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AzTrials

Hepatocellular CarcinomaPhase 3NCT02576509

An Investigational Immuno-therapy Study of Nivolumab Compared to Sorafenib as a First Treatment in Patients With Advanced Hepatocellular Carcinoma

A Phase 3 study testing Nivolumab and Sorafenib in people with Hepatocellular Carcinoma, run by Bristol-Myers Squibb at 138 sites in 22 countries.

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

The purpose of this study is to determine if nivolumab or sorafenib is more effective in the treatment of Advanced Hepatocellular Carcinoma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatocellular Carcinoma
What is being tested?
Nivolumab and Sorafenib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
743 participants
Where
138 sitesin 22 countries
Study dates
7 Dec 2015to 7 Feb 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

  • Histologically confirmed advanced hepatocellular carcinoma, not eligible for surgical and/or locoregional therapies; or progressive disease after surgical and /or locoregional therapies
  • Locoregional therapy for hepatocellular carcinoma (HCC) must be completed at least 4 weeks prior to the baseline scan
  • Child-Pugh Class A
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

Who cannot join

  • Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
  • Prior liver transplant
  • Active, known, or suspected autoimmune disease
  • Other protocol-defined inclusion/exclusion criteria apply

Trial locations and contacts

138 sites in 22 countries.

138 sites in 22 countries

China24 sites

  • Local Institution - 0139

    Beijing, Beijing Municipality, 100050

  • Local Institution - 0137

    Beijing, Beijing Municipality, 100071

  • Local Institution - 0140

    Beijing, Beijing Municipality, 100142

  • Local Institution - 0141

    Beijing, Beijing Municipality, 100142

  • Local Institution - 0136

    Changchun, Jilin, 130012

  • Local Institution - 0163

    Changchun, Jilin, 130021

  • Local Institution - 0148

    Changsha, Hunan, 410013

  • Local Institution - 0162

    Changsha, Hunan, 410013

  • Local Institution - 0169

    Changzhou, Jiangsu, 213003

  • Local Institution - 0166

    Dalian, Liaoning, 116000

  • Local Institution - 0152

    Fuzhou, Fujian, 350025

  • Local Institution - 0161

    Guangzhou, Guangdong, 510060

  • Local Institution - 0157

    Guangzhou, Guangdong, 510080

  • Local Institution - 0144

    Guangzhou, Guangdong, 510515

  • Local Institution - 0173

    Hangzhou, Zhejiang, 310003

  • Local Institution - 0146

    Hangzhou, Zhejiang, 310022

  • Local Institution - 0142

    Harbin, Heilongjiang, 155040

  • Local Institution - 0164

    Hefei, Anhui, 230061

  • Local Institution - 0135

    Nanjing, Jiangsu, 210002

  • Local Institution - 0158

    Nanning, Guangxi, 530021

  • Local Institution - 0145

    Shanghai, Shanghai Municipality, 200032

  • Local Institution - 0151

    Shanghai, Shanghai Municipality, 200032

  • Local Institution - 0159

    Tianjin, Tianjin Municipality, 300060

  • Local Institution - 0138

    Xi'an, Shan3xi, 710038

Other trials in China

Japan19 sites

  • Local Institution - 0100

    Chiba, Chiba, 2608670

  • Local Institution - 0131

    Chiyoda-ku, Tokyo, 101-0062

  • Local Institution - 0101

    Hiroshima, 734-8551

  • Local Institution - 0105

    Kanazawa, Ishikawa-ken, 9208641

  • Local Institution - 0110

    Kawasaki-shi, Kanagawa, 2138587

  • Local Institution - 0107

    Kurume-shi, Fukuoka, 8300011

  • Local Institution - 0111

    Kyoto, Kyoto, 6028566

  • Local Institution - 0103

    Matsuyama, Ehime, 7900024

  • Local Institution - 0114

    Mitaka-shi, Tokyo, 181-8611

  • Local Institution - 0108

    Musashino-shi, Tokyo, 180-8610

  • Local Institution - 0127

    Ogaki-shi, Gifu, 5038502

  • Local Institution - 0106

    Osaka-Sayama-Shi, Osaka, 5898511

  • Local Institution - 0115

    Saga, Saga-ken, 8408571

  • Local Institution - 0102

    Sapporo, Hokkaido, 0600033

  • Local Institution - 0130

    Sapporo, Hokkaido, 0608648

