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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01915602




Registration number
NCT01915602
Ethics application status
Date submitted
24/07/2013
Date registered
5/08/2013
Date last updated
15/05/2017

Titles & IDs
Public title
Refametinib in Combination With Sorafenib in RAS Mutant Hepatocellular Carcinoma (HCC)
Scientific title
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)
Secondary ID [1] 0 0
2013-000241-39
Secondary ID [2] 0 0
16728
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Carcinoma, Hepatocellular 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Refametinib (BAY86-9766)
Treatment: Drugs - Sorafenib (BAY43-9006)

Experimental: Refametinib and Sorafenib (Nexavar) - In Cycle 1 reduced sorafenib dose (600 mg daily; 200 mg in the morning + 400 mg in the evening) is administered, which is escalated to the standard dose in Cycle 2, if no Hand-foot skin reaction (HFSR), fatigue, or gastrointestinal (GI) toxicities of grade 2 or higher occur. For the purposes of data recording, the treatment period will be divided into 3-week cycles. Patients will continue on treatment until at least one of the following occurs (main criteria): Progressive Disease (PD) {PD as defined by mRECIST criteria or clinical progression [e.g. Eastern Cooperative Oncology Group performance status (ECOG PS) of =3], treatment may be continued past radiological progression, provided the patient derives clinical benefit as judged by the treating physician.}, Death, Unacceptable toxicity, Subject withdraws consent, Treating physician determines discontinuation of treatment is in the subject's best interest, Substantial non-compliance with the protocol


Treatment: Drugs: Refametinib (BAY86-9766)
Patients will receive refametinib 50 mg (2x20 mg + 1x10mg capsules or 50 mg tablets) bid

Treatment: Drugs: Sorafenib (BAY43-9006)
Patients will receive sorafenib 400 mg (2 x 200 mg tablets) bid.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review
Timepoint [1] 0 0
Approximately 36 months
Secondary outcome [1] 0 0
Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review
Timepoint [1] 0 0
Approximately 36 months
Secondary outcome [2] 0 0
Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators
Timepoint [2] 0 0
Approximately 36 months
Secondary outcome [3] 0 0
Disease control (central and investigator's assessment)
Timepoint [3] 0 0
Approximately 36 months
Secondary outcome [4] 0 0
Overall survival
Timepoint [4] 0 0
Approximately 36 months
Secondary outcome [5] 0 0
Time to radiographic tumor progression (central and investigator's assessment)
Timepoint [5] 0 0
Approximately 36 months
Secondary outcome [6] 0 0
Duration of response (central and investigator's assessment)
Timepoint [6] 0 0
Approximately 36 months
Secondary outcome [7] 0 0
Time to objective response (central and investigator's assessment).
Timepoint [7] 0 0
Approximately 36 months
Secondary outcome [8] 0 0
Change in tumor size (central and investigator's assessment)
Timepoint [8] 0 0
Approximately 36 months
Secondary outcome [9] 0 0
Best overall response (central and investigator's assessment)
Timepoint [9] 0 0
Approximately 36 months
Secondary outcome [10] 0 0
Progression-free survival (central and investigator's assessment)
Timepoint [10] 0 0
Approximately 36 months
Secondary outcome [11] 0 0
Number of participants with adverse events as a measure of safety and tolerability
Timepoint [11] 0 0
Approximately 36 months

Eligibility
Key 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.

- 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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)].

- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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United States of America
State/province [2] 0 0
District of Columbia
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United States of America
State/province [3] 0 0
Kansas
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United States of America
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Kentucky
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United States of America
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Michigan
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United States of America
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New York
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United States of America
State/province [7] 0 0
Ohio
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Austria
State/province [8] 0 0
Wien
Country [9] 0 0
Belgium
State/province [9] 0 0
Bruxelles - Brussel
Country [10] 0 0
Belgium
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Edegem
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Belgium
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Leuven
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Belgium
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Liege
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China
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Guangdong
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China
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Jiangsu
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China
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Beijing
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China
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Shanghai
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Czechia
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Hradec Kralove
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Czechia
State/province [18] 0 0
Olomouc
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Czechia
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Praha 5
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France
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Bordeaux
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France
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Caen Cedex
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France
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Clichy
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France
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Lille
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France
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Lyon
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France
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Marseille
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France
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Nice Cedex 3
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France
State/province [27] 0 0
Paris
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France
State/province [28] 0 0
Saint-priest-en-jarez
Country [29] 0 0
France
State/province [29] 0 0
Vandoeuvre-les-nancy
Country [30] 0 0
Germany
State/province [30] 0 0
Baden-Württemberg
Country [31] 0 0
Germany
State/province [31] 0 0
Hessen
Country [32] 0 0
Germany
State/province [32] 0 0
Niedersachsen
Country [33] 0 0
Germany
State/province [33] 0 0
Nordrhein-Westfalen
Country [34] 0 0
Germany
State/province [34] 0 0
Sachsen-Anhalt
Country [35] 0 0
Germany
State/province [35] 0 0
Berlin
Country [36] 0 0
Germany
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Hamburg
Country [37] 0 0
Hong Kong
State/province [37] 0 0
Hong Kong
Country [38] 0 0
Hungary
State/province [38] 0 0
Budapest
Country [39] 0 0
Hungary
State/province [39] 0 0
Debrecen
Country [40] 0 0
Hungary
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Pecs
Country [41] 0 0
Hungary
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Zalaegerszeg
Country [42] 0 0
Israel
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Beer Sheva
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Rehovot
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Israel
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Tel Aviv
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Italy
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Emilia-Romagna
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Italy
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Lazio
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Italy
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Lombardia
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Fukuoka
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Japan
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Kanagawa
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Japan
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Osaka
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Japan
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Saitama
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Japan
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Tokyo
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Japan
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Kyoto
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Korea, Republic of
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Seoul Teugbyeolsi
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Korea, Republic of
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Daegu
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Korea, Republic of
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Seoul
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New Zealand
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Auckland
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Singapore
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Singapore
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Spain
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A Coruña
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Spain
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Asturias
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Spain
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Barcelona
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Spain
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Pontevedra
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Spain
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Madrid
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Switzerland
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Bern
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Taiwan
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Tainan
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Taiwan
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Taipei
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Taiwan
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Taoyuan
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Thailand
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Chiang Mai
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Thailand
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Khon Kaen
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Thailand
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Songkhla
Country [76] 0 0
Turkey
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Istanbul
Country [77] 0 0
Turkey
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Mersin
Country [78] 0 0
United Kingdom
State/province [78] 0 0
Birmingham
Country [79] 0 0
United Kingdom
State/province [79] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Bayer
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01915602
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bayer Study Director
Address 0 0
Bayer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications