Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC).

Abstract

3608^ Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.