A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination with Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma
The purpose of this study is to find out if an investigational drug called PV-10, given in combination with another drug called pembrolizumab (also called Keytruda®) can help people with melanoma.
The primary objective of the initial, single-arm Phase 1b portion of the study, is to assess safety and preliminary efficacy (objective response rate and progression free survival) of the combination (i.e., PV-10 + pembrolizumab) in treating metastatic melanoma. Potential immunomodulatory impact of study treatment will also be assessed.
Histologically or cytologically confirmed diagnosis of melanoma.
Stage IV or Stage III (unresectable, in-transit or satellite) melanoma.
At least 1 Injectable Lesion (i.e., cutaenous, subcutaneous, soft tissue, superficial nodal or palpable nodal melanoma lesion) with longest diameter at least 5 mm that is stuitable for injection with PV-10).
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 in longest diameter or 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)
Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1.
Clinical laboratories: (a) absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L and platelet count ≥100 x 10^9/L; (b) estimated creatinine clearance (CrCl, by Cockcroft-Gault formula) or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2; (c) total bilirubin ≤ 3 times the upper limit of normal (ULN); (d) aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤ 5 times the upper limit of normal (ULN).
Thyroid function abnormality ≤ Common Toxicity Criteria for Adverse Effects (CTCAE) Grade 2.
> Untreated or clinically active melanoma brain metastases. Potential participants 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. Potential participants > 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 patient is not taking prednisone at >10 mg or equivalent daily.
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, (b) who progressed after more than 12 weeks of checkpoint inhibition, or (c) who exhibited documented, clinically significant progression after less than 12 weeks of checkpoint inhibition, are eligible for study participation in the Phase 1b Expansion Cohort 1 without washout period for checkpoint inhibition.
Other prior cancer therapy or anti-cancer vaccine, including intralesional biologics, within the lesser of 4 weeks or 5 half lives before initial study treatment.
Known sensitivity to any of the products or components to be administered during dosing.
Concurrent or Intercurrent Illness: (a) History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other systemic autoimmune disease. (b) Evidence of clinically significant immunosuppression. (c) Impaired wound healing or other extremity complications due to severe or uncontrolled diabetes mellitus in subjects whose Injectable Lesions are located in an extremity. (d Severe peripheral vascular disease (i.e., severe claudication [pain occurring after less than 200 meters of walking], rest pain, ischemic ulceration or gangrene) in patients whose Injectable Lesions are located in an extremity. (e) Significant concurrent or intercurrent illness, psychiatric disorders, or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise the participant's safety or compliance or interfere with interpretation of study results. (f) Uncontrolled thyroid disease or cystic fibrosis. (g) Clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological, endocrine, or central nervous system disorders. (h) 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.
Females who are pregnant or lactating.
Females who have positive serum pregnancy test taken within 14 days of initiation of study treatment.
Females of childbearing potential who are not using highly effective contraception.
Males who are unwilling to use acceptable method of effective contraception.
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