Regorafenib Plus Pembrolizumab in First Line Systemic Treatment of HCC

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

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

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

Germany

Universitätsklinikum Köln

Köln, Nordrhein-Westfalen, Germany, 50937

Universitätsmedizin der Johannes Gutenberg Universität Mainz

Mainz, Rheinland-Pfalz, Germany, 55131

Sponsors and Collaborators

Bayer

Merck Sharp & Dohme LLC

More Information

• 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
• 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.

• 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:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action