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HCC - Hepatocellular CarcinomaPhase 2/3TRIPLETNCT05665348

Study Evaluating the Benefit of Adding Ipilimumab to the Combination of Atezolizumab and Bevacizumab in Patients With Hepatocellular Carcinoma Receiving First-line Systemic Therapy

A Phase 2/3 study testing Ipilimumab Injection, Atezolizumab Injection and Bevacizumab in people with HCC - Hepatocellular Carcinoma and Metastatic Cancer, run by Federation Francophone de Cancerologie Digestive at 45 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

TRIPLET HCC is a phase II-III trial that assess the effectivness of addition of ipilimumab to the combination atezolizumab-bevacizumab, on global survival and response to the treatment, for patients with advanced or metastatic hepatocellular carcinoma. The theoretical duration of the study is 5 years. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ipilimumab Injection, Atezolizumab Injection and Bevacizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
229 participants
Where
45 sitesFrance
Study dates
9 Mar 2023to 12 May 2025
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years
  • 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.
  • 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.
  • Advanced (BCLC-C) or intermediate (BCLC-B) HCC after failure or contraindication of the CEL
  • Normal Troponin-T
Show all 15Show fewer
  • Patients with controlled cardiovascular disease for at least 6 months
  • No clinically evident ascites, no history of clinical ascites, or encephalopathy due to liver failure
  • 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 associated cirrhosis)
  • Hematological (hemoglobin > 8.5 g/dL, platelets > 60 G/L, PNN > 1.5 G/L) and renal function (creatinine clearance ≥ 40ml/min according to the appropriate MDRD formula)
  • 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

Who cannot join

  • Patients who have already received systemic therapy for HCC
  • Bleeding related to portal hypertension in the last 6 months
  • History of abdominal or oesophageal fistula, gastrointestinal perforation or intra-abdominal abscess, diverticulitis or colitis within 6 months prior to randomisation
  • Patients on double anti-platelet aggregation 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
Show all 31Show fewer
  • 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 one of the components of Chinese hamster ovary cells.
  • Other malignant tumours 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 curedHistory 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
  • Alive attenuated vaccine within 28 days prior to randomisation
  • 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 before 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
  • 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

Trial locations and contacts

45 sites in 1 country.

45 sites in 1 country

France45 sites

  • Chu Amiens Picardie

    Amiens

  • CHU

    Angers

  • Privé LES BONNETTES

    Arras

  • Chu Avicienne

    Bobigny

  • Privé Bordeaux Nord

    Bordeaux

  • Ch Duchenne

    Boulogne-sur-Mer

  • Chu Morvan

    Brest

  • Centre Hospitalier

    Cholet

  • Chu Estaing

    Clermont-Ferrand

  • Chu Beaujon

    Clichy

  • CH HCC

    Colmar

  • Chu Francois Mitterand

    Dijon

  • CHD Vendée

    La Roche-sur-Yon

  • Chu Dupuytren

    Limoges

  • Chu La Croix Rousse

    Lyon

  • CAC Paoli Calmettes

    Marseille

  • Chu La Timone

    Marseille

  • Privé Saint-Joseph

    Marseille

  • Chu Saint-Eloi

    Montpellier

  • CHU Hôtel Dieu

    Nantes

  • Privé CONFLUENT

    Nantes

  • Chu L'Archet

    Nice

  • Chu La Pitie Salpetriere

    Paris

  • Chu Saint Antoine

    Paris

  • Privé Saint-Joseph

    Paris

  • Centre Hospitalier

    Pau

  • CH Saint-Jean

    Perpignan

  • Chu Haut Leveque

    Pessac

  • Chu Haut-Leveque

    Pessac

  • Privé HPCA

    Plérin

  • Chu La Miletrie

    Poitiers

  • Ch Annecy Genevois

    Pringy

  • Centre Hospitalier

    Quimper

  • CHU Robert Debré

    Reims

  • CAC Eugène Marquis

    Rennes

  • Chu Charles Nicolle

    Rouen

  • Chu Saint-Etienne

    Saint-Priest-en-Jarez

  • Centre Hospitalier

    St-Malo

  • Cac Icans

    Strasbourg

  • Privé Sainte Anne

    Strasbourg

  • Chu Rangueil

    Toulouse

  • CHRU Hôpitaux de Tours

    Tours

  • Centre Hospitalier

    Valence

  • Chu Brabois

    Vandœuvre-lès-Nancy

  • CAC Gustave Roussy

    Villejuif

Other trials in France

About this study

Official title: Randomised, 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

TRIPLET HCC is a phase II-III trial that assess the effectivness of addition of ipilimumab to the combination atezolizumab-bevacizumab, on global survival and response to the treatment, for patients with advanced or metastatic hepatocellular carcinoma. The theoretical duration of the study is 5 years. In the scope of this study, each patient will have 2 years of treatment and 2 years of follow-up from their enrollment date.

Read the detailed description

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks fourth in terms of cancer-related mortality worldwide . Unfortunately, the diagnosis of HCC is often made late in the cure of the disease when the tumour has spread outside the liver parenchyma as portal vein invasion or distant metastases. In the history of HCC patients, a significant proportion will sooner or later face systemic therapies as they are no longer eligible for radical or locoregional therapies. Cytotoxic chemotherapy and hormonal therapies have never shown significant benefit on overall survival (OS) . The first systemic therapy to show a significant beneficial impact on HCC outcome was the tyrosine kinase inhibitor (TKI) sorafenib, an anti-angiogenic agent (AAA) with anti-proliferative properties on HCC . For nearly a decade, all systemic therapies tested in randomised controlled trials as first-line systemic therapy (1L) head-to-head with sorafenib, or as 2L after sorafenib failure have not shown significant benefit. In 2018, Kudo et al. showed that lenvatinib, another TKI with anti-angiogenic properties, was at least equivalent to sorafenib in 1L in the REFLECT non-inferiority trial [5]. Other AAA TKIs with anti-cancer properties on HCC cells have demonstrated efficacy in 2L: regorafenib after progression on sorafenib in 2017 , and cabozantinib after progression on or intolerance to sorafenib in 2018 . In addition, ramucirumab, a monoclonal antibody targeting VEGFR-2, has shown significant benefit in a specific subpopulation of HCC patients with high baseline alpha-fetoprotein levels ≥ 400 ng/ml . However, all these options were strictly palliative with no long-term survivors and lack of potential recovery. Immuno-oncology (IO) approaches have completely revolutionised the paradigm of systemic HCC therapies with nonetheless a significant increase in median OS in IO-based combination strategies, but also the emergence of the possibility of long-term survivors and, for some patients, hope for a complete response and possibly a final cure.

Being tested
Ipilimumab Injection, Atezolizumab Injection, Bevacizumab
Keywords
immunotherapy
Medical subject headings
Carcinoma, Hepatocellular, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ipilimumab InjectionDrug

    Also called Atezolizumab, Bevacizumab

    Administration of a combine treatment by atezolizumab and bevacizumab, with addition of ipilimumab for patients enrolled in the experimental arm

  • Atezolizumab InjectionDrug

    One of the standard treatment's product for HCC management

  • BevacizumabDrug

    One of the standard treatment's product for HCC management

Study groups in NCT05665348
Study groupRoleWhat they receive
DOULET ATEZOLIZUMAB-BEVACIZUMABActive comparatorStandard treatment of HCC by the combination atezolizumab-bevacizumab, 1 cure each 3 weeks during 24 months
Receives: Drug: Atezolizumab Injection; Drug: Bevacizumab
TRIPLET ATEZOLIZUMAB BEVACIZUMAB IPILIMUMABExperimentalStandard treatment of HCC by the combination atezolizumab-bevacizumab with addition of ipilimumab for the 4 firsts cures of treatment each 3 weeks, then only treatment by the doublet atezolizumab-bevacizumab each 3 weeks. The total duration of treatment is 24 months.
Receives: Drug: Ipilimumab Injection; Drug: Atezolizumab Injection; Drug: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective response of treatment (Phase II)

    Assess the percentage of patients with an objective response (complete response or partial response) according to the investigator (RECIST v1.1) for both treatments arms,

    Measured: 24 months after beginning of treatment

  2. Overall survival (Phase III)

    The overall survival is defined as the time to death (whatever the cause) or date of last news

    Measured: From randomization until death or last news for alive patients, up to 2 years

Secondary outcomes (2)

  1. Progression-free survival (PFS)

    Progression is based on CT-Scan and only radiological progression have to be taking into account. Progression-free survival is defined as the time from randomization to radiological progression or death. Patients alive without progression will be censored at date of last news.

    Measured: From randomization until progression, death or last news for alive patients, up to 2 years

  2. Objective response rate (OR) under treatment (Phase III)

    Assess the percentage of patients with an objective response (complete response or partial response) according to the investigator (RECIST v1.1) for both treatments

    Measured: 24 months after beginning of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Dec 2022
  2. Study start9 Mar 2023
  3. Primary completion12 May 2025
  4. Study completion12 May 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
229 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05665348
Sponsor's protocol ID
FFCD 2101-PRODIGE 81
Other IDs
2022-501217-31
Acronym
TRIPLET
Status last verified
Sep 2024
First submitted
16 Dec 2022
Last updated
9 Mar 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Merle P, Blanc JF, Le Malicot K, Peron JM, Bourgeois V, Bouattour M, Touchefeu Y, Vitellius C, Akouz FK, Heurgue A, Girot P, Assenat E, Nguyen-Khac E, Bronowicki JP, Viaud J, Ben Abdelghani M, Manfredi S, Edeline J, Phelip JM; TRIPLET-HCC study investigators. Addition of ipilimumab to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma (PRODIGE 81-FFCD 2101-TRIPLET HCC): phase 2 results from a randomised, multicentre, open-label, phase 2-3 trial. Lancet Gastroenterol Hepatol. 2026 Aug;11(8):700-712. doi: 10.1016/S2468-1253(26)00115-9. Epub 2026 Jun 22.

    PubMed 42330996

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Ipilimumab Injection, Atezolizumab Injection and Bevacizumab in people with HCC - Hepatocellular Carcinoma and Metastatic Cancer, run by Federation Francophone de Cancerologie Digestive at 45 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 45 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective response of treatment (Phase II) (time frame: 24 months after beginning of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05665348, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Mar 2026.

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