Trial of pIL-12/MK-3475 in Metastatic Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Pembrolizumab; pIL-12
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pembrolizumab; Intratumoral pIL-12 Electroporation; Tumor-infiltrating lymphocyte melanoma

Summary:

      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.
    

Eligibility criteria:

        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.