Clinical trial NCT01915602: Refametinib in Combination With Sorafenib in RAS Mutant Hepatocellular Carcinoma (HCC)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Hepatocellular
Keywords: Hepatocellular Carcinoma
Mitogen-activated Extracellular-signal-regulated kinase (MEK) inhibitor
Sorafenib
Objective tumor response rate (ORR)
modified RECIST criteria
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2013-08-05
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.
* 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.

Primary outcomes:
measure: Objective tumor response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by central radiological review
timeFrame: Approximately 36 months
Secondary outcomes:
measure: Objective tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by central radiological review
timeFrame: Approximately 36 months
measure: Objective tumor response according to RECIST 1.1 and mRECIST assessed by investigators
timeFrame: Approximately 36 months
measure: Disease control (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Overall survival
timeFrame: Approximately 36 months
measure: Time to radiographic tumor progression (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Duration of response (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Time to objective response (central and investigator's assessment).
timeFrame: Approximately 36 months
measure: Change in tumor size (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Best overall response (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Progression-free survival (central and investigator's assessment)
timeFrame: Approximately 36 months
measure: Number of participants with adverse events as a measure of safety and tolerability
timeFrame: Approximately 36 months
Other outcomes:
Locations:
city: Louisville
country: United States
state: Kentucky
city: Wien
country: Austria
city: Bruxelles - Brussel
country: Belgium
city: Edegem
country: Belgium
city: Leuven
country: Belgium
city: Liege
country: Belgium
city: Guangzhou
country: China
state: Guangdong
city: Beijing
country: China
city: Shanghai
country: China
city: Hradec Kralove
country: Czechia
city: Olomouc
country: Czechia
city: Bordeaux
country: France
city: Caen Cedex
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Nice Cedex 3
country: France
city: Paris
country: France
city: Saint-priest-en-jarez
country: France
city: Vandoeuvre-les-nancy
country: France
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: Tübingen
country: Germany
state: Baden-Württemberg
city: Frankfurt
country: Germany
state: Hessen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Magdeburg
country: Germany
state: Sachsen-Anhalt
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Hong Kong
country: Hong Kong
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Pecs
country: Hungary
city: Zalaegerszeg
country: Hungary
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Petach Tikva
country: Israel
city: Tel Aviv
country: Israel
city: Bologna
country: Italy
state: Emilia-Romagna
city: Roma
country: Italy
state: Lazio
city: Milano
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Nagoya
country: Japan
state: Aichi
city: Chiba-shi
country: Japan
state: Chiba
city: Fukuoka-shi
country: Japan
state: Fukuoka
city: Yokohama
country: Japan
state: Kanagawa
city: Osakasayama-shi
country: Japan
state: Osaka
city: Irima-gun
country: Japan
state: Saitama
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Itabashi-ku
country: Japan
state: Tokyo
city: Kyoto
country: Japan
city: Osaka
country: Japan
city: Osaka
country: Japan
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Daegu
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Auckland
country: New Zealand
city: Singapore
country: Singapore
city: Santiago de Compostela
country: Spain
state: A Coruña
city: Oviedo
country: Spain
state: Asturias
city: Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Vigo
country: Spain
state: Pontevedra
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Bern
country: Switzerland
city: Tainan
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Chiang Mai
country: Thailand
city: Khon Kaen
country: Thailand
city: Songkhla
country: Thailand
city: Istanbul
country: Turkey
city: Istanbul
country: Turkey
city: Istanbul
country: Turkey
city: Mersin
country: Turkey
city: Birmingham
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References: