KRAS or NRAS mutant unresectable or metastatic Hepatocellular carcinoma (HCC)
Conditions
Interventions
Product Name: Refametinib
Product Code: BAY 86-9766, Capsule 10 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Refametinib
CAS Number: 923032-37-5
Current Sponsor code: BAY 86-9766
Other d
Sponsors
Bayer Healthcare AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Eligibility criteria for RAS mutation testing: •Ability to understand and willingness to sign written informed consent (IC). Signed informed consent from (ICF) for RAS mutation testing has to be obtained before any study specific procedure. •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. •ECOG performance state 0 or 1. •Life expectancy of at least 12 weeks. •No prior use of targeted agents, experimental therapy or systemic anticancer treatment for HCC (except sorafenib) (changed by Amendment 1, only sorafenib allowed as prior systemic anticancer therapy). •No prior use of targeted agents, experimental therapy or systemic anticancer treatment (except sorafenib and/or cytotoxic chemotherapy). •No previous treatment with refametinib. Criteria for study treatment eligibility: •Ability to understand and willingness to sign written IC. Signed ICF for study treatment eligibility has to be obtained before any study specific procedure. •Patient must harbor KRAS or NRAS mutation based on BEAMing plasma test. •Patients must have at least one uni-dimensional measurable lesion by CT or MR according to RECIST 1.1 and mRECIST (specified in Section 14.4) 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). •Patients who have received local therapy such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation are eligible. Previously treated lesions are only selected as target lesions when they have progressed (to be confirmed by central image review of an initial set of scans taken after the local treatment and another showing progression. At least 8 weeks are needed between the scans). Local therapy has to be completed at least 4 weeks prior to the baseline scan. •Resolution of all acute toxic effects of any prior local therapy to Common Toxicity Criteria for Adverse Events (CTCAE 4.03) grade =1. •ECOG performance status of 0 or 1. •Liver function status of Child-Pugh Class A. •The following laboratory criteria must be met: Platelet count = 60 x 109/L Hemoglobin = 8.5 g/dL Absolute neutrophil count (ANC) = 1.5 x 109/L Total bilirubin = 3.0 mg/dL Alanine aminotransferase (ALT) = 5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) = 5 x ULN Albumin = 2.8 g/dL Amylase and lipase = 1.5 x ULN Serum creatinine = 1.5 x ULN Prothrombin time-international normalized ratio (PT-INR) =2.3, or PT = 6 seconds above control. •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 b
Exclusion criteria
Exclusion criteria: •Any Cancer curatively treated 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. •Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management). •Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B is allowed if no active replication (defined as abnormal ALT >2xULN associated with HBV DNA >20,000 IU/mL ) is present (45). Hepatitis C is allowed if no antiviral treatment is required. •Known human immunodeficiency virus (HIV) infection. •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. •Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days prior to start of screening. •Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months prior to start of screening. •History of organ allograft, cornea transplantation will be allowed. •Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results. •Known or suspected hypersensitivity to any of the study drugs, study drug classes, or components in the formulation given during the course of this study. •Patients unable to take oral medication, requiring intravenous alimentation, who had malabsorption syndrome or any other conditions affecting GI absorption, or who have active peptic ulcer disease. •Any condition that was unstable or which could jeopardize the safety of the patient and his/her compliance in the study. •Pregnant or lactating women. •Uncontrolled ascites (defined as not easily controlled with diuretic treatment). •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. •Non-healing wound, ulcer, or bone fracture. •Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention: beta blockers or endoscopic treatment. Assessment of esophageal varices should be performed by endoscopy within 6 months prior to start of study treatment and within 12 months for patients in whom conventional medical intervention for known esophageal varices is already in place. •Patients with seizure disorder requiring medication. Excluded previous therapies and medications: •Radiotherapy within 4 weeks prior to start of screening. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The primary efficacy variable, for both stages of this study, is the central radiological assessment of ORR [confirmed complete response (CR) plus partial response (PR)] according to mRECIST. ORR is defined as the proportion of patients with the best tumor response (confirmed PR or CR) that is achieved during the study. Radiologic tumor assessments (central image review and investigator's assessment) will be done at Screening and then every 6 weeks during treatment. A further radiologic tumor assessment will be done within 14 days after last study medications intake, not needed if the previous tumor evaluation was performed within 4 weeks. In case of clinical progression, every effort should be made to provide radiological images for central image review to confirm the progression radiologically. Analysis will be performed separately for each stage. The analysis of the primary efficacy variable of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment. At that timepoint, an exploratory analysis of all other safety and efficacy variables will be performed. If the study is not continued into Stage 2, the final analysis of Stage 1 will be performed 12 months after the last Stage 1 patient's first treatment. The primary analysis of the primary efficacy variable of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment. At that time point, an exploratory analysis of all other safety and efficacy variables will be performed. Efficacy variables will be analyzed for both the FAS and the PPS. At Stage 1 and Stage 2, the analysis based on the FAS, full-analysis set (all patients assigned to study treatment) will be considered primary. As Stage 1 is exploratory, there will be no statistical testing at the end of Stage 1; all analyses will be descriptive only. ORR will be tested at Stage 2 against the null hypothesis that the true ORR is less than or equal to 0.45 at a one-sided type-1 error le | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Overall response rate (ORR) by investigator's assessment according to mRECIST and RECIST 1.1 Overall response rate (ORR) confirmed according to RECIST (Version 1.1) Disease control rate (DCR), central and investigator's assessment Overall survival (OS) Time to radiographic tumor progression (TTP), central and investigator's assessment Duration of Response (DOR), central and investigator's assessment Time to objective response (CR or PR), 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 (PFS), central and investigator's assessment Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Biomarker analysis PK analysis Patient Reported Outcome (PRO) / Health Related Quality of Life (HRQoL) at Stage 2 only Safety Secondary efficacy variables will be evaluated and presented by means of descriptive statistics. Time-to-event variables will be displayed by Kaplan-Meier estimates and corresponding graphs.;Timepoint(s) of evaluation of this end point: An exploratory analysis of all other safety and efficacy variables of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment. An exploratory analysis of all other safety and efficacy variables of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment. The final analysis of all secondary efficacy and safety variables, and an additional exploratory analysis of the primary efficacy variable will be performed when the median time to radiological tumor progression can be determined (i.e. when the majority of patients have experienced progression). | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, New Zealand, Philippines, Russian Federation, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States, Vietnam
Contacts
Public ContactBayer Clinical Trials Contact
Bayer Healthcare AG
Outcome results
None listed