PV-10-based Cancer Combination Therapy Clinical Trial Design Wins Australasian Gastro-Intestinal Trials Group's New Concepts Award

Tuesday August 27, 2019
  • Two-stage, 34-patient, Phase 2 study combines PV-10 and Keytruda® (pembrolizumab) for treatment of metastatic neuroendocrine tumors
  • Combination powered for 19% ORR vs 3.7% ORR for Keytruda (KEYNOTE-158)
  • Interim assessment conducted 24 weeks after initial treatment of 9th patient
  • AGITG: Only GI cancer-focused research organization in Australasian region

KNOXVILLE, TN, August 27, 2019 -- Provectus (OTCQB: PVCT) today announced that the Company's lead investigational cancer immunotherapy PV-10 was the subject of oral and poster presentations about the treatment of metastatic neuroendocrine tumors (mNET) at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting (ASM), held in Adelaide, Australia from August 21-23, 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.1-5 Lysosome-targeting PV-10 is administered percutaneously when delivered to primary or metastatic tumors of the liver, such as mNET, hepatocellular carcinoma, and metastatic uveal melanoma.

Presentation #1 (oral): The cancer combination study design entitled "A phase 2 study of oncolytic immunotherapy of metastatic neuroendocrine tumours using intralesional rose bengal disodium in combination with pembrolizumab," which was presented by Dr. Mark McGregor of The Queen Elizabeth Hospital (TQEH) in Adelaide, won AGITG ASM's Best of New Concepts Award.

Dr. McGregor's other Australian teammates included Dr. Timothy Price of TQEH (the lead principal investigator for the Company's ongoing Phase 1 clinical trial of single-agent PV-10 for the treatment of mNET), Dr. Ian Kirkwood of Royal Adelaide Hospital (RAH), Dr. Ruben Sebben of TQEH, Associate Professor Susan Neuhaus of RAH, and Professor Guy Maddern of TQEH.

Key trial design features include:

  • Size: A 34-patient, single-arm study consisting of an initial group of 9 patients and a follow-on group of 25 subjects, and using a Simon's two-stage design, a significance level of 5%, and a power of 80%,
  • Comparison: A 19% objective response rate (ORR) for the combination versus an historical response of 3.7% ORR for single-agent Keytruda (Phase 2 KEYNOTE-158 study of pre-treated NET patients and unselected for PD-L1 status; NCT02628067), and
  • Interim assessment: An efficacy assessment conducted 24 weeks after the initial treatment of the final patient in the initial group.

This Phase 2 study design may be found on pages 41-44 of the AGITG ASM Proceedings Book at https://asm.gicancer.org.au/wp-content/uploads/2019/08/AGITG-ASM-Proceedings-Book-2019.pdf.

Presentation #2 (poster): The Company also presented information about its ongoing Phase 1 mNET clinical trial of single-agent PV-10. A copy of the AGITG ASM poster presentation is currently available on Provectus' website at https://www.provectusbio.com/media/docs/publications/AGTIG2019_Poster_PV-10_NET.23Aug19.pdf.

 

Dominic Rodrigues, Vice Chair of Provectus' Board of Directors stated, "We are grateful to Dr. Price, Dr. McGregor, and the rest of the Australian investigator team for their collaboration designing this new cancer combination study and their continued leadership of the Company's PV-10 monotherapy trial. We are very excited for their award achievement and well deserved recognition. Combining PV-10 with a checkpoint inhibitor drug for this patient population may provide another tool for physicians to further address the unmet medical need created by metastatic neuroendocrine tumors."

Mr. Rodrigues added, "We are also grateful to the patients, and their caregivers and families, who participate in our neuroendocrine tumor clinical trial, and the hospital staffs who support the patients and the trial. Because of them, Provectus has the opportunity to better assess clinical treatment in order to advance our PV-10 drug development program for this disease area."

Mr. Rodrigues concluded, "Neuroendocrine tumors have a moderate level of PD-L1 expression, but they possess a low tumor mutation burden. Monotherapy treatment with checkpoint inhibitor drugs have demonstrated minimal anti-tumor activity. We are very encouraged by disease-specific clinician interest, expertise, and experience to demonstrate that PV-10 may overcome the tumor microenvironment, enable tumor recognition by the immune system, and significantly enhance the response of ‘cold' tumor types like neuroendocrine tumors to checkpoint inhibitor drugs."

About PV-10

PV-10 causes acute oncolytic destruction of injected tumors, releasing 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. PV-10 treatment, leading to cell death, also mediates the poly-ADP ribose polymerase (PARP) signaling pathway. T cell function can be further augmented by combining PV-10 with CI drugs.

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 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 9,107,887, 9,808,524, and 9,839,688, and a US patent application number is 15/804,357 (allowed, but 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. Swift et al. Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory neuroblastoma. Onco Targets Ther 12:1293-1307, 2019.

Trademarks

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," "would," "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.

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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