Trial Condition(s):

Hepatocellular carcinoma

Regorafenib plus pembrolizumab in patients with advanced or spreading liver cancer who have been previously treated with PD-1/PD-L1 Immune Checkpoint Inhibitors

Bayer Identifier:

21469

ClinicalTrials.gov Identifier:

NCT04696055

EudraCT Number:

2020-003555-16

Recruitment Complete

Trial Purpose

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 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:
a. 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. 
b. 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).

Trial Summary

Enrollment Goal
95
Trial Dates
black-arrow
Phase
2
Could I receive a placebo?
No
Products
Regorafenib/Pembrolizumab (BAY73-4506)
Accepts Healthy Volunteers
No

Where to Participate

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Locations
Status
LocationsStatus
Locations

Eberhard-Karls-Universität Tübingen

Tübingen, Germany, 72076

Status
Completed
 
Locations

Istituto Clinico Humanitas - Humanitas Mirasole S.p.A.

Milano, Italy, 20089

Status
Active, not recruiting
 
Locations

Istituto Oncologico Veneto IRCCS (IOV)

Padova, Italy, 35128

Status
Active, not recruiting
 
Locations

Klinikum der Universität München Grosshadern

München, Germany, 81377

Status
Completed
 
Locations

Universitätsklinikum Köln

Köln, Germany, 50937

Status
Completed
 
Locations

Universitätsmedizin der Johannes Gutenberg Universität Mainz

Mainz, Germany, 55131

Status
Active, not recruiting
 
Locations

University of California Irvine Medical Center

Orange, United States, 92868-3201

Status
Completed
 
Locations

University of Miami Miller School of Medicine

Miami, United States, 33136

Status
Completed
 
Locations

H. Lee Moffitt Cancer Center & Research Institute

Tampa, United States, 33612-9416

Status
Completed
 
Locations

City of Hope National Medical Center

Duarte, United States, 91010-3012

Status
Completed
 
Locations

A.O.U. Pisana

Pisa, Italy, 56126

Status
Active, not recruiting
 
Locations

Asan Medical Center

Seoul, South Korea, 138-736

Status
Active, not recruiting
 
Locations

Samsung Medical Center

Seoul, South Korea, 06351

Status
Completed
 
Locations

Seoul National University Hospital

Seoul, South Korea, 110-744

Status
Active, not recruiting
 
Locations

Seattle Cancer Care Alliance

Seattle, United States, 98109

Status
Completed
 
Locations

University of Arizona Cancer Center

Tucson, United States, 85719

Status
Completed
 
Locations

Massachusetts General Hospital

Boston, United States, 02114

Status
Completed
 
Locations

Tel-Aviv Sourasky Medical Center

Tel Aviv, Israel, 6423906

Status
Active, not recruiting
 
Locations

Clalit Health Services Rabin Medical Center-Beilinson Campus

Petah Tikva, Israel, 4941492

Status
Completed
 
Locations

Rambam Health Corporation

Haifa, Israel, 3109601

Status
Active, not recruiting
 
Locations

Heinrich-Heine-Universität Düsseldorf

Düsseldorf, Germany, 40225

Status
Completed
 
Locations

University of Southern California

Los Angeles, United States, 90033

Status
Completed
 
Locations

Hospital Clínic i Provincial de Barcelona

Barcelona, Spain, 08036

Status
Completed
 
Locations

Institut Català d'Oncologia Hospitalet

Hospitalet de Llobregat, Spain, 08907

Status
Completed
 
Locations

Hospital General Universitario Gregorio Marañón | Digestivo

Madrid, Spain, 28007

Status
Active, not recruiting
 
Locations

Hôpital Paul Brousse - Villejuif

VILLEJUIF, France, 94800

Status
Active, not recruiting
 
Locations

Hôpital de la Croix Rousse

LYON, France, 69004

Status
Active, not recruiting
 
Locations

Hôpital Claude Huriez - Lille

LILLE, France, 59037

Status
Active, not recruiting
 
Locations

Hôpital Beaujon - Clichy

CLICHY, France, 92110

Status
Active, not recruiting
 
Locations

Centre François Magendie - Pessac

PESSAC, France, 33600

Status
Active, not recruiting
 
Locations

Center Hospitalier Michallon - Grenoble

LA TRONCHE, France, 38700

Status
Active, not recruiting
 
Locations

Hôpital Saint-Eloi

MONTPELLIER CEDEX, France, 34295

Status
Completed
 
Locations

National Cancer Center Hospital East

Kashiwa-shi, Japan, 277-8577

Status
Completed
 
Locations

Chiba University Hospital

Chiba-shi, Japan, 260-8677

Status
Completed
 
Locations

Medical Oncology Hematology Consultants, PA

Newark, United States, 19713

Status
Completed
 
Locations

Japanese Red Cross Society Musashino Red Cross Hospital

Musashino-shi, Japan, 180-8610

Status
Completed
 
Locations

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milano, Italy, 20122

Status
Completed
 
Locations

Centre Hospitalier Universitaire de Nancy

Vandoeuvre les Nancy, France, 54500

Status
Active, not recruiting
 
Locations

Hôpital de la Timone - Marseille

MARSEILLE, France, 13005

Status
Active, not recruiting
 

Trial Design