A Randomized Phase II Study of FOLFOX6/Bevacizumab With or Without Pelareorep in Patients With Metastatic Colorectal Cancer: IND.210, a Canadian Cancer Trials Group Trial

Clin Colorectal Cancer. 2018 Sep;17(3):231-239.e7. doi: 10.1016/j.clcc.2018.03.001. Epub 2018 Mar 8.

Abstract

Background: Oncolytic reovirus pelareorep might preferentially infect and destroy rat sarcoma (RAS)-activated cells, and has preclinical and early clinical activity against colorectal cancer (CRC).

Patients and methods: After a 6-patient safety run-in, 103 patients with metastatic CRC were randomly assigned to standard first-line leucovorin/5-FU/oxaliplatin (FOLFOX6)/bevacizumab (FOLFOX/BEV) every 2 weeks with (n = 51) or without (n = 52) pelareorep 3 × 1010 tissue culture infective dose 50 on days 1 to 5 (cycles 1, 2, 4, and alternate cycles thereafter). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life, and correlative analyses.

Results: At 13 months' median follow-up, PFS was inferior in the pelareorep arm (median 7 vs. 9 months; hazard ratio [HR], 1.59 [80% confidence interval (CI), 1.18-2.15]; P = .046). There was no statistical difference in OS (median, 19.2 vs. 20.1 months; HR, 1.22; P = .38). An increased ORR was observed with pelareorep (adjusted odds ratio, 2.52 [80% CI, 1.44-4.41]; P = .03), but with a shorter median duration of response (5 vs. 9 months; P = .028). Pelareorep patients experienced more hypertension and proteinuria, and were more likely to omit bevacizumab before progression. A trend to lower dose intensity and shorter oxaliplatin and bevacizumab treatment duration was observed with pelareorep.

Conclusion: Combination pelareorep with FOLFOX/BEV was tolerable with an increased ORR, but PFS was inferior. Subgroup analysis of baseline variables including Kirsten rat sarcoma oncogene did not identify subgroups with PFS benefit. Decreased treatment intensity with standard agents likely contributed to the lack of benefit with pelareorep. Future studies might consider alternate pelareorep/chemotherapy strategies or combination therapy with novel agents.

Trial registration: ClinicalTrials.gov NCT01622543.

Keywords: Chemotherapy; Oncolytic virus; RAS; Reolysin; Reovirus.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / therapeutic use*
  • Canada / epidemiology
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy*
  • Combined Modality Therapy / adverse effects
  • Combined Modality Therapy / methods
  • Female
  • Fluorouracil / therapeutic use
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Leucovorin / therapeutic use
  • Male
  • Mammalian orthoreovirus 3 / genetics
  • Middle Aged
  • Oncolytic Virotherapy / adverse effects
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / genetics
  • Organoplatinum Compounds / therapeutic use
  • Progression-Free Survival
  • Quality of Life*
  • Response Evaluation Criteria in Solid Tumors

Substances

  • Organoplatinum Compounds
  • Bevacizumab
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol

Associated data

  • ClinicalTrials.gov/NCT01622543