Sanjiv S. Agarwala, MD, wrote "Intralesional therapy for advanced melanoma: promise and limitation," and enumerated three key points:
• Risk for recurrence, progression and metastasis is high among patients with unresectable, multiple or advanced locally/regionally metastatic stage IIIB/C or stage IV M1a melanoma.• Most recent clinical trials of intralesional therapies show promise for their response rates, low toxicity and likely systemic immunological effects.• Ongoing and planned clinical trials will test T-VEC in combination with systemic immunological therapies and PV-10 as monotherapy versus chemotherapy in patients who have failed or are ineligible for systemic immunological therapy.
Dr. Agarwala is Professor of Medicine, Chief, Oncology & Hematology, St Luke's Cancer Center and Temple University, and his article has been published in the March issue of Current Opinion in Oncology (now available online). Dr. Agarwala notes that for decades, the standard of care has been dacarbazine chemotherapy and high-dose interleukin (IL)-2 as they are the only US Food and Drug Administration (FDA)-approved agents for advanced disease, however, both drugs are limited in their efficacy and application.
With the advent of agents targeting the MAP-kinase pathway and the discovery of more effective immunologic agents, several new drugs have been approved in the past two years.
Among the new approaches, Dr. Agarwala discusses intralesional therapies with agents that may not only shrink the tumor directly but also stimulate a systemic immune response by modifying the tumor's antigenic milieu through intratumoral injection of therapeutic agents. These are promising treatments because melanoma has a unique and close relationship with the immune system, with tumor infiltration by lymphocytes often indicating the attempt of the immune system to eliminate the tumor.The paper delves into the research history of the first intralesional treatment Bacille Calmette-Guerin (BCG), as well as the newer treatments Allovectin-7 (velimogene aliplasmid), plasmid IL-12, talimogene laherparepvec (T-VEC) and Provectus Biopharmaceutical's PV-10.
Dr. Agarwala's findings stated,
After promising phase 2 results with Allovectin-7 (velimogene aliplasmid), overall survival in a phase 3 study was shorter for Allovectin-7 than for dacarbazine/temozolomide (median 18.8 versus 24.1 months). In a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 among 28 patients with advanced melanoma, the primary endpoint of best overall response rate within 24 weeks of first treatment was 32.2% for objective response and 10.7% for complete response. In the phase 3 OPTiM trial of talimogene laherparepvec, the intralesional agent that is furthest along in clinical testing, the primary endpoint of durable response rate was 16% for talimogene laherparepvec and 2% for granulocyte macrophage colony-stimulating factor. In the PV-10 phase 2 trial among 80 patients with stage III–IV melanoma, the overall response rate was 51%, with a 26% complete response rate.
Provectus Biopharmaceuticals, the developer of PV-10, recently held a meeting with the FDA to refine its proposed phase 3 study of PV-10. Topics formally reviewed included subject eligibility requirements, primary and secondary study end points, and study lesion definitions and conventions for defining disease progression. Provectus is incorporating the FDA’s comments from this meeting into its protocol and intends to issue the final version before the end of February. No further review is necessary from the FDA to begin enrolling the PV-10 phase 3 melanoma study after the changes to the protocol discussed already with the FDA are made this month. The Company has 8 sites, 4 in the US and 4 in Australia, that will receive this final version and begin the study immediately upon receipt, and Provectus is in the process of qualifying many more to join in the study.
Dr. Agawala states that interest in emerging intralesional therapies is justified by their strong ablative effects, lack of toxicity and their stimulation of local and systemic immunological responses. He maintains this despite the development of systemic immunotherapies, which have brought significant improvements in outcomes for patients with metastatic melanoma.
He concludes, “What remains unclear at this early stage of experience with the agents in current development is how clinically significant the evoked systemic effects will be, and further, what combinations of intralesional therapy and systemic immune therapy will reap the greatest benefits for patients. Future clinical trials, it is hoped, will help answer these questions and provide yet another potentially effective approach to treat our patients with melanoma.”
The entire article may be found at: http://journals.lww.com/co-oncology/Fulltext/2015/03000/Intralesional_therapy_for_advanced_melanoma__.12.aspx
About Provectus Biopharmaceuticals, Inc. Provectus Biopharmaceuticals specializes in developing oncology and dermatology therapies. PV-10, its novel investigational drug for cancer, is designed for injection into solid tumors (intralesional administration), thereby reducing potential for systemic side effects. Its oncology focus is on melanoma, breast cancer and cancers of the liver. The Company has received orphan drug designations from the FDA for its melanoma and hepatocellular carcinoma indications. PH-10, its topical investigational drug for dermatology, is undergoing clinical testing for psoriasis and atopic dermatitis. Provectus has recently completed Phase 2 trials of PV-10 as a therapy for metastatic melanoma, and of PH-10 as a topical treatment for atopic dermatitis and psoriasis. Information about these and the Company's other clinical trials can be found at the NIH registry, www.clinicaltrials.gov. For additional information about Provectus please visit the Company's website at http://www.pvct.com or contact Porter, LeVay & Rose, Inc.
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