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Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1 / PD-L1 Immune Checkpoint Inhibitors

Trial Status: Active

Researchers are looking for a better way to treat people suffering from 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. 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.

Inclusion Criteria

  • ≥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 had prior 1L immunotherapy treatment with a PD-1/PD-L1 checkpoint inhibitor administered either as monotherapy or in combination with other therapies. This also includes patients receiving prior treatment with pembrolizumab as monotherapy or in combination. A wash out period of at least 28 days or 5 half-lives, whichever is shorter, must be completed for eligibility in this trial. In case of discontinuation due to progression, the following criteria are required in order to define PD-1/PD-L1 treatment progression:
  • Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.
  • Has demonstrated disease progression after PD-1/PD-L1 as defined by RECIST 1.1. The initial evidence of PD is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression. In cases of unequivocal progression (clinical or radiological), PD 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. i. Progressive disease is determined according to iRECIST ii. This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
  • Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of liver cancer and have disease recurrence (unresectable loco-regional disease or distant metastases) are eligible if they progressed while on active treatment or within 6 months of stopping anti-PD-1 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. 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.
  • 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 anti-viral 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

Exclusion Criteria

  • 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
  • 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 > 150 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).


Banner University Medical Center - Tucson
Status: ACTIVE


City of Hope Comprehensive Cancer Center
Status: ACTIVE
Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: ACTIVE
Contact: Lia Etheridge
Phone: 310-825-7174
UC Irvine Health / Chao Family Comprehensive Cancer Center
Status: ACTIVE


Massachusetts General Hospital Cancer Center
Status: ACTIVE


Oklahoma City
University of Oklahoma Health Sciences Center
Status: ACTIVE
Contact: Jaclyn Case Arterburn
Phone: 405-271-8777ext48161


Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Bayer Corporation

  • Primary ID 21469
  • Secondary IDs NCI-2021-00841, 2020-003555-16, Keynote B70, MK-3475-B70
  • ID NCT04696055