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

Primary Purpose

Carcinoma, Hepatocellular

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Refametinib (BAY86-9766)
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carcinoma, Hepatocellular focused on measuring Hepatocellular Carcinoma, Mitogen-activated Extracellular-signal-regulated kinase (MEK) inhibitor, Objective tumor response rate (ORR), modified RECIST criteria

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Refametinib (BAY86-9766)

Arm Description

For 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): Death Unacceptable toxicity Subject withdraws consent Substantial non-compliance with the protocol Treating physician determines discontinuation of treatment is in the subject's best interest. Radiological progression as determined by RECIST (Version 1.1) or mRECIST criteria or clinical progression (e.g. Eastern Cooperative Oncology group performance status - ECOG PS ≥3) patients may continue to receive study treatment if identified as having continued clinical benefit as judged by the treating physician.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review
Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators
Disease control (central and investigator's assessment)
Overall survival
Time to radiographic tumor progression (central and investigator's assessment)
Duration of response (central and investigator's assessment)
Time to objective response (central and investigator's assessment)
Change in tumor size (central and investigator's assessment)
Best overall response (central and investigator's assessment)
Progression-free survival (central and investigator's assessment)
Number of participants with adverse events as a measure of safety and tolerability

Full Information

First Posted
July 24, 2013
Last Updated
April 6, 2021
Sponsor
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT01915589
Brief Title
Refametinib(BAY86-9766) in RAS Mutant Hepatocellular Carcinoma (HCC)
Official Title
A Prospective, Single-arm, Multicenter, Uncontrolled, Open-label Phase II Trial of Refametinib (BAY86-9766) in Patients With RAS Mutant Hepatocellular Carcinoma (HCC)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
September 16, 2013 (Actual)
Primary Completion Date
October 8, 2014 (Actual)
Study Completion Date
October 8, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Hepatocellular
Keywords
Hepatocellular Carcinoma, Mitogen-activated Extracellular-signal-regulated kinase (MEK) inhibitor, Objective tumor response rate (ORR), modified RECIST criteria

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Refametinib (BAY86-9766)
Arm Type
Experimental
Arm Description
For 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): Death Unacceptable toxicity Subject withdraws consent Substantial non-compliance with the protocol Treating physician determines discontinuation of treatment is in the subject's best interest. Radiological progression as determined by RECIST (Version 1.1) or mRECIST criteria or clinical progression (e.g. Eastern Cooperative Oncology group performance status - ECOG PS ≥3) patients may continue to receive study treatment if identified as having continued clinical benefit as judged by the treating physician.
Intervention Type
Drug
Intervention Name(s)
Refametinib (BAY86-9766)
Intervention Description
All patients who meet the entry criteria will receive refametinib 50 mg (2x20 mg + 1x10 mg capsules or 50 mg tablet) bid.
Primary Outcome Measure Information:
Title
Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review
Time Frame
Approximately 36 months
Secondary Outcome Measure Information:
Title
Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review
Time Frame
Approximately 36 months
Title
Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators
Time Frame
Approximately 36 months
Title
Disease control (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Overall survival
Time Frame
Approximately 36 months
Title
Time to radiographic tumor progression (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Duration of response (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Time to objective response (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Change in tumor size (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Best overall response (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Progression-free survival (central and investigator's assessment)
Time Frame
Approximately 36 months
Title
Number of participants with adverse events as a measure of safety and tolerability
Time Frame
Approximately 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007-2197
Country
United States
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
City
Graz
ZIP/Postal Code
8036
Country
Austria
City
Bruxelles - Brussel
ZIP/Postal Code
1070
Country
Belgium
City
Bruxelles - Brussel
ZIP/Postal Code
1200
Country
Belgium
City
Charleroi
ZIP/Postal Code
6000
Country
Belgium
City
Gent
ZIP/Postal Code
9000
Country
Belgium
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
City
Praha 2
ZIP/Postal Code
128 08
Country
Czechia
City
CLERMONT-FERRAND Cedex 1
ZIP/Postal Code
63003
Country
France
City
Creteil
ZIP/Postal Code
94010
Country
France
City
Lille
ZIP/Postal Code
59037
Country
France
City
Marseille
ZIP/Postal Code
13005
Country
France
City
Montpellier Cedex
ZIP/Postal Code
34059
Country
France
City
Vandoeuvre-les-nancy
ZIP/Postal Code
54511
Country
France
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany
City
München
State/Province
Bayern
ZIP/Postal Code
81377
Country
Germany
City
Hannover
State/Province
Niedersachsen
ZIP/Postal Code
30625
Country
Germany
City
Essen
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
45136
Country
Germany
City
Mainz
State/Province
Rheinland-Pfalz
ZIP/Postal Code
55131
Country
Germany
City
Berlin
ZIP/Postal Code
13353
Country
Germany
City
Shatin
Country
Hong Kong
City
Budapest
ZIP/Postal Code
1062
Country
Hungary
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20089
Country
Italy
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20133
Country
Italy
City
Kashiwa-shi
State/Province
Chiba
ZIP/Postal Code
277-8577
Country
Japan
City
Kobe
State/Province
Hyogo
ZIP/Postal Code
650-0017
Country
Japan
City
Moriguchi
State/Province
Osaka
ZIP/Postal Code
570-8507
Country
Japan
City
Osaka-shi
State/Province
Osaka
ZIP/Postal Code
541-8567
Country
Japan
City
Osakasayama-shi
State/Province
Osaka
ZIP/Postal Code
589-8511
Country
Japan
City
Sunto
State/Province
Shizuoka
ZIP/Postal Code
411-8777
Country
Japan
City
Shimotsuke
State/Province
Tochigi
ZIP/Postal Code
329-0498
Country
Japan
City
Chuo-ku
State/Province
Tokyo
ZIP/Postal Code
104-0045
Country
Japan
City
Osaka
ZIP/Postal Code
543-8555
Country
Japan
City
Shizuoka
ZIP/Postal Code
420-8527
Country
Japan
City
Busan
ZIP/Postal Code
49241
Country
Korea, Republic of
City
Daegu
ZIP/Postal Code
41404
Country
Korea, Republic of
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
City
Seoul
ZIP/Postal Code
05505
Country
Korea, Republic of
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
City
Auckland
ZIP/Postal Code
1023
Country
New Zealand
City
Santiago de Compostela
State/Province
A Coruña
ZIP/Postal Code
15706
Country
Spain
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
City
Alicante
ZIP/Postal Code
03010
Country
Spain
City
Pontevedra
ZIP/Postal Code
36071
Country
Spain
City
Valencia
ZIP/Postal Code
46010
Country
Spain
City
Genève 14
State/Province
Genève
ZIP/Postal Code
1211
Country
Switzerland
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
City
Kaohsiung City
ZIP/Postal Code
8330
Country
Taiwan
City
Tainan
ZIP/Postal Code
704
Country
Taiwan
City
Bangkok
ZIP/Postal Code
10210
Country
Thailand
City
Bangkok
ZIP/Postal Code
10330
Country
Thailand
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
City
Birmingham
State/Province
West Midlands
ZIP/Postal Code
B15 2TT
Country
United Kingdom

12. IPD Sharing Statement

Links:
URL
https://clinicaltrials.bayer.com/
Description
Click here to find results for studies related to Bayer Healthcare products.
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Learn more about this trial

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

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