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

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:

  1. Lactate dehydrogenase (LDH): \<4 x upper limit of normal (ULN)
  2. Adequate hematological function:

     1. Absolute neutrophil count (ANC): \>=1,500/μL
     2. Platelets: \>=100,000/μL
     3. Hemoglobin: \>= 9 g/dL
  3. Adequate hepatic function:

     1. Serum total bilirubin: ≤1.5 x ULN OR Direct bilirubin \<= ULN for patients with total bilirubin levels \>1.5 ULN
     2. 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
  4. Adequate renal function:

     1\. Serum creatinine: ≤1.5 x ULN
  5. Coagulation:

     1. 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).
     2. 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.