  • Local Institution - 0126

    Shinjuku-ku, Tokyo, 1628655

  • Local Institution - 0113

    Suita, Osaka, 5650871

  • Local Institution - 0112

    Yokohama, Kanagawa, 2320024

  • Local Institution - 0104

    Yokohama, Kanagawa, 2418515

Other trials in Japan

United States17 sites

  • Local Institution - 0066

    Birmingham, Alabama, 35294

  • Local Institution - 0016

    Charlotte, North Carolina, 28204

  • Local Institution - 0061

    Chicago, Illinois, 60637

  • UT Southwestern Medical Center

    Dallas, Texas, 75390

  • Local Institution - 0020

    Los Angeles, California, 90095

  • Local Institution - 0050

    Madison, Wisconsin, 53792

  • Ochsner Clinic Foundation

    New Orleans, Louisiana, 70121

  • Local Institution - 0083

    New York, New York, 10029

  • Local Institution - 0093

    New York, New York, 10065

  • Local Institution - 0095

    Philadelphia, Pennsylvania, 19104

  • Local Institution - 0019

    Philadelphia, Pennsylvania, 19107

  • Local Institution - 0017

    San Antonio, Texas, 78229

  • Local Institution - 0015

    San Francisco, California, 94115

  • Local Institution - 0084

    San Francisco, California, 94143

  • Local Institution - 0026

    Seattle, Washington, 98101

  • University of Washington - Seattle Cancer Care Alliance

    Seattle, Washington, 98109

  • Scott & White Memorial Hospital And Clinic

    Temple, Texas, 76508

Other trials in United States

Germany9 sites

  • Local Institution - 0036

    Berlin, 13353

  • Local Institution - 0037

    Essen, 45136

  • Local Institution - 0167

    Frankfurt, 60590

  • Local Institution - 0034

    Hamburg, 20246

  • Local Institution - 0031

    Leipzig, 04103

  • Local Institution - 0035

    Mainz, 55131

  • Local Institution - 0033

    Munich, 81366

  • Local Institution - 0032

    Regensburg, 93053

  • Local Institution - 0030

    Tübingen, 72076

Other trials in Germany

France8 sites

  • Local Institution - 0071

    La Tronche, 38700

  • Local Institution - 0072

    Lille, 59037

  • Local Institution - 0069

    Lyon, 69004

  • Local Institution - 0073

    Montpellier, 34295

  • Local Institution - 0067

    Paris, 75651

  • Local Institution - 0068

    Pessac, 33604

  • Local Institution - 0070

    Rennes, 35042

  • Local Institution - 0074

    Toulouse, 31059

Other trials in France

South Korea8 sites

  • Local Institution - 0125

    Daegu, 41944

  • Local Institution - 0116

    Goyang-si, 10408

  • Local Institution - 0118

    Jeollanam-do, 58128

  • Local Institution - 0117

    Seoul, Seocho-gu, 06591

  • Local Institution - 0123

    Seoul, 03080

  • Local Institution - 0119

    Seoul, 03722

  • Local Institution - 0122

    Seoul, 05505

  • Local Institution - 0124

    Seoul, 06351

Other trials in South Korea

Taiwan7 sites

  • Local Institution - 0129

    Kaohsiung County, 83301

  • Local Institution - 0133

    Taichung, 40447

  • Local Institution - 0121

    Tainan, 704

  • Local Institution - 0132

    Tainan, 736

  • Local Institution - 0099

    Taipei, 10002

  • Local Institution - 0120

    Taipei, 11217

  • Local Institution - 0128

    Taoyuan County, 33305

Other trials in Taiwan

Australia6 sites

  • Local Institution - 0007

    Adelaide, South Australia, 5000

  • Local Institution - 0005

    Camperdown, New South Wales, 2050

  • Local Institution - 0001

    Clayton, Victoria, 3168

  • Local Institution - 0002

    Heidelberg, Victoria, 3084

  • Local Institution - 0008

    Nedlands, Western Australia, 6009

  • Local Institution - 0003

    Prahran, Victoria, 3181

Other trials in Australia

Italy5 sites

  • Local Institution - 0054

    Benevento, 82100

  • Local Institution - 0062

    Bergamo, 0

  • Local Institution - 0055

    Milan, 20133

  • Local Institution - 0063

    Orbassano, 10043

  • Local Institution - 0064

    Siena, 53100

Other trials in Italy

Israel4 sites

  • Local Institution - 0082

    Haifa, 31096

  • Local Institution - 0060

    Jerusalem, 91120

  • Local Institution - 0058

    Petah Tikva, 49100

  • Local Institution - 0059

