Following the FDA’s recent decision to deny a ‘breakthrough therapy designation’ for PV-10 in melanoma, Provectus Biopharmaceuticals, Inc. has laid out the ‘path forward’ for a phase 3 trial expected to generate sufficient data for a new drug application (NDA).

In a conference call for investors held during ASCO, Provectus announced their plan to initiate a phase 3 randomised controlled trial where 210 patients with unresectable locally advanced cutaneous melanoma will be randomised 2:1 to PV-10 or systemic chemotherapy.

The patients will have failed or be ineligible for systemic immunotherapy.

“Breakthrough therapy designation is one of the available paths to expedite a development programme. Not having this designation does not derail the development of PV-10. We don’t need this designation to move forward,” said Eric Wachter, Chief Technology Officer of Provectus.

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.

The expanded access or compassionate use sites currently offering PV-10 to patients in the US and Australia, the company believes, can be used to expedite early recruitment.

PV-10, a 10% solution of Rose Bengal 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, minimising the potential for side effects.

Results from the sub analysis of a phase 2 trial, presented as an abstract at ASCO¹, show that when all existing lesions of patients with refractory cutaneous melanoma were injected with PV-10, a complete response (where tumours were no longer detectable ) occurred in 50% of patients (CI: 31-69%).

“Results in these patients support the potential of PV-10 as a single agent and provide rationale for a phase 3 randomised controlled trial,” said Wachter.

Furthermore, interim results from the first eight patients in a pilot clinical study showed local and systemic immunological effects after intralesional injection of their melanoma with PV-10.

The study conducted at Moffitt Cancer Center, Tempa, Florida, also presented at ASCO², show that following intralesional PV-10 post treatment biopsies of both PV-10-injected and uninjected study lesions led to pathologic complete response (pCR) in four of the eight patients and that all eight patients exhibited at least partial regression of the injected lesion.

One to two weeks after injection significant increases were detected in peripheral blood T-cells, 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” said 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. PV-10 might offer the perfect way to prime the immune system.”

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, J Clin Oncol 32:5s, 2014 (suppl; abstr 9027).

2. Amod Sarnaik. "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions." ASCO 2014, J Clin Oncol 32:5s, 2014 (suppl; abstr 9028).