ELUCIDATION OF REOVIRUS PHARMACODYNAMICS IN A PHASE I TRIAL IN PATIENTS WITH KRAS MUTATED COLORECTAL CANCER.

Purpose: KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS mutated cells, and is synergistic with irinotecan. Patients and Methods: A dose escalation trial of FOLFIRI/bevacizumab (irinotecan (150-180 mg/m2) and pelareorep (1x1010 TCID50-3x1010 TCID50) was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Results: Among FOLFIRI naive patients, the highest dose of FOLFIRI/bevacizumab (180mg/m2 irinotecan) and pelareorep (3x1010 TCID50) was well tolerated, without a DLT. At the RPTD, three of six patients (50%) had a partial response; the median progression free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). Conclusions: The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T cell activation, and homes and replicates in the tumor.