Klinische Studien

BAY 73-4506 / 19497

BAY 73-4506 / 194972017-003202-40

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.

Status: Active

Purpose / Objectives

Primary Outcome

To determine the safety and tolerability of regorafenib in combination with pembrolizumab.


Secondary Outcomes

To define the maximum tolerated dose (MTD), or maximum administered dose (MAD) and the recommended Phase II dose (RP2D) of regorafenib in combination with pembrolizumab.

To obtain a preliminary assessment of the anti-tumor activity of regorafenib in combination with pembrolizumab.



Patient attributes



Inclusion criteria

Patients must provide a signed informed consent before any
screening procedures.
 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
 For patients recruited in the expansion cohort only, provision of
archival 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 cytotoxic T-lymphocyteassociated
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
disease-modifying 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
 Diagnosis of immunodeficiency or patient 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.
 Patients with chronic HCV infection with less than 4 weeks
between completion of HCV therapy and start of study drug. Note:
patients with chronic infection with HCV who are untreated or
noncuratively treated HCV are allowed on study.
 Pleural effusion or ascites that causes respiratory compromise
(≥ NCI-CTCAE v. 4.03 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 ≥ NCICTCAE
v. 4.03 Grade 2 diarrhea of any etiology.

Trial design

  • Phase I
  • Multicenter
  • Prospective
  • Two-arm
  • Single-blind

Documents (password protected)

Responsibilities in overall trial

Bayer HealthCare AG

    Study Sites

    Universitätsklinikum Köln

    Study office



    Principal Investigator

    Dr. med. Dirk Waldschmidt

    Contact at Site

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