Phase 1 clinical trial of single agent PV-10 for the treatment of symptomatic neuroendocrine tumors (NET) metastatic to the liver

An interesting trial from Provectus Biopharmaceuticals Inc.  Phase 1 results were presented at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, held in Chicago, IL from May 31-June 4, 2019

In an ogoing Phase 1 clinical trial of single agent PV-10 for the treatment of symptomatic neuroendocrine tumors (NET) metastatic to the liver. Intralesional injection of oncolytic immunotherapy PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells. PV-10 clinical development includes cutaneous melanoma, hepatocellular carcinoma, and metastatic liver cancers such as uveal melanoma in single-agent and combination therapy settings.

What is PV-10?

Described above as “Oncolytic Immunotherapy” but elsewhere as “Ablative Immunotherapy”, the latter indicates the method of administering the therapy i.e. tumour ablation.  It’s more well known for trials in treating Melanoma where tumour ablation (albeit subcutaneous) is more common as a treatment.

Scientific Description: PV-10 causes acute oncolytic destruction of injected tumors, releasing damage associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. T cell function can be further augmented by combining PV-10 with immune checkpoint inhibition.  Sometimes it’s known as its short name “Rose Bengal“.

What is ‘Rose Bengal’?

It’s actually a 135 year old chemical stain, originally discovered in 1882, and for more than half a century used as a dye in cancer diagnosis.

Rose Bengal, in a 10% solution known as PV-10, has displayed greatest promise in the treatment of melanoma, where it was shown in an 80-patient Phase II trial to achieve a complete response rate in 50% of patients’ tumours and an overall response in 71%. A bystander effect was also seen in untreated lesions, suggesting a positive immune response, although it was more effective when all lesions were injected with PV-10.

Scientific Description: PV-10’s active pharmaceutical ingredient is rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt), a small molecule halogenated xanthene. PV-10 drug product is a bright rose red solution containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of solution and administered without dilution to solid tumors via intratumoral injection.

What is the trial doing and where is the trial located?

This single-center Phase 1 study is being conducted at The Queen Elizabeth Hospital in Adelaide, Australia to evaluate the potential safety, tolerability, and preliminary efficacy of PV-10 in metastatic NET patients (NCT02693067). The primary endpoint for the trial is safety, and secondary endpoints include objective response rate (ORR) of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the second cohort can receive PV-10 injection of multiple lesions per cycle (2 of 6 patients in the second cohort have received at least one cycle of PV-10 thus far).

Results of Cohort 1 as follows:

Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior Somatostatin Analogues (SSA) and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway

Further reading:

The NET Clinical Trial document: click here

The ASCO poster for the NET trial: click here

ASCO trial update: click here

Thanks for listening

 

Author: Ronny Allan

Facebook: https://m.facebook.com/NETCancerBlog and https://m.facebook.com/RonnyAllanBlog twitter: @ronnyallan1 twitter: @netcancerblog

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