Hepatocellular Carcinoma (HCC)
Conditions
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).
Interventions
BIOLOGICALPexastimogene Devacirepvec (Pexa Vec)
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
DRUGNivolumab
Nivolumab will be administered intravenously every 2 weeks (from week 2)
Sponsors
Transgene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
France
Participant flow
Recruitment details
First participant signed informed consent on 04 July 2017. Last participant last visit occurred on 03 February 2021.
Pre-assignment details
Of 14 screened participants, 12 met eligibility criteria and were included in the trial. This was a Phase I/IIa trial with Phase I: single cohort of 6 patients assessing the safety of standard Pexa-Vec and nivolumab doses and Phase IIa: extension of the Phase I to up to 30 patients, assessing the efficacy and safety of Pexa-Vec and nivolumab. The trial was terminated prematurely during the Phase IIa due to the failure of Pexa-Vec and nivolumab in their respective pivotal trials in HCC.
Participants by arm
| Arm | Count |
|---|---|
| Pexa-Vec Combined With Nivolumab - Phase I 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). | 7 |
| Pexa-Vec Combined With Nivolumab - Phase IIa 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). | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 1 |
Baseline characteristics
| Characteristic | Pexa-Vec Combined With Nivolumab - Phase IIa | Total | Pexa-Vec Combined With Nivolumab - Phase I |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 18 | 65.7 years STANDARD_DEVIATION 12.6 | 67.7 years STANDARD_DEVIATION 8.1 |
| ECOG (Eastern Cooperative Oncology Group) performance status 0 | 5 Participants | 9 Participants | 4 Participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 1 | 0 Participants | 3 Participants | 3 Participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 2 | 0 Participants | 0 Participants | 0 Participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 3 | 0 Participants | 0 Participants | 0 Participants |
| ECOG (Eastern Cooperative Oncology Group) performance status 4 | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 5 Participants |
| Stage of HCC per BCLC (Barcelona Clinic Liver Cancer) Stage 0 | 0 Participants | 0 Participants | 0 Participants |
| Stage of HCC per BCLC (Barcelona Clinic Liver Cancer) Stage A | 0 Participants | 0 Participants | 0 Participants |
| Stage of HCC per BCLC (Barcelona Clinic Liver Cancer) Stage B | 0 Participants | 0 Participants | 0 Participants |
| Stage of HCC per BCLC (Barcelona Clinic Liver Cancer) Stage C | 5 Participants | 12 Participants | 7 Participants |
| Stage of HCC per BCLC (Barcelona Clinic Liver Cancer) Stage D | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 1 / 5 |
| other Total, other adverse events | 7 / 7 | 5 / 5 |
| serious Total, serious adverse events | 6 / 7 | 4 / 5 |
Outcome results
Primary
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.
Time frame: 6 months from the first study drug administration
Population: The overall response rate (ORR) was calculated on the total number of participants included in Phase I and Phase IIa who received at least one dose of either study drug. Phase I and IIa patients did not differ in terms of eligibility criteria and study treatment and represented a total of 12 patients. Thus a single analysis of the ORR on the phase I/IIa sample size is more relevant than two separate analyses on very low sample sizes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pexa-Vec Combined With Nivolumab - Phase I | Overall Response Rate (ORR) According to RECIST 1.1. | 33.3 Percentage of participants |
Primary
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: 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.
Time frame: 4 weeks from the first study drug administration
Population: Participants who received at least one dose of either study drug (excluding one patient who did not complete the 4 week-period from the first study drug administration).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pexa-Vec Combined With Nivolumab - Phase I | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
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.
Time frame: 4 weeks from the first study drug administration
Population: Participants who received at least one dose of either study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pexa-Vec Combined With Nivolumab - Phase I | Phase I: Number of Participants With Serious Adverse Events (SAEs) | 6 Participants |