Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade

Summary: This is a single center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary objective of the study is to determine the safety of sequential treatment with ONCOS-102 followed by pembrolizumab. The protocol aims to enroll 6 patients into each of two cohorts: prior PD1 monotherapy or prior combination PD1 plus ipilimumab combination therapy.


Eligibility: Inclusion Criteria:
  -  Adults 18 years of age or older.
  -  Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a Food and Drug Administration (FDA) approved anti-PD1 agent, with or without ipilimumab, as the most recent systemic intervention.
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
  -  Measurable disease according to RECIST 1.1.
  -  Acceptable coagulation status: international normalised ratio (INR) of blood clotting, prothrombin time and activated partial thromboplastin time within ≤1.5 x upper limit of normal (ULN).
  -  Completion of local therapy, such as radiation, surgical resection, injectable immunebased therapy, or topical pro-inflammatory agent, 21 days prior to first dose of protocol therapy.
  -  Resolution or stabilization of clinically significant immune-mediated adverse events from prior therapy such that continued PD1 blockade is not contraindicated in the opinion of the principal investigator.
  -  Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.
  -  Acceptable liver and renal functions defined as:
  -  Total bilirubin ≤1.5 x ULN (does not include patients with Gilbert's Disease)
  -  Aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) ≤3.0 x ULN
  -  Serum creatinine ≤1.5 x ULN
  -  Acceptable haematological function defined as (Patients can be transfused to meet the haemoglobin entry criteria):
  -  Haemoglobin ≥10 g/dL
  -  Neutrophils ≥1.5 x 10^9/L
  -  Platelet count ≥75 x 10^9/L
  -  Able to provide valid written informed consent.
  -  All women of childbearing potential must have a negative urine or serum pregnancy test at screening.
  -  All patients must agree to use barrier contraception (i.e. condom) during study treatment and for 2 months after the last virus treatment and 4 months after the last dose of chemotherapy and pembrolizumab.
  Exclusion Criteria:
  -  A concomitant medical condition requiring receipt of a therapeutic anticoagulant that in the opinion of the treating physician cannot safely be held to allow for therapeutic injection of ONCOS-102 and tumor biopsies.
  -  A concomitant medical condition that in the opinion of the treating physician would pose unreasonable additional risk to therapeutic injection of ONCOS-102.
  -  Receipt of any systemic therapy for melanoma, other than an anti-PD1 agent, after the most recent episode of documented progression on an anti-PD-1 agent (with or without ipilimumab) prior to enrollment. Targeted therapies such as dabrafenib and/or trametinib and injectable therapy with talimogene laherparepvec are allowed if they were followed by progression on anti-PD1 therapy.
  -  Any symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease, ulcerative colitis) that requires administration of >10mg of prednisone equivalent. Lower dose steroids for conditions such as hypophysitis are allowed.
  -  Any prior severe adverse event attributed to prior anti-PD1 therapy that, in the Principal investigator's opinion, would contraindicate pembrolizumab administration such as:
  -  Grade 2 or higher pneumonitis
  -  Grade 4 AST or ALT elevation
  -  Grade 3 or higher colitis attributable to PD1 blockade; note that colitis attributable to ipilimumab is not excluded
  -  Note: in the absence of clinical symptoms of pancreatitis, elevations of amylase or lipase are not contraindications to therapy on this trial
  -  Known active infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV. Cleared HBV/HCV infection is not an exclusion, nor is HIV infection with cluster of differentiations 4 (CD4) counts >500 and an undetectable viral load.
  -  Active bacterial, viral, or fungal infections, requiring systemic therapy.
  -  History of organ transplant.
  -  Patients requiring chronic systemic immunosuppressants, including steroids (prednisone daily equivalent of >10 mg).
  -  Brain metastases that are clinically unstable (e.g. showing unequivocal growth on imaging, requiring radiation therapy, or steroids >10mg of prednisone equivalent) within 4 weeks of first dose of study drug.
  -  Known severe congenital or acquired cellular or humoral immunodeficiency such as common variable immunodeficiency.
  -  Women who are pregnant or breast-feeding currently or are planning to do so during or up to 3 months after the end of protocol therapy.

Relevance to patient case: not relevant