A Phase 2 study of intralesional rose bengal disodium 10% (PV-10, Provectus Biopharmaceuticals) for refractory cutaneous melanoma had promising results and suggested induction of a systemic immune response that was confirmed in a separate pilot trial. Phase 3 launched in March 2015.
Chicago – Rose bengal disodium 10% (PV-10, Provectus Biopharmaceuticals) demonstrates efficacy as an intralesional treatment for refractory cutaneous melanoma. Through induction of a systemic immune response, the benefit of localized treatment with this chemoablative agent may extend to untreated lesions, according to research presented at the annual meeting of the American Society of Clinical Oncology.
Sanjiv S Agarwala, M.D., chief of hematology & oncology, St. Luke’s Cancer Center, Easton, PA, and professor of medicine, Temple University School of Medicine, Philadelphia, presented the results of a Phase 2 study1 investigating intralesional PV-10 in patients with cutaneous or subcutaneous melanoma refractory to multiple previous therapies (median 6). He told Dermatology Times that “PV-10 is taken up quickly and selectively by tumor cells where it concentrates in the lysosome. The treatment rapidly leads to cell rupture and induces a tumor-specific T-cell response within 7 days,” he explained.
“The initial goal was to develop PV-10 as an intralesional treatment that might reduce the morbidity of recurrent locoregional melanoma with minimal risk of systemic toxicity. Based on the encouraging Phase 2 results, the sponsor is moving ahead with a Phase 3 randomized trial comparing intralesional PV-10 with systemic chemotherapy in patients with unresectable locally advanced cutaneous melanoma.”
NEXT: Phase 3 trial
The Phase 3 trial launched in March, 2015. Enrollment is planned for 225 patients who are BRAF V600 wild-type, have cutaneous disease only (1-5 target lesions with a maximum diameter of at least 10 mm per lesion), and failed, did not tolerate, or are ineligible for treatment with ipilimumab or another immune checkpoint inhibitor.
Participants will be randomized 2:1 to treatment with intralesional PV-10 or systemic chemotherapy with intravenous dacarbazine or oral temozolomide. Endpoints will include progression-free survival and overall survival in addition to complete response rate. Patients in the active comparator arm who meet the study definition of disease progression and do not have evidence of metastasis will be eligible for crossover to PV-10.
Meanwhile, Peter Culpepper, Chief Operating Officer and Chief Financial Officer of Provectus Biopharmaceuticals, Knoxville, TN, tells Dermatology Times that the company continues to treat patients under its Compassionate Use Program,2 whether they were in other PV-10 clinical studies or not.
“Therefore, the Compassionate Use Program has been helpful for new patients to PV-10, in addition to existing patients,” he said.
NEXT: Phase 2 outcomes
Phase 2 outcomes
In the Phase 2 study, each patient could receive treatment in up to 20 lesions (10 target and 10 non-target lesions), and each lesion could be retreated up to 3 times, based on assessment of response at 8, 12, and 16 weeks after the first injection. One or two “bystander” (untreated) lesions were also designated for assessment during follow-up in some patients.
In the intent-to-treat analysis including data from all 80 patients, the complete response rate for all 260 treated target lesions was 53%.
Subgroup analyses focused on patients who had only cutaneous disease (no visceral metastases) and all lesions followed. Among 28 patients who had all lesions treated, 50% achieved a complete response and with most lesions requiring just 1 or 2 injections. Among 26 patients being followed for changes in bystander lesions, 23% achieved a complete response for both treated and untreated lesions. Response of the untreated lesions was highly correlated with the objective response of treated target lesions.
Median time to response in the various subgroups analyzed ranged from 1.8 to 2.5 months, and the responses were often durable throughout follow-up to 12 months for both the treated and bystander lesions. The safety review showed adverse events were mainly limited to injection site reactions, including pain, edema, swelling, vesicles, itching, and erythema/discoloration. Pain was reported as severe by 10% of patients, but other local adverse events were almost always mild to moderate in severity. The only systemic adverse event was headache, which was reported by 16% of patients and was almost always mild.
Documenting the immunologic mechanism
The observation of the bystander effect of intralesional PV-10 led Amod A. Sarnaik, M.D., and colleagues to undertake studies that would demonstrate an immune mechanism of action for the investigational agent. After first demonstrating in a murine model that intralesional PV-10 led to regression of treated and untreated lesions and induced anti-tumor T-cell responses, they undertook a small clinical trial in patients with metastatic melanoma. Eligible patients had at least one dermal or subcutaneous tumor that could serve as a target lesion for injection and a second lesion to be used as a control. Eight patients were treated, of which six had metastatic disease refractory to two or more previous treatments.
At baseline, a partial biopsy was taken of both the target and control lesions, and blood samples were collected for phenotyping of peripheral blood mononuclear cells. One week after PV-10 was injected into the target lesion, both the injected and control tumors were excised for histology and immunochemistry evaluation, and another blood sample was drawn.
At 1 week, at least partial regression was observed for all injected tumors and uninjected lesions. Assessment of the post-treatment biopsies with H&E staining and for melanin A expression documented complete response of both the injected and uninjected lesions in four (50%) patients, all of who had been refractory to previous treatment.
Analyses of the blood samples showed statistically significant post-treatment increases in circulating cytotoxic CD3+/CD8+ and natural killer T-cell counts. The addition of autologous tumor cells to purified CD8+ cells obtained from the post-treatment blood sample of one patient stimulated release of interferon-gamma, the “quintessential antitumor cytokine”, said Dr. Sarnaik, surgical oncologist, department of cutaneous oncology, Moffitt Cancer Center, and assistant professor of oncology and surgery, University of South Florida, Tampa.
“We believe our research provides the first validation that PV-10 induces a systemic immune response, and it shows that intralesional PV-10 enhances tumor-specific reactivity in circulating T cells,” he told Dermatology Times.
“Now we are building on the identification of this mechanism of action by planning a study that will investigate intralesional PV-10 combined with systemic immunotherapy in patients with metastatic melanoma.”
Dr. Agarwala and Dr. Sarnaik received research funding from Provectus Biopharmaceuticals.
1. Thompson JF, Agarwala SS, Smithers BM, et al. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Ann Surg Oncol. 2014
2. The Compassionate Use Protocol is available at: https://www.clinicaltrials.gov/ct2/show/NCT01260779