Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Trial of pIL-12/MK-3475 in Metastatic Melanoma

Summary: This is a multi-center, Phase II, open label, single-arm trial of intratumoral pIL-12 EP in combination with pembrolizumab in patients with low TIL melanoma. Patients will initiate treatment of pembrolizumab concurrently with the first cycle of intratumoral pIL-12 EP. Pembrolizumab will be administered at 200 mg flat dose every 3 weeks. Cycles of intratumoral pIL-12 EP (each cycle consisting of treatment on days 1, 5 and 8) will occur every 6 weeks as long as patients have accessible lesions for EP. Patients will be evaluated for response every 12 weeks by RECIST v1.1. Patients will continue on therapy if they have stable disease or better, defined under investigator evaluation at the time of disease evaluations. Therapy will be given until disease progression or unacceptable toxicity. The only exception will be those patients who experience a confirmed CR and who have been on treatment for at least 6 months; these patients may discontinue treatment at the investigator's discretion. Patients may reinitiate either therapy post-complete remission relapse if the study remains open and the patient meets the conditions outlined in the protocol. Patients will be followed continually for safety and tolerability by assessment of adverse events.


Eligibility: 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 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
  -  Patient has agreed to two newly obtained biopsies of tumor (that can be biopsied on investigator's assessment) and to providing the acquired tissue for biomarker analysis. Analysis by a central laboratory of one of the fresh biopsy samples must show <70% PD-1hiCD8+CTLA4+ in the CD45+ gate based on flow cytometry. A second fresh biopsy sample is required, not for eligibility purposes, but for further biomarker analysis and confirmation at a later date of low PD-L1 expression using Merck's PD-L1 IHC assay (clone 22C33). Archival tissue from a biopsy obtained for other purposes (i.e. not a protocol procedure) may be used for low PD-L1 expression confirmation given that: tissue must not be previously irradiated; no systemic antineoplastic therapy received by the patient between the time of the biopsy and the first administration of study treatment. Even if archival tissue is collected, two newly obtained biopsies are still required at baseline.
  -  Life expectancy of at least 6 months.
  -  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/mcL
  -  Platelets ≥100,000/mcL
  -  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
  -  AST (SGOT) and ALT (SGPT) ≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases
  -  Adequate renal function:
  -  Serum creatinine ≤1.5 x ULN
  -  Coagulation:
  -  International normalized ration (INR) or Prothrombin Time (PT) ≤1.5 x ULN (Only if not using anticoagulants*)
  -  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 of 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) and men must agree to use adequate contraception: 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or abstain from heterosexual activity throughout the study, starting with the first study treatment 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. Men treated or enrolled on this protocol must also agree to use adequate contraception starting with the first dose of study drug through 120 days after the last dose of study therapy.
  -  Ability to understand a written informed consent document, and the willingness to sign 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 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 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.
  -  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.

Relevance to patient case: not relevant