An investigational agent for metastatic melanoma (PV-10, Provectus Biopharmaceuticals, Inc), which is injected directly into skin lesions, has shown rapid complete responses in a high proportion of patients in early clinical trials, and a phase 3 study is now planned.
Results from a phase 2 study were published online October 28 in the Annals of Oncology, and details of results from this study were reported at recent meetings.
An analysis of the responses seen in a subset of 28 patients (from a total of 80 patients in the phase 2 study) was reported in a poster presentation at the recent annual meeting of the European Society of Medical Oncology.
Lead investigator Sanjiv Agarwala, MD, section chief of hematology/oncology at St. Luke's Hospital and Health Network in Bethlehem, Pennsylvania, highlighted the timing of the responses that were seen after PV-10 was injected directly into cutaneous melanoma lesions.
The importance of the response analysis, Dr Agarwala explained, is that it shows that PV-10 responses occur before chemotherapy responses would be expected. "In a trial comparing PV-10 to chemotherapy, we should see a difference very quickly between PV-10 and chemotherapy responses," he said.
The 80 patients in the overall trial had disease refractory to a median of 6 prior interventions. All had received initial treatment with PV-10 in up to 20 cutaneous, subcutaneous, or nodal lesions. New lesions or incompletely responsive lesions were retreated at weeks 8, 12, or 16, with follow-up to 52 weeks. Investigators were allowed to leave one or two lesions untreated (which included some visceral lesions). The primary endpoint was response rate of injected lesions.
The subset of 28 patients that Dr Agarwala focused on in his presentation had had all their lesions treated. Patients had a median of eight study lesions (range, 1 - 22), with a median time to response of 1.8 months. The complete response rate among these 28 patients was 50% (confidence interval [CI], 31% - 70%), and the partial response rate was 21%; both of these together (complete plus partial responses) gave an objective response rate of 71%. A further 11% of patients had stable disease.
The median progression-free survival in these 28 patients was 9.8 months. For comparison, in the uninjected bystander lesion group, progression-free survival was 8.9 months.
Among 232 complete responses in 363 lesions (64%), about half were seen after the first injection: 121 complete responses were observed after one injection, 84 after two injections, 22 after three, and five after four injections. The finding of such rapid responses, Dr Agarwala said in an interview, "has really helped us toward finalizing our phase 3 trial design. Based on these data, we will treat all lesions in the phase 3 trial, and include only BRAF wild-type patients (who do not respond to BRAF inhibitors) and those who have become refractory to systemic immunotherapy or are not candidates because of advanced age or comorbidities."
For the phase 3 trial, plans are to enroll 219 patients with locoregional disease only. They will be randomly assigned in a 2:1 ratio to receive intralesional PV-10 or systemic chemotherapy with either dacarbazine (multiple brands) or temozolomide (Temodar, Merck Sharp & Dohme).
Responses in the Overall Patients Group
Dr Agarwala had previously reported on the responses in the overall patient group of 80 patients treated in the phase 2 trial during the 2012 annual meeting of the American Society of Clinical Oncology (ASCO). At that time, he reported that the objective response rate (OR) in the overall patient group was 51% in target lesions (25% complete response and 26% partial response), with a 69% disease control rate in those same lesions (combined complete-, partial-, and stable-response patients).
In a subgroup of 38 patients with bystander lesions, the objective response rate was 33%, and the disease control rate was 50%. Response in bystander lesions was highly correlated with outcome in treated target lesions, with a bystander lesion OR of 61% in patients achieving complete or partial response in their target lesions vs 18% in patients who did not achieve this level or response in their target lesions.
PV-10 benefits, in general, were greater for patients with stage III disease than for those with stage IV disease, Dr Agarwala reported. Mean overall survival was at least 12.6 months (the median was not reached during the study interval) for patients with stage III disease vs 7.3 months for those with stage IV disease.
Mean progression-free survival for all patients was 8.5 months. The safety and efficacy profile of PV-10 compared favorably with available and emerging options for this patient population, Dr Agarwala noted.
Adverse events, in general, were predominantly mild to moderate, and no grade 4 or 5 adverse events were reported. He noted that because PV-10 is a small-molecule immune-chemoablative agent, any drug that escapes the tumor after injection is cleared rapidly from blood circulation, minimizing the potential for systemic side effects. Almost all adverse events reported with PV-10 are local injection-site side effects, such as erythema, edema, pain, and blistering, Dr Agarwala said.
"Very Impressive" Bystander Lesion Response
Commenting on the phase 2 findings in an interview, Merrick Ross, MD, chief of the melanoma section in the Department of Surgical Oncology at MD Anderson Cancer Center in Houston, Texas, said the objective response rate among bystander lesions was "very impressive."
"This actually confirms that there is a systemic host immune response that can lead either to protection at distant sites or regression of other sites that are not injected," Dr Ross commented.
Elucidating the Mechanism of Action
The high-percent response rates in bystander lesions underscored the importance of elucidating the mechanism underlying PV-10's activity. That meant going back to bench investigations. The operant question for researchers, according to Shari A. Pilon-Thomas, PhD, Moffitt Cancer Center Immunology Program, was: "Is it just because you inject the drug and it goes everywhere and then kills tumor cells at other sites? Or is injecting PV-10 inducing a T-cell response, such that T-cells travel throughout the body and kill tumors in their various locations?"
