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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04696055
Recruitment Status : Active, not recruiting
First Posted : January 6, 2021
Results First Posted : May 30, 2023
Last Update Posted : May 30, 2023
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):

Brief 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). 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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Pembrolizumab Drug: Regorafenib (Stivarga, BAY73-4506) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 3, 2021
Actual Primary Completion Date : May 5, 2022
Estimated Study Completion Date : May 15, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer

Arm Intervention/treatment
Experimental: Regorafenib+Pembrolizumab
Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.
Drug: Pembrolizumab
Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).
Other Name: Keytruda / MK-3475

Drug: Regorafenib (Stivarga, BAY73-4506)
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.

Primary Outcome Measures :
  1. Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment [ Time Frame: 15 months ]
    Objective/overall response rate (ORR) is defined as the proportion 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 (Full analysis set).

Secondary Outcome Measures :
  1. Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment [ Time Frame: Approximately 45 months ]
    Objective/overall response rate (ORR) is defined as the proportion of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review will be reported (full analysis set).

  2. Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment [ Time Frame: Approximately 45 months ]
    Duration of response (DOR) for partial response (PR) and complete response (CR) defined as the time (in days and months) from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression is documented). DOR defined for confirmed responders only, i.e., participants with a CR or PR.

  3. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Approximately 45 months ]
    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.

  4. Number of Participants With Safety-relevant Changes in Clinical Parameters [ Time Frame: Approximately 45 months ]
  5. Number of Participants With Dose Modification [ Time Frame: Approximately 45 months ]
    Dose modification includes dose interruption, dose reduction, dose discontinuation.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 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:

    1. 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.
    2. 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.

    i. 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.

ii. In cases of unequivocal clinical or radiological progression, disease progression confirmation may not be required after documented discussion and approval by the sponsor.

c. 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:

  1. a second assessment to confirm disease progression beyond recurrence is not required; and
  2. 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.

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 ≥ 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04696055

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Sponsors and Collaborators
Merck Sharp & Dohme LLC
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] June 8, 2021
Statistical Analysis Plan  [PDF] June 12, 2022

Additional Information:
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Responsible Party: Bayer Identifier: NCT04696055    
Other Study ID Numbers: 21469
MK-3475-B70 ( Other Identifier: Merck )
Keynote B70 ( Other Identifier: Merck )
2020-003555-16 ( EudraCT Number )
First Posted: January 6, 2021    Key Record Dates
Results First Posted: May 30, 2023
Last Update Posted: May 30, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description:

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 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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Advanced or metastatic hepatocellular carcinoma (HCC)
Liver cancer
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action