    Tel Aviv, 64239

Other trials in Israel

Spain4 sites

  • Local Institution - 0065

    Alicante, 03010

  • Local Institution - 0085

    Majadahonda - Madrid, 28222

  • Local Institution - 0009

    Pamplona, 31008

  • Local Institution - 0010

    Santiago Compostela, 15706

Other trials in Spain

United Kingdom4 sites

  • Local Institution - 0079

    Glasgow, Lanarkshire, G12 0YN

  • Local Institution - 0081

    Liverpool, L7 8YA

  • Local Institution - 0080

    London, Greater London, NW3 2QG

  • Local Institution - 0078

    London, Greater London, SE5 9RS

Other trials in United Kingdom

Belgium3 sites

  • Local Institution - 0075

    Brussels, 1000

  • Local Institution - 0091

    Leuven, 3000

  • Local Institution - 0077

    Liège, 4000

Other trials in Belgium

Canada3 sites

  • Local Institution - 0043

    Calgary, Alberta, T2N 4N2

  • Local Institution - 0042

    Québec, Quebec, G1R 2J6

  • Local Institution - 0044

    Vancouver, British Columbia, V5Z 4E6

Other trials in Canada

Czechia3 sites

  • Local Institution - 0029

    Brno, 656 53

  • Local Institution - 0027

    Hradec Králové, 500 05

  • Local Institution - 0028

    Olomouc, 779 00

Other trials in Czechia

Poland3 sites

  • Local Institution - 0023

    Gdansk, 80952

  • Local Institution - 0056

    Warsaw, 02-781

  • Local Institution - 0045

    Wroclaw, 50-556

Other trials in Poland

Austria2 sites

  • Local Institution - 0039

    Graz, 8036

  • Local Institution - 0038

    Vienna, 1090

Other trials in Austria

Hong Kong2 sites

  • Local Institution - 0011

    Hong Kong, 0

  • Local Institution - 0012

    Hong Kong

Other trials in Hong Kong

Singapore2 sites

  • Local Institution - 0013

    Singapore, 168583

  • Local Institution - 0014

    Singapore, 308433

Other trials in Singapore

Sweden2 sites

  • Local Institution - 0088

    Gothenburg, 413 45

  • Local Institution - 0087

    Stockholm, 141 86

Other trials in Sweden

Switzerland2 sites

  • Local Institution - 0040

    Basel, 4031

  • Local Institution - 0041

    Bern, 3010

Other trials in Switzerland

Russia1 site

  • Local Institution - 0096

    Moscow, 115478

Other trials in Russia

About this study

Official title: A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459)

The purpose of this study is to determine if nivolumab or sorafenib is more effective in the treatment of Advanced Hepatocellular Carcinoma.

Being tested
Nivolumab, Sorafenib
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

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

  • NivolumabDrug

    Specified Dose on Specified Days

  • SorafenibDrug

    Specified Dose on Specified Days

Study groups in NCT02576509
Study groupRoleWhat they receive
NivolumabExperimentalNivolumab specified dose on specified days
Receives: Drug: Nivolumab
SorafenibActive comparatorSorafenib specified dose on specified days
Receives: Drug: Sorafenib

What is being measured

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

  1. Overall Survival (OS)

    OS is defined as the time from the date of randomization to the date of death due to any cause in all randomized participants. Participants who are alive will be censored at the last known alive dates.

    Based on Kaplan-Meier Estimates.

    Measured: time from the date of randomization to the date of death due to any cause, assessed up to June 2019 (approximately 41 months)

Secondary outcomes (4)

  1. Objective Response Rate (ORR) Per BICR RECIST 1.1

    ORR is defined as the proportion of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR). BOR is defined as the best response designation, as determined based on BICR-assessed tumor response according to RECIST 1.1, recorded between the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For participants without documented progression or subsequent anti-cancer therapy, all available response designations will contribute to the BOR determination. For a BOR of CR or PR, the initial response assessment must be confirmed by a consecutive assessment no less than 4 weeks (28 days) later.

