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

Study Overview
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Brief Summary
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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.

Official Title
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A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After PD1 Blockade

Conditions
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Advanced or Unresectable Melanoma Progressing After PD1 Blockade

Intervention / Treatment
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* Biological: ONCOS-102
* Drug: Cyclophosphamide
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab<br>Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24). Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose). | Biological: ONCOS-102<br>* Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)<br>Drug: Cyclophosphamide<br>* Pre-treatment<br>Drug: Pembrolizumab<br>* PD1 blockade<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates by RECIST 1.1 and irRECIST. |  | 6 months | 
| Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab. |  | 6 months | 
| Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab. |  | 6 months | 
| Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR). |  | 6 months | 
| Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST. |  | 6 months | 
| Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease. |  | 6 months | 
| Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease. |  | 6 months | 
| Change in Size in Individual Lesions. |  | 6 months |