Tony Reid

PURPOSE: Treatment options for metastatic melanoma are limited. We conducted this phase II trial to assess the efficacy of JS1/34.5-/47-/granulocyte-macrophage colony-stimulating factor (GM-CSF) in stages IIIc and IV disease. PATIENTS AND METHODS: Treatment involved intratumoral injection of up to 4 mL of 10(6) pfu/mL of JS1/34.5-/47-/GM-CSF followed 3 weeks later by up to 4 mL of 10(8) pfu/mL every 2 weeks for up to 24 treatments. Clinical activity (by RECIST [Response Evaluation Criteria in Solid Tumors]), survival, and safety parameters were monitored. RESULTS: Fifty patients (stages IIIc, n = 10; IVM1a, n = 16; IVM1b, n = 4; IVM1c, n = 20) received a median of six injection sets; 74% of patients had received one or more nonsurgical prior therapies for active disease, including dacarbazine/temozolomide or interleukin-2 (IL-2). Adverse effects were limited primarily to transient flu-like symptoms. The overall response rate by RECIST was 26% (complete response [CR], n = 8; partial response [PR], n = 5), and regression of both injected and distant (including visceral) lesions occurred. Ninety-two percent of the responses had been maintained for 7 to 31 months. Ten additional patients had stable disease (SD) for greater than 3 months, and two additional patients had surgical CR. On an extension protocol, two patients subsequently achieved CR by 24 months (one previously PR, one previously SD), and one achieved surgical CR (previously PR). Overall survival was 58% at 1 year and 52% at 24 months. CONCLUSION: The 26% response rate, with durability in both injected and uninjected lesions including visceral sites, together with the survival rates, are evidence of systemic effectiveness. This effectiveness, combined with a limited toxicity profile, warrants additional evaluation of JS1/34.5-/47-/GM-CSF in metastatic melanoma. A US Food and Drug Administration-approved phase III investigation is underway.

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.

Abstract Purpose: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. Patients and Methods: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. Results: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. Conclusions: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262) See related commentary by Salas-Benito et al., p. 5435