Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayer.com apply to the contents of this file.

2 15-MAY-2017 Study no Page: 2 of 13 Date of study report: 14 JUL 2015 Study title: Sponsor s study number: A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY ) in patients with RAS mutant Hepatocellular Carcinoma (HCC) NCT number: NCT EudraCT number: Sponsor: Bayer Clinical phase: Phase II Study objectives: The primary objective of this study was to evaluate the efficacy of refametinib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. The secondary objective was to evaluate the safety of refametinib. Test drug: Refametinib (BAY ) Name of active ingredient(s): Route of administration: Refametinib Dose: 50 mg twice daily (bid) given as capsules (2x20 mg capsule + 1x10 mg capsule) or tablets (1x 50 mg tablet) bid (in the study only refametinib tablets were used). Oral Duration of treatment: Treatment was to be continued until disease progression as defined by modified Response Evaluation Criteria in Solid Tumors (mrecist) or clinical progression [e.g. Eastern Cooperative Oncology Group performance status (ECOG PS) of 3], or until another criterion was met for withdrawal from the study. Treatment could be continued past radiological progression assessed by central image review, provided the patient derived clinical benefit as judged by the treating physician. Reference drug: Not applicable Indication: KRAS or NRAS mutant unresectable or metastatic HCC

3 15-MAY-2017 Study no Page: 3 of 13 Diagnosis and main criteria for inclusion: Study design: Methodology: Inclusion criteria Male or female patients ( 18 years of age) with unresectable or metastatic HCC harboring RAS mutation. Patients were to be Child-Pugh A, were to have life expectancy of at least 12 weeks, and ECOG PS of 0 or 1. Patients could have received prior local therapy but no systemic therapy except for sorafenib. Prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial. The study was to be conducted in 2 stages; analysis was to be performed separately for each stage. For Stage 1, about 350 patients were planned to be tested for KRAS or NRAS mutations via BEAMing (Beads, emulsions, amplification, and magnetic) technology to identify approximately 15 RAS mutant patients who were to be treated until disease progression as defined by mrecist or clinical progression (e.g. ECOG PS of 3), or until another criterion was met for withdrawal from study treatment. Depending on efficacy (at least 5 responders out of 15 patients) and a general benefit/risk result assessment after Stage 1, the sponsor was to decide to continue the study to Stage 2 including about 80 patients with RAS mutation. As the minimum of 5 responders out of the first 15 treated patients was not achieved in Stage 1, the study did not proceed to Stage 2. After confirmation of basic eligibility criteria at the visit for testing of RAS mutation, a plasma sample for genotyping of free tumor DNA was collected to identify patients carrying a RAS mutation (KRAS or NRAS). Patients carrying RAS mutation were then evaluated for study treatment eligibility during screening. All patients who met the entry criteria were to receive refametinib 50 mg bid. For the purposes of data recording, the treatment period was divided into 3-week cycles. The start of the treatment period was defined by the first administration of study treatment. Treatment was continued until the occurrence of progressive disease (PD) as defined by the mrecist criteria (assessed by central image review) or clinical progression (e.g. ECOG performance status of 3), or until another criterion was met for withdrawal from study. An end of treatment (EOT) visit was performed within 7 days after discontinuation of study treatment and a safety follow-up visit (end of study visit) took place 30 (+ 5) days after the last administration of study drug. All patients who discontinued treatment were to be followed for overall survival. Safety evaluations were done during screening (within 28 days of the first dose of study drug), on the first day of study treatment administration (Cycle 1 Day 1), and then weekly for the first 9 weeks, and thereafter every 3 weeks.

4 15-MAY-2017 Study no Page: 4 of 13 Tumor assessments based on contrast enhanced computed tomography (CT) or magnetic resonance (MR) imaging were done during screening and then every 6 weeks during study treatment. A further radiologic tumor assessment was to be done within 14 days after the last study drug intake. However, this assessment was not needed if the previous tumor evaluation was performed within 4 weeks. Investigators assessed treatment response according to mrecist and RECIST v All images needed to be submitted to the central image review in digital format. Treatment response according to mrecist decisive for the primary endpoint was centrally assessed in a continuously performed central image review. An online safety review and monitoring of all available medical data were conducted throughout the study. Study center(s): There were 58 study centers in 17 countries: Austria (1), Belgium (5), Czech Republic (1), France (6), Germany (6), Hong Kong (1), Hungary (2), Italy (2), Japan (10), New Zealand (1), South Korea (5), Spain (5), Switzerland (2), Thailand (3), Taiwan (2), Great Britain (1), United States of America (5). Publication(s) based on the study (references): None Study period: Study Start Date: 16 SEP 2013 Early termination: Not applicable Study Completion Date: 08 OCT 2014 Number of subjects: Planned: 350 Criteria for evaluation Analyzed: 16 Efficacy: The primary efficacy variable was the objective tumor response rate (ORR) [confirmed complete response (CR) plus partial response (PR)] assessed by central radiological review according to mrecist. Secondary efficacy variables included centrally assessed ORR according to RECIST v. 1.1, investigator assessed ORR according to both mrecist and RECIST v. 1.1, overall survival (OS), disease control rate (DCR), time to radiographic tumor progression (TTP), duration of response (DOR), time to objective response, change in tumor size, best overall response (BOR), and progression-free survival (PFS). Other efficacy variables included radiographic PFS according to

