PV-10 For Metastatic Melanoma

Future Plans

• Based on the recommendations of senior U.S. FDA officials during the March 2011 end-of-Phase 2 meeting, a third end-of-Phase 2 meeting is expected to provide the remaining groundwork to allow reaching a consensus on a Phase 3 design suitable for Special Protocol Assessment.
• Well over 176 cancer patients have been treated with PV-10, including 12 in a Phase 1 recurrent breast cancer study, 6 in a Phase 1 metastatic liver cancer study, 20 in a Phase 1 melanoma study, 80 in a Phase 2 melanoma study, and well over 50 patients have enrolled in the Compassionate Use Program for PV-10. Additionally, 8 of the 80 Phase 2 melanoma study subjects are continuing treatments in the Compassionate Use Program.

Phase 2 Clinical Trial

• In June 2011, data was presented by two of Provectus's Principal Investigators for the Phase 2 melanoma study. Professor Merrick Ross, M.D., of the MD Anderson Cancer Center in Houston, Texas, gave a presentation entitled "Intralesional Therapy for Systemic Disease: Implications for Success and Failure," at the HemOnc Today Conference in New York City, providing a comprehensive review of modern intralesional therapies, including PV-10.

  Dr. Sanjiv Agarwala, M.D., Chief of Medical Oncology and Hematology at St. Luke's Hospital and Health Network in Bethlehem, PA, gave a presentation entitled "Chemoablation of Metastatic Melanoma with PV-10" at the 7th EADO (European Association of Dermato-Oncology) Conference in Nantes, France. In his presentation, Dr. Agarwala reviewed Phase 2 data on PV-10 and outlined primary design parameters for a Phase 3 randomized controlled trial of PV-10, noting that the design is based on guidance obtained in meetings with the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA).

