Phase 1b Trial of Biweekly Intravenous Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus in Colorectal Cancer

Abstract

Fifteen patients with treatment-refractory colorectal cancer were enrolled on a phase 1b study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia designed to selectively replicate in cancer cells. Pexa-Vec was administered intravenously every 14 days, at dose levels of 1 × 10(6), 1 × 10(7), or 3 × 10(7) plaque-forming units (pfu)/kg. The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and pharmacodynamics as well as antitumor activity. Patients were heavily pretreated (mean 4.5 lines of therapy). All patients received at least two Pexa-Vec doses (median = 4; range = 2-4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most common adverse events were grade 1/2 flu-like symptoms, generally lasting <24 hours. During the first and last cycles, genome pharmacokinetics were unchanged. Infectious pfu could be detected in plasma up to 2 hours after cycle 1 and up to 30 minutes after cycle 4 (when antivaccinia antibody titers are known to have peaked). Ten patients (67%) had radiographically stable disease. Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenous Pexa-Vec, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.

Figure 1

Pexa-Vec-related skin pustules. Pexa-Vec related pustule onset and resolution of two pustules in patient JX14-1009 (a) and one pustule in patient JX14-1007 (b).

Figure 2

Pexa-Vec pharmacokinetics following multiple IV infusions. (a) Quantitative polymerase chain reaction detection of Pexa-Vec genomes in blood after cycles 1–4. Mean genomes/ml were calculated after removing individual patient values that were below the limit of detection (LOD). The solid marker indicates that the mean value at a time point is based on three samples for Cohorts 1 and 2 and nine samples (D1 and D15), eight samples (D29), or seven samples (D43) for Cohort 3. The “x” marker indicates that there were only two samples above the LOD used to calculate the mean value. The unfilled marker indicates that the value of the time point is based on only one sample above the LOD. (b) Pexa-Vec pfu detection in plasma after cycle 1. (c) Pexa-Vec pfu detection in plasma after cycle 4.

Figure 3

Cytokine detection in plasma. Cytokine concentrations were measured in plasma before and after each cycle of Pexa-Vec treatment. (a) IL-6, (b) MIP-1α, (c) MCP-1, (d) IL-8, (e) IL-18, (f) MIP-1β, (g) TNF-α, (h) IL-2, (i) IL-10, (j) IFN-γ, (k) GM-CSF.

Figure 4

Waterfall plot showing maximum percent changes of the sum of longest diameters of target lesions compared to baseline. X-axis: patient numbers.