5 15-MAY-2017 Study no Page: 5 of 13 mrecist and RECIST v. 1.1, investigator and central assessments (exploratory analysis). Safety: The secondary safety variable was the number of subjects with adverse events. Other safety variables were physical examinations, vital signs, electrocardiogram (ECG), cardiac function, laboratory analyses, ophthalmic examinations, and neurologic examinations. Furthermore, Child-Pugh, ECOG PS, and Barcelona Clinic Liver Cancer (BCLC) stage were assessed. Statistical methods: As Stage 1 was exploratory, there was no statistical testing at the end of Stage 1; all analyses were descriptive only. Adverse events were classified according to CTCAE (version 4.03) and MedDRA (version 17.1). Substantial protocol changes: The original CSP, dated 03 MAY 2013, was amended once. Amendment 1, dated 27 NOV 2013, was implemented globally; it specified the following modifications: Wording regarding use of refametinib tablets was clarified. Based on final pharmacokinetic results from a clinical relative bioavailability study (15221), tablets exhibit comparable bioavailability to capsules. Therefore tablets could be used as an alternative for capsules. It was also indicated that tablets may be taken with or without a meal. Prior cytotoxic chemotherapy was not allowed according to Amendment 1. The removal of prior cytotoxic chemotherapy was deemed necessary to exclude a population of overtreated patients who may have been potentially different from the patients conventionally treated with sorafenib. In order to characterize the cardiovascular safety at anticipated maximum plasma concentrations of the study treatment, additional safety ECGs were added.

6 15-MAY-2017 Study no Page: 6 of 13 Subject disposition and baseline Disposition The data presented in this report were accumulated up to the final database cut-off date of 08 OCT 2014 when LPLV occurred and all safety evaluations ended. Of note, there was one survival follow-up contact (on 04 NOV 2014) that took place after the cut-off date of the study. A total of 498 patients signed informed consent [IC] for RAS mutation testing via BEAMing technology. Of these, the RAS mutation test was performed for 493 patients (99.0%). Five patients (1.0%) were not tested due to failure of inclusion and exclusion criteria. The RAS mutation test was positive in 32 patients (6.4%) while 461 patients (92.6%) were RAS mutation negative. The mutation rate was slightly higher in the Asia population (7.5%) vs. the Rest of world (RoW) population (5.8%). Of the 32 RAS mutant patients 7 were not included in the Screening for the treatment phase: 1 patient withdrew the consent and for 6 patients it became evident that they would not meet the eligibility criteria. Altogether 25 patients (5.0%) signed the main IC resulting in a total of 16 patients who were assigned to treatment: 7 patients in the Asia population and 9 patients in the RoW population. Nine RAS mutant HCC patients were screening failures with the primary reasons of adverse event (1 patient) and screening failures / eligibility criteria not met (8 patients). All 16 patients who were assigned to treatment also started study treatment. At the time of the database cut-off for this final analysis, all 16 patients (100.0%) had completed treatment. The most common primary reasons for treatment termination were withdrawal by patient and progressive disease (radiological progression) in 3 patients (42.9%) each in the Asia population and AEs associated with clinical disease progression, AEs not associated with clinical disease progression and progressive disease (clinical progression) in 2 patients (22.2%) each in the RoW population. A total of 14 patients (87.5%) started the safety follow-up and 10 of them (62.5%) completed it. All 4 patients (25.0%) who prematurely discontinued the safety follow-up were from the RoW population. The primary reasons for discontinuation of the safety follow-up were death (3 patients, 18.8%) and withdrawal by the patient (1 patient, 6.3%). A total of 11 patients (68.8%) entered the survival follow-up period. However, considering the clearly negative outcome of the study, the sponsor decided that further follow-up of survival events would not be necessary. Analysis sets The full analysis set (FAS) consisted of all patients assigned to study treatment. All efficacy variables were analyzed in the FAS, which was the primary analysis set. A total of 16 patients were included in the FAS. Per protocol set (PPS) consisted of all FAS patients who received treatment and who did not have any major protocol deviations affecting the primary efficacy evaluation. As none of the patients had major protocol deviations, the PPS and FAS were the same populations. Therefore no separate results are shown for the PPS. The safety analysis set (SAF) consisted of patients with at least one intake of study drug. All 16 patients received treatment and were part of the SAF.

