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

NCT04696055 | Completed Phase 2 Results FDA Drug

• 4 other identifiers: 21469MK-3475-B70Keynote B702020-003555-16
• Study Type: interventional
• Target: 95
• Locations: 8 countries
• Sites: 39

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.

Conditions

Hepatocellular Carcinoma

Keywords

Advanced or metastatic hepatocellular carcinoma (HCC); Liver cancer

Outcome Measures

Primary Outcomes (1)

• 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

  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

  Up to 38 months

• Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment

  Up to 38 months

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to 38 months

• Number of Participants With Safety-relevant Changes in Clinical Parameters

  Up to 38 months

• Percentage of Participants With Dose Modification

  Up to 38 months

Study Arms (1)

Regorafenib+Pembrolizumab

EXPERIMENTAL

Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.

Drug: Pembrolizumab; Drug: Regorafenib (Stivarga, BAY73-4506)

Interventions

Pembrolizumab DRUG

Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).

Also known as: Keytruda / MK-3475

Regorafenib+Pembrolizumab

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.

Regorafenib+Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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.
• 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:
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bayer: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (39)

University of Arizona Cancer Center

Tucson, Arizona, 85724, United States

Location

City of Hope - Duarte Cancer Center

Duarte, California, 91010, United States

Location

USC Norris Hospital and Clinics

Los Angeles, California, 90033, United States

Location

University of California Irvine Medical Center

Orange, California, 92868-3201, United States

Location

Medical Oncology Hematology Consultants, PA

Newark, Delaware, 19713, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114-2696, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109-1023, United States

Location

Hôpital Beaujon - Clichy

Clichy, 92110, France

Location

Center Hospitalier Michallon - Grenoble

Grenoble, 38043, France

Location

Hopital Claude Huriez - Lille

Lille, 59037, France

Location

Hôpital de la Croix Rousse

Lyon, 69004, France

Location

AP-HM - Hopital de la Timone

Marseille, 13005, France

Location

Hôpital Saint-Eloi

Montpellier, 34059, France

Location

Centre François Magendie - Pessac

Pessac, 33600, France

Location

Centre Hospitalier Universitaire de Nancy

Vandœuvre-lès-Nancy, 54500, France

Location

Hôpital Paul Brousse - Villejuif

Villejuif, 94800, France

Location

Eberhard-Karls-Universität Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Klinikum der Universität München Grosshadern

München, Bavaria, 81377, Germany

Location

Universitätsklinikum Köln

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Heinrich-Heine-Universität Düsseldorf

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Universitätsmedizin der Johannes Gutenberg Universität Mainz

Mainz, Rhineland-Palatinate, 55101, Germany

Location

Rambam Health Corporation

Haifa, 3109601, Israel

Location

Rabin Medical Center | Beilinson Hospital - Internal Medicine C Department

Petah Tikva, 4941492, Israel

Location

Tel-Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Humanitas Mirasole S.p.A.

Milan, Lombardy, 20089, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Lombardy, 20122, Italy

Location

Azienda Ospedaliero Universitaria Pisana_Santa Chiara - UO Oncologia 2

Pisa, Tuscany, 56126, Italy

Location

Istituto Oncologico Veneto_Padova - UOC Oncologia 1

Padua, Veneto, 35128, Italy

Location

Chiba University Hospital

Chiba, Chiba, 260-8677, Japan

Location

National Cancer Center Hospital East

Kashiwa, Chiba, 277-8577, Japan

Location

Japanese Red Cross Society Musashino Red Cross Hospital

Musashino, Tokyo, 180-8610, Japan

Location

Asan Medical Center

Seoul, Seoul Teugbyeolsi, 05505, South Korea

Location

Seoul National University Hospital

Seoul, Seoul Teugbyeolsi, 3080, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Institut Català d'Oncologia Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Hospital Clínic i Provincial de Barcelona

Barcelona, 8036, Spain

Location

Hospital General Universitario Gregorio Marañón | Digestivo

Madrid, 28007, Spain

Location

Related Links

• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

pembrolizumab; regorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer AG

clinical-trials-contact@bayer.com

1-888-8422937

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2021
• First Posted: January 6, 2021
• Study Start: February 3, 2021
• Primary Completion: May 5, 2022
• Study Completion: April 23, 2024
• Last Updated: May 13, 2025
• Results First Posted: May 30, 2023

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4); FR (9); KR (3); US (9); IL (3); JP (3); DE (5); ES (3)