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

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT01915589

Collaborator

(none)

Enrollment

Locations

Arm

12.7

Actual Duration (Months)

0.3

Patients Per Site

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Refametinib (BAY86-9766)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Sep 16, 2013

Actual Primary Completion Date :

Oct 8, 2014

Actual Study Completion Date :

Oct 8, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Refametinib (BAY86-9766) 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.	Drug: Refametinib (BAY86-9766) All patients who meet the entry criteria will receive refametinib 50 mg (2x20 mg + 1x10 mg capsules or 50 mg tablet) bid.

Arm

Intervention/Treatment

Experimental: Refametinib (BAY86-9766)

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.

Drug: Refametinib (BAY86-9766)

All patients who meet the entry criteria will receive refametinib 50 mg (2x20 mg + 1x10 mg capsules or 50 mg tablet) bid.

Outcome Measures

Primary Outcome Measures

Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review [Approximately 36 months]

Secondary Outcome Measures

Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review [Approximately 36 months]
Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators [Approximately 36 months]
Disease control (central and investigator's assessment) [Approximately 36 months]
Overall survival [Approximately 36 months]
Time to radiographic tumor progression (central and investigator's assessment) [Approximately 36 months]
Duration of response (central and investigator's assessment) [Approximately 36 months]
Time to objective response (central and investigator's assessment) [Approximately 36 months]
Change in tumor size (central and investigator's assessment) [Approximately 36 months]
Best overall response (central and investigator's assessment) [Approximately 36 months]
Progression-free survival (central and investigator's assessment) [Approximately 36 months]
Number of participants with adverse events as a measure of safety and tolerability [Approximately 36 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Washington	District of Columbia	United States	20007-2197
2	Miami	Florida	United States	33136
3	Tampa	Florida	United States	33612
4	New York	New York	United States	10029
5	Rochester	New York	United States	14642
6	Graz		Austria	8036
7	Bruxelles - Brussel		Belgium	1070
8	Bruxelles - Brussel		Belgium	1200
9	Charleroi		Belgium	6000
10	Gent		Belgium	9000
11	Leuven		Belgium	3000
12	Praha 2		Czechia	128 08
13	CLERMONT-FERRAND Cedex 1		France	63003
14	Creteil		France	94010
15	Lille		France	59037
16	Marseille		France	13005
17	Montpellier Cedex		France	34059
18	Vandoeuvre-les-nancy		France	54511
19	Heidelberg	Baden-Württemberg	Germany	69120
20	München	Bayern	Germany	81377
21	Hannover	Niedersachsen	Germany	30625
22	Essen	Nordrhein-Westfalen	Germany	45136
23	Mainz	Rheinland-Pfalz	Germany	55131
24	Berlin		Germany	13353
25	Shatin		Hong Kong
26	Budapest		Hungary	1062
27	Debrecen		Hungary	4032
28	Milano	Lombardia	Italy	20089
29	Milano	Lombardia	Italy	20133
30	Kashiwa-shi	Chiba	Japan	277-8577
31	Kobe	Hyogo	Japan	650-0017
32	Moriguchi	Osaka	Japan	570-8507
33	Osaka-shi	Osaka	Japan	541-8567
34	Osakasayama-shi	Osaka	Japan	589-8511
35	Sunto	Shizuoka	Japan	411-8777
36	Shimotsuke	Tochigi	Japan	329-0498
37	Chuo-ku	Tokyo	Japan	104-0045
38	Osaka		Japan	543-8555
39	Shizuoka		Japan	420-8527
40	Busan		Korea, Republic of	49241
41	Daegu		Korea, Republic of	41404
42	Seoul		Korea, Republic of	03080
43	Seoul		Korea, Republic of	05505
44	Seoul		Korea, Republic of	135-710
45	Auckland		New Zealand	1023
46	Santiago de Compostela	A Coruña	Spain	15706
47	Barcelona	Catalunya	Spain	08035
48	Alicante		Spain	03010
49	Pontevedra		Spain	36071
50	Valencia		Spain	46010
51	Genève 14	Genève	Switzerland	1211
52	Bern		Switzerland	3010
53	Kaohsiung City		Taiwan	8330
54	Tainan		Taiwan	704
55	Bangkok		Thailand	10210
56	Bangkok		Thailand	10330
57	Bangkok		Thailand	10700
58	Birmingham	West Midlands	United Kingdom	B15 2TT