A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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This is a study to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC).

Official Title
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A Phase I/IIa Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC)

Conditions
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Hepatocellular Carcinoma (HCC)

Intervention / Treatment
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* Biological: Pexastimogene Devacirepvec (Pexa Vec)
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological/cytological diagnosis of primary HCC, excluding cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma Advanced stage HCC per EASL-EORTC (European Association for the Study of the Liver-European Organisation for Research and Treatment of Cancer) guidelines, i.e. patients who are not candidates for curative interventions and not candidates for locoregional modalities Patients naïve to systemic therapy for HCC Tumor status (as determined by radiology evaluation): At least one measurable viable tumor in the liver, ≥1 cm longest diameter (LD), using a dynamic imaging technique (arterial phase of triphasic computerized tomography [CT] scan, or dynamic contrast-enhanced magnetic resonance imaging [MRI]), and injectable under imaging-guidance (CT or ultrasound) At least one tumor that has not received prior local-regional treatment, or that has exhibited definitive growth of viable tumor since prior local-regional treatment of HCC undertaken at least 4 weeks prior to enrolment or 3 months prior to enrolment for radioembolization Child-Pugh Class A. Note: paracentesis, albumin infusion or diuretic treatment cannot be used to downgrade Child-Pugh score (e.g., to improve from severe to moderate/mild or from moderate to mild ascites) Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Adequate hematological, hepatic, and renal function Additional inclusion criteria exist Exclusion Criteria: Histological diagnosis of cholangiocarcinoma, hepatocholangiocarcinoma, fibrolamellar carcinoma and hepatoblastoma Symptomatic cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months Current or past history of cardiovascular disease (e.g., past history of myocardial infarction, ischemic cardiomyopathy) unless cardiology consultation and clearance has been obtained for study participation History of moderate or severe ascites, bleeding esophageal varices, hepatic encephalopathy or pleural effusions related to liver insufficiency within 6 months of screening; patients with adequately treated esophageal varices are allowed Active, known or suspected significant immunodeficiency due to underlying illness including HIV/AIDS, autoimmune diseases, and/or immune-suppressive medication including high-dose corticosteroids History of severe eczema and/or ongoing severe inflammatory skin condition (as determined by the Investigator) requiring medical treatment Any known allergy or reaction to any component of nivolumab formulation or its excipients Additional exclusion criteria exist

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pexa-Vec combined with Nivolumab - Phase I<br>Participants were administered Pexa-Vec (pexastimogene devacirepvec) as 3 bi-weekly intratumoral (IT) injections of 10^9 pfu at day 1 and weeks 2 and 4 and nivolumab intravenously every 2 weeks (from week 2). | Biological: Pexastimogene Devacirepvec (Pexa Vec)<br>* Pexa-Vec (pexastimogene devacirepvec) will be administered as 3 bi-weekly intratumoral (IT) injections of 10^9 pfu at day 1 and weeks 2 and 4<br>Drug: Nivolumab<br>* Nivolumab will be administered intravenously every 2 weeks (from week 2)<br>|
| Experimental: Pexa-Vec combined with Nivolumab - Phase IIa<br>Participants were administered Pexa-Vec (pexastimogene devacirepvec) as 3 bi-weekly intratumoral (IT) injections of 10^9 pfu at day 1 and weeks 2 and 4 and nivolumab intravenously every 2 weeks (from week 2). | Biological: Pexastimogene Devacirepvec (Pexa Vec)<br>* Pexa-Vec (pexastimogene devacirepvec) will be administered as 3 bi-weekly intratumoral (IT) injections of 10^9 pfu at day 1 and weeks 2 and 4<br>Drug: Nivolumab<br>* Nivolumab will be administered intravenously every 2 weeks (from week 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs are occurrence of any following AE related to study drugs occurring during 4 weeks after 1st Pexa-Vec injection: Grade 3-4 non-hematologic toxicity representing a 2-grade increase over baseline, excluding: nausea, vomiting, diarrhea, fever>40.0°C lasting less than 24h (grade 3), alopecia, grade 3 fatigue* and grade 3 laboratory/metabolic abnormalities* (*returning to grade 2 or less within 72h) Grade ≥ 3 acute immune-related AE involving major organs Grade ≥ 3 injection site reaction AST or ALT ≥ 10xULN unless related to liver metastases progression; AST or ALT doubling concurrent with total bilirubin doubling Any toxicity resulting in treatment delay of 2 or more weeks Grade ≥ 3 or ≥ 2-grade neutropenia increase over baseline lasting >7 days, neutropenic fever, grade 4 thrombocytopenia (or grade 3 with bleeding) Association of LVEF less than LLN, blood troponin T or I increase above ULN and any ECG abnormality indicating grade 3 cardiac disorder. | 4 weeks from the first study drug administration | 
| Phase I: Number of Participants With Serious Adverse Events (SAEs) | A Serious Adverse Event (SAE) is defined as any untoward medical occurrence or effect in a patient, whether or not considered related to the protocol treatment, that at any dose: (i) results in death, (ii) is life-threatening, (iii) requires inpatient's hospitalization or prolongation of existing inpatients´ hospitalization, (iv) results in persistent or significant disability or incapacity, (v) is a congenital anomaly or birth defect, (vi) results in any other medically important condition. | 4 weeks from the first study drug administration | 
| Overall Response Rate (ORR) According to RECIST 1.1. | Overall Response Rate (ORR): proportion of patients, whose best overall response is either complete response (CR) or partial response (PR), confirmed at least 4 weeks after initial documentation. | 6 months from the first study drug administration |