PV-10: Update on an Emerging Melanoma Therapy

What is PV-10 and how does it work to treat melanoma?

PV-10 is a chemoablative agent for intralesional injection that is under investigation for the treatment of localized melanoma tumors. It is derived from Rose Bengal, a cosmetic dye that also has been used as a diagnostic imaging dye. The fluorescein derivative appears to selectively target tumor cells to induce local necrosis.

Data reported thus far have been promising. In a phase II open label, single-arm trial, 80 subjects with AJCC Stage III/ IV melanoma received treatment for one to 10 target lesions and up to 10 non-target lesions; at least one target lesion had to have biopsy confirmation of the diagnosis. Target lesions were >0.2cm diameter. Intralesional dosing was provided at 50 percent of the calculated lesion volume. Retreatment was allowed at weeks 8, 12, or 16, and all subjects were followed for 52 weeks. According to final outcome data provided by Provectus Pharmaceuticals, a Complete Response (CR) of PV-10 injected lesions was achieved in 26 percent of subjects, Partial Response (PR: at least a 30 percent reduction in tumor volume) was seen in 25 percent of subjects, and Stable Disease (SD: less than 20 percent increase in tumor volume) was seen in 18 percent of subjects. Less than one-third (31 percent) of subjects experienced Disease Progression (DP: 20 percent or greater increase in tumor volume).

Since those data were first reported, “There are now data for longer follow-up periods that show those initial results are holding up,” says Sanjiv S. Agarwala, MD, Professor of Medicine at Temple University School of Medicine in Philadelphia and Chief, Oncology & Hematology at St. Luke's Cancer Center in Bethlehem, PA. In addition, there are non-clinical data regarding immunologic effects of PV-10 and possible combination approaches, as discussed below.

Importantly, Dr. Agarwala says, Provectus, the company developing PV-10, “is close to finalizing design and implementation of phase III trials for PV-10 for localized melanoma.” Important clinical endpoints will be increased survival, as well as improved outcomes, such as decrease or delay in progression and reductions of new melanomas in treated patients, Dr. Agarwala says.

You can read more about PV-10 in the January 2012 edition, online at PracticalDermatology.com.

Research Summary: PV-10's Immunologic Mechanism

A Moffitt Cancer Center study examining the immunologic mechanism of PV-10 treatment in murine models of breast cancer and melanoma found that IL injection of PV-10 led to regression of injected and untreated contralateral subcutaneous lesions in the MT-901 breast cancer model, with a significant increase in survival in mice treated with IL PV-10 versus those treated with IL saline. In melanoma models, ablation of the flank tumor with PV-10 led to a dramatic reduction of lung metastases (mean of 4 metastases per animal) vs. control (mean of more than 81 metastases).

Splenocytes harvested from PV-10-treated mice exhibited tumor-specific enhancement of interferon-gamma production and cytotoxicity against the treated cell line, along with adoptive transfer of immunity upon implantation in naïve mice.

The researchers concluded, “These murine studies confirm that PV-10 chemoablation results in both a direct effect on injected lesions as well as a systemic response that leads to regression of uninjected subcutaneous and lung lesions. Intralesional PV-10 treatment leads to the induction of tumor-specific immunity.”

What is the evidence for the immunologic activity of PV-10?

PV-10 has shown evidence of a distant effect or by-stander effect, according to Dr. Agarwala, something that is now under investigation, as well. “We only see this effect in patients who have responded at the injection site,” Dr. Agarwala says, noting that it is not possible currently to predict distant response. “Right now we consider such a response to be a bonus clinically, and it is not something that the phase III trials will investigate.”

A phase I trial begun earlier this year is investigating the bystander effect. The study at the Moffitt Cancer Center is looking for potential immune biomarkers in both tumor tissue and peripheral blood after intralesional PV-10 injection of melanoma tumors.

“Based on preliminary data, it appears that injection leads to local necrosis and recruitment of immune cells that may lead to a bystander effect,” Dr. Agarwala says. “We don't have data to show the duration of immunological effects at this time,” he adds.

Will dermatologists be able to deliver PV-10?

Whereas most chemotherapeutic agents used in the management of melanoma tend to be administered by oncologists, PV-10 injection “is very doable in a dermatologist's office,” Dr. Agarwala maintains. At some centers, physician assistants and nurse practitioners administer PV-10, a model that can be replicated in dermatology offices.

There is also interest in exploring the use of PV-10 in combination with surgical excision, which would also lend itself to treatment in the dermatology clinic, Dr. Agarwala explains. Pre-operative injection of the tumor may stimulate an immune response that may target any residual tumor cells and, depending on what the evidence shows, target distant tumors, as well.

Non-clinical data also support the combined use of PV-10 with other chemotherapeutic agents, specifically systemic anti-CTLA-4 antibody therapy, which was investigated in murine models of melanoma. The ability to use PV-10 in combination with other agents would be attractive, Dr. Agarwala says, because the investigational compound is “relatively non-toxic.”

Dr. Agarwala is an investigator for Provectus.

Sanjiv S. Agarwala, MD is Professor of Medicine at Temple University School of Medicine and Chief, Oncology & Hematology at St. Luke's Cancer Center in Bethlehem, PA.