Hepatocellular CarcinomaPhase 2NCT04696055
Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors
A Phase 2 study testing Pembrolizumab and Regorafenib (Stivarga, BAY73-4506) in people with Hepatocellular Carcinoma, run by Bayer at 39 sites in 8 countries.
Trial summary
Researchers are looking for a better way to treat people diagnosed with liver cancer which may have spread to nearby tissue and is unlikely to be cured or controlled with treatment (advanced metastatic hepatocellular carcinoma, HCC). 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?
- Pembrolizumab and Regorafenib (Stivarga, BAY73-4506)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 95 participants
- Where
- 39 sitesin 8 countries
- Study dates
- 3 Feb 2021to 23 Apr 2024
- Phase
- Phase 2
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
- ≥ 18 years of age on the day of signing informed consent.
- Histological or cytological confirmation of HCC or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants.
- Unresectable advanced HCC eligible for systemic therapy.
- Participants must have progressed after only one prior line of systemic immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. A wash out period of at least 28 days or 5 half-lives, whichever is shorter, must be completed for eligibility in this trial. PD-1/PD-L1 treatment progression is defined by meeting all of the following criteria:
- Has received at least 2 doses of an approved anti PD-1/PD-L1 mAb or received PD-1/PD-L1 treatment for 8 weeks, whichever is longer.
- Has demonstrated disease progression after PD-1/PD-L1 treatment as defined by RECIST 1.1. In the absence of rapid clinical progression, the initial evidence of RECIST 1.1 disease progression is to be confirmed using iRECIST by a second assessment no less than four weeks from the date of the first documented progressive disease.
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- This determination is made by the investigator. Once progressive disease is confirmed, the initial date of RECIST 1.1 progressive disease documentation will be considered that date of disease progression.
- In cases of unequivocal clinical or radiological progression, disease progression confirmation may not be required after documented discussion and approval by the sponsor.
- Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb.
- Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of liver cancer and have disease recurrence (unresectable locoregional disease or distant metastases) are eligible if they progressed while on active treatment or within 6 months of stopping anti-PD-1 therapy. This will be considered the first line of systemic therapy.
- For these participants, the following applies:
- a second assessment to confirm disease progression beyond recurrence is not required; and
- they must have received at least 2 prior doses of anti-PD-1/PD-L1 mAb.
- Barcelona Clinic Liver Cancer (BCLC) stage B or C.
- Liver function status should be Child-Pugh (CP) Class A within 7 days prior to the first dose of study intervention. CP status should be calculated based on clinical findings and laboratory results during the screening period.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 within 7 days prior to the first dose of study intervention.
- At least one measurable lesion by CT scan or MRI according to RECIST 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion.
- Participants with controlled (treated) hepatitis B virus (HBV) infection will be allowed if they meet the following criteria:
- Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study intervention.
- Participants on active HBV therapy with viral loads under 500 IU/ml should stay on the same therapy throughout study treatment.
- Participants who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV viral load under 500 IU/mL that do not require HBV antiviral prophylaxis.
- Provision of recent tumor tissue (as defined below) is mandatory at screening. Exceptions will be accepted for participants with no recent baseline tumor tissues after documented discussion and approval by the sponsor.
- Tumor tissue obtained within 180 days of enrollment and after the last dose of most recent anti-cancer therapy.
- Or a new biopsy.
Who cannot join
- Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes.
- Patients with disease that is suitable for local therapy administered with curative intent.
- Patients who experienced any Common Terminology Criteria for Adverse Events (CTCAE) ≥ 3 or any other immune- related toxicities that led to permanent discontinuation of treatment with immune checkpoint inhibitors in 1 L.
- Persistent proteinuria of CTCAE Grade 3 or higher.
- Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study interventions.
- Active autoimmune disease.
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- History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Any hemorrhage or bleeding event CTCAE Grade ≥ 3 within 28 days prior to the start of study medication.
- Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention.
