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

Study Description

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Brief Summary:

This is an international multicenter, open-label, sequential phase study of intralesional (IL) PV-10 in combination with immune checkpoint inhibition. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab 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).

Condition or disease	Intervention/treatment	Phase
Melanoma	Drug: PV-10; Drug: Pembrolizumab	Phase 1; Phase 2

Detailed Description:

Up to 24 eligible subjects will be enrolled in the Phase 1b portion of the study. Each subject in this cohort will receive the combination of IL PV-10 and pembrolizumab.

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 portion of the study.

Subjects assigned to receive PV-10 in Phase 1b and 2 will receive initial IL PV-10 to their injectable cutaneous and subcutaneous lesions commencing on study Day 1 for up to 13 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 cutaneous and subcutaneous lesions until all injectable cutaneous and subcutaneous 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	144 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma
Study Start Date :	October 2015
Estimated Primary Completion Date :	April 2019
Estimated Study Completion Date :	November 2023

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Phase 1b; PV-10 (intralesional) and pembrolizumab (2 mg/kg every 3 weeks)	Drug: PV-10; PV-10 will be administered by intralesional injection every 3 weeks at Day 1 (Week 1), Week 4, Week 7, Week 10 and Week 13; Other Name: Rose Bengal Disodium; Drug: Pembrolizumab; Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1)
Experimental: Phase 2 (Arm 1); PV-10 (intralesional) and pembrolizumab (2 mg/kg every 3 weeks)	Drug: PV-10; PV-10 will be administered by intralesional injection every 3 weeks at Day 1 (Week 1), Week 4, Week 7, Week 10 and Week 13; Other Name: Rose Bengal Disodium; Drug: Pembrolizumab; Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1)
Active Comparator: Phase 2 (Arm 2); Pembrolizumab (2 mg/kg every 3 weeks)	Drug: Pembrolizumab; Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1)

Outcome Measures

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Primary Outcome Measures :

1. 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 ]
   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
2. Progression Free Survival (PFS) [ Time Frame: Up to 24 months from initiation of study treatment ]
   Phase 2: Response evaluated by blinded independent review committee assessment per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Secondary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: Up to 24 months from initiation of study treatment ]
   Phase 1b: Response evaluated per RECIST 1.1
2. Objective Response Rate (ORR) [ Time Frame: Up to 24 months from initiation of study treatment ]
   Phase 1b and 2: Response evaluated per RECIST 1.1
3. Change in immune biomarkers [ Time Frame: Up to 28 weeks from initiation of study treatment ]
   Phase 1b: Peripheral Blood Mononuclear Cells (PBMCs) assessed vs. baseline values for changes in T cell populations
4. Overall Survival (OS) [ Time Frame: 24 months from initiation of study treatment for last subject randomized ]
   Phase 1b and 2
5. 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 ]
   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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Age 18 years or older, male or female.
2. Histologically or cytologically confirmed diagnosis of melanoma.
3. Stage IV melanoma for which surgery is not recommended.
4. At least 1 cutaneous or subcutaneous Injectable Lesion with longest diameter at least 5 mm.
5. A minimum of 1 measurable Target Lesion (i.e., ≥ 10 mm longest diameter).
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 anti-PD-1 antibody

   • Subjects previously treated with any anti-PD-L1 antibody are eligible for study participation).
3. Prior cancer therapy or anti-cancer vaccine within 4 weeks of 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.

Contacts and Locations

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Locations

United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, Pennsylvania
St Luke's University Hospital and Health Network
Easton, Pennsylvania, United States, 18045
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77230
Australia, Queensland
Princess Alexandra Hospital
Brisbane, Queensland, Australia, 4102

Sponsors and Collaborators

Provectus Biopharmaceuticals, Inc.

Investigators

Study Director:	Eric Wachter, Ph.D.	Provectus Pharmaceuticals, Inc.

More Information

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Responsible Party:	Provectus Biopharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT02557321 History of Changes
Other Study ID Numbers:	PV-10-MM-1201
First Posted:	September 23, 2015
Last Update Posted:	May 10, 2018
Last Verified:	May 2018

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type	Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Pembrolizumab; Antineoplastic Agents