Trial Condition(s):

Carcinoma, Hepatocellular

Refametinib(BAY86-9766) in RAS mutant Hepatocellular Carcinoma (HCC)

Bayer Identifier:

16553

ClinicalTrials.gov Identifier:

NCT01915589

EudraCT Number:

2013-000311-25

Study Completed

Trial Purpose

This is a study to investigate the potential clinical benefit of refametinib in patients with unresectable or metastatic HCC carrying a RAS mutation. The study will be conducted in 2 stages. Approximately 95 patients (15 at Stage 1/ 80 at Stage 2) will be accrued to this study to receive treatment. Stage 2 of the trial will only be conducted if at least 5 out of 15 patients at Stage 1 show at least confirmed partial response (PR) according to modified response evaluation criteria in solid tumors (mRECIST) assessed by central image review.
Refametinib is an oral (i.e. taken by mouth) protein kinase inhibitor. A kinase inhibitor targets certain key proteins that are essential for the survival of the cancer cell. By specifically targeting these proteins, refametinib may stop cancer growth. The growth of the tumor may be decreased by preventing these specific proteins from functioning.
The primary endpoint (the most meaningful result to be tracked) of this study is based on the rate of response, i.e. the disease getting smaller. The aim is to show that the therapy with refametinib improves the response rate in this RAS mutation patient population.

Inclusion Criteria
Eligibility criteria for RAS mutation testing
 - Unresectable or metastatic HCC, confirmed either by histology or clinically according to the American Association for the Study of Liver Disease (AASLD) criteria for cirrhotic patients. For non-cirrhotic patients, histological confirmation is mandatory.
 - Male or female ≥18 years of age.
 - Eastern Cooperative Oncology Group (ECOG) performance state 0 or 1.
 - Life expectancy of at least 12 weeks.
 - No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment for HCC (except sorafenib) 
 - No previous treatment with refametinib(BAY86-9766).
Criteria for study treatment eligibility
 - Patient must harbor GTPase Kirsten rat sarcoma viral oncogene homolog (KRAS) or Neuroblastoma RAS viral oncogene homolog (NRAS) mutation based on Beads, emulsions, amplification, and magnetic technology, sensitive mutation detection (BEAMing) plasma test.
 - Patients must have at least one uni-dimensional measurable lesion by Computed tomography (CT) or Magnetic resonance (MR) according to RECIST 1.1 and mRECIST which is either naïve (not previously treated by local therapy such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) or previously treated and has progressed until baseline (both measureable lesion and/or progressed lesion have to be confirmed by central image review of baseline and progression scan).
 - ECOG performance status of 0 or 1.
 - Liver function status of Child-Pugh Class A.
 - Adequate bone morrow, liver, and renal function
 - Patient has within normal range cardiac function confirmed by the enrolling clinical institute as measured by echocardiogram or multiple gated acquisition (MUGA) scan.
 - Patients who are therapeutically anti-coagulated with an agent such as warfarin or heparin are allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until International normalized ratio (INR) is stable (within Child Pugh class A threshold) based on a measurement at pre-dose, as defined by the local standard of care.
Exclusion Criteria
- Any Cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ (CIS), treated basal cell carcinoma, and superficial bladder tumors [Staging: noninvasive papillary tumor (Ta), CIS carcinoma (Tis) and tumor invades lamina propria (T1)]
 - Subjects who are eligible for surgery, liver transplantation, ablation or transarterial chemoembolization for HCC.
 - History of cardiac disease
 - Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management).
 - Ongoing infection > Grade 2 according to National Cancer Institute - Common Toxicity Criteria for Adverse Events version 4.03 (NCI-CTCAE version 4.03) Hepatitis B is allowed if no active replication (defined as abnormal Alanine aminotransferase [ALT] >2x Upper limit normal [ULN] associated with Hepatitis B virus [HBV] DNA >20,000 IU/mL) is present. Hepatitis C is allowed if no antiviral treatment is required.
 - Known history of, or symptomatic metastatic brain or meningeal tumors (head CT or MR at Screening to confirm the absence of central nervous system [CNS] disease if patient had symptoms suggestive or consistent with CNS disease).
 - History of interstitial lung disease (ILD).
 - History of hepatic encephalopathy.
 - History of organ allograft, cornea transplantation will be allowed.
 - History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
 - Visible retinal pathology as assessed by ophthalmologic exam that was considered a risk factor for RVO or CSR.

