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Carcinoma, HepatocellularPhase 3AMETHISTANCT04487067

A Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista

A Phase 3 study testing Atezolizumab and Bevacizumab in people with Carcinoma, Hepatocellular, run by Hoffmann-La Roche at 21 sites in Italy.

Completed

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

Official record
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Trial summary

This is a Phase IIIb, one arm, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab + bevacizumab in patients with unresectable HCC who have received no prior systemic treatment. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Hepatocellular
What is being tested?
Atezolizumab and Bevacizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
152 participants
Where
21 sitesItaly
Study dates
25 Aug 2020to 13 Aug 2024
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

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

  • Unresectable HCC with diagnosis confirmed by histology, with a biopsy within 6 months from recruitment;
  • Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies;
  • No prior systemic therapy for HCC;
  • At least one measurable untreated lesion;
  • Patients who received prior local therapy are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1;
  • ECOG Performance Status of 0 or 1 within 7 days prior to recruitment;
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  • Child-Pugh class A within 7 days prior to recruitment;
  • Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed. In case of varices at high risk of bleeding (corresponding to medium (F2) or large (F3) varices, or F1 varices with cherry red spots or red wale marking) prophylatic treatment per local standard of care must be adopted prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure provided they had no varices at high risk of bleeding;
  • Adequate hematologic and end-organ function
  • Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade <= 1 prior to study entry, with the exception of alopecia
  • Negative HIV test at screening with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥200µL, and have an undetectable viral load;
  • In patients with viral HCC, documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test;
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs.
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.

Who cannot join

  • History of leptomeningeal disease or brain metastases;
  • Active or history of autoimmune disease or immune deficiency;
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan;
  • Known active tuberculosis;
  • Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina;
  • History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death;
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  • Prior allogeneic stem cell or solid organ transplantation;
  • Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab and 6 months after the last dose of bevacizumab;
  • Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC;
  • Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding;
  • A prior bleeding event due to oesophageal and/or gastric varices within 6 months prior to initiation of study treatment;
  • Clinically evident ascites;
  • Co-infection of HBV and HCV;
  • Co-infection with HBV and hepatitis D viral infection;
  • Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases;
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures;
  • Clinically significant uncontrolled or symptomatic hypercalcemia;
  • Inadequately controlled arterial hypertension;
  • Significant vascular disease within 6 months prior to initiation of study treatment;
  • History of haemoptysis;
  • Evidence of bleeding diathesis or significant coagulopathy;
  • History of gastrointestinal (GI) fistula, GI perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment;
  • History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment;
  • Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume;
  • Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure.

Trial locations and contacts

21 sites in 1 country.

21 sites in 1 country

Italy21 sites
  • Ospedali Riuniti - Bergamo

    Bergamo, Lombardy, 24128

  • A.O. S. Orsola Malpighi

    Bologna, Emilia-Romagna, 40138

  • A.O.U. Cagliari-P.O. Monserrato

    Cagliari, Sardinia, 09100

  • A.O.U Careggi

    Florence, Tuscany, 50124

  • A.O. Universitaria S. Martino Di Genova

    Genoa, Liguria, 16132

  • Fondazione IRCCS Ospedale Maggiore Policlinico

    Milan, Lombardy, 20122

  • Istituto Nazionale Dei Tumori

    Milan, Lombardy, 20133

  • Fondazione Pascale

    Naples, Campania, 80100

  • Azienda Osp Uni Seconda Università Degli Studi Di Napoli

    Naples, Campania, 80131

  • Ospedale del Mare

    Naples, Campania, 80147

  • IOV - Istituto Oncologico Veneto - IRCCS

    Padova, Veneto, 35128

  • A.O.U. Policlinico Paolo Giaccone

    Palermo, Sicily, 90127

  • Azienda Ospedaliera Di Rilievo Nazionale E Di Alta Specializzazione Garibaldi

    Palermo, Sicily, 90127

  • Azlenda Ospendaliero-Universitaria Pisana

    Pisa, Tuscany, 56100

  • Arcispedale Santa Maria Nuova

    Reggio Emilia, Emilia-Romagna, 42100

  • Azienda Ospedaliera San Camillo Forlanini

    Rome, Lazio, 00151

  • Policlinico Universitario Agostino Gemelli

    Rome, Lazio, 00168

  • Istituto Clinico Humanitas

    Rozzano, Lombardy, 20089

  • IRCCS Ospedale Casa Sollievo Della Sofferenza

    San Giovanni Rotondo, Apulia, 71013

  • Clinica Oncologica-Ospedali Riuniti Ancona

    Torrette, Tuscany, 60020

  • Azienda Ospedaliera Ordine Mauriziano di Torino

    Turin, Piedmont, 10128

Other trials in Italy

About this study

Official title: A Phase IIIB, Single Arm, Multicenter Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista

This is a Phase IIIb, one arm, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab + bevacizumab in patients with unresectable HCC who have received no prior systemic treatment.

Medical subject headings
Carcinoma, Hepatocellular

What participants receive

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

  • AtezolizumabDrug

    Also called Tecentriq

    Atezolizumab 1200 mg IV infusion q3w

  • BevacizumabDrug

    Also called Avastin

    Bevacizumab 15 mg/kg IV Q3W

Study groups in NCT04487067
Study groupRoleWhat they receive
Atezolizumab + BevacizumabExperimentalParticipants will receive atezolizumab 1200 mg intravenous (IV) infusions Q3W (dosed in 3-week cycles) + bevacizumab 15 mg/kg IV Q3W (dosed in 3-week cycles)
Receives: Drug: Atezolizumab; Drug: Bevacizumab

What is being measured

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

  1. Number of Participants With Grade 3-5 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE V5) Bleeding/Haemorrhage

    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Severity of AEs was graded using NCI CTCAE v5.0. Grade 3=Severe/medically significant but not immediately life-threatening, hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4=Life-threatening consequences, urgent intervention indicated; Grade 5=Death related to AE.

    Measured: Up to approximately 47.6 months

Secondary outcomes (9)
  1. Overall Survival (OS)

    OS was defined as the time from initiation of study treatment to death from any cause. Kaplan-Meier (K-M) method was used to estimate the OS.

    Measured: Up to approximately 47.6 months

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

    An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are defined as AEs with onset date on or after the start of the first study treatment component. Number of participants with any TEAEs are reported here.

    Measured: Up to approximately 47.6 months

  3. Progression-free Survival (PFS)

    PFS was defined as the time from initiation of study treatment to the first occurrence of disease progression (PD) or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm). Participants alive and without any PD were censored at the last assessment date. K-M method was used to estimate the PFS.

    Measured: Up to approximately 47.6 months

  4. Objective Response Rate (ORR)

    ORR was defined as the percentage of participants with complete or partial response (CR or PR), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.

    Measured: Up to approximately 47.6 months

  5. Time to Progression (TTP)

    TTP was defined as the time from initiation of study treatment to the first occurrence of PD, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants without any PD were censored at the last assessment date. K-M method was used to estimate the TTP.

    Measured: Up to approximately 47.6 months

  6. Duration of Response (DOR)

    DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants who were alive and without any PD were censored at the last assessment date. K-M method was used to estimate the DOR.

    Measured: Up to approximately 47.6 months

  7. Post-progression Survival (PPS)

    PPS was defined as the time from the first occurrence of PD as determined by the investigator according to RECIST v1.1 to death from any cause. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants who were alive were censored at the last assessment date. K-M method was used to estimate the PPS.

    Measured: Up to approximately 47.6 months

  8. Number of Participants Reporting Severe Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire

    Participants self-reported symptomatic AEs using PRO-CTCAE, a validated item bank used to characterize presence, frequency of occurrence, severity, \&/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxicities. PRO-CTCAE contains questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence,severity,\& interference with daily function). Treatment toxicities can occur with observable signs (e.g.,vomiting)/ non-observable symptoms (e.g.,nausea). A subset of 14 symptoms most applicable to current treatments were selected for this study. Symptoms were selected based on toxicities associated with the drug's class, mechanism of action, or mode of administration, and toxicities reported with the drug in another indication. Number of participants who reported severe symptoms per the PRO-CTCAE questionnaire on Day 1 of each cycle is reported here.

    Measured: From Cycle 1 Day 1 to Cycle 63 Day 1 (1 Cycle = 21 days)

  9. Number of Participants Reporting Very Severe Symptoms in PRO-CTCAE Questionnaire

    Participants self-reported symptomatic AEs using PRO-CTCAE, a validated item bank used to characterize presence, frequency of occurrence, severity, \&/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxicities. PRO-CTCAE contains questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence,severity,\& interference with daily function). Treatment toxicities can occur with observable signs (e.g.,vomiting)/ non-observable symptoms (e.g.,nausea). A subset of 14 symptoms most applicable to current treatments were selected for this study. Symptoms were selected based on toxicities associated with the drug's class, mechanism of action, or mode of administration, \&toxicities reported with the drug in another indication. Number of participants who reported very severe symptoms per the PRO-CTCAE questionnaire on Day 1 of each cycle is reported here.

    Measured: From Cycle 1 Day 1 to Cycle 63 Day 1 (1 Cycle = 21 days)

Timeline

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

  1. First posted27 Jul 2020
  2. Study start25 Aug 2020
  3. Primary completion13 Aug 2024
  4. Study completion13 Aug 2024

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 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
152 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04487067
Sponsor's protocol ID
ML42243
Acronym
AMETHISTA
Status last verified
Sep 2025
First submitted
23 Jul 2020
Last updated
22 Sep 2025
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).

Publications

  • Piscaglia F, Masi G, Martinelli E, Cabibbo G, Di Maio M, Gasbarrini A, Iavarone M, Antonuzzo L, Mazzaferro V, Ballestrero A, Garufi C, Bergamo F, Celsa C, Marino D, Tovoli F, Ponziani FR, Pressiani T, Astolfi C, Gazzoli GC, Ciardiello F, Daniele B, Rimassa L. Atezolizumab plus bevacizumab as first-line treatment of unresectable hepatocellular carcinoma: interim analysis results from the phase IIIb AMETHISTA trial. ESMO Open. 2025 Feb;10(2):104110. doi: 10.1016/j.esmoop.2024.104110. Epub 2025 Jan 27.

    PubMed 39874903

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Atezolizumab and Bevacizumab in people with Carcinoma, Hepatocellular, run by Hoffmann-La Roche at 21 sites in Italy.

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 14 inclusion and 25 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 22 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 21 sites in Italy. 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 phase mean?

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?

Yes. Results are posted in the registry (first posted 22 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Number of Participants With Grade 3-5 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE V5) Bleeding/Haemorrhage (time frame: Up to approximately 47.6 months). 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 NCT04487067, 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 22 Sep 2025.

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