KRAS mutation is a biomarker of exclusion of anti-EGFR agents in patients with mCRC, who have limited options once they progress on oxaliplatin and irinotecan-based regimens. Reo is a naturally occurring, ubiquitous, non-enveloped double stranded RNA virus that selectively replicates in tumor cells harboring KRAS mutations. Reo is synergistic with irinotecan (IRI) in in vitro and in vivo models.
This was a phase I dose escalation study of FOLFIRI/B and Reo to determine maximum tolerated dose (MTD) and recommended phase two dose (RPTD). Eligible pts were adults with oxaliplatin refractory KRAS-mutant mCRC. Both, IRI (150-180 mg/m2) and Reo (1x1010 TCID50 to 3x1010 TCID50) were escalated. Reo was given intravenously over 1 hour on days 1-5 every 4 weeks (wk). FOLFIRI/B was delivered every 2 wk as per standard protocol. Pharmacokinetics (PK), on study tumor biopsies, and immune response was studied.
36 pts enrolled; 23 females (64%), median age 63 years, FOLFIRI naïve (24) and pre-treated (12). At the highest dose of 180 mg/m2 of IRI, among FOLFIRI pretreated pts, 2 had dose-limiting toxicity (DLT) in cycle 1; one suffered from grade 4 thrombocytopenia, and another developed febrile neutropenia and urosepsis. However, in FOLFIRI naïve patients, none/6 had a DLT. Common (>10%) toxicities included neutropenia, anemia, thrombocytopenia, fatigue, and diarrhea. One patient died of acute renal failure. The MTD was the highest individual dose of FOLFIRI/B (180 mg/m2 IRI) and reovirus (3x1010 TCID50), and is the RPTD. At this dose, 3 of 6 patients (50%) had a PR and the median progression free survival (PFS) and overall survival (OS) were 65.6 wk and > 98.3 wk (as of May 9, 2018), respectively. There was no PK interaction noted. Immunogold staining against viral capsid protein σ demonstrated viral “homing” in the tumor cells. Flow cytometry revealed rapid dendritic cell maturation with subsequent activation of cytotoxic T cells.
The combination of reovirus with FOLFIRI/B is safe, and well tolerated. The PFS and OS is superior to historic data and this combination deserves further exploration.
Clinical trial identification
Legal entity responsible for the study
Conquer Cancer Foundation and Oncolytics Inc.
S. Goel, A. Ocean: Oncolytics funding to conduct clinical investigations with reovirus. M. Coffey: Employee, Stock owner: Oncolytics Inc. All other authors have declared no conflicts of interest.