton University Medical Center, Omaha, NE, USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Mitesh
authors.initials: M
authors.lastname: Borad
authors.affiliation: Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA. Alberts.steven@mayo.edu.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib