A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma Agop Y. Bedikian a , Jon Richards b , Dmitri Kharkevitch c , Michael B. Atkins d , Eric Whitman e and Rene Gonzalez f Allovectin-7, a bicistronic plasmid encoding human leukocyte antigen-B7 and b-2 microglobulin formulated with a cationic lipid system, is an immunotherapeutic agent designed to express allogeneic major histocompatibility complex class I antigen upon intralesional administration. A phase 2 dose-escalation study (VCL-1005-208) was conducted to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy, an Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal lactate dehydrogenase, or any lesion greater than 100 cm 2 were excluded. Patients received six weekly intralesional injections followed by 3 weeks of observation and evaluation. Overall response was assessed using Response Evaluation Criteria in Solid Tumors guidelines. Patients with stable or responding disease were eligible to receive additional cycles of Allovectin-7. All 133 patients were evaluated for safety and 127 patients (2 mg, high dose) were evaluated for efficacy. Fifteen patients (11.8%, 95% confidence interval: 6.2–17.4) achieved an objective response with median duration of response of 13.8 months (95% confidence interval: 8.5, not estimable). A histological examination of tissue from two responding patients who had their lesions resected has shown no evidence of melanoma. Median time-to-progression in this study was 1.6 months. In conclusion, these results indicate that high-dose Allovectin-7 seems to be an active, well-tolerated treatment for selected stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. Melanoma Res 20:218–226  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Melanoma Research 2010, 20:218–226 Keywords: Allovectin-7, clinical trial, human leukocyte antigen-B7 and b2-microglobulin genes, phase 2, immunotherapy, metastatic melanoma, plasmid DNA a Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas, b Oncology Specialists Research Institute, Park Ridge, Illinois, c Department of Clinical Development, Vical Incorporated, San Diego, California, d Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, e Office of Grants and Research, Atlantic Melanoma Center, Morristown, New Jersey and f Department of Cutaneous Oncology, University of Colorado Health Sciences Center, Aurora, Colorado, USA Correspondence to Dmitri Kharkevitch, MD, PhD, Vical Incorporated, 10390 Pacific Center Court, San Diego, CA 92121, USA Tel: +1 858 646 1230; fax: +1 858 334 1467; e-mail: dkharkevitch@vical.com Received 11 May 2009 Accepted 27 January 2010 Introduction Cutaneous melanoma has one of the most rapidly increasing incidence rates of any cancer in the USA. The incidence was an estimated 60 000 new cases in 2007 with an estimated 8100 deaths [1]. The lifetime risk for an individual in the USA developing melanoma is now approximately one in 75 (1.3%). Early detection and surgical excision of melanoma can be curative, but once the disease spreads beyond the initial primary tumor site, it becomes one of the most deadly forms of cancer. The median survival for metastatic melanoma is short, generally in the range of only 6–9 months. No new agents have been approved for the treatment of melanoma in the past decade, although some have reached phase 3 trials [2]. Current choices of therapy for advanced disease are limited and 5-year survival rates for these patients are generally less than 5% [3,4]. In the USA, two single-agent therapies are approved for first-line, nonsurgical treatment of metastatic melanoma: dacarbazine [5] (DTIC-Dome, Bayer Pharmaceuticals, West Haven, Connecticut, USA) and aldesleukin, a human recombinant interleukin-2 [6] (Proleukin, Novartis, Emery- ville, California, USA). Response rates for DTIC in stage III/IV disease ranged from approximately 7–12% in recent randomized studies [7–9]. DTIC-Dome has a median duration of response of 3–4 months [10]. Proleukin seems to offer a significantly increased duration of response for a subset of patients, but at the expense of significant toxicity [9,11]. New agents are still needed for the treat- ment of metastatic melanoma because no evidence of survival prolongation with existing therapy has been established [12]. As melanoma has been considered a highly immunogenic tumor, it has become a target for active and/or specific immunotherapy. Allovectin-7 (Vical Incorporated, San Diego, California, USA) is an immunotherapeutic currently under phase 3 investigation in patients with metastatic melanoma. The product contains the plasmid DNA (pDNA) VCL-1005 that encodes the human leukocyte antigen-B7 (HLA-B7) heavy chain and b2-microglobulin proteins and is 218 Original article 0960-8931  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CMR.0b013e3283390711 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.