| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| KRAS or NRAS mutant unresectable or metastatic Hepatocellular carcinoma (HCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| RAS mutant advanced Hepatocellular carcinoma (HCC ) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the efficacy of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to evaluate the safety of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. Additional objectives are the analysis of biomarkers, pharmacokinetics (PK), and patient reported outcomes (PRO, stage 2 only). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 anti-cancer treatment.
•No previous treatment with sorafenib or 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 Appendix 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 be performed until INR is stable (within Child Pugh class A threshold) based on a measurement at pre-dose, as defined by the local standard of care.
|
|
| E.4 | Principal exclusion criteria |
•Any Cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors(Staging: Ta, Tis and T1)
•Patients who are eligible for surgery, liver transplantation, ablation or transarterial chemoembolization for HCC
•Renal failure requiring hemo- or peritoneal dialysis
•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 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
•Pregnant or lactating women. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of study treatment and a negative result must be documented before first dose of study drug . Note: Women of childbearing potential and men enrolled in this trial must agree to use adequate contraception (barrier method of birth control) since signing of the ICF until at least 3 months after the last study treatment administration. Adequate contraception is defined in this study as any medically recommended method (or combination of methods) as per standard of care
•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 prior therapies and medication:
•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 evidence of PD if this is the only site of disease
•Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, hormonal therapy and experimental or approved therapies
•Any drug that targets angiogenesis, especially vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)
•Tyrosine-kinase inhibitors
•Major surgery or significant traumatic injury within 4 weeks prior to start of screening.
•Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte colony-stimulating factor (GM-CSF), within 3 weeks prior to start of screening (these may be used in the management of acute toxicity such as febrile neutropenia or CTCAE 4.03 grade 3-4 neutropenia at the discretion of the investigator; however they may not be substituted for a required dose reduction)
•Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should be stopped 2 weeks prior to start of screening
•Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptable provided that the dose is stable for 1 month prior to start of screening and thereafter) |
|
| E.5 End points |
| E.5.1 | 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 level of 0.025. A point estimate and the 95% confidence intervals for ORR will be calculated. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis will be performed for both stages approximately 12 weeks after the last patient
started study treatment
|
|
| E.5.2 | 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. |
|
| E.5.2.1 | 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). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| China |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| New Zealand |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
The primary completion date for this study according to the Food and Drug Administration (FDA) Amendment Act is specified in a separate document (not part of this Clinical Study ProtocolCSP).
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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