check_circleStudy Completed

Carcinoma, Hepatocellular

Refametinib in combination with sorafenib in RAS mutant Hepatocellular Carcinoma (HCC)

Trial purpose

This is a study to investigate the potential clinical benefit of refametinib when given in combination with sorafenib as first line treatment 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 partial response according to an objective criteria to evaluate tumor size based on contrast enhancement [modified response evaluation criteria in solid tumors (mRECIST)] assessed by external independent radiologists.
Refametenib 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 in combination with sorafenib 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 in combination with sorafenib improves the response rate in this patient population compared to historical results observed with the sorafenib only.

Key Participants Requirements

Sex

Both

Age

18 - N/A
  • 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.
    - No previous treatment with sorafenib or refametinib.
    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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Modified Response Evaluation Criteria in Solid Tumors (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.
  • - 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)].
    - Patients who are eligible for surgery, liver transplantation, ablation or transarterial chemoembolization for HCC.
    History of cardiac disease:
    - Congestive heart failure New York Heart Association (NYHA) > class 2.
    - Unstable angina (angina symptoms at rest, new-onset angina i.e. within the last 3 months) or myocardial infarction (MI) within the past 6 months prior to start of screening.
    - Cardiac arrhythmias requiring anti-arrhythmic therapy.
    - QTc (corrected QT interval) > 480 ms
    - 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 is considered a risk factor for RVO or CSR.

Trial summary

Enrollment Goal
14
Trial Dates
September 2013 - February 2017
Phase
Phase 2
Could I Receive a placebo
No
Products
Refametinib (BAY86-9766)
Accepts Healthy Volunteer
No

Where to participate

StatusInstitutionLocation
Completed
Wien, 1090, Austria
Completed
Singapore, 169610, Singapore
Withdrawn
Ann Arbor, 48109, United States
Completed
Hospitalet de Llobregat, 08907, Spain
Completed
Oviedo, 33011, Spain
Completed
Madrid, 28007, Spain
Completed
Hong Kong, NA, Hong Kong
Completed
Madrid, 28050, Spain
Completed
LYON, 69004, France
Withdrawn
CLICHY, 92110, France
Completed
CAEN CEDEX, 14033, France
Completed
BORDEAUX, 33000, France
Completed
PARIS, 75012, France
Withdrawn
Cleveland, 44106-2602, United States
Completed
Seoul, 06351, Korea, Republic Of
Completed
Seoul, 03722, Korea, Republic Of
Completed
Seoul, 05505, Korea, Republic Of
Completed
Seoul, 08308, Korea, Republic Of
Completed
Taipei, 10002, Taiwan
Withdrawn
Taoyuan, 333423, Taiwan
Completed
London, SE5 9RS, United Kingdom
Completed
EDEGEM, 2650, Belgium
Completed
LIEGE, 4000, Belgium
Completed
Bologna, 40138, Italy
Completed
Milano, 20122, Italy
Completed
Roma, 00168, Italy
Completed
Frankfurt, 60596, Germany
Completed
Hamburg, 20246, Germany
Completed
Tübingen, 72076, Germany
Completed
Magdeburg, 39120, Germany
Completed
Essen, 45147, Germany
Completed
Jerusalem, 9112001, Israel
Completed
Petach Tikva, 4941492, Israel
Completed
Tel Aviv, 64239, Israel
Completed
Haifa, 3109601, Israel
Withdrawn
Rehovot, 7610001, Israel
Withdrawn
Beer Sheva, 8410101, Israel
Completed
Chiang Mai, 50200, Thailand
Completed
Khon Kaen, 40002, Thailand
Completed
Songkhla, 90110, Thailand
Withdrawn
La Jolla, 92093, United States
Completed
Olomouc, 775 20, Czechia
Withdrawn
Praha 5, 150 06, Czechia
Completed
Hradec Kralove, 500 05, Czechia
Completed
Pecs, 7932, Hungary
Completed
Zalaegerszeg, 8900, Hungary
Completed
Istanbul, 34349, Turkey
Completed
Istanbul, 34093, Turkey
Completed
Istanbul, 34899, Turkey
Completed
Mersin, 33070, Turkey
Completed
Seoul, 06591, Korea, Republic Of
Completed
NICE CEDEX 3, 06202, France
Completed
Chiba-shi, 260-8677, Japan
Completed
Nagoya, 466-8560, Japan
Completed
Fukuoka-shi, 810-8563, Japan
Completed
Osaka, 534-0021, Japan
Completed
Kyoto, 606-8507, Japan
Completed
Irima-gun, 350-0495, Japan
Completed
Bunkyo-ku, 113-8655, Japan
Completed
Osaka, 545-8586, Japan
Completed
Yokohama, 241-8515, Japan
Completed
Itabashi-ku, 173-8610, Japan
Completed
Daegu, 700-721, Korea, Republic Of
Completed
Seoul, 110-744, Korea, Republic Of
Completed
SAINT-PRIEST-EN-JAREZ, 42270, France
Completed
Tainan, 736, Taiwan
Completed
LEUVEN, 3000, Belgium
Completed
BRUXELLES - BRUSSEL, 1070, Belgium
Completed
Berlin, 10967, Germany
Completed
VANDOEUVRE-LES-NANCY, 54511, France
Completed
MARSEILLE, 13005, France
Withdrawn
LILLE, 59037, France
Completed
Birmingham, B15 2TH, United Kingdom
Completed
Heidelberg, 69120, Germany
Completed
Debrecen, 4032, Hungary
Completed
Budapest, 1062, Hungary
Completed
Osakasayama-shi, 589-8511, Japan
Completed
Bern, 3010, Switzerland
Completed
Auckland, 1023, New Zealand
Completed
Milano, 20133, Italy
Completed
Vigo, 36071, Spain
Completed
Santiago de Compostela, 15706, Spain
Completed
Tainan, 704, Taiwan
Completed
Louisville, 40202, United States
Withdrawn
New York, 10029, United States
Completed
Hong Kong, Hong Kong
Completed
Essen, 45136, Germany
Withdrawn
Washington, 20007-2197, United States
Completed
Shanghai, 200032, China
Withdrawn
Beijing, 100853, China
Completed
Guangzhou, 510515, China
Completed
Beijing, 100071, China
Withdrawn
Nanjing, 210009, China
Withdrawn
Fairway, 66205, United States
Withdrawn
Hannover, 30625, Germany

Primary Outcome

  • Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No

Secondary Outcome

  • Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Disease control (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Overall survival
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Time to radiographic tumor progression (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Duration of response (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Time to objective response (central and investigator’s assessment).
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Change in tumor size (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Best overall response (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Progression-free survival (central and investigator’s assessment)
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    No
  • Number of participants with adverse events as a measure of safety and tolerability
    date_rangeTime Frame:
    Approximately 36 months
    enhanced_encryption
    Safety Issue:
    Yes

Trial design

A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY86-9766) in combination with sorafenib as first line treatment in patients with RAS mutant Hepatocellular Carcinoma (HCC)
Trial Type
Interventional
Intervention Type
Drug
Trial Purpose
Treatment
Allocation
N/A
Blinding
Open Label
Assignment
Single Group Assignment
Trial Arms
1