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication.
- Ongoing infection CTCAE Grade > 2 requiring systemic therapy.
- Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
- Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg) on more than 2 separate measurements despite optimal medical management.
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
- Myocardial infarction less than 6 months before start of study intervention.
- Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥ 2 dyspnea).
- Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to study entry.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable.
- Significant acute gastrointestinal disorders with diarrhea as a major symptom.
- Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L.
- Prior treatment with regorafenib, in combination regimens with immune checkpoint inhibitors.
- Transfusion of blood products within 7 days prior to signing informed consent, or administration of colony stimulating factors within 4 weeks prior to signing informed consent.
- Previous assignment to treatment during this study.
- Previous (at least a minimum of 28 days, or 5 half-lives of an investigational drug before the start of study treatment, whichever is shorter) or concomitant participation in another clinical study with investigational medicinal product(s).
Trial locations and contacts
39 sites in 8 countries.
39 sites in 8 countries
United States9 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114-2696
City of Hope - Duarte Cancer Center
Duarte, California, 91010
USC Norris Hospital and Clinics
Los Angeles, California, 90033
University of Miami Miller School of Medicine
Miami, Florida, 33136
Medical Oncology Hematology Consultants, PA
Newark, Delaware, 19713
University of California Irvine Medical Center
Orange, California, 92868-3201
Seattle Cancer Care Alliance
Seattle, Washington, 98109-1023
Moffitt Cancer Center
Tampa, Florida, 33612
University of Arizona Cancer Center
Tucson, Arizona, 85724
France9 sites
Hôpital Beaujon - Clichy
Clichy, 92110
Center Hospitalier Michallon - Grenoble
Grenoble, 38043
Hopital Claude Huriez - Lille
Lille, 59037
Hôpital de la Croix Rousse
Lyon, 69004
AP-HM - Hopital de la Timone
Marseille, 13005
Hôpital Saint-Eloi
Montpellier, 34059
Centre François Magendie - Pessac
Pessac, 33600
Centre Hospitalier Universitaire de Nancy
Vandœuvre-lès-Nancy, 54500
Hôpital Paul Brousse - Villejuif
Villejuif, 94800
Germany5 sites
Universitätsklinikum Köln
Cologne, North Rhine-Westphalia, 50937
Heinrich-Heine-Universität Düsseldorf
Düsseldorf, North Rhine-Westphalia, 40225
Universitätsmedizin der Johannes Gutenberg Universität Mainz
Mainz, Rhineland-Palatinate, 55101
Klinikum der Universität München Grosshadern
München, Bavaria, 81377
Eberhard-Karls-Universität Tübingen
Tübingen, Baden-Wurttemberg, 72076
Italy4 sites
Humanitas Mirasole S.p.A.
Milan, Lombardy, 20089
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, Lombardy, 20122
Istituto Oncologico Veneto_Padova - UOC Oncologia 1
Padova, Veneto, 35128
Azienda Ospedaliero Universitaria Pisana_Santa Chiara - UO Oncologia 2
Pisa, Tuscany, 56126
Israel3 sites
Rambam Health Corporation
Haifa, 3109601
Rabin Medical Center | Beilinson Hospital - Internal Medicine C Department
Petah Tikva, 4941492
Tel-Aviv Sourasky Medical Center
Tel Aviv, 6423906
Japan3 sites
Chiba University Hospital
Chiba, Chiba, 260-8677
National Cancer Center Hospital East
Kashiwa, Chiba, 277-8577
Japanese Red Cross Society Musashino Red Cross Hospital
Musashino, Tokyo, 180-8610
South Korea3 sites
Asan Medical Center
Seoul, Seoul Teugbyeolsi, 05505
Seoul National University Hospital
Seoul, Seoul Teugbyeolsi, 3080
Samsung Medical Center
Seoul, 06351
Spain3 sites
Hospital Clínic i Provincial de Barcelona
Barcelona, 8036
Institut Català d'Oncologia Hospitalet
L'Hospitalet de Llobregat, Barcelona, 08907
Hospital General Universitario Gregorio Marañón | Digestivo
Madrid, 28007
About this study
Official title: An Open-Label Study of Regorafenib in Combination With Pembrolizumab in Patients With Advanced or Metastatic Hepatocellular Carcinoma (HCC) After PD1/PD-L1 Immune Checkpoint Inhibitors
Researchers are looking for a better way to treat people diagnosed with liver cancer which may have spread to nearby tissue and is unlikely to be cured or controlled with treatment (advanced metastatic hepatocellular carcinoma, HCC). Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how it works.
In this trial, the researchers will learn more about the trial treatment, regorafenib, in a small number of participants. They will study the results when the trial treatment is taken with another cancer treatment called pembrolizumab.
Read more
There will be 2 parts to this trial. The part 1 (pilot phase) will include about 52 men and women. The part 2 (expansion phase) will include about 67 men and women. All of the participants will have HCC and will be aged 18 years or older. All of the participants will have tried other treatments that did not help their HCC. These other treatments (PD-1/PD-L1 Immune Checkpoint Inhibitors) are designed to work by stopping the activity of certain proteins in the immune system thought to play a role in HCC.
During both parts of the trial, the participants will take regorafenib and receive pembrolizumab. In the pilot phase, there will be 2 groups of participants. The group that each participant joins will be based on the treatment they already received for their HCC. The researchers will review the results in each group to learn if regorafenib and pembrolizumab are helping one group of participants more than others. Outcome of this review will determine the population to be treated in the expansion phase.
- Conditions
- Hepatocellular Carcinoma
- Being tested
- Pembrolizumab, Regorafenib (Stivarga, BAY73-4506)
- Keywords
- Advanced or metastatic hepatocellular carcinoma (HCC), Liver cancer
- Medical subject headings
- Carcinoma, Hepatocellular, Liver Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabDrug
Also called Keytruda / MK-3475
Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).
Regorafenib (Stivarga, BAY73-4506)Drug
Regorafenib to be given orally (p.o.) at a starting dose of 90 mg QD for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily is well tolerated the dose should be escalated to 120 mg starting after the first 4-week cycle of regorafenib.
| Study group | Role | What they receive |
|---|---|---|
| Regorafenib+Pembrolizumab | Experimental | Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy. Receives: Drug: Pembrolizumab; Drug: Regorafenib (Stivarga, BAY73-4506) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment
Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR per RECIST 1.1 by independent central assessment is reported). RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Measured: Up to 15 months. Data up to 38 months are now available and are also reported for full transparency.
Secondary outcomes (5)
Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment
Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review is reported. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Measured: Up to 38 months
Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment
Duration of response (DOR) for partial response (PR) and complete response (CR) was defined as the time from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression was documented). DOR was defined for confirmed responders only, i.e., participants with a CR or PR. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Measured: Up to 38 months
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was considered as treatment-emergent (TEAE) if arising or worsening after start of first study intervention administration until 30 days after administration of any study intervention. In addition, any AEs qualifying as a serious adverse event (SAE) were collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy had been initiated.
Measured: Up to 38 months
Number of Participants With Safety-relevant Changes in Clinical Parameters
Number of participants with clinically relevant trends observed in laboratory data, ECG data, or ECOG performance status is reported.
Measured: Up to 38 months
Percentage of Participants With Dose Modification
Dose modification included dose interruption, dose reduction, dose discontinuation.
Measured: Up to 38 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2021
- Study start3 Feb 2021
- Primary completion5 May 2022
- Study completion23 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by BayerThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 95 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bayer
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04696055
- Sponsor's protocol ID
- 21469
- Other IDs
- MK-3475-B70, Keynote B70, 2020-003555-16
- Status last verified
- May 2025
- First submitted
- 4 Jan 2021
- Last updated
- 13 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.