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.
The results indicate that Polyphenon E ointment is an efficacious and safe patient-applied topical treatment for external genital and perianal warts. Its use in intra-anal, intravaginal and cervical condylomas and other intraepithelial lesions warrants further clinical investigation.
Polyphenon(R) E 15% ointment, composed of a defined green tea extract, proved to be efficacious and safe for both gender in the treatment of external genital warts.
Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13-74%; P < 0.02). One of three individuals at the 10(8) level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50-98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects.
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