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
Condition: Advanced or Unresectable Melanoma Progressing After PD1 Blockade
MeSH terms: Melanoma
Intervention: ONCOS-102; Cyclophosphamide; Pembrolizumab
Intervention description: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF); Pre-treatment; PD1 blockade
Intervention MeSH terms: Cyclophosphamide; Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a multi 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 patients into two cohorts: Part I: up
      to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab.
      Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by
      a treatment phase with ONCOS-102 in combination with pembrolizumab.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adults 18 years of age or older.

          -  For US sites: 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.

          -  For European sites: Histopathologically confirmed melanoma with an injectable
             cutaneous or lymph node metastasis that has progressed in the opinion of the treating
             investigator despite administering a regulatory approved anti-PD1 agent, with or
             without ipilimumab.

          -  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.

          -  Adverse events from previous cancer therapies (excluding alopecia) must have recovered
             to grade 1 (CTCAE, most recent version). Stable grade 2 AEs such as endocrine
             conditions are allowed, and other chronic stable AEs may be considered on a case by
             case basis by 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 ≥9 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.

          -  For US sites: 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.

          -  For European sites: All patients must agree to use highly effective contraception for
             at least 6 months (according to the latest country specific SmPC) after administration
             of CPO, up to 4 months after last dose of pembrolizumab, and up to 2 months after last
             dose of ONCOS-102, whichever comes last.

          -  For European sites: All women of child-bearing potential must agree to perform
             pregnancy testing throughout the study starting at baseline, every 3 weeks from day 22
             until last dose of study medication (ONCOS-102 and pembrolizumab) and then every month
             for at least 6 months.

        Exclusion Criteria:

          -  A concomitant medical condition requiring receipt of a therapeutic anticoagulant that
             in the opinion of the treating physician cannot safely allow for therapeutic injection
             of ONCOS-102 and tumor biopsies. Local clinical practice can be followed with regard
             to holding a therapeutic anticoagulant during invasive procedures such as biopsies.

          -  A concomitant medical condition that in the opinion of the treating physician would
             pose unreasonable additional risk to therapeutic injection of ONCOS-102.

          -  For US sites: Receipt of Investigational agents within 28 days prior to first dose of
             protocol therapy.

          -  For European sites: Current participation or participation in a study of an
             investigational agent within 28 days prior to first dose of protocol therapy. Note:
             participants who have entered the follow-up phase of an investigational study may
             participate as long as it has been 4 weeks after the last dose of the previous
             investigational agent.

          -  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 apart from
             anti-viral maintenance therapy for HIV.

          -  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.

          -  For US sites: Women who are pregnant or breast-feeding currently or are planning to
             conceive during or up to 4 months after end of protocol therapy.

          -  For European sites: Women who are currently pregnant or breast-feeding or are planning
             to conceive during or up to 6 months after end of protocol therapy.