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.
Oncolytic virotherapy poses unique challenges to the evaluation of tumor response. We hypothesized that the addition of [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to standard computed tomography (CT) evaluation would improve diagnostic and prognostic power of the measurement of tumor response to oncolytic virotherapy. A phase I/II trial was conducted to investigate treatment of hepatic metastases from colorectal carcinoma using intra-arterial administration of the oncolytic herpes virus NV1020. Both contrast-enhanced CT and FDG PET were obtained on each patient at each time point. Quantitative FDG PET and CT responses were correlated with each other and with clinical outcome metrics. A majority of patients showed initial post-viral infusion increases in tumor size (69%) or in standardized uptake value (SUV) (80%) large enough to qualify as progressive disease. Most showed subsequent decreases in tumor size (64%) or SUV (83%) enough to be reclassified as partial response or stable disease. Late PET and CT imaging results correlated well with each other and with clinical outcomes, but results from early in the treatment scheme did not correlate with each other, with later results, or with clinical outcomes. The addition of FDG PET to the evaluation of tumor response to the oncolytic virus NV1020 did not provide useful diagnostic or prognostic data. More sophisticated molecular imaging will need to be developed to monitor the effects of this novel class of antineoplastic agents.
Sixty nine patients with chronic duodenal or juxtapyloric ulceration were studied in a prospective double blind randomised trial to compare the efficacy of antacid and placebo at high (30 ml seven times daily) and low (10 ml as required) doses. After four weeks ulcers had healed in 12 out of 18 patients (67%) receiving "low dose" antacid compared with in six out of 17 patients (35%) receiving low dose placebo; ulcers had also healed in six out of 19 patients (32%) receiving "high dose" antacid compared with in two out of 15 patients (13%) receiving high dose placebo. Overall, the effect of antacid was superior to that of placebo in healing ulcers (p<0 05) and the effect of low dose treatment was superior to that ofhigh dose treatment (p <0 01). There were no significant differences between antacid and placebo at eight weeks. Antacid was better than placebo in relieving pain, but the difference was not significant. Poor compliance and high incidence of diarrhoea made high dose antacid an impractical treatment. Low dose antacid was associated with a significantly better rate of healing than high dose antacid and was far better tolerated.This low dosage of antacid should be considered to be an active treatment in trials of ulcer healing.
4089 Background: NV1020 is a genetically engineered oncolytic Herpes virus. Published Phase 1 dose-ranging results reported no significant related toxicity except for a mild (<24 hr) viral syndrome. Initial Phase 2 tumor response data using the optimal biological dose (OBD) are now presented. Methods: Patients with heavily pretreated, progressing liver mCRC received 4 doses of NV1020 (1 X108 pfu) by weekly hepatic artery infusion followed by two cycles of conventional chemotherapy. Follow-up (≥1 year) evaluation included 4 X 3-monthly scans, then telephone contact to determine survival. Blinded, independent radiologists interpreted CT (modified RECIST) and FDG PET (EORTC) scans. Results: All 22 patients had prior 5FU-based treatment: 77% and 58% also had oxaliplatin or irinotecan, respectively (50% both agents); 86% had one targeted therapy (24% ≥2 such agents); 29% had radiofrequency ablation. Mean time from primary resection was 95 weeks, mean CEA was 182 ng/mL, and 55% had pulmonary lesions. Two patients received only 2 NV1020 infusions due to rapidly progressing disease. Virus tolerability was unchanged from Phase 1 and no related, serious or Grade 4 toxicity was found. NV1020 neutralizing antibodies rose in all patients but no NV1020 was shed (saliva, skin). After NV1020 alone, 10/22 (45%) and 8/20 (40%) on CT and PET, respectively, showed stable disease. 21 patients subsequently received chemotherapy, 45% with drugs to which they were previously refractory and 36% with only one new drug. 14% refused both planned cycles. Best response observed with CT was 55% (1 CR, 1 PR, 10 SD) and 59% (5 PR, 8 SD) with PET. Despite intrahepatic delivery, some remote responses were observed. Response did not correlate with initial tumor size, SUV, or CEA, with time since primary resection, pre- or post NV1020 chemotherapy type. Nine (41%) remain alive > 1 year. Kaplan-Meier median time to progression is 28 weeks (95% CI [9–37]); median survival probability is 52 weeks (95% CI [36–90]). Conclusions: NV1020 stabilizes liver metastases in highly advanced mCRC and may sensitize tumors to salvage chemotherapy resulting in extended overall survival. A controlled Phase 2/3 trial is justified. [Table: see text]
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