by ecancer reporter Janet Fricker

Injecting cutaneous lesions in Stage III-IV melanoma patients refractory to other treatments with PV-10 provides a viable strategy for maintaining long-term locoregional control, concluded the final analysis of an open label phase 2 trial presented as an abstract at the 2013 European Cancer Congress, 27 September to 1 October, Amsterdam.

Furthermore, the study showed that the number of lesions injected and presence of blistering were both prognostic for outcome.
Provectus Pharmaceuticals, Inc, (Knoxville, Tennessee, USA), the company behind PV-10 development, believes they now have sufficient information to seek regulatory approval.

Sanjiv Agarwala, Principal Investigator of the study, said, “The take home message is that if you have injectable tumours and inject them with PV-10 there’s a one in two chance that you will achieve a clinical response, and for those patients an additional one in two chance of a non injected lesion responding.”

This, he added was remarkable in a population of patients who were refractory to a median of six previous interventions, over half of whom were aged over 70 years.

PV-10, a 10% solution of Rose Bengal, has been developed to selectively target and destroy cancer cells without harming surrounding healthy tissue, minimizing the potential for systemic side effects.

First used as a synthetic wool dye and later as an agent to stain necrotic tissue in the cornea and for liver imaging, Rose Bengal’s use in melanoma was identified by Provectus while screening different chemicals for use in photodynamic cancer therapy.

They discovered that PV-10, a formulation developed for administration directly into solid tumours, could destroy tumours without requiring light activation. PV-10 is believed to work by accumulating selectively in the lysosomes of cancer cells, eliciting autolysis and triggering an immune response.

“PV-10 was found to have a unique ability to concentrate in the lysosomes of cancer cells and result in the destruction of lysosomes, leading to the rupture of tumour cells and an induced T cell response,” explained Eric Wachter, Chief Technology Officer at Provectus, who led the development.
In the single arm trial 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 intralesional PV-10 at day 0 and could receive up to three further treatment cycles (at weeks 8, 12 and 16) if tumour remained. Furthermore, up to two bystander lesions were identified that underwent biopsy to confirm melanoma, but did not receive treatment.

The subjects, recruited at three centres in Australia and four in the USA, all had locally advanced disease refractory to a median of six previous interventions. The primary endpoint was best overall response rate (BORR) judged by modified RECIST (mRECIST) in each subject’s target lesions.
Subjects received a median of two treatment cycles, with 35% of patients in the study having all their lesions injected.

Results showed that for all subjects, BORR was 51% (26% complete response, 25% partial response) with the amount of tumour burden accessible to PV-10 injection prognostic for outcome. Subjects who had uninjected bystander lesions achieved a BORR of 54% compared to 71% for subjects who had all their lesions injected.

An additional analysis was undertaken of response rates relative to locoregional blistering, a phenomenon affecting 40% of subjects which generally occurred within seven days of PV-10 injection, and typically resolved within four weeks.

Results showed that BORR was 66% for subjects with blisters versus 42% for those without. Furthermore 91% of subjects with blisters achieved stable disease or better versus 54% without blisters.

“If blistering occurs you can reassure patients that they’re likely to achieve a good response. It provides further evidence for an immunological basis for the mechanism of action,” said Agarwala, from St. Luke's Hospital and Health Network, Bethlehem, Pennsylvania.

The immunologic mechanism of PV-10 was elucidated in a study published in July in PLoS ONE where Paul Toomey and colleagues, from the Moffitt Cancer Center, demonstrated adoptive transfer of immunity via T cells.

When T cells were isolated from mice whose melanoma had been treated with PV-10 and injected into untreated mice (bearing the same melanoma clone), untreated mice also demonstrated tumour regression.

“Now we have the mechanistic explanation for our bystander effect, that we’re inducing a highly-specific T cell mediated response,” said Wachter. Data on the immunological mechanism of action, he added, suggested that PV-10 might be particularly relevant for patients with inhomogeneous clonal populations.

“This might provide one explanation why patients in the current study who had all their lesions injected did better than those who didn’t,” he said.
Based on the immune mechanism of action, said Agarwala, PV-10 was likely to be a good treatment to combine with other immunotherapies, such as ipilimumab.

References

S.S. Agarwala, J.F. Thompson, B.M. Smithers, et al. Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal. Abstract No. 3.755.

P Toomey, K Kodumudi, A Weber, et al. Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer. PLoS ONE 8(7): e68561. doi:10.1371/journal.pone.0068561