Trial Summary

Enrollment Goal
16
Trial Dates
black-arrow
Phase
2
Could I receive a placebo?
No
Products
Refametinib (BAY86-9766)
Accepts Healthy Volunteers
No

Where to Participate

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Locations
Status
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Locations

Investigative Site

Bern, Switzerland, 3010

Status
Completed
 
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Rochester, United States, 14642

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Completed
 
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Barcelona, Spain, 08035

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Completed
 
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Alicante, Spain, 03010

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Completed
 
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Valencia, Spain, 46010

Status
Completed
 
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Santiago de Compostela, Spain, 15706

Status
Completed
 
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Shatin, Hong Kong, China

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Completed
 
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Graz, Austria, 8036

Status
Completed
 
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Pontevedra, Spain, 36071

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Completed
 
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Miami, United States, 33136

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Completed
 
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LILLE, France, 59037

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Completed
 
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VANDOEUVRE-LES-NANCY, France, 54511

Status
Completed
 
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MONTPELLIER CEDEX, France, 34059

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Completed
 
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CLERMONT-FERRAND Cedex 1, France, 63003

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Completed
 
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CRETEIL, France, 94010

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Completed
 
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MARSEILLE, France, 13005

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Completed
 
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Daegu, South Korea, 41404

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Completed
 
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Busan, South Korea, 49241

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Completed
 
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Seoul, South Korea, 03080

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Completed
 
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Auckland, New Zealand, 1023

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Completed
 
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Kaohsiung City, Taiwan, China, 8330

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Completed
 
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Tainan, Taiwan, China, 704

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Completed
 
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Birmingham, United Kingdom, B15 2TT

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Completed
 
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Washington, United States, 20007-2197

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Completed
 
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LEUVEN, Belgium, 3000

Status
Completed
 
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BRUXELLES - BRUSSEL, Belgium, 1200

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Completed
 
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GENT, Belgium, 9000

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Completed
 
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BRUXELLES - BRUSSEL, Belgium, 1070

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Completed
 
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Bangkok, Thailand, 10700

Status
Completed
 
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Bangkok, Thailand, 10330

Status
Completed
 
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Bangkok, Thailand, 10210

Status
Completed
 
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Hannover, Germany, 30625

Status
Completed
 
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München, Germany, 81377

Status
Completed
 
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Heidelberg, Germany, 69120

Status
Completed
 
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Berlin, Germany, 13353

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Completed
 
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Essen, Germany, 45136

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Completed
 
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Mainz, Germany, 55131

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Completed
 
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New York, United States, 10029

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Completed
 
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Milano, Italy, 20089

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Completed
 
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Milano, Italy, 20133

Status
Completed
 
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Praha 2, Czech Republic, 128 08

Status
Completed
 
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Debrecen, Hungary, 4032

Status
Completed
 
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Budapest, Hungary, 1062

Status
Completed
 
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Charleroi, Belgium, 6000

Status
Completed
 
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Osakasayama-shi, Japan, 589-8511

Status
Completed
 
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Shimotsuke, Japan, 329-0498

Status
Completed
 
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Moriguchi, Japan, 570-8507

Status
Completed
 
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Sunto, Japan, 411-8777

Status
Completed
 
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Chuo-ku, Japan, 104-0045

Status
Completed
 
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Kashiwa-shi, Japan, 277-8577

Status
Completed
 
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Osaka, Japan, 543-8555

Status
Completed
 
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Osaka-shi, Japan, 541-8567

Status
Completed
 
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Kobe, Japan, 650-0017

Status
Completed
 
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Shizuoka, Japan, 420-8527

Status
Completed
 
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Genève 14, Switzerland, 1211

Status
Completed
 
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Tampa, United States, 33612

Status
Completed
 
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Seoul, South Korea, 135-710

Status
Completed
 
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Investigative Site

Seoul, South Korea, 05505

Status
Completed
 

Trial Design