Back to resultsA 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)
Primary Purpose
Hepatocellular Carcinoma (HCC)
Status
Terminated
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Pexastimogene Devacirepvec (Pexa Vec)
Nivolumab
Sponsored by
About this trial
This is an interventional treatment trial for Hepatocellular Carcinoma (HCC)
Eligibility Criteria
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
Sites / Locations
- Site No 0102
- Site No 0101
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pexa-Vec combined with Nivolumab - Phase I
Pexa-Vec combined with Nivolumab - Phase IIa
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03071094
Brief Title
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)
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
The decision was taken to stop prematurely the trial due to the failure of Pexa-Vec and nivolumab in their respective pivotal trials (i.e., PHOCUS and CheckMate 459).
Study Start Date
July 27, 2017 (Actual)
Primary Completion Date
September 30, 2020 (Actual)
Study Completion Date
February 3, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Transgene
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma (HCC)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pexa-Vec combined with Nivolumab - Phase I
Arm Type
Experimental
Arm Description
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).
Arm Title
Pexa-Vec combined with Nivolumab - Phase IIa
Arm Type
Experimental
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
Pexastimogene Devacirepvec (Pexa Vec)
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
Nivolumab will be administered intravenously every 2 weeks (from week 2)
Primary Outcome Measure Information:
Title
Phase I: Number of Participants With Dose Limiting Toxicities (DLTs)
Description
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.
Time Frame
4 weeks from the first study drug administration
Title
Phase I: Number of Participants With Serious Adverse Events (SAEs)
Description
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.
Time Frame
4 weeks from the first study drug administration
Title
Overall Response Rate (ORR) According to RECIST 1.1.
Description
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.
Time Frame
6 months from the first study drug administration
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Site No 0102
City
Nancy
Country
France
Facility Name
Site No 0101
City
Paris
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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)
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