Clinical Trials /

PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma

NCT02557321

Description:

This is an international multicenter, open-label, sequential phase study of intralesional (IL) PV-10 in combination with immune checkpoint inhibition. Metastatic melanoma patients (Stage IV or Stage III unresectable, in-transit or satellite disease) with at least one injectable lesion who are candidates for pembrolizumab (both treatment naïve patients and treatment refractory patients who have failed to achieve a complete or partial response to or previously progressed on one or more checkpoint inhibitor) 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).

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma
  • Official Title: A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: PV-10-MM-1201
  • NCT ID: NCT02557321

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
PV-10Rose Bengal DisodiumPhase 1b
PembrolizumabPhase 1b

Purpose

This is an international multicenter, open-label, sequential phase study of intralesional (IL) PV-10 in combination with immune checkpoint inhibition. Metastatic melanoma patients (Stage IV or Stage III unresectable, in-transit or satellite disease) with at least one injectable lesion who are candidates for pembrolizumab (both treatment naïve patients and treatment refractory patients who have failed to achieve a complete or partial response to or previously progressed on one or more checkpoint inhibitor) 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).

Detailed Description

      Phase 1b. Up to 24 eligible subjects will be enrolled in an initial cohort in the Phase 1b
      portion of the study (Main Cohort). Up to an additional 24 eligible subjects who have failed
      to achieve a complete or partial response to or progressed on prior checkpoint inhibition
      will be enrolled in a first expansion cohort (Expansion Cohort 1). Up to an additional 24
      eligible subjects with Stage III unresectable, in-transit or satellite melanoma will be
      enrolled in a second expansion cohort (Expansion Cohort 2). Each subject in each Phase 1b
      cohort will receive the combination of IL PV-10 and pembrolizumab.

      Phase 2. A total of an estimated 120 eligible 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 and initial Phase 2 portions of the
      study.

      Subjects assigned to receive PV-10 in Phase 1b and 2 will receive initial IL PV-10 to their
      injectable lesions commencing on study Day 1 for up to 12 weeks (i.e., investigational
      Treatment Phase of the study). PV-10 may be re-administered at 21-day (3-week) intervals
      during the Treatment Phase of the study to any remaining, uninjected injectable lesions until
      all injectable 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1bExperimentalPV-10 (intralesional) and pembrolizumab (2 mg/kg every 3 weeks)
  • PV-10
  • Pembrolizumab
Phase 2 (Arm 1)ExperimentalPV-10 (intralesional) and pembrolizumab (2 mg/kg every 3 weeks)
  • PV-10
  • Pembrolizumab
Phase 2 (Arm 2)Active ComparatorPembrolizumab (2 mg/kg every 3 weeks)
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Age 18 years or older, male or female.

          2. Histologically or cytologically confirmed diagnosis of melanoma.

          3. Stage IV or Stage III (unresectable, in-transit or satellite) melanoma.

          4. At least 1 Injectable Lesion (i.e., cutaneous, subcutaneous, soft tissue, superficial
             nodal or palpable nodal lesion with longest diameter at least 5 mm that is suitable
             for injection with PV-10).

          5. A minimum of 1 measurable Target Lesion that can be accurately measured by calipers,
             computed tomography (CT) or magnetic resonance imaging (MRI) consisting of at least
             one of the following:

               -  at least one cutaneous lesion (each lesion ≥ 10 mm longest diameteror up to 5
                  lesions in aggregate having a sum of longest diameters ≥ 10 mm); and/or

               -  at least one subcutaneous or soft tissue lesion (each lesion ≥ 10 mm in longest
                  diameter by CT or MRI); and/or

               -  at least one nodal lesion (each lesion ≥ 15 mm in short axis diameter by CT or
                  MRI); and/or

               -  at least one visceral lesion (each lesion ≥ 10 mm in longest diameter by CT or
                  MRI).

          6. Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1.

          7. Clinical Laboratories:

               -  absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥100 x 109/L

               -  estimated creatinine clearance (CrCl, by Cockcroft-Gault formula) or estimated
                  glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2

               -  total bilirubin ≤ 3 times the upper limit of normal (ULN)

               -  aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase
                  (ALP) ≤ 5 times the upper limit of normal (ULN)

          8. Thyroid function abnormality ≤ Common Toxicity Criteria for Adverse Effects (CTCAE)
             Grade 2.

        Exclusion Criteria:

          1. Untreated or clinically active melanoma brain metastases.

               -  Subjects with ≤ 3 brain metastases and each ≤ 1 cm size that were treated with
                  either surgical resection and/or radiation therapy are eligible for study
                  participation provided (a) there is no evidence of progressive central nervous
                  system (CNS) disease on brain imaging at least 30 days after definitive treatment
                  and (b) the subject is not taking prednisone at >10 mg or equivalent daily.