• In March 2011, a second end-of-Phase 2 meeting was held with the U.S. FDA to address topics central to definition of the applicable patient population and primary endpoint for a Phase 3 randomized controlled trial.
• In November 2010, a second meeting with the Australian Therapeutic Goods Administration was held to discuss milestones for approval of PV-10 for treatment of metastatic melanoma. The proposed Phase 3 primary endpoint of progression free survival was deemed appropriate for assessment of efficacy in light of established European Medicines Agency (EMEA) standards adopted by the TGA.
• In November 2010, Sanjiv Agarwala, M.D. presented fully monitored study data from the entire population of 80 subjects at the Melanoma 2010 Congress in Sydney, Australia. Key 52-week data from the 80 subjects in the Phase 2 study include:
  • A Complete Response (CR) of PV-10 injected lesions was achieved in 24% of subjects, Partial Response (PR, requiring at least a 30% reduction in tumor volume) in 25% of subjects and Stable Disease (SD, requiring less than 20% increase in tumor volume) in 18% of subjects, with 23% of subjects experiencing disease progression (PD, 20% or greater increase in tumor volume)
  • Response was considerably higher in the 55 subjects with cutaneous or nodal disease only (55% OR and locoregional disease control in 78% of subjects) than in the 25 subjects with visceral metastases (35% OR with a 56% rate of disease control)
  • An OR was achieved in untreated bystander lesions in 37% of subjects having an evaluable bystander lesion at baseline, with 55% of subjects achieving locoregional disease control in their bystander lesions
  • Bystander response was closely correlated with successful ablation of injected lesions, with 67% of subjects achieving an OR of their bystander lesions if they achieved an OR in their injected lesions vs. 5% in subjects who did not achieve an OR in their injected lesions
  • Mean Progression Free Survival was 8.2 months for all subjects, while the OR cohort had a significantly longer PFS estimated to be 11.7 months vs. 4.1 months for SD or PD subjects; subjects with cutaneous or nodal disease achieved a mean PFS of 8.8 months vs. 6.2 months for subjects with visceral metastases
  • Adverse Experiences ("AE") during the study interval were generally mild to moderate, locoregional and transient, with no deaths or life-threatening experiences attributable to PV-10
• In June 2010, Sanjiv Agarwala, M.D. presented and abstract at the American Society of Clinical Oncology 2010 Annual Meeting, announcing positive data on changes in visceral and nodal metastases following chemoablation of cutaneous melanoma lesions with PV-10.
• In April 2010, an End-of-Phase 2 meeting with the US FDA was held.
• In March 2010, Sanjiv Agarwala, M.D. presented at the Seventh International Symposium on Melanoma and Other Cutaneous Malignancies, commenting on the involvement of the immune system in response to PV-10 therapy and its role in the "bystander effect" in treating metastatic melanoma.
• A peer-reviewed article, entitled "A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series", was published in the February 2010 issue of Melanoma Research.
• In November 2009, John F. Thompson, M.D. presented interim Phase 2 survival data at the 3rd World Meeting of Interdisciplinary Melanoma/Skin Cancer Centers in Berlin, Germany. The data shows markedly longer overall and disease specific survival for subjects responsive to PV-10.
• In October 2009, the Compassionate Use Program for PV-10 was expanded into the US at St. Luke's Hospital & Health Network in Bethlehem, PA, under the direction of Sanjiv Agarwala, M.D.
• In September 2009, all protocol-allowed treatments were completed for all 80 subjects, marking the end of the treatment phase of the study.
• In June 2009, a Compassionate Use Program for PV-10 was initiated at certain centers in Australia.
• In June 2009, Sanjiv Agarwala, M.D. presented an abstract, based on interim data from the first 40 subjects, at the American Society of Clinical Oncology 2009 Annual Meeting in Orlando, Florida.
• In May 2009, Sanjiv Agarwala, M.D. presented interim data from the Phase 2 study at the Joint Meeting of the 7th World Congress on Melanoma and 5th Congress of the European Association of Dermato-Oncology in Vienna, Austria.
• In May 2009, patient accrual and initial treatment of all 80 subjects was completed.
• In March 2009, Professor John F. Thompson, M.D. presented interim Phase 2 safety and efficacy results at the Sixth International Symposium on Melanoma and Other Cutaneous Malignancies in New York.
• In December 2008, the seventh clinical site, the University of Louisville in Louisville, Kentucky, began enrolling subjects. The principal investigator at this site is Charles Scoggins, M.D.
• In November 2008, the 40th subject received treatment at Royal Adelaide Hospital, marking the halfway point of the Phase 2 clinical study.
• In November 2008, a sixth clinical site, California Pacific Medical Center in San Francisco, began enrolling subjects. The principal investigator at this site is David Minor, M.D.
• In October 2008, a fifth clinical site, St Luke's Hospital & Health Network in Bethlehem, Pennsylvania, began enrolling subjects. The principal investigator at this site is Sanjiv Agarwala, M.D.
• In October 2008, a fourth clinical site, Royal Adelaide Hospital in Adelaide, Australia, began enrolling subjects. The principal investigator at this site is Brendon J. Coventry, M.D.
• In October 2008, Professor John F. Thompson, M.D. presented Phase 2 clinical data at the "Perspectives in Melanoma XII" conference in The Hague, The Netherlands.
• In July 2008, the study was expanded to clinical sites in the US, and subject enrollment began at a third clinical site, the M.D. Anderson Cancer Center in Houston, TX. The principal investigator at this site is Professor Merrick Ross, M.D.
• In July 2008, the first 20 subjects had received IL PV-10 treatment. Professor John F. Thompson, M.D. presented preliminary clinical results at the Sydney Cancer Conference 2008 in Sydney, Australia.
• In December 2007, subject enrollment began at a second clinical site, Princess Alexandra Hospital in Brisbane, Australia. The principal investigator at this center is Mark Smithers, M.D.
• Subject enrollment began in September 2007 at the Sydney Melanoma Unit in Sydney, Australia. The principal investigator at this center is Professor John F. Thompson, M.D.
• A Phase 2 study of PV-10 for the treatment of metastatic melanoma was initiated in September 2007. The primary objective of this study is to investigate the effectiveness of intralesional (IL) PV-10 for locoregional treatment of metastatic melanoma. This study will also include assessment of response in untreated bystander lesions following intralesional injection of PV-10 into targeted lesions. Additional objectives are to determine the safety profile of PV-10 following intralesional injection, and assess the pharmacokinetic profile of PV-10 in the bloodstream following intralesional injection. Subjects will receive intralesional injection of PV-10 into each of up to twenty (20) Study Lesions. Additionally, one to two measurable Bystander Lesions may remain untreated and will be followed for assessment of bystander response. To accurately reflect anticipated clinical use, repeat dosing of treated lesions will be allowed at the Investigator's discretion at weeks 8, 12 and 16 following initial treatment for those lesions not exhibiting complete response. Subjects will be followed for 52 weeks following initial treatment with PV-10.

