PV-10 For Melanoma

Overview

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). Its oncology focus is on melanoma, breast cancer and cancers of the liver. Provectus has received orphan drug designations from the FDA for its melanoma and hepatocellular carcinoma indications .

Status

  • In November 2015 data from the phase 1 PV-10 mechanism of action study were presented at the Society for Immunotherapy of Cancer 30th Annual Meeting by Moffitt Cancer Center researchers in a poster presentation entitled "Intralesional Rose Bengal in Melanoma Elicits Tumor Immunity via High Mobility Group Box 1". In the reported work, the authors showed that tumor-specific T cells were increased in the blood after tumor ablation with PV-10. This was initiated by tumor cell necrosis, leading to release of High Mobility Box Group 1 (HMBG1), one of a class Damage-Associated Molecular Pattern molecules (DAMPs) released by dying cancer cells that can lead to activation of dendritic cells. HMBG1 release was observed in vitro and after ablation of melanoma tumors. This was also correlated with dendritic cell activation and infiltration into lymph nodes draining ablated tumors.
  • In April 2015 patient enrollment began for a phase 3 clinical trial of PV-10. The study is an international multicenter, open-label, randomized controlled trial (RCT) of single-agent intralesional PV-10 versus systemic chemotherapy with dacarbazine (DTIC) or temozolomide (TMZ) to assess treatment of locally advanced cutaneous melanoma in patients who are BRAF V600 wild-type and have failed or are not otherwise candidates for ipilimumab or another immune checkpoint inhibitor.

  • Over 270 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, 10 in an investigator-initiated study of PV-10 chemoablation followed by radiotherapy, and over 140 patients enrolled in an active Compassionate Use Program for PV-10. Additionally, 11 of the 80 Phase 2 melanoma study subjects continued with the Compassionate Use Program.

Phase 3 Clinical Trial

  • Patient enrollment was opened in April 2015.
  • A Phase 3 study of PV-10 for locally advanced cutaneous melanoma (ClinicalTrials.gov ID: NCT02288897) was initiated in April 2015. This is an international multicenter, open-label, randomized controlled trial (RCT) of single-agent intralesional PV-10 versus systemic chemotherapy with dacarbazine (DTIC) or temozolomide (TMZ) to assess treatment of locally advanced cutaneous melanoma in patients who are BRAF V600 wild-type and have failed or are not otherwise candidates for at least one immune checkpoint inhibitor. Subjects in the comparator arm will receive the Investigator's choice of dacarbazine or temozolomide as determined by Investigator preference and/or local availability of the agent. Effectiveness will be assessed by comparison of progression-free survival (PFS) between all intent-to-treat (ITT) subjects in the two study treatment arms.

    Primary Outcome Measures:

    • Progression-free survival (PFS) [ Time Frame: Assessed every 12 weeks up to 18 months ]

    Secondary Outcome Measures

    • Complete response rate (CRR) [ Time Frame: Assessed every 12 weeks up to 18 months ]
    • Duration of complete response [ Time Frame: Assessed every 12 weeks up to 18 months ]
    • Overall survival (OS) [ Time Frame: Assessed every 12 weeks up to 18 months ]
    • Number of participants with adverse events [ Time Frame: Assessed every 4 weeks until 28 days after last treatment ]

    Safety and tolerability will be assessed by monitoring the frequency, duration, severity and attribution of adverse events and evaluating changes in laboratory values and vital signs.

      Other Outcome Measures:

    • Change in domain scores from baseline using the patient reported Skindex-16 instrument [ Time Frame: Assessed 12 weeks after Day 1 ]
  • In March 2015 an amended phase 3 protocol was been submitted to the U.S. FDA. There were a number of minor changes made to the protocol that were addressed during the February Type C meeting. The Company does not require additional FDA review to start the phase 3 study, and has begun the process of gaining IRB approval for the amended protocol. Details regarding the amended protocol are available at ClinicalTrials.gov.

