PRODIGE 81-FFCD 2101-TRIPLET: Randomized, open-label, phase II-III study evaluating the benefit of adding Ipilimumab to the combination of Atezolizumab and Bevacizumab in patients with hepatocellular carcinoma receiving first-line systemic therapy
- Trial ID
- 2022-501217-31-00
- Protocol
- PRODIGE81-TRIPLET
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of adding **Ipilimumab** to the combination of **Atezolizumab** and **Bevacizumab** in patients with **hepatocellular carcinoma** receiving first-line systemic therapy. In Phase II, the focus is on assessing the percentage of patients achieving an objective response, defined as a complete or partial response, within the first 24 weeks (9 cycles) according to the investigator's assessment using RECIST v1.1 criteria. This is clinically relevant as it provides insight into the potential enhanced therapeutic benefit of the triplet regimen over the standard doublet therapy. In Phase III, the study aims to compare overall survival between the triplet and doublet treatment arms, which is crucial for determining the long-term benefits and potential survival advantage of the additional treatment component.
Secondary objectives include evaluating various clinical outcomes such as:
- Radiation progression-free survival (PFS)
- Objective response rate (OR) under treatment
- Rate of disease control (complete response, partial response, or stability)
- Response time (DDR)
- Median time to progression
- Median time to WHO degradation >2
- Time to objective response
- Tolerance assessed by NCI CTC v4.0 for treatment and non-treatment related adverse events
- Rate of permanent discontinuation of protocol treatment due to study treatment-related effects
- Quality of life according to the EORTC QLQ-C30 and its HCC supplement EORTC QLQ-HCC18, including time to deterioration of the quality of life score
- Overall survival (median) for Phase II patients
These secondary objectives are essential for understanding the broader impact of the treatment regimen on disease progression, patient quality of life, and treatment tolerability.
Participants
The clinical trial involves participants diagnosed with **hepatocellular carcinoma**. The study population includes both male and female subjects, aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of hepatocellular carcinoma, with the disease not amenable to curative treatment by surgery, thermo-ablation, or liver transplantation. The trial includes individuals with advanced or intermediate stages of the disease, specifically BCLC-C or BCLC-B, after failure or contraindication of previous treatments. Participants must have adequate liver, haematological, and renal function, and controlled cardiovascular disease for at least six months. The trial population was selected based on specific inclusion criteria, including the ability to understand and sign an informed consent form, and affiliation to a social security scheme. Lifestyle considerations such as the use of contraception for women of childbearing potential and men who have sex with women of childbearing potential are required during the trial and for at least six months after discontinuation of the experimental treatments. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, phase II-III study to evaluate the efficacy of adding **Ipilimumab** to a combination of **Atezolizumab** and **Bevacizumab** in patients with **hepatocellular carcinoma**. The trial aims to assess the objective response rate and overall survival between the treatment arms. The study is expected to run until April 2028, with recruitment having commenced in November 2022. Participants will be involved in the trial for a maximum treatment period of 24 months, depending on their assigned treatment arm and response to therapy.
The trial includes several key study visits. Initially, a screening visit will determine eligibility based on criteria such as age, liver function, and histological confirmation of hepatocellular carcinoma. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and adverse events. These visits will occur every three weeks, aligning with the treatment cycles. The end-of-study visit will evaluate the final outcomes, including overall survival and quality of life assessments.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse reactions to the study drugs, disease progression, or withdrawal of consent. The trial's primary endpoints focus on the objective response within the first 24 weeks and overall survival comparison between the treatment arms. Secondary endpoints include progression-free survival, disease control rate, and quality of life measures.
Treatment
The clinical trial involves the administration of several treatments, including **Atezolizumab**, **Ipilimumab**, and **Bevacizumab**, each with specific roles and administration protocols. **Atezolizumab** is provided as a solution for infusion, with a maximum daily dose of 1200 mg. It is administered intravenously over a treatment period of up to 24 weeks. The pharmaceutical form is a concentrate for solution for infusion, and it is not a pediatric formulation. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.
**Ipilimumab**, marketed as Yervoy, is also administered as a concentrate for solution for infusion. The maximum daily dose is 1 mg/kg, and it is delivered intravenously. The treatment period for Ipilimumab is up to 3 weeks. This medication is not formulated for pediatric use, and its administration is carefully monitored to maintain compliance with the study protocol.
**Bevacizumab** is another treatment used in the trial, provided as a solution for infusion. The maximum daily dose is 15 mg/kg, administered intravenously. The treatment period can extend up to 24 weeks. Like the other medications, Bevacizumab is not a pediatric formulation, and its administration is closely monitored to ensure participant compliance and adherence to the dosing schedule.