  Primary Outcome Measures:

  • Objective response rate (ORR) of PV-10 treated lesions [ Time Frame: 52 weeks ]

  Secondary Outcome Measures

  • [ Time Frame: 52 weeks ]
    1. Objective response rate of untreated bystander lesions;
    2. Progression free survival (PFS) of treated lesions;
    3. Duration of objective response of treated lesions;
    4. Survival;
    5. Assessment of systemic and locoregional Adverse Events

Phase 1 Clinical Trial

• A peer-reviewed paper based on Phase 1 study findings was published in the December 2008 edition of Melanoma Research.

• In September 2007, summary results of the Phase 1 study were released. A total of 114 tumors were injected and 39 bystander tumors were observed in the study. Subjects were followed for 4 to 27 weeks. Study treatments were well tolerated and elicited minimal side effects, the most common being mild to moderate pain at the injection site. Using the RECIST (Response Evaluation Criteria in Solid Tumors) approach, after injection with a single dose of PV-10, the following results were obtained: 20% of subjects achieved CR of their injected tumors, 20% achieved PR, 35% achieved SD and 25% achieved PD, corresponding to an objective response (CR+PR) in 40% of subjects and local disease control (CR+PR+SD) in 75% of subjects. Among those subjects achieving an objective response of their treated tumors, 25% achieved an objective response of their untreated bystander tumors, and 100% exhibited disease control in their bystander tumors. In contrast, for those subjects failing to achieve an objective response of their treated tumors, only 8% achieved an objective response of their bystander tumors, and 92% exhibited progressive disease in their bystander tumors. These differences in response of bystander lesions as a function of response of target lesions were statistically significant and support the occurrence of a bystander effect in subjects whose target lesions have been responsive to PV-10 chemoablation.

• In August 2007, the Phase 1 study was completed successfully. 20 subjects received IL PV-10 treatment.

• In April 2007, treatment of all 20 enrolled subjects was completed.

• In January 2007, PV-10 for the treatment of metastatic melanoma received Orphan Drug Designation from the FDA.

• In May 2006, the scope of the study was expanded to include a third subject group to receive treatment of up to 20 lesions. The maximum lesion diameter was doubled and study eligibility expanded to include Stage IV subjects.

• In May 2006, a second group of subjects had been treated, meeting the initial Phase 1 objectives. PV-10 treatment was well tolerated by all subjects, with no evidence of systemic or serious local side effects. Most subjects exhibited evidence of efficacy, ranging from tumor shrinkage to complete ablation.

• In August 2005, the first patients were treated at two clinical centers in Australia , Sydney Melanoma Unit (Lead investigator: Professor John F. Thompson, M.D.) and Newcastle Melanoma Unit (Principal Investigator: Professor Peter Hersey, M.D.)

• A Phase 1 study was initiated in August 2005 to investigate the safety of intralesional (IL) PV-10 for the treatment of metastatic melanoma. This study also includes a preliminary assessment of response of treated and untreated lesions by clinical evaluation at follow-up of 12 to 24 weeks following IL PV-10 treatment. Subjects with at least two measurable melanoma lesions will receive a single intralesional injection of PV-10 into each of one to twenty target lesions. Additionally, one to three measurable untreated non-target lesions will be followed for assessment of bystander response. Systemic and locoregional adverse events will be monitored over the study interval. Dose escalation will be made only if no subjects at the first dose level have a Grade 3 non-hematological or Grade 4 hematological toxicity over a period of two weeks after PV-10 administration.

  Primary Outcome Measures:

  • Safety: adverse experience

  Secondary Outcome Measures

  • Efficacy: objective response rate of target lesions and untreated non-target lesions