  • In January 2015 a Type C meeting was held with the US FDA to review certain operational aspects of the protocol for the planned phase 3 clinical trial of PV-10 for melanoma. Details regarding the endpoints of the study and current inclusion and exclusion criteria are available at ClinicalTrials.gov.

  • In November 2014 a phase 3 protocol for evaluation of PV-10 for treatment of locally advanced cutaneous melanoma was submitted to the FDA.

Investigator-initiated Study of Intralesional PV-10 Plus Radiotherapy

  • An independent single center investigator-initiated study of intralesional PV-10 chemoablation followed by radiotherapy (XRT) is currently underway. Study parameters include:
    • Single center investigator-initiated study of PV-10 chemoablation followed by XRT
    • Based on observations of "impressive response without significant increase in radiation reaction" in three PV-10 patients (Foote et al., Mel Res 2010; 20: 48-51)
    • Single intralesional PV-10 dosing; if CR not achieved 6 fractions x 5 Gy at 6-10 weeks post-PV-10
    • Up to 25 subjects anticipated; 11 subjects enrolled as of Dec 2013

Phase 2 Clinical Trial

  • In October 2014 Phase 2 data were published in the Annals of Surgical Oncology in a peer-reviewed article entitled "Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma".
  • In September 2014, subgroup analyses of completed Phase 2 data were presented at the European Society For Medical Oncology 2014 Congress in a poster presentation entitled "Subgroup Efficacy in Patients Receiving Intralesional Rose Bengal to All Existing Melanoma in Phase II Study PV-10-MM-02". The presentation showed that PV-10 elicits a high rate of response in injected tumors through its ablative effect, and additionally, that the durability of response as well as the bystander response in uninjected tumors implicate an additional immunologic mechanism secondary to ablation. Tumors were no longer detectable (complete response or CR) in 26% of the study population. This response was particularly evident in patients who had all existing lesions injected with PV-10 (i.e., All Lesions Treated subgroup, 50% CR; Confidence Interval: 31-69%). These 28 patients had as many as 20 lesions confined to the skin, and experienced a mean PFS of 9.8 months. For an additional 26 patients who had all their disease treated with the exception of 1-2 designated, untreated bystander lesions, mean PFS was 8.9 months.
  • In June 2014, a poster presentation entitled "Efficacy of intralesional rose bengal in patients receiving injection in all existing melanoma in phase II study PV-10-MM-02" was presented at ASCO 2014. The subgroup analysis of completed Phase 2 data showed that in the phase 2 PV-10 trial, when all existing lesions were injected with PV-10, tumors were no longer detectable (complete response) in 50% of the patients (Confidence Interval: 31-69%).
  • On March 24, 2014, as a result of a Type C meeting held with the FDA's Division of Oncology Products 2 on December 16, 2013, Phase 2 study data were submitted to the FDA in an application to receive Breakthrough Therapy Designation (BTD) for PV-10 for treating melanoma.
  • In September 2013, exploratory analyses of completed Phase 2 data were presented at European Cancer Congress 2013 in a poster session entitled "Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal". The analyses show that that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR).

    Additional new data analyses explored response rates relative to locoregional blistering, a specific reaction observed in 40% of subjects. This phenomenon generally occurred within seven days of PV-10 injection but with no clear pattern of incidence, and typically resolved within four weeks. Appearance of this potentially immune-mediated effect was strongly predictive of outcome. Subjects who developed blisters had 66% BORR (44% CR) vs. 42% (15% CR) for those not developing blisters. The correlation between occurrence of blisters and locoregional disease control was even stronger: among subjects with blisters, 91% achieved stable disease or better vs. 54% of subjects without blisters.

