A multicenter phase I study of intravenous administration of reolysin in combination with irinotecan/fluorouracil/leucovorin (FOLFIRI) in patients (pts) with oxaliplatin-refractory/intolerant KRAS-mutant metastatic colorectal cancer (mCRC).

Abstract

450 Background: Reolysin (reovirus serotype 3) contains a naturally occurring, ubiquitous, non-enveloped human dearing strain reovirus. Reovirus replicates in KRAS-mutant cells resulting in cell lysis. In phase I evaluation, CRC pts received single agent Reolysin with tumor stabilization and CEA response without significant toxicity. Reolysin and irinotecan (IRI) are synergistic in KRAS-mutant preclinical CRC models, providing rationale for this phase I study. Methods: This was a phase I dose escalation study of FOLFIRI + Reolysin. Eligible pts were >18 yrs with histologically confirmed KRAS-mutant mCRC, measurable disease, ECOG PS 0-1, <3 metastatic regimens, and adequate organ function. Standard FOLFIRI was administered with escalating Reolysin doses (range 1x1010 TCID50 to 3x1010 TCID50) in cohorts of 3-6 pts. Reolysin was given IV over 1 hr days 1-5 every 28d (1 cycle). Primary objectives were dose-limiting toxicity (DLT) to determine MTD and pharmacokinetics. Secondary endpoints were antitumor activity, response rate, progression-free and overall survival (PFS and OS). Results: 21 pts enrolled; median age 62 (range 39-77); 5 M; 16 F; FOLFIRI-naïve: 9/21 pts. 2 pts had DLTs in cycle 1 at the highest dose of 180 mg/m2 of IRI. Common (>10%) grade 3-4 toxicity include: neutropenia (n=11), anemia (n=4), and thrombocytopenia (n=3). One patient died of acute renal failure. The DLT is neutropenia. The recommended phase II dose is IRI 150 mg/m2 and Reolysin at 3x1010 TCID50 on days 1-5, q 28 days. 18 pts evaluable for response: PR (1pt; 5%), SD (9 pts; 50%), PD (8pts; 44%). 3 pts taken off study before evaluation. Median PFS: FOLFIRI-naïve pts = 7.4 mo. (95% CI = 1.9 mo., 12.9 mo.); Median PFS FOLFIRI non-naïve pts was not reached; overall median PFS = 7.4 mo. (95% CI = 0.6 mo., 14.1 mo.) Conclusions: The combination of Reolysin and FOLFIRI in pts with KRAS-mutant mCRC was safe, well tolerated and resulted in disease control in the majority of pts, including pts who previously progressed on IRI. We are encouraged by this activity and safety profile, and are planning additional studies. Clinical trial information: NCT01274624.

Oncolytic virus therapy: A new era of cancer treatment at dawn

“…The most common treatment‐related adverse events were nausea (79%), vomiting (58%), erythema at the injection site (42%), fevers/chills (37%) and transient flu‐like symptoms (32%) . Further phase I studies demonstrated the safety and broad anticancer activity of Reolysin in prostate cancer, malignant glioma, metastatic colorectal cancer, multiple myeloma and solid cancers . Multiple phase II studies have investigated intralesional injection of Reolysin together with local irradiation for the treatment of refractory or metastatic solid tumors, intravenous administration of Reolysin for metastatic melanoma and intravenous administration of Reolysin in combination with chemotherapy for head and neck cancer or lung squamous cell carcinoma …”

Past, Present and Future of Oncolytic Reovirus

“…Reovirus has now undergone further evaluation in phase I and II clinical trials across a range of indications; summarised in Table 1. Historically, the tumours most heavily targeted within the reovirus programme have been melanoma, myeloma and glioma [142,171,172], although trials have also included pancreatic, lung, breast, colorectal, prostate, and head and neck cancers [108,109,[173][174][175][176]. Initial trials deployed reovirus as a monotherapy, the majority utilising i.v.…”

Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements towards Individualizing the Treatment

“…Furthermore, reovirus serotype 3 has been studied in a phase I trial of patients with mCRC and results suggest that patients mounted an adequate immune response resulting in robust lysis of mCRC cells [ 110 ]. Another phase I trial of reovirus serotype 3 has shown to be safe and well-tolerated with FOLFIRI co-treatment in KRAS mutant mCRC patients who had progression of disease on prior chemotherapy [ 111 ]. Ongoing trials continue to assess the safety and tolerability of various OVs in the treatment of CRC, but they have not yet succeeded to the advanced phases.…”