Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver

Abstract

This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3 × 10(6), 1 × 10(7), 3 × 10(7), and 1 × 10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1 × 10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.

FIG. 1.

Maximal change in hepatic tumor diameter after NV1020 administration. Progression is defined as a ≥20% increase in the size of all measurable hepatic lesions, partial response is ≥30%, and stable disease is intermediate change. (A) Phase I dose ranging: NV1020, 3 × 10⁶–1 × 10⁸ PFU; n = 13. (B) Optimal biological dose: NV1020, 1 × 10⁸ PFU; n = 22.

FIG. 2.

Tumor progression and overall survival (in months) after NV1020 administration at the optimal biological dose, n = 22. (A) Kaplan–Meier graph for overall survival. (B) Kaplan–Meier graph for time to progression.

FIG. 3.

Patient 401. Posterior views of distant antitumor response in a 40-year-old white male after NV1020 hepatic artery infusion. (A) PET scan after failing FOLFOX (5-fluorouracil, folinic acid, oxaliplatin) shows extensive hepatic with pulmonary metastases, with local recurrence of sigmoid colon adenocarcinoma. (B) PET scan 5 months after four 1 × 10⁸ PFU infusions of NV1020 followed by repeat FOLFOX shows marked regression of hepatic metastases, together with complete clearance of pulmonary and pelvic tumor.