    Estimate of (Nivolumab - Sorafenib) is based on CMH method of weighting, stratified by stratification factors

    Measured: the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

  2. Progression-Free Survival (PFS)

    PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by BICR according to RECIST 1.1 or death due to any cause in all randomized participants. Participants who die without a reported prior progression and without initiation of subsequent anti-cancer therapy will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who did not have baseline tumor assessment will be censored on the date they were randomized. Participants who did not have any on study tumor assessments and did not die will be censored on the date they were randomized. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to subsequent anti-cancer therapy.

    Measured: time from the date of randomization to the date of the first objectively documented tumor progression or death, assessed up to May 2019 (approximately 40 months)

  3. Efficacy Based on PD-L1 Expression - OS and PFS

    PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as:

    Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling.

    Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate).

    PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression:

    • PD-L1 > X %: ≥ X % PD-L1 expression
    • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored.

    Confidence interval based on the Clopper and Pearson method.

    Measured: the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

  4. Efficacy Based on PD-L1 Expression - ORR

    PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as:

    Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling.

    Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate).

    PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression:

    • PD-L1 > X %: ≥ X % PD-L1 expression
    • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored.

    Confidence interval based on the Clopper and Pearson method.

    Measured: the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

Timeline

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

  1. First posted15 Oct 2015 (estimated)
  2. Study start7 Dec 2015
  3. Primary completion30 May 2019
  4. Study completion7 Feb 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
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
743 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02576509
Sponsor's protocol ID
CA209-459
Status last verified
Jan 2025
First submitted
13 Oct 2015
Last updated
17 Feb 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Neely J, Yao J, Kudo M, Finn RS, Sangro B, Melero I, El-Khoueiry AB, Yau T, Harding JJ, Rosmorduc O, Tschaika M, Novosiadly R, Cruz A, Kelley RK. Biomarkers associated with efficacy of first-line nivolumab vs. sorafenib in advanced hepatocellular carcinoma: results from the CheckMate 459 phase III trial. JHEP Rep. 2026 Sep 19:102038. doi: 10.1016/j.jhepr.2026.102038. Online ahead of print.

    PubMed 42762856

  • Bitar R, Salem R, Finn R, Greten TF, Goldberg SN, Chapiro J. Interventional Oncology Meets Immuno-oncology: Combination Therapies for Hepatocellular Carcinoma. Radiology. 2024 Nov;313(2):e232875. doi: 10.1148/radiol.232875.

    PubMed 39560477

  • Zhou X, Cao J, Topatana W, Xie T, Chen T, Hu J, Li S, Juengpanic S, Lu Z, Zhang B, Wang K, Feng X, Shen J, Chen M. Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis. Immunotherapy. 2023 Apr;15(5):353-365. doi: 10.2217/imt-2022-0168. Epub 2023 Feb 27.

    PubMed 36852452

  • Li Y, Liang X, Li H, Chen X. Atezolizumab plus bevacizumab versus nivolumab as first-line treatment for advanced or unresectable hepatocellular carcinoma: A cost-effectiveness analysis. Cancer. 2022 Nov 15;128(22):3995-4003. doi: 10.1002/cncr.34457. Epub 2022 Sep 16.

    PubMed 36111952

  • Shi J, Liu J, Tu X, Li B, Tong Z, Wang T, Zheng Y, Shi H, Zeng X, Chen W, Yin W, Fang W. Single-cell immune signature for detecting early-stage HCC and early assessing anti-PD-1 immunotherapy efficacy. J Immunother Cancer. 2022 Jan;10(1):e003133. doi: 10.1136/jitc-2021-003133.

    PubMed 35101942

  • Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022 Jan;23(1):77-90. doi: 10.1016/S1470-2045(21)00604-5. Epub 2021 Dec 13.

    PubMed 34914889

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nivolumab and Sorafenib in people with Hepatocellular Carcinoma, run by Bristol-Myers Squibb at 138 sites in 22 countries.

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 4 inclusion and 4 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 17 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 138 sites in China, Japan, United States, Germany, France and 17 more countries. 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 26 Jun 2020). 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?

Overall Survival (OS) (time frame: time from the date of randomization to the date of death due to any cause, assessed up to June 2019 (approximately 41 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 NCT02576509, which also lists 6 linked publications.

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 17 Feb 2025.

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