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 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 TILs 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.

- 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. AST (SGOT) and ALT (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 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
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 ≥ 38.3ºC (100.9°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 HCV Ab positive or HBSAg positive.