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Clinical Trials

Date: 2017-10-18

Type of information: Presentation of results at a congress

phase: 1b-2

Announcement: presentation of results at the Society for Melanoma Research 2017 Congress

Company: Provectus Pharmaceuticals (USA - TN)

Product: PV-10 and pembrolizumab

Action mechanism:

  • monoclonal antibody/immune checkpoint inhibitor. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. MK-3475 is currently being studied in three clinical trials for advanced melanoma including a Phase III trial of MK-3475 versus ipilimumab in ipilimumab-naïve advanced melanoma patients (PN 006). Enrollment is complete in the advanced melanoma cohorts in the company’s Phase IB trial (PN 001) and the Phase II trial (PN 002) comparing two doses of MK-3475 versus chemotherapy in patients with advanced melanoma who have progressed after prior therapy. Pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide. In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA. Keytruda® is the first approved drug that blocks the PD-1 cellular pathway.
  • PV-10 is an investigational new drug containing a proprietary injectable formulation of rose bengal disodium, a water-soluble xanthene dye currently in use in a topical opthalmic diagnostic. PV-10 is designed for injection into solid tumors (intralesional administration).

Disease: melanoma

Therapeutic area: Cancer - Oncology

Country: Australia, USA

Trial details:

  • This phase 1b/2 study is an international multicenter, open-label, sequential phase study of intralesional (IL) PV-10 in combination with immune checkpoint inhibition. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab will be eligible for study participation. In the Phase 1b portion of the study, all participants will receive the combination of IL PV-10 and pembrolizumab (i.e., PV-10 + standard of care). In the subsequent Phase 2 portion of the study participants will be randomized 1:1 to receive either the combination of IL PV-10 and pembrolizumab or pembrolizumab alone (i.e., PV-10 + standard of care vs. standard of care). (NCT02557321)

Latest news:

  • • On October 18, 2017, Provectus Biopharmaceuticals announced that results from the ongoing Phase 1b/2 study of IL PV-10 in combination with Keytruda® (pembrolizumab), Merck's systemic anti-PD-1 (programmed death receptor-1) antibody agent, were presented at the Society for Melanoma Research 2017 Congress, held in Brisbane. IL injection of PV-10 induces immunogenic cell death that results in tumor-specific reactivity in circulating CD8+ T cells.
  • The Phase 1b portion of the study continues to enroll patients with metastatic melanoma at clinical sites in the U.S. and Australia ; Stage IV patients with at least one injectable lesion who are candidates for Keytruda® are eligible. A total of up to 24 patients would receive the combination of IL PV-10 and Keytruda® every three weeks for five cycles (i.e., for up to 12 weeks, with no further PV-10 administered after week 12), followed by only Keytruda® every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial is safety and tolerability; objective response rate and progression-free survival are key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).
  • IL PV-10 Results from the Phase 1b Trial Presented at SMR: Baseline characteristics (safety population, N=12): 92% men; median age of 71.5 years (range 28-81), 67% > 65 years; 67% Stage IV M1b/c.
  • Subject characteristics (safety population): 2.5 median number of cutaneous/subcutaneous lesions (range 1-40); patients had substantial non-injected systemic disease burden in addition to their injectable cutaneous and/or subcutaneous lesions; patients received a median of 5 cycles of PV-10 (mean 3.8, range 1-5); PV-10 was not administered after week 12.
  • Preliminary safety (safety population): adverse events were consistent with the established patterns for each drug; there were no unexpected toxicities or evidence of compounded toxicity.Preliminary target lesion efficacy (efficacy evaluable population, N=10): 50% complete response; 80% objective response; maximum response.
  • Preliminary overall efficacy (efficacy evaluable population): 10% complete response; 50% objective response; 60% clinical benefit; highest responses observed in M1c patients; per RECIST 1.1.
  • • On January 12, 2016, Provectus Biopharmaceuticals confirmed that patients have been dosed in its Phase 1b/2 clinical trial of PV-10 in combination with Merck's anti-PD-1 therapy Keytruda® (pembrolizumab) in patients with Stage IV melanoma.  Up to 24 subjects will be enrolled in the Phase 1b portion of the study. Each subject in this cohort will receive the combination of IL PV-10 and pembrolizumab. The expected completion date is in 2016 for the Phase 1b portion of the study.
  • A total of an estimated 120 subjects will be randomized in a 1:1 ratio to the two treatment arms (i.e., PV-10 + pembrolizumab or pembrolizumab alone) in the Phase 2 portion of the study. This number of subjects may be modified based on emerging evidence of preliminary efficacy and effect size from the Phase 1b portion of the study. Subjects assigned to receive PV-10 in Phase 1b and 2 will receive initial IL PV-10 to their injectable cutaneous and subcutaneous lesions commencing on study Day 1 for up to 13 weeks (i.e., the investigational treatment phase of the study). PV-10 may be re-administered at 21-day (3-week) intervals during this period to any remaining, uninjected cutaneous and subcutaneous lesions until all injectable cutaneous and subcutaneous lesions have been injected. Lesions that fail to exhibit complete ablation may be re-injected on this schedule. Pembrolizumab will be administered at 21-day (3-week) intervals per prescribing information (label) commencing on study Day 1 for up to 24 months or until disease progression, toxicity requiring discontinuation of study treatment or study termination. Response assessment in both phases of the study will be based on PFS using RECIST 1.1 criteria.
  • • On September 23, 2015, Provectus Biopharmaceuticals announced it has completed development of the protocol for Phase1b/2 testing of its investigational cancer drug PV-10 in combination with pembrolizumab (Keytruda® - Merck&Co) in patients with Stage IV melanoma. PV-10 is Provectus's novel investigational drug for cancer that is injected into solid tumors (intralesional administration); it is currently undergoing Phase 3 clinical testing in patients with Stage III melanoma. Clinical testing under the new Phase 1b/2 protocol is expected to commence before the end of the year. The combination protocol enables initial clinical testing of concepts at the center of a patent held by Provectus, U.S. Patent number 9,107,887, which Pfizer, Inc. (PFE) jointly owns. Specifically, the patent covers the use of PV-10 in combination with systemic inhibitors of immune system down-regulation, such as anti-CTLA-4, PD-1 and PD-L1 immune checkpoint inhibiting antibodies. Pembrolizumab is an anti-PD-1 antibody. Pre-clinical testing of PV-10 used in combination with these important classes of drugs demonstrated potential importance for treatment of advanced cancers. The Phase 1b/2 study will incorporate a modest sized single arm Phase 1b component of 24 subjects with expedited safety and efficacy end points. This is designed to support expansion to a larger randomized Phase 2 component. Combined, these two arms will enable assessment of the potential safety and clinical benefit of PV-10 when used with pembrolizumab for treatment of advanced melanoma.
  • The mechanism of action study's preliminary clinical findings, reported last year, showed that the immunologic effects of tumor ablation with PV-10 may be complementary to immune checkpoint inhibition. Companion pre-clinical testing of PV-10 in murine models of melanoma, also reported last year, showed that the therapeutic effects of PV-10 and immune checkpoint inhibition are increased when the two are used in combination.

Is general: Yes