All treatments are administered intravenously, and the study protocol includes measures to monitor participant compliance with the dosing schedules. The trial aims to evaluate the efficacy of these treatments in patients with hepatocellular carcinoma, with specific objectives for both phase II and phase III of the study.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the **objective response** (complete response or partial response) within the first 24 weeks (9 cycles) for both treatment arms in Phase II, and overall survival between the triplet and doublet arms in Phase III. Secondary endpoints encompass a range of measures such as radiation progression-free survival (PFS), objective response rate under treatment, rate of disease control (complete response, partial response, or stability), response time, median time to progression, median time to WHO degradation greater than 2, time to objective response, and tolerance assessed by NCI CTC v4.0 for treatment and non-treatment related adverse events. Additionally, the rate of permanent discontinuation of protocol treatment due to study treatment-related effects and quality of life, as measured by the EORTC QLQ-C30 and its HCC supplement EORTC QLQ-HCC18, will be evaluated. The time to deterioration of the quality of life score and overall survival (median) for Phase II patients are also included as secondary endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Advanced (BCLC-C) or intermediate (BCLC-B) HCC after failure or contraindication of the CEL
- Normal Troponin-T
- No clinically evident ascites or history of clinical ascites, liver failure encephalopathy
- Adequate liver function: AST and ALT ≤ 5 x ULN (upper normal limit), total bilirubin ≤ 35 μM/L, albumin ≥ 28 g/L and Child-Pugh A score (if cirrhosis associated).
- Adequate haematological and renal function (haemoglobin > 8.5 g/dl, platelets > 60 G/L, PNN > 1.5 G/L) and renal function (creatinine clearance ≥ 40ml/min according to MDRD formula)
- Patients with controlled cardiovascular disease for at least 6 months
- At least one target lesion measurable according to RECIST v1.1 criteria
- Oesophageal endoscopy less than 6 months old. All patients with varicose veins of any grade should be treated with β-blockers prior to initiation of therapy, in the absence of contraindications.
- Women of childbearing potential must agree to use contraception during the trial treatment and for at least 6 months after discontinuation of the experimental treatments. Men who have sex with women of childbearing potential must agree to use contraception during treatment and for at least 6 months after discontinuation of the experimental treatments
- Ability of the patient to understand, sign and date the informed consent form before randomisation
- Patient affiliated to a social security scheme
- Histologically proven hepatocellular carcinoma (HCC) on biopsy less than two years old. If not histologically proven, it is necessary to perform a tumour (mandatory) and non-tumour (optional) liver biopsy.
- WHO 0 or 1
- HCC not amenable to curative treatment by surgery, thermo-ablation or liver transplantation, or to intra-arterial palliative treatment (IAP) for intermediate BCLC-B HCC.
- Histologically proven hepatocellular carcinoma (HCC) on biopsy less than two years old. If no histological evidence, a tumour (mandatory) and non-tumour (optional) liver biopsy is required.
Exclusion Criteria
- Patients who have already received systemic therapy for HCC
- History of severe active life-threatening autoimmune disease
- Interstitial lung disease
- Chronic HBV infection with HBV DNA > 500 IU/ml, infected patients, cirrhotic or not, should be treated with nucleotide/nucleoside analogues
- Known HIV infection
- Immunosuppression, including subjects with conditions requiring systemic corticosteroid treatment (>10 mg/day prednisone equivalent)
- History of organ transplantation
- Non-healing decaying wound, active ulcer or untreated bone fracture
- Proteinuria ≥ 2+ on urine dipstick if confirmation of 24h proteinuria showing a level ≥ 2 g/24 hours
- Medically uncontrolled hypertension (≥ 150 mm Hg and/or diastolic blood pressure superior to 90 mm Hg)
- History of arterial aneurysm at high risk of bleeding
- Bleeding related to portal hypertension in the last 6 months
- Alive attenuated vaccine within 28 days prior to randomisation
- Pregnant or breastfeeding women.
- Person under guardianship, or person deprived of liberty.
- Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons
- History of abdominal or oesophageal fistula, gastrointestinal perforation or intra-abdominal abscess, diverticulitis or colitis within 6 months prior to randomisation
- Patients on dual anti-platelet therapy
- Patients on chronic non-steroidal anti-inflammatory drugs (except aspirin)
- History of intra-abdominal inflammatory process within 6 months prior to initiation of treatment - including but not limited to - active peptic ulcer, diverticulitis or colitis
- Major surgery or significant traumatic injury within 28 days prior to treatment, abdominal surgery or significant abdominal traumatic injury within 60 days prior to treatment, or the need for major surgery during the therapeutic trial
- Hypersensitivity to any of the study drugs or their excipients
- Allergy to any component of Chinese hamster ovary cells. Other malignancies within the last 2 years, except for carcinoma in situ of the uterus or basal cell or squamous cell skin carcinoma or any other carcinoma in situ, considered cured
- History of pericardial abnormalities possibly immune-related (pericarditis or cardiac tamponade)
- Patient who has received immunotherapy (including anti-CTLA-4, anti-PD-1 or anti-PD-L1 agents) or anti-VEGF antibody therapy
- Patients who has previously received external radiotherapy up to 1 month before the start of the study treatment, or 3 months beofre the start of the study treatment in case of radio embolization
- Central nervous system metastases
- Active bacterial infection
- Patients with uncontrolled cardiovascular disease
- History of arterial thromboembolic events, including stroke, transient ischemic attack and myocardial infarction, if less than 6 months old and unresolved
- History of venous thromboembolic disease, if less than 6 months old
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Nov 2022 | 574 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ATEZOLIZUMAB | Test | — | INTRAVENOUS | 1200 | 24 | SUB178312 |
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1 | 3 | PRD363755 |
Tecentriq 1,200 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1200 | 24 | PRD5434939 |
BEVACIZUMAB | Comparator | — | INTRAVENOUS | 15 | 24 | SUB16402MIG |
BEVACIZUMAB | Test | — | INTRAVENOUS | 15 | 24 | SUB16402MIG |