  • In October 2012, final top-line data from the Phase 2 trial of PV-10 for metastatic melanoma were presented at the European Society for Medical Oncology 2012 Congress in Vienna, Austria. The poster presentation, authored by S. Agarwala, J.F. Thompson, B.M. Smithers, M. Ross, B.J. Coventry, D.R. Minor, C.R. Scoggins and E. Wachter, was presented by Dr. Sanjiv Agarwala and demonstrated key results, including:
    • An Objective Response Rate (OR) of 51% in subjects' target lesions (25% Complete Response and 26% Partial Response);
    • 69% disease control in these lesions (combined Complete, Partial and Stable Response subjects);
    • 33% of subjects having an untreated bystander melanoma lesion achieved an OR in their bystander lesions while 50% achieved disease control in these lesions;
    • Response of bystander lesions was highly correlated with outcome in treated target lesions, with a bystander lesion OR of 61% in subjects achieving complete or partial response in their target lesions versus 18% bystander lesion OR in subjects that did not achieve this level or response in their target lesions;
    • Stage III subjects experienced a substantially higher target lesion response rate (60% OR and 79% disease control) versus Stage IV subjects (22% and 33%, respectively);
    • Similar trends were noted in response metrics for bystander lesions between these two subpopulations;
    • Analysis of temporal data showed that Stage III subjects also experienced significantly greater mean Progression Free Survival (PFS) of at least 9.7 months, versus 3.1 months for Stage IV subjects (median PFS for Stage III subjects was not reached during the 12-month study interval);
    • Overall survival (OS) data were also presented by disease stage, with Stage III subjects achieving a mean overall survival of at least 12.6 months (median not reached during the study interval) versus 7.3 months for Stage IV subjects.
    • Case studies on several subjects illustrated potential stasis or regression of untreated visceral lesions following PV-10 treatment of their cutaneous lesions, while data on long-term treatment of one study participant demonstrated successful management of the disease over a period exceeding 3 years.
  • In June 2012, preliminary top-line data from the Phase 2 trial of PV-10 for metastatic melanoma were presented at the 2nd European Post-Chicago Melanoma Meeting 2012, Interdisciplinary Global Conference on Developing New Treatments for Melanoma by Dr. Sanjiv Agarwala. Key final data from the 80 subjects in the Phase 2 study include:
    • An Objective Response Rate (OR) of 50% in subjects' target lesions (25% Complete Response and 25% Partial Response);
    • 70% disease control in these lesions (combined Complete, Partial and Stable Response subjects);
    • 33% of subjects having an untreated bystander melanoma lesion achieved an OR in their bystander lesions while 50% achieved disease control in these lesions;
    • Response rates were analyzed by disease stage for the first time:
      • Stage III subjects experienced a substantially higher response rate (58% OR and 81% disease control) versus Stage IV subjects (22% and 33%, respectively);
      • Similar trends were noted in response metrics for bystander lesions between these two subpopulations;
      • Analysis of temporal data showed that Stage III subjects also experienced significantly greater mean Progression Free Survival (PFS) of at least 9.6 months, versus 3.1 months for Stage IV subjects. Median PFS for Stage III subjects was not reached during the 12-month study interval;
    • Higher response rates were noted among "evaluable subjects" (subjects that continued in the study for at least 8 weeks, enabling their responses to PV-10 to be assessed).
    The full presentation is available at:
    2nd European Post-Chicago Melanoma Meeting Munich, Germany - June 2012
  • In January 2012, Provectus received guidance from the U.S. FDA to submit its Phase 3 protocol for review, either via standard review or a request for Special Protocol Assessment. This guidance was in response to Provectus's request of a final end-of-Phase 2 meeting to achieve consensus on design of a pivotal Phase 3 randomized controlled trial of PV-10 for metastatic melanoma. The FDA indicated that an additional end-of-Phase 2 meeting is not required.
  • In October 2011, a third end-of-Phase 2 meeting with the U.S. FDA was held. The meeting addressed several topics central to definition of the applicable patient population and primary endpoint for a planned pivotal Phase 3 randomized controlled trial of PV-10 for metastatic melanoma. Due to an extensive reorganization of the FDA in 2011, senior FDA officials reccomended a fourth end-of-Phase 2 meeting to finalize the trial design with the newly created Division of Oncology Products 2 ("DOP2").
  • 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

NEWSLETTER
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