Half of patients with locally advanced cutaneous melanoma who had all their lesions injected with the investigational agent PV-10 achieved a complete response in a phase 2 study, according to a presentation at the 50th American Society of Clinical Oncology meeting, held in Chicago, IL, May 30th to June 2nd.
PV-10 is a 10% solution of Rose Bengal, which was originally used as an agent to stain necrotic tissue in the cornea and as an IV diagnostic of liver impairment. Its novel use in melanoma was discovered by Provectus Biopharmaceuticals, Inc. (Knoxville, TN) while exploring different formulations for use in photodynamic cancer therapy.
By serendipity, the company discovered that PV-10, a formulation developed to be administered directly into solid tumors, destroyed tumors without the need for light activation.
Between October 2007 and May 2010, 80 patients with Stage IIIB-IV melanoma received up to four treatment cycles of intralesional (IL) PV-10. Altogether, up to 10 cutaneous or subcutaneous target lesions and up to 10 additional non-target lesions received IL PV-10 at day 0 and could receive up to three further treatment cycles at weeks 8, 12 and 16 if the tumor remained.
Furthermore, up to two "bystander" lesions were identified that underwent biopsy to confirm melanoma, but they did not receive treatment.
The subjects, recruited from seven centers in the US and Australia, all had locally advanced cutaneous disease refractory to a median of six previous interventions.
'Results maximized when all lesions are treated'
In the current abstract, Sanjiv Agarwala, from St. Luke's Hospital and Health Network, Bethlehem, PA, explored the subgroup of 54 patients from the phase 2 study who were able to have most or all of their lesions injected, leaving out patients with more advanced disease where substantial numbers of lesions went untreated.
Results showed that for the 28 patients who had all their existing melanoma lesions injected with PV-10 (i.e., had no uninjected lesions), the overall response rate was 71% (CI 51-87%) with 50% achieving a complete response (CI 31-69%).
Furthermore, the abstract showed that in the combined analysis, 121 lesions required a single injection for complete response, 84 required two injections, 22 required three injections and five required four injections. Of the 28 uninjected bystander lesions, 10 achieved complete response.
Eric Wachter, the chief technology officer at Provectus, who co-developed PV-10, says:
"These sub-analyses show PV-10 injection results are maximized when all lesions get treated. The response observed in this heavily pre-treated or refractory patient population with locally advanced cutaneous melanoma who have unmet medical need is notable since, unlike patients with more advanced disease, limited treatment options are available or on the horizon."
Phase 3 trial to commence soon
In a second abstract, presented in the same session, investigators from Moffitt Cancer Center in Tampa, FL, reported interim data from a study investigating the immunological mechanism of the "bystander effect," where uninjected tumors may undergo complete response.
The study showed that following intralesional PV-10, both PV-10-injected and uninjected study lesions had pathologic complete response (pCR) in four of the eight patients and that all eight patients exhibited at least partial regression of the injected lesion.
Between 1-2 weeks after injection, significant increases in T-cells were detected in peripheral blood, including CD8+ (p=0.03), CD4+ (p=0.06), CD3+ (p=0.03), and NKT (p=0.05). It is noteworthy that six of eight patients had metastatic disease refractory to previous ipilimumab, anti PD-1 and/or vemurabenib therapy.
"This data provides more and more evidence that you are altering both local and systemic immunity in a positive way," says Jeffrey Weber, the senior author of the abstract, from Moffitt Cancer Center. "It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab."
Following the Food and Drug Administration's decision in May to deny a "breakthrough therapy designation" for PV-10 in melanoma, Provectus held a conference call for investors during ASCO to lay out the "path forward" for a phase 3 trial expected to generate sufficient data for a new drug application.
In the trial, 210 patients with unresectable locally advanced cutaneous melanoma, who have failed or are ineligible for systemic immunotherapy, will be randomized 2:1 to PV-10 or systemic chemotherapy.
The endpoints of the study, expected to start accrual in the second half of 2014, include progression free survival (by RECIST 1.1), complete response rate (by RECIST 1.1), overall survival and changes in patient reported outcomes related to melanoma symptoms.
"Breakthrough therapy designation is one of the available paths to expedite a development program. Not having this designation does not derail the development of PV-10. We don't need this designation to move forward," says Wachter.