In a poster presentation at the 2013 meeting of the American Association of Cancer Research, she pointed to evidence suggesting that an immune-mediated process underlies PV-10 responses in untreated lesions. First, responses in untreated lesions occurred only when responses had occurred in injected lesions, and second, responses in bystander lesions typically were delayed in comparison with responses in injected lesions, Dr Pilon-Thomas noted.
Dr Pilon-Thomas has previously shown in murine models that induced flank tumors treated with PV-10, as compared with placebo, were about a third of the size, and bystander lesions were about 30% smaller. At the same time, concentrations of interferon-gamma, a cytokine critical for innate and adaptive immunity (including tumor control) and for activating macrophages, were increased more than fivefold.
These findings, along with those from other studies, led Dr Pilon-Thomas to conclude, "We think that when you inject PV-10 into a tumor, it destroys the tumor, releasing tumor fragments that are then taken up by immune cells. The immune cells travel to the lymph nodes where they 'educate' or activate T-cells, which can in turn travel anywhere in the body."
Her research also showed that PV-10-induced immunity is tumor specific.
Further evidence of immune responses induced by PV-10 come from another study conducted at the Moffitt Cancer Center, this time involving eight patients with dermal and/or subcutaneous metastatic melanoma. The findings, presented at this year's ASCO annual meeting in a highlighted poster session by Amod Sarnaik, MD, a surgical oncologist at the Moffitt Cancer Center, showed that intralesional PV-10 was associated with a significant increase (P = .03) in circulating cytotoxic CD8+ T-cells, a potential mechanism for a tumor-specific immunologic effect secondary to tumor ablation.
In this study of eight patients, each patient had two study lesions that were sampled by biopsy before treatment; one of the two lesions was injected with intralesional PV-10, and then both residual sites were completely excised 1 to 2 weeks after PV-10 injection. Tumors were compared before and after treatment to determine pathologic complete response (pCR).
PV-10 resulted in pCR in the posttreatment biopsy specimens of both PV-10-injected and uninjected study lesions in four of the eight patients, and all eight exhibited at least partial regression of the injected lesion.
Six of these eight patients had metastatic disease that was refractory to previous treatment with immunologics (ipilimumab [Yervoy, Bristol-Meyers Squibb Company] and anti-PD-1 therapy) and BRAF-mutation inhibitor (vemurafenib [Zelboraf, Hoffman-La Roche]). After PV-10, four of these six patients had pCRs in both the injected and uninjected lesions.
Where Is It Likely to Fit In?
Dr Ross commented that there is interest in intralesional therapies for metastatic melanoma, even though there have been lots of developments in recent years in systemic therapies. Although these new developments have made headlines with their unprecedented response rates, there are issues with the new therapies. Dr Ross pointed out that responses to BRAF inhibition in patients with mutated BRAFgenes are robust but not durable, and he also noted that although responses to the novel immunologic ipilimumab have been durable, the overall response rates are low (10% - 15%) and are accompanied by problematic adverse events and by a high risk for significant morbidities related to uncontrolled locoregional disease.
Dr Ross noted further that many patients will have recurrences in the extremity or the trunk or the head and neck region that can be the source of significant morbidity. "Left untreated, these lesions will ulcerate, bleed, cause pain, invade deeper, and even if you can resect all the sites, those who have not already developed distant disease are at high risk for it." Mortality in this subset is greater than 50%. "So in addition to controlling the disease locally, some of these agents probably elicit an immune response that can have an impact on the natural history of the disease."
Speculating as to the likely future application of PV-10, Dr Ross said that PV-10 can potentially be used as a monotherapy, especially among patients who are not good candidates for systemically administered agents that can cause toxicity ― some elderly patients with comorbidities. "Probably the more exciting platform would be in combination with the new therapies like ipilimumab and anti-PD1 agents. I think these agents, PV-10 in particular, but all of the injectables, have very low toxicity, and it would be very easy to combine them with these other systemic therapies."
Beyond melanoma, PV-10 is currently also being evaluated in treatment of primary and metastatic tumors of the liver.
Rose Bengal and the Origins of PV-10
The PV-10 product that is now being developed for use in cutaneous melanoma was originally discovered in a research project at Photogen Technologies Inc, Knoxville, Tennessee, in the mid 1990s, during a search for photodynamic drugs.
The researchers homed in on a product known as rose bengal, which had been used as a fabric dye (and later also as food coloring). Its name was based on its deep rose color, like that of the middle-of-the-forehead dot designating married status among women of Bengal and other regions of India. It also has a considerable history of medical use, principally as a diagnostic stain.
Initially, it was thought that laser activation was needed to allow the product to penetrate the tumor, but this turned out not to be the case. The company evolved from Photogen to Provectus. Preclinical studies with the product started in 2001, and then clinical trials began, with first results reported in 2005. Interestingly, when the company was carrying out due diligence on the product, it found animal toxicology studies that had been conducted with the same compound used as a food coloring agent (food red no. 105). The mouse studies showed a dose-dependent decrease in tumors. "It was a crazy bit of data hiding in plain sight," commented Eric Wachter, PhD, chief technical officer at Provectus, who had been involved in the initial discovery of PV-10. "It gave us the confidence that what we were seeing in our own in-house testing was not a fluke," he said.
The phase 2 study was funded by Provectus. Dr Agarwala and Dr Sarniak report receiving research funding from Provectus. Dr Pilon-Thomas reports no relevant financial relationships.
Ann Oncol. Published online 28 October. Abstract
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