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

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT01915602

Collaborator

(none)

Enrollment

Locations

Arm

40.4

Actual Duration (Months)

0.2

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 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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Refametinib (BAY86-9766) Drug: Sorafenib (BAY43-9006)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

14 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 Combination With Sorafenib as First Line Treatment in Patients With RAS Mutant Hepatocellular Carcinoma (HCC)

Actual Study Start Date :

Sep 27, 2013

Actual Primary Completion Date :

Jul 29, 2015

Actual Study Completion Date :

Feb 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Refametinib (BAY86-9766) Patients will receive refametinib 50 mg (2x20 mg + 1x10mg capsules or 50 mg tablets) bid Drug: Sorafenib (BAY43-9006) Patients will receive sorafenib 400 mg (2 x 200 mg tablets) bid.

Arm

Intervention/Treatment

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

Drug: Refametinib (BAY86-9766)

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

Drug: Sorafenib (BAY43-9006)

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

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.

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Louisville	Kentucky	United States	40202
2	Wien		Austria	1090
3	Bruxelles - Brussel		Belgium	1070
4	Edegem		Belgium	2650
5	Leuven		Belgium	3000
6	Liege		Belgium	4000
7	Guangzhou	Guangdong	China	510515
8	Beijing		China	100071
9	Shanghai		China	200032
10	Hradec Kralove		Czechia	500 05
11	Olomouc		Czechia	775 20
12	Bordeaux		France	33000
13	Caen Cedex		France	14033
14	Lyon		France	69004
15	Marseille		France	13005
16	Nice Cedex 3		France	06202
17	Paris		France	75012
18	Saint-priest-en-jarez		France	42270
19	Vandoeuvre-les-nancy		France	54511
20	Heidelberg	Baden-Württemberg	Germany	69120
21	Tübingen	Baden-Württemberg	Germany	72076
22	Frankfurt	Hessen	Germany	60596
23	Essen	Nordrhein-Westfalen	Germany	45136
24	Essen	Nordrhein-Westfalen	Germany	45147
25	Magdeburg	Sachsen-Anhalt	Germany	39120
26	Berlin		Germany	10967
27	Hamburg		Germany	20246
28	Hong Kong		Hong Kong
29	Budapest		Hungary	1062
30	Debrecen		Hungary	4032
31	Pecs		Hungary	7932
32	Zalaegerszeg		Hungary	8900
33	Haifa		Israel	3109601
34	Jerusalem		Israel	9112001
35	Petach Tikva		Israel	4941492
36	Tel Aviv		Israel	64239
37	Bologna	Emilia-Romagna	Italy	40138
38	Roma	Lazio	Italy	00168
39	Milano	Lombardia	Italy	20122
40	Milano	Lombardia	Italy	20133
41	Nagoya	Aichi	Japan	466-8560
42	Chiba-shi	Chiba	Japan	260-8677
43	Fukuoka-shi	Fukuoka	Japan	810-8563
44	Yokohama	Kanagawa	Japan	241-8515
45	Osakasayama-shi	Osaka	Japan	589-8511
46	Irima-gun	Saitama	Japan	350-0495
47	Bunkyo-ku	Tokyo	Japan	113-8655
48	Itabashi-ku	Tokyo	Japan	173-8610
49	Kyoto		Japan	606-8507
50	Osaka		Japan	534-0021
51	Osaka		Japan	545-8586
52	Seoul	Seoul Teugbyeolsi	Korea, Republic of	08308
53	Daegu		Korea, Republic of	700-721
54	Seoul		Korea, Republic of	03722
55	Seoul		Korea, Republic of	05505
56	Seoul		Korea, Republic of	06351
57	Seoul		Korea, Republic of	06591
58	Seoul		Korea, Republic of	110-744
59	Auckland		New Zealand	1023
60	Singapore		Singapore	169610
61	Santiago de Compostela	A Coruña	Spain	15706
62	Oviedo	Asturias	Spain	33011
63	Hospitalet de Llobregat	Barcelona	Spain	08907
64	Vigo	Pontevedra	Spain	36071
65	Madrid		Spain	28007
66	Madrid		Spain	28050
67	Bern		Switzerland	3010
68	Tainan		Taiwan	704
69	Tainan		Taiwan	736
70	Taipei		Taiwan	10002
71	Chiang Mai		Thailand	50200
72	Khon Kaen		Thailand	40002
73	Songkhla		Thailand	90110
74	Istanbul		Turkey	34093
75	Istanbul		Turkey	34349
76	Istanbul		Turkey	34899
77	Mersin		Turkey	33070
78	Birmingham		United Kingdom	B15 2TH
79	London		United Kingdom	SE5 9RS