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Regorafenib Plus Pembrolizumab in First Line Systemic Treatment of HCC

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.
ClinicalTrials.gov Identifier: NCT03347292
Recruitment Status : Completed
First Posted : November 20, 2017
Last Update Posted : September 15, 2022
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):

Brief Summary:
This study will determine if the combination of regorafenib and pembrolizumab is safe and tolerated in patients with advanced liver cancer. In addition, the study will explore the anti-tumor activity of this combination as well as potentially identifying blood and tissue biomarkers associated with disease activity, status or response. The study will also investigate how the drugs behave in your body

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: Regorafenib(Stivarga, BAY73-4506) Drug: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Non-randomized, Open-label Dose Escalation Phase Ib Study of Regorafenib in Combination With Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma (HCC) With no Prior Systemic Therapy
Actual Study Start Date : June 18, 2018
Actual Primary Completion Date : December 17, 2020
Actual Study Completion Date : September 6, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
Drug: Regorafenib(Stivarga, BAY73-4506)
Regorafenib 80mg/120mg/160mg q.d., 3 weeks on / 1 week off + pembrolizumab 200mg i.v. every 3 weeks

Drug: Pembrolizumab
200 mg i.v.(Intravenous(ly)) every 3 weeks (Q3W). This dose will not be escalated or deescalated and the dosing schedule will not be changed

Experimental: Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30-35 patients per cohort is reached.
Drug: Regorafenib(Stivarga, BAY73-4506)
Regorafenib 80mg/120mg/160mg q.d., 3 weeks on / 1 week off + pembrolizumab 200mg i.v. every 3 weeks

Drug: Pembrolizumab
200 mg i.v.(Intravenous(ly)) every 3 weeks (Q3W). This dose will not be escalated or deescalated and the dosing schedule will not be changed

Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse event(TEAEs) [ Time Frame: Up to 30 days after last dose of study drug ]
    The incidence of treatment-emergent adverse events and treatment-emergent drug-related adverse events summarized in frequency tables using worst CTCAE v4.03 grade.

  2. Severity of TEAEs [ Time Frame: Up to 30 days after last dose of study drug ]
  3. Dose Limiting Toxicities(DLTs) [ Time Frame: Up to 42 days after first treatment administration ]

Secondary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: After approximately 18 months ]
    The MTD is defined as the highest dose that can be given so that toxicity probability is below the target toxicity PT =35%.

  2. Progression-free survival (PFS) [ Time Frame: After approximately 36 months ]
  3. Time to progression (TTP) [ Time Frame: After approximately 36 months ]
  4. Overall survival (OS) [ Time Frame: After approximately 36 months ]
  5. Overall response rate (ORR) [ Time Frame: After approximately 36 months ]
  6. Disease control rate (DCR) [ Time Frame: After approximately 36 months ]
  7. Duration of response (DOR) [ Time Frame: After approximately 36 months ]
  8. Duration of stable disease [ Time Frame: After approximately 36 months ]

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:

  • Male or female patients ≥ 18 years of age on day of signing informed consent.
  • Histological or cytological confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis.
  • Barcelona Clinic Liver Cancer (BCLC) stage B or C that cannot benefit from treatments of established efficacy such as resection, local ablation, chemoembolization.
  • Liver function status Child-Pugh (CP) Class A. CP status should be calculated based on clinical findings and laboratory results during the screening period.
  • Any local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥ 4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intra-arterial chemotherapy, without lipiodol or embolizing agents are not eligible.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
  • At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1) and no older than 28 days before start of the study treatment. 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.
  • Life expectancy of at least 3 months.
  • Adequate bone marrow and organ function as assessed by the laboratory tests performed within 7 days before of treatment initiation.
  • For patients recruited in the expansion cohort only, provision of archival (block) or fresh tumor tissue samples at baseline is mandatory. If archival tumor tissue is not available, patients should be willing to undergo a biopsy for provision of fresh tumor samples

Exclusion Criteria:

  • Prior systemic therapy for HCC; prior exposure to regorafenib.
  • Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1), or cytotoxicT-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy for HCC.
  • Previous treatment with live vaccine within 30 days of planned start of study drugs (seasonal flu vaccines that do not contain a live virus are permitted).
  • Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of diseasemodifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
  • Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies).
  • Dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
  • Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2 dyspnea).
  • Known history of metastatic brain or meningeal tumors.
  • Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease,malabsorption, or CTCAE Grade ≥ 2 diarrhea of any etiology.

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 ClinicalTrials.gov identifier (NCT number): NCT03347292

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United States, California
USC Norris Hospital and Clinics
Los Angeles, California, United States, 90033
United States, Florida
University of Florida Health Sciences Center
Gainesville, Florida, United States, 32610-0286
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
United States, New York
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, Washington
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109-1023
Universitätsklinikum Köln
Köln, Nordrhein-Westfalen, Germany, 50937
Universitätsmedizin der Johannes Gutenberg Universität Mainz
Mainz, Rheinland-Pfalz, Germany, 55131
Sponsors and Collaborators
Merck Sharp & Dohme LLC
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03347292    
Other Study ID Numbers: 19497
KN-743 ( Other Identifier: Merck Sharp & Dohme )
2017-003202-40 ( EudraCT Number )
First Posted: November 20, 2017    Key Record Dates
Last Update Posted: September 15, 2022
Last Verified: September 2022
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 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.

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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:
Liver cell carcinoma
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