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PV-10 data for break through therapy designation application highlighted by ASCO

by ecancer reporter Janet Fricker

Half of patients with locally advanced cutaneous melanoma who had all their lesions injected with the investigational agent PV-10 achieved a complete response, reports a subgroup analysis of an open label phase 2 study.

The sub-group analysis, released as an ASCO abstract (May 14, 2014), provides the basis for the pending breakthrough therapy designation application for PV-10 submitted to the FDA in March 2014.

PV-10, a 10% solution of Rose Bengal that was originally used as an agent to stain necrotic tissue in the cornea, has been developed to selectively target and destroy cancer cells without harming surrounding healthy tissue, minimizing the potential for side effects.

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 tumour remained.

Furthermore, up to two ‘bystander’ lesions were identified that underwent biopsy to confirm melanoma, but did not receive treatment.

The subjects, recruited from seven centres in the USA and Australia, all had locally advanced disease refractory to a median of six previous interventions.

In the current abstract, Sanjiv Agarwala, from St. Luke's Hospital and Health Network, Bethlehem, Pennsylvania, 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 from the analysis.

Results showed that for 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%).

In a second analysis when these 28 patients who had all their lesions injected were considered together with a group of 26 patients who had up to two lesions left untreated (to investigate bystander effects) a complete response was achieved in 232 of the 363 injected lesions (64%).

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.

“These sub-analyses show PV-10- injection results are maximized when all lesions get treated. What we’re seeing here is a remarkable response in a heavily pre treated or refractory patient population with locally advanced cutaneous melanoma who have unmet medical needs since, unlike patients with more advanced disease, limited treatment options are available,” said Eric Wachter, the Chief Technology Officer at Provectus, who co-developed PV-10.
That 56% of lesions in the sub-analysis only required one or two injections to achieve a complete response, he added, underlines the simplicity of PV-10 treatment regimens.

“These results support a premise that not only is PV-10 safe and effective, but unlike many other intralesional therapies, requires limited injections. This could prove highly advantageous for both patients and clinicians,” said Wachter.

In a second abstract Amod Sarnaik, from Moffitt Cancer Center Tampa, Florida, investigated the immunological mechanism of the ‘bystander effect’ where uninjected tumours undergo complete response.

In the study eight patients with dermal and/or subcutaneous metastatic melanoma had two lesions sampled bybiopsy prior to treatment, then one of the two lesions was injected with IL PV-10, and both residual sites were completely excised one to two weeks later.

Six of eight patients had metastatic disease refractory to previous ipilimumab, anti-PD-1 and/or vemurafenib therapy. Peripheral blood was collected pre-treatment, at the time of resection and four weeks after PV-10 injection.

Results showed treatment with PV-10 led to pathological complete response (pCR) in post-treatment biopsies of both PV-10-injected and uninjected bystander lesions in four of the eight patients, and all eight exhibited at least partial regression of the injected lesion. IL PV-10 was associated with an increase in circulating cytotoxic CD3 /CD8 T cells (paired t test, p=0.008).

“What’s really powerful about these results is that patients responded even after being refractory to the latest drugs including ipilimumab, anti PD-1 and/or vemurafenib,” said Wachter, adding it was unprecedented for a small molecule ablative agent to have this kind of immune system activity detectable in the peripheral blood of patients.

Both abstracts will be featured in the Poster Highlights Session, Melanoma/Skin Cancers, on June 2, 2014 during the American Society of Clinical Oncology (ASCO) Annual meeting in Chicago, Illinois.
 

References: 

1. Sanjiv S. Agarwala. “Efficacy of intralesional rose bengal in patients receiving injection in all existing melanoma in phase II study PV-10-MM-02.” ASCO 2014, Abstract 132320. Permanent ID 9027.

2. Amod Sarnaik. "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions." ASCO 2014, Abstract 132288. Permanent ID 9028.

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