               -  Subjects with > 1 cm or > 3 in number treated brain metastases are eligible for
                  study participation provided (a) there is no evidence of progressive CNS disease
                  on brain imaging at least 90 days after treatment with surgery and/or radiation
                  therapy and (b) if the subject is not taking prednisone at >10 mg or equivalent
                  daily.

          2. Prior treatment with PV-10 or any checkpoint inhibitor; however, subjects (a) who have
             failed to achieve a complete or partial response within 24 weeks following initiation
             of checkpoint inhibition or (b) who progressed after more than 12 weeks of checkpoint
             inhibition are eligible for study participation in the Phase 1b Expansion Cohort 1
             without washout period for checkpoint inhibition.

          3. Other prior cancer therapy or anti-cancer vaccine within the lesser of 4 weeks or 5
             half-lives before initial study treatment.

          4. Known sensitivity to any of the products or components to be administered during
             dosing.

          5. Concurrent or Intercurrent Illness:

               -  History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis,
                  vasculitis, or other systemic autoimmune disease.

               -  Evidence of clinically significant immunosuppression.

               -  Impaired wound healing or other extremity complications due to severe or
                  uncontrolled diabetes mellitus in subjects whose Injectable Lesions are located
                  in an extremity.

               -  Severe peripheral vascular disease (i.e., severe claudication [pain occurring
                  after less than 200 meters of walking], rest pain, ischemic ulceration or
                  gangrene) in subjects whose Injectable Lesions are located in an extremity.

               -  Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol
                  or chemical dependence that would, in the opinion of the Investigator, compromise
                  the subject's safety or compliance or interfere with interpretation of study
                  results.

               -  Uncontrolled thyroid disease or cystic fibrosis.

               -  Clinically significant acute or unstable cardiovascular, cerebrovascular
                  (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or
                  central nervous system disorders.

               -  Malignancy other than melanoma within 2 years of enrollment except for:
                  adequately treated (i.e., with curative intent) basal or squamous cell carcinoma,
                  in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in
                  situ prostate cancer, or limited stage bladder cancer.

          6. Pregnancy:

               -  Female subjects who are pregnant or lactating.

               -  Female subjects who have positive serum pregnancy test taken within 14 days of
                  initiation of study treatment.

               -  Female subjects of childbearing potential (defined as having a menstrual cycle
                  within the past 12 months and not having had a surgical procedure to accomplish
                  sterilization) who are not using highly effective contraception (e.g., oral
                  contraceptives, intrauterine devices, double barrier methods such as condoms and
                  diaphragms, abstinence or equivalent measures).

               -  Male subjects who are unwilling to use acceptable method of effective
                  contraception.

          7. Subjects unable to comprehend and give informed consent are excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of the combination regimen assessed by adverse events (AEs)
Time Frame:Start of treatment until 4 weeks after final administration of PV-10
Safety Issue:
Description:Phase 1b: Safety and tolerability of the combination regimen will be assessed by monitoring the frequency, duration, severity and attribution of adverse events (AEs) and toxicities requiring discontinuation of study treatment, and evaluating changes in laboratory values and vital signs

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Up to 24 months from initiation of study treatment
Safety Issue:
Description:Phase 1b: Response evaluated per RECIST 1.1
Measure:Objective Response Rate (ORR)
Time Frame:Up to 24 months from initiation of study treatment
Safety Issue:
Description:Phase 1b and 2: Response evaluated per RECIST 1.1
Measure:Change in immune biomarkers
Time Frame:Up to 28 weeks from initiation of study treatment
Safety Issue:
Description:Phase 1b: Peripheral Blood Mononuclear Cells (PBMCs) assessed vs. baseline values for changes in T cell populations
Measure:Overall Survival (OS)
Time Frame:24 months from initiation of study treatment for last subject randomized
Safety Issue:
Description:Phase 1b and 2
Measure:Safety and tolerability of the combination regimen assessed by adverse events (AEs)
Time Frame:Start of treatment until 4 weeks after final administration of PV-10
Safety Issue:
Description:Phase 2: Safety and tolerability of the combination regimen will be assessed by monitoring the frequency, duration, severity and attribution of adverse events (AEs) and toxicities requiring discontinuation of study treatment, and evaluating changes in laboratory values and vital signs

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Provectus Biopharmaceuticals, Inc.

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