Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer

Clin Colorectal Cancer. 2014 Sep;13(3):156-163.e2. doi: 10.1016/j.clcc.2014.04.001. Epub 2014 Jun 23.

Abstract

Background: Although CRC is the third most commonly diagnosed cancer in the United States, second-line CRC treatment is limited. In this trial we examined the efficacy and safety of linifanib, an oral, potent, selective tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor families, with mFOLFOX6, compared with bevacizumab and mFOLFOX6, in previously treated metastatic CRC.

Patients and methods: One hundred forty-eight patients with advanced CRC previously treated with fluoropyrimidine or irinotecan received bevacizumab (10 mg/kg, intravenous), low-dose linifanib (7.5 mg), or high-dose linifanib (12.5 mg), with mFOLFOX6. The primary end point was progression-free survival (PFS). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety.

Results: No statistically significant differences in PFS occurred between bevacizumab and linifanib doses (low, hazard ratio [HR], 1.453 [95% confidence interval [CI], 0.830-2.539]; high, HR, 1.257 [95% CI, 0.672-2.351]). Median OS values were similar for bevacizumab and high-dose linifanib (bevacizumab, 16.5 months [95% CI, 13.0-not available]; high-dose linifanib, 16.4 months [95% CI, 11.9-21.7]; low-dose linifanib, 12.0 months [95% CI, 10.1-13.0]). ORRs were similar (bevacizumab, 34.7% [95% CI, 21.7-49.6]; low-dose linifanib, 24.0% [95% CI, 13.1-38.2]; high-dose linifanib, 22.4% [95% CI, 11.8-36.6]). Median cycles of 5-fluorouracil were reduced in the linifanib arms, versus the bevacizumab arm. Grade 3/4 adverse event occurrences were more frequent with linifanib. Palmar-plantar erythrodysesthesia, hypothyroidism, and thrombocytopenia were more common with high-dose linifanib than bevacizumab.

Conclusion: Combining linifanib with mFOLFOX6 as a second-line treatment for metastatic CRC did not improve PFS, radiographic findings, or duration of response versus bevacizumab and mFOLFOX6.

Keywords: ABT-869; Advanced colorectal cancer; Colon cancer; Second-line; TKI.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology*
  • Disease-Free Survival
  • Female
  • Fluorouracil / administration & dosage
  • Hand-Foot Syndrome / etiology
  • Humans
  • Hypothyroidism / chemically induced
  • Indazoles / administration & dosage
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Organoplatinum Compounds / administration & dosage
  • Phenylurea Compounds / administration & dosage
  • Survival Rate
  • Thrombocytopenia / chemically induced
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • Indazoles
  • Organoplatinum Compounds
  • Phenylurea Compounds
  • Bevacizumab
  • linifanib
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol