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Carcinoma, HepatocellularPhase 2NCT01915602

Refametinib in Combination With Sorafenib in RAS Mutant Hepatocellular Carcinoma (HCC)

A Phase 2 study testing Refametinib (BAY86-9766) and Sorafenib (BAY43-9006) in people with Carcinoma, Hepatocellular, run by Bayer at 79 sites in 21 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Hepatocellular
What is being tested?
Refametinib (BAY86-9766) and Sorafenib (BAY43-9006)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
14 participants
Where
79 sitesin 21 countries
Study dates
27 Sep 2013to 8 Feb 2017
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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 locations and contacts

79 sites in 21 countries.

79 sites in 21 countries

Japan11 sites

  • Study site

    Bunkyo-ku, Tokyo, 113-8655

  • Study site

    Chiba, Chiba, 260-8677

  • Study site

    Fukuoka, Fukuoka, 810-8563

  • Study site

    Irima-gun, Saitama, 350-0495

  • Study site

    Kyoto, 606-8507

  • Study site

    Nagoya, Aichi-ken, 466-8560

  • Study site

    Osaka, 534-0021

  • Study site

    Osaka, 545-8586

  • Study site

    Osakasayama-shi, Osaka, 589-8511

  • Study site

    tabashi City, Tokyo, 173-8610

  • Study site

    Yokohama, Kanagawa, 241-8515

Other trials in Japan

France8 sites

  • Study site

    Bordeaux, 33000

  • Study site

    Caen, 14033

  • Study site

    Lyon, 69004

  • Study site

    Marseille, 13005

  • Study site

    Nice, 06202

  • Study site

    Paris, 75012

  • Study site

    Saint-Priest-en-Jarez, 42270

  • Study site

    Vandœuvre-lès-Nancy, 54511

Other trials in France

Germany8 sites

  • Study site

    Berlin, 10967

  • Study site

    Essen, North Rhine-Westphalia, 45136

  • Study site

    Essen, North Rhine-Westphalia, 45147

  • Study site

    Frankfurt am Main, Hesse, 60596

  • Study site

    Hamburg, 20246

  • Study site

    Heidelberg, Baden-Wurttemberg, 69120

  • Study site

    Magdeburg, Saxony-Anhalt, 39120

  • Study site

    Tübingen, Baden-Wurttemberg, 72076

Other trials in Germany

South Korea7 sites

  • Study site

    Daegu, 700-721

  • Study site

    Seoul, Seoul Teugbyeolsi, 08308

  • Study site

    Seoul, 03722

  • Study site

    Seoul, 05505

  • Study site

    Seoul, 06351

  • Study site

    Seoul, 06591

  • Study site

    Seoul, 110-744

Other trials in South Korea

Spain6 sites

  • Study site

    L'Hospitalet de Llobregat, Barcelona, 08907

  • Study site

    Madrid, 28007

  • Study site

    Madrid, 28050

  • Study site

    Oviedo, Principality of Asturias, 33011

  • Study site

    Santiago de Compostela, A Coruña, 15706

  • Study site

    Vigo, Pontevedra, 36071

Other trials in Spain

Belgium4 sites

  • Study site

    Bruxelles - Brussel, 1070

  • Study site

    Edegem, 2650

  • Study site

    Leuven, 3000

  • Study site

    Liège, 4000

Other trials in Belgium

Hungary4 sites

  • Study site

    Budapest, 1062

  • Study site

    Debrecen, 4032

  • Study site

    Pécs, 7932

  • Study site

    Zalaegerszeg, 8900

Other trials in Hungary

Israel4 sites

  • Study site

    Haifa, 3109601

  • Study site

    Jerusalem, 9112001

  • Study site

    Petah Tikva, 4941492

  • Study site

    Tel Aviv, 64239

Other trials in Israel

Italy4 sites

  • Study site

    Bologna, Emilia-Romagna, 40138

  • Study site

    Milan, Lombardy, 20122

  • Study site

    Milan, Lombardy, 20133

  • Study site

    Rome, Lazio, 00168

Other trials in Italy

Turkey (Türkiye)4 sites

  • Study site

    Istanbul, 34093

  • Study site

    Istanbul, 34349

  • Study site

    Istanbul, 34899

  • Study site

    Mersin, 33070

Other trials in Turkey (Türkiye)

