Provectus Announces Presentation of Updated Results from Phase 1B Trial of PV-10® in Combination with KEYTRUDA® for Treatment of Checkpoint-Naïve Advanced Melanoma at SMR 2019 Congress

11/21, 3:00 PM (Source: GlobeNewswire)
  • Full accrual of 21 checkpoint-naïve melanoma patients
  • No safety concerns identified; no significant overlap of toxicities
  • 95% 12-month OS rate; 100% 12-month DSS rate; Median PFS of 11.7 months
  • 10% CR and 67% ORR (RECIST 1.1) overall; 82% ORR for Stage M1b-c

KNOXVILLE, TN, Nov. 21, 2019 (GLOBE NEWSWIRE) -- Provectus (OTCQB: PVCT) today announced that data from the Company's ongoing Phase 1b/2 study of lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) in combination with KEYTRUDA (pembrolizumab) for the treatment of checkpoint inhibition-naïve advanced cutaneous melanoma patients were presented at the 16th International Congress of the Society for Melanoma Research (SMR 2019 Congress), held in Salt Lake City, Utah from November 20-24, 2019. Intralesional (aka intratumoral) injection with PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

The Phase 1b portion of the study completed enrollment of 23 patients with metastatic melanoma in April 2018 at clinical sites in the U.S. (NCT02557321); of these patients, 21 were naïve to checkpoint inhibition treatment. Patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of 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 was safety and tolerability. Objective response rate and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

Updated Checkpoint-Naïve Results from the Presentation at SMR 2019 Congress:

  • Baseline characteristic: median age of 69 years (range 28-82).
  • Disease characteristics: 52% Stage IV M1b-c; median of 2 injectable lesions (range 1-15)5; most patients had substantial uninjected systemic disease burden.
  • Treatment summary: patients received a median of 5 cycles of PV-10 (mean 3.8, range 1-5) and a median of 5 total injections of PV-10 (mean 11.7, range 1-82); PV-10 was not administered after week 12.
  • Safety: adverse events were consistent with the established patterns for the single-agent use of each drug; principally Grade 1-2 injection site reactions to PV-10; principally Grade 1-3 immune-mediated reactions to KEYTRUDA.
  • Injected target lesion efficacy (best overall response [BORR]): 75% complete response (CR), 79% objective response rate (ORR), and 86% disease control rate (DCR) for 28 injected lesions in 21 patients; 85% CR and 92% DCR for 13 injected lesions in 11 M1b-c patients.
  • Overall patient efficacy (BORR, RECIST 1.1): 10% CR and 67% ORR for 21 patients; 9% CR and 82% ORR for M1b-c patients.
  • Durability: 95% 12-month overall survival (OS) rate; 100% 12-month disease-specific survival (DSS) rate; median OS and DSS were not reached; median progression-free survival (PFS) of 11.7 months.

Dominic Rodrigues, Vice Chair of the Company's Board of Directors, said, "These maturing data reinforce the complementary mechanistic and orthogonal safety profiles of PV-10 and checkpoint inhibition. The data demonstrate that minimal PV-10 intervention can achieve substantial tumor destruction and bring net tumor burden within the range of effective checkpoint blockade activation. We believe additional PV-10 treatment, as part of combination therapy with either single-agent or dual-agent checkpoint blockade, can lead to even greater improvements in clinical response and treatment durability."

A copy of the poster presentation is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/SMR2019_PV-10-MM_1201_CI_Naive-web.pdf.

About PV-10

Provectus has shown that PV-10 selectively accumulates in the lysosomes of only cancer cells upon contact, disrupts them, and causes the cancer cells to die1,6, a mechanism that has been reproduced by external collaborators7. Provectus, external collaborators, and independent researchers have further shown that PV-10 treatment (RB application) can trigger each of the three major and distinct lysosomal cell death pathways of apoptosis, autophagy, and necrosis, and does so in a disease-dependent manner.2,3,7-10

PV-10 causes acute oncolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways to date, such as the release of danger-associated molecular patterns (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. Other mediated immune signaling pathways that have been identified include poly-ADP ribose polymerase (PARP) cleavage, and a third pathway currently being investigated that plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, temporally-distinct, immune system signaling pathways.11

PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma), and preclinical study for pediatric solid tumor cancers (like neuroblastoma5, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).

Orphan drug designation status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

PV-10 is an injectable formulation of rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt), which is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. 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.

Provectus’ intellectual property (IP) includes a family of US and international patents that protect the process by which pharmaceutical grade RB and related xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Conference on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company's IP also includes a family of US and international patents that protect the combination of PV-10 and systemic immunomodulatory therapy (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,8879,808,524, and 9,839,688, and a US patent application number is 15/804,357 (allowed, but not yet awarded), with expirations ranging from 2032 to 2035.

About Provectus

Provectus Biopharmaceuticals, Inc. (Provectus or the Company) is a clinical-stage biotechnology company developing a new class of drugs based on an entirely- and wholly-owned family of chemical small molecules called halogenated xanthenes. Information about the Company’s clinical trials can be found at the NIH registry, www.clinicaltrials.gov. For additional information about Provectus, please visit the Company's website at www.provectusbio.com.

References

1. Wachter et al. Functional Imaging of Photosensitizers using Multiphoton Microscopy. Proceedings of SPIE 4620, 143, 2002.

2. Liu et al. Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1. Oncotarget 7, 37893, 2016.

3. Qin et al. Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death. Cell Death and Disease 8, e2584, 2017.

4. Liu et al. T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model. PLoS One 13, e0196033, 2018.

5. Two patients with baseline burden too numerous to count (TNC) were excluded from this calculation.

6. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.

7. Swift et al. Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory neuroblastoma. OncoTargets and Therapy 12, 1293, 2019.

8. Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.

9. Zamani et al. Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Journal of Immunotoxicology, 11(4), 367, 2014.

10. Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.

11. Panzarini et al. Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy. Cell Death & Disease 2, 169, 2011.

Trademark

PV-10® is a registered trademark of Provectus, Knoxville, Tennessee, U.S.A.

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Kenilworth, New Jersey, U.S.A.

FORWARD-LOOKING STATEMENTS: This release contains forward-looking statements as defined under U.S. federal securities laws. These statements reflect management's current knowledge, assumptions, beliefs, estimates, and expectations and express management's current views of future performance, results, and trends and may be identified by their use of terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “will,” and other similar terms. Forward-looking statements are subject to a number of risks and uncertainties that could cause our actual results to materially differ from those described in the forward-looking statements. Readers should not place undue reliance on forward-looking statements. Such statements are made as of the date hereof, and we undertake no obligation to update such statements after this date. No claims with respect to PV-10, Provectus’ investigational drug for oncology, or PH-10, the Company’s investigational drug for dermatology, are intended regarding safety or efficacy in the context of any forward-looking statements made in this press release.

Risks and uncertainties that could cause our actual results to materially differ from those described in forward-looking statements include those discussed in our filings with the Securities and Exchange Commission (including those described in Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2018).

Contact:

Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer
Phone: (866) 594-5999

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