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)

Phase 1

Terminated

Conditions: Hepatocellular Carcinoma (HCC)

Interventions: Biological: Pexastimogene Devacirepvec (Pexa Vec)
Drug: Nivolumab

Registration Number: NCT03071094

Lead Sponsor: Transgene

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pexa-Vec combined with Nivolumab - Phase I	Pexastimogene Devacirepvec (Pexa Vec)	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).
Pexa-Vec combined with Nivolumab - Phase IIa	Pexastimogene Devacirepvec (Pexa Vec)	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).
Pexa-Vec combined with Nivolumab - Phase I	Nivolumab	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).
Pexa-Vec combined with Nivolumab - Phase IIa	Nivolumab	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).

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) According to RECIST 1.1.	6 months from the first study drug administration	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.
Phase I: Number of Participants With Dose Limiting Toxicities (DLTs)	4 weeks from the first study drug administration	DLTs are occurrence of any following AE related to study drugs occurring during 4 weeks after 1st Pexa-Vec injection: 1. 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) 2. Grade ≥ 3 acute immune-related AE involving major organs 3. Grade ≥ 3 injection site reaction 4. AST or ALT ≥ 10xULN unless related to liver metastases progression; AST or ALT doubling concurrent with total bilirubin doubling 5. Any toxicity resulting in treatment delay of 2 or more weeks 6. Grade ≥ 3 or ≥ 2-grade neutropenia increase over baseline lasting \>7 days, neutropenic fever, grade 4 thrombocytopenia (or grade 3 with bleeding) 7. Association of LVEF less than LLN, blood troponin T or I increase above ULN and any ECG abnormality indicating grade 3 cardiac disorder.
Phase I: Number of Participants With Serious Adverse Events (SAEs)	4 weeks from the first study drug administration	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.