China3 sites

  • Study site

    Beijing, 100071

  • Study site

    Guangzhou, Guangdong, 510515

  • Study site

    Shanghai, 200032

Other trials in China

Taiwan3 sites

  • Study site

    Tainan, 704

  • Study site

    Tainan, 736

  • Study site

    Taipei, 10002

Other trials in Taiwan

Thailand3 sites

  • Study site

    Chiang Mai, 50200

  • Study site

    Khon Kaen, 40002

  • Study site

    Songkhla, 90110

Other trials in Thailand

Czechia2 sites

  • Study site

    Hradec Králové, 500 05

  • Study site

    Olomouc, 775 20

Other trials in Czechia

United Kingdom2 sites

  • Study site

    Birmingham, B15 2TH

  • Study site

    London, SE5 9RS

Other trials in United Kingdom

United States1 site

  • Study site

    Louisville, Kentucky, 40202

Other trials in United States

Austria1 site

  • Study site

    Vienna, 1090

Other trials in Austria

Hong Kong1 site

  • Study site

    Hong Kong

Other trials in Hong Kong

New Zealand1 site

  • Study site

    Auckland, 1023

Other trials in New Zealand

Singapore1 site

  • Study site

    Singapore, 169610

Other trials in Singapore

Switzerland1 site

  • Study site

    Bern, 3010

Other trials in Switzerland

About this study

Official 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)

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.

Being tested
Refametinib (BAY86-9766), Sorafenib (BAY43-9006)
Keywords
Hepatocellular Carcinoma, Mitogen-activated Extracellular-signal-regulated kinase (MEK) inhibitor, Sorafenib, Objective tumor response rate (ORR), modified RECIST criteria
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Refametinib (BAY86-9766)Drug

    Patients will receive refametinib 50 mg (2x20 mg + 1x10mg capsules or 50 mg tablets) bid

  • Sorafenib (BAY43-9006)Drug

    Patients will receive sorafenib 400 mg (2 x 200 mg tablets) bid.

Study groups in NCT01915602
Study groupRoleWhat they receive
Refametinib and Sorafenib (Nexavar)ExperimentalIn 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
Receives: Drug: Refametinib (BAY86-9766); Drug: Sorafenib (BAY43-9006)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review

    Measured: Approximately 36 months

Secondary outcomes (11)

  1. Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review

    Measured: Approximately 36 months

  2. Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators

    Measured: Approximately 36 months

  3. Disease control (central and investigator's assessment)

    Measured: Approximately 36 months

  4. Overall survival

    Measured: Approximately 36 months

  5. Time to radiographic tumor progression (central and investigator's assessment)

    Measured: Approximately 36 months

  6. Duration of response (central and investigator's assessment)

    Measured: Approximately 36 months

  7. Time to objective response (central and investigator's assessment).

    Measured: Approximately 36 months

  8. Change in tumor size (central and investigator's assessment)

    Measured: Approximately 36 months

  9. Best overall response (central and investigator's assessment)

    Measured: Approximately 36 months

  10. Progression-free survival (central and investigator's assessment)

    Measured: Approximately 36 months

  11. Number of participants with adverse events as a measure of safety and tolerability

    Measured: Approximately 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Aug 2013 (estimated)
  2. Study start27 Sep 2013
  3. Primary completion29 Jul 2015
  4. Study completion8 Feb 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01915602
Sponsor's protocol ID
16728
Other IDs
2013-000241-39
Status last verified
Apr 2021
First submitted
24 Jul 2013
Last updated
8 Apr 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Refametinib (BAY86-9766) and Sorafenib (BAY43-9006) in people with Carcinoma, Hepatocellular, run by Bayer at 79 sites in 21 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 79 sites in Japan, France, Germany, South Korea, Spain and 16 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review (time frame: Approximately 36 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01915602.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2021.

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