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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



Februar 2021

Letztes Update:

Pembrolizumab, Regorafenib (Stivarga, BAY73-4506)

Indikation (Clinical Trials):
Carcinoma, Carcinoma, Hepatocellular


Erwachsene (18+)

Phase 2


Merck Sharp & Dohme Corp.


Bayer Clinical Trials Contact
Phone: (+)1-888-84 22937
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Eberhard-Karls-Universität Tübingen
72076 Tübingen
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Klinikum der Universität München Grosshadern
81377 München
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Heinrich-Heine-Universität Düsseldorf
40225 Düsseldorf
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Universitätsklinikum Köln
50937 Köln
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Universitätsmedizin der Johannes Gutenberg Universität Mainz
55131 Mainz
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Medizinische Fakultät der Otto-von-Guericke Universität
39120 Magdeburg
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Universitätsklinikum Hamburg Eppendorf (UKE)
20246 Hamburg
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University of Arizona Cancer Center
85719 Tucson
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City of Hope National Medical Center
91010-3012 Duarte
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90033 Los Angeles
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92868-3201 Orange
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University of California
90404-2125 Santa Monica
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Rocky Mountain Cancer Centers
80012 Aurora
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Medical Oncology Hematology Consultants, PA
19713 Newark
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MedStar Georgetown University Hospital
20007-2197 Washington
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32610 Gainesville
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University of Miami Miller School of Medicine
33136 Miami
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H. Lee Moffitt Cancer Center & Research Institute
33612-9416 Tampa
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Massachusetts General Hospital
02114 Boston
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Levine Cancer Institute
28204-2990 Charlotte
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Stephenson Cancer Center
73104 Oklahoma City
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97227 Portland
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75246 Dallas
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Texas Oncology- Tyler
75702 Tyler
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98109-1023 Seattle
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38700 La Tronche
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59037 Lille
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34295 Montpellier Cedex
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94800 Villejuif
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Istituto Clinico Humanitas - Humanitas Mirasole S.p.A.
20089 Milano
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Istituto Oncologico Veneto IRCCS (IOV)
35128 Padova
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Japanese Red Cross Society Musashino Red Cross Hospital
180-8610 Musashino-shi
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Samsung Medical Center
06351 Seoul
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Seoul National University Hospital
110-744 Seoul
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Asan Medical Center
138-736 Seoul
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Hospital Clínico Universitario de Santiago de Compostela
15706 Santiago de Compostela
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Institut Català d'Oncologia Hospitalet
08907 Hospitalet de Llobregat
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Ciutat Sanitària i Universitaria de la Vall d'Hebron
08035 Barcelona
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08036 Barcelona
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28007 Madrid
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31008 Pamplona
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Brief Summary:

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


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


- Unresectable advanced HCC eligible for systemic therapy

- Participants must have had prior 1L immunotherapy treatment with a PD-1/PD-L1

checkpoint inhibitor administered either as monotherapy or in combination with other

therapies. This also includes patients receiving prior treatment with pembrolizumab as

monotherapy or in combination. A wash out period of at least 28 days or 5 half-lives,

whichever is shorter, must be completed for eligibility in this trial. In case of

discontinuation due to progression, the following criteria are required in order to

define PD-1/PD-L1 treatment progression:

1. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.

2. Has demonstrated disease progression after PD-1/PD-L1 as defined by RECIST 1.1.

The initial evidence of PD is to be confirmed by a second assessment no less than

four weeks from the date of the first documented PD, in the absence of rapid

clinical progression.

In cases of unequivocal progression (clinical or radiological), PD confirmation

may not be required after documented discussion and approval by the sponsor.

3. Progressive disease has been documented within 12 weeks from the last dose of

anti-PD-1/PD-L1 mAb.

i. Progressive disease is determined according to iRECIST ii. This determination is

made by the investigator. Once PD is confirmed, the initial date of PD documentation

will be considered the date of disease progression.

- Participants who receive anti-PD-1 therapy as adjuvant treatment following complete

resection of liver cancer and have disease recurrence (unresectable loco-regional

disease or distant metastases) are eligible if they progressed while on active

treatment or within 6 months of stopping anti-PD-1 therapy.

For these participants, the following applies:

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


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. CP status should be

calculated based on clinical findings and laboratory results during the screening


- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

- 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

anti-viral 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


- 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


- 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 > 150 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


- Myocardial infarction less than 6 months before start of study intervention.

- Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥2


- 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


- 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


- 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).


Primary outcome:

1. Objective response rate (ORR) per RECIST 1.1a by central assessment (Time Frame - Approximately 21 months):
ORR is defined as the proportion of participants with best overall response of confirmed complete response (CR) or partial response (PR). RECIST: Response Evaluation Criteria in Solid Tumors

Secondary outcome:

1. Duration of response (DOR) per RECIST 1.1 by central assessment (Time Frame - Approximately 45 months):
DOR is defined as the time (in days) from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death. RECIST: Response Evaluation Criteria in Solid Tumors

2. Objective response rate (ORR) per RECIST 1.1 by investigator assessment (Time Frame - Approximately 45 months)

3. Duration of response (DOR) per RECIST 1.1 by investigator assessment (Time Frame - Approximately 45 months)

4. Number of participants with adverse events (AEs) (Time Frame - Approximately 45 months)

5. Number of participants with serious adverse events (SAEs) (Time Frame - Approximately 45 months)

6. Number of participants with safety-relevant changes in clinical parameters (Time Frame - Approximately 45 months)

7. Number of participants with dose modification (Time Frame - Approximately 45 months):
Dose modification includes dose interruption, dose reduction, dose discontinuation.

Geprüfte Regime

  • Pembrolizumab (Keytruda / MK-3475):
    Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).
  • Regorafenib (Stivarga, BAY73-4506):
    Regorafenib will 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.


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