Trial of pIL-12/MK-3475 in Metastatic Melanoma

Study Overview
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Brief Summary
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This is a multicenter, Phase II, open-label, 42-patient single-arm trial of intratumoral pIL-12 electroporation (EP) in combination with pembrolizumab in patients with melanoma. Patients will be evaluated in 2 parts. Part A patients will be selected using a flow cytometric assay that quantifies intratumoral PD-1hiCD8+CTLA4+ exhausted lymphocytes in the tumor. Part B will enroll patients who have or are failing pembrolizumab at least 12 weeks after starting Programmed cell death protein 1 (PD-1) antibody alone or in combination, or, who have been selected using a flow cytometric assay that quantifies intratumoral PD-1hiCD8+CTLA4+ exhausted lymphocytes in the tumor.

Detailed Description
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Closed to enrollment earlier than expected due to high response rate in order to advance to phase 2b in proven PD-1-refractory patients. A total of 24 patients were consented instead of the planned enrollment of 42 patients.

Official Title
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An Open-label, Phase II, Multicenter Study of Enhancing Pembrolizumab Responses in Melanoma Through Intratumoral pIL-12 Electroporation

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: pIL-12


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histological or cytological diagnosis of melanoma with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. At least one measurable tumor accessible for intratumoral injection and EP on investigator's assessment. Patients may have had prior chemotherapy or immunotherapy or radiation therapy. All prior therapies must be stopped 4 weeks prior to first dose of study treatment, with the exception of patients who have received ipilimumab, which must be stopped 6 weeks prior to first dose of study treatment. Patients are prohibited from receiving live vaccines within 30 days prior to first dose of study treatment. Age >= 18 years Part A: Patient has agreed to two newly obtained tumor biopsies and as required re-biopsies (that can be biopsied on investigator's assessment) and to providing the acquired tissue for biomarker analysis. Analysis of one of the fresh biopsy samples for PD-1hiCD8+CTLA4hi in the CD8+CD45+ gate based on flow cytometry will be done. A second fresh biopsy sample is required for further biomarker analysis and confirmation at a later date of low PD-L1 expression using an Immunohistochemistry (IHC) assay for PD-L1 expression. A valid flow cytometry result is not required for study participation, but repeated biopsy for reanalysis is strongly recommended for patient with insufficient tumor-infiltrating lymphocytes (TIL) in the first tissue sample. Or: Part B: Anti-PD-1 non-responders are defined as those showing disease progression according to RECIST v1.1 after at least 12 weeks of therapy with a PD-1 antibody either alone or in combination with approved checkpoint inhibitor or targeted therapies according to their label. There is no serological requirement. Life expectancy of at least 6 months. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Adequate organ function within 4 weeks of administration of study therapy: Lactate dehydrogenase (LDH): <4 x upper limit of normal (ULN) Adequate hematological function: Absolute neutrophil count (ANC): >=1,500/μL Platelets: >=100,000/μL Hemoglobin: >= 9 g/dL Adequate hepatic function: Serum total bilirubin: ≤1.5 x ULN OR Direct bilirubin <= ULN for patients with total bilirubin levels >1.5 ULN aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT): <=2.5 x ULN OR ≤5 x ULN for patients with liver metastases Adequate renal function: 1. Serum creatinine: ≤1.5 x ULN Coagulation: International normalized ration (INR) or Prothrombin Time (PT): ≤1.5 x ULN (Only if not using anticoagulants. If patient is receiving anticoagulants, then value must be within therapeutic range for the condition that patient is being treated for). Activated partial thromboplastin time (aPTT): <=1.5 x ULN (Only if not using anticoagulants. If patient is receiving anticoagulants, then value must be within therapeutic range for the condition that patient is being treated for). Female patient of childbearing potential has a negative serum or urine pregnancy test within 14 days prior to administration of study therapy. The effects of pIL-12 EP and pembrolizumab on the developing human fetus are unknown. For this reason women of child-bearing potential (not free from menses for >2 years, post hysterectomy/oophorectomy, or surgically sterilized) must agree to use two methods of contraception, or abstain from heterosexual activity, during participation in study, from the time of consent through 120 days after the last dose of study therapy. The two methods must include at least one barrier method. Barrier methods are diaphragms, cervical caps, cervical shields, male condoms, and female condoms. The second method of contraception may be another barrier method, a copper containing intrauterine device (IUD), spermicidal foams, sponges and films, or hormone-based contraception (for example, hormone pills, hormone rings, hormone patches, hormone-releasing IUDs, or Depo Provera). Men with partners who are capable of getting pregnant must agree to use one of the barrier methods of contraception listed above during participation in the study, starting with the first dose of study drug through 120 days after the last dose of study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability to understand a written informed consent document, and the willingness to sign and date it. Exclusion Criteria: Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of study therapy. Patient is expected to require any other form of antineoplastic therapy while on study; including systemic chemotherapy, biological therapy, immunotherapy not specified in this protocol. Patient has uveal melanoma. Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable without the use of systemic steroids for at least 8 weeks prior to study entry. Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess, and abdominal carcinomatosis). Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb). Patient has a history of history of (non-infectious) pneumonitis or interstitial lung disease. Patient has active infection at time of study entry that require systemic antibiotics and/or with an oral temperature of >= 38.3 degrees Celsius (°C)(100.9 degrees Fahrenheit (°F)) within 5 days of first treatment. Patients with electronic pacemakers or defibrillators are excluded from this study, as the effect of electroporation on these devices is unknown. Patients with lower extremity lesions may be discussed with the medical monitor. Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism that is stable on hormone replacement will not be excluded from the study. Patient has a medical condition that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication. However, patients using physiologic replacement doses of hydrocortisone, or its equivalent, will be considered eligible for this study; up to 20 mg hydrocortisone (or 5 mg of prednisone) in the morning and 10 mg hydrocortisone (or 2.5 mg of prednisone) in the evening. Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects upon treatment with pIL-12 EP + pembrolizumab is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pIL-12 EP + pembrolizumab breastfeeding should be discontinued if the mother is treated with pIL-12 EP + pembrolizumab. Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible. Patient is Hepatitis C Virus (HCV) Ab positive or HBSAg positive.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Pembrolizumab: 200 mg IV, Day 1 of each cycle pIL-12: 1/4 tumor volume at concentration of 0.5 mg/mL intratumoral, Days 1, 5, and 8 of each odd cycle | Drug: Pembrolizumab<br> <br> Drug: pIL-12<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Objective Response Rate (ORR) Within 24 Weeks Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Best overall ORR within 24 weeks of first treatment with pIL-12 electroporation (EP) and pembrolizumab will be determined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI. The ORR is the proportion of participants with either a Complete Response (CR) defined as a disappearance of all target lesions determined by 2 separate scans conducted not < 4 weeks apart and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (the sum may not be 0 if there are target nodes) and no appearance of new lesions or a Partial Response (PR) defined as a >=30% decrease in the sum of the longest diameter of target lesions with no appearance of new lesions. ORR = CR + PR. | Up to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall ORR Determined by Immune Related-Response Criteria (irRC) | Best overall objective response rate is defined as the proportion of participants with a demonstrated complete or partial response according to irRC. In the irRC, an immune-related Complete Response (irCR) is the disappearance of all lesions, measured or unmeasured, and no new lesions; an immune-related Partial Response (irPR) is a 50% drop in tumour burden from baseline as defined by the irRC. | Up to 5 years | 
| Twenty-Four Week Landmark Progression Free Survival (PFS) | Twenty-four week landmark PFS (PFS at 24) is defined as the percentage of patients, who have progressed at the 24 week time point (+ / - 2 days visit tolerance). Tumor response determinations were assessed by RECIST v1.1. | At 24 weeks after treatment initiation | 
| Number of Participants With Treatment-related Adverse Events | The study will use the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 with an adverse or serious adverse event determination of possible, probable, or definite attribution. Analyses will be performed for all patients having received at least one dose of study drug. | Up to 2 years | 
| Median PFS | PFS is defined as the duration between the date of treatment initiation to the first date of either disease progression where progression is assessed by RECIST v1.1, or death. | Up to 5 years | 
| Duration of Response (DOR) Estimate | DOR is defined as the number of days from the initial documentation of an objective response (CR or PR) per RECIST v1.1 criteria to the final evaluation of that response (censored duration), or to documentation of progression using Kaplan-Meier (KM) estimates . | Up to 5 years | 
| Overall Survival (OS) Estimate | OS is defined as the duration between the date of treatment initiation to the date of death, regardless of the cause of death using KM estimates. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pembrolizumab, Intratumoral pIL-12 Electroporation, Tumor-infiltrating lymphocyte melanoma