7 15-MAY-2017 Study no Page: 7 of 13 Demographics and baseline characteristics Out of the 498 patients enrolled in RAS mutation testing phase, 493 patients were tested for RAS mutations and 5 patients were not tested due to failure of inclusion and exclusion criteria. Of those tested for RAS mutations, 186 were from Asia and 307 from the RoW. All patients from Asia were Asians. The population from the RoW region consisted of 237 white patients, 4 black or African American, 8 Asian, 2 native Hawaiian or other Pacific Islander patients. The race was not available for 56 patients. The majority of the patients enrolled in the RAS mutation testing phase (416, 84.4%) were male, 154 (31.2%) in Asia and 262 (53.1%) in the RoW region. The mean age was 64.4 ± 10.8 years, with approximately half of the patients (262, 52.6%) being younger than 65 years (Asia: 23.9%; RoW: 28.7%). Overall there were no significant differences in the demographics and baseline cancer characteristics between the RAS mutant and Wild Type patients (N = 32 and 463, respectively, Missing N = 3). In the FAS, 9 of the 16 treated patients were white and 7 were Asians; the majority were male (13 patients, 81.3%). In the Asia population, 4 of the patients (57.1%) were male and 3 (42.9%) female. All 9 patients (100.0%) in the RoW population were male. The mean age at the time of enrollment was 65.8 ± 12.3 years (median 69.0 years), with the majority of patients (9, 56.3%) being older than 65 years. In the Asia population, more patients were in the age group of 65 (4 patients, 57.1%) while it was opposite in the RoW population (6 patients, 66.7% were >65). At baseline, the mean weight was ± kg, mean height was ± 10.9 cm and mean body mass index was ± 3.80 kg/m 2. Regarding the ECOG performance status at baseline, 7 patients (43.8%) had ECOG 0 (fully active) and 9 patients (56.3%) had ECOG 1 (restricted active). Four patients (57.1%) in the Asia population and 3 patients (33.3%) in the RoW population were fully active. Histological examination verified HCC diagnosis was available for 14 patients (87.5%). All 16 patients had a Child Pugh A classification at baseline. According to mrecist, at baseline all (100.0%) patients had at least one lesion in the liver. One target lesion was present in 2 (12.5%) patients, two target lesions in 10 (62.5%) and 3 target lesions in 4 (25.0%) patients. In 6 patients (37.5%), symptoms of HCC were present at initial diagnosis. The most frequent etiology of the underlying liver disease was alcohol use in 6 patients (37.5%), followed by hepatitis C in 3 patients (18.8%). Two patients (12.5%) had mixed etiology (alcohol use / hepatitis B) and 2 patients (12.5%) had hepatitis B. Liver cirrhosis was reported in 14 (87.5%) patients, of which 4 (25.0%) were confirmed histologically and 10 (62.5%) clinically. At baseline 8 patients (50.0%) had TNM stage IVB disease. Macrovascular invasion was observed in 4 patients (25.0%). In 10 patients (62.5%) extrahepatic spread was present, of these 6 patients (37.5%) presented with lymph node metastasis followed by other sites in 5 patients (31.3%). The location of tumor in bone and lung was present in 3 patients (18.8%) each. The BCLC stage was C (advanced stage) in 14 (87.5%) patients. In the Asia population, the median time from the initial diagnosis to treatment start was weeks, time since first progression was weeks and time from most recent progression to treatment start was 9.64 weeks. In the RoW population, the respective median times were weeks, weeks and 7.14 weeks, respectively.

8 15-MAY-2017 Study no Page: 8 of 13 Efficacy Primary efficacy variable The primary efficacy variable was the ORR (confirmed CR plus PR) assessed by central radiological review according to mrecist. None of the patients in the FAS achieved confirmed CR or PR, and therefore the ORR was 0. Secondary efficacy variables Based on the independent assessment according to RECIST v. 1.1, and investigator assessments according to both mrecist and RECIST v. 1.1, none of the patients in the FAS had confirmed CR or PR, and therefore the ORR was 0. According to the independent assessment (mrecist) 1 patient in the RoW population (6.3%) was classified with a best overall response of unconfirmed PR. A total of 8 patients (50.0%) achieved a best response of stable disease (SD), including 5 patients in the RoW population and 3 patients in the Asia population. Overall, 3 patients (18.8%) had a best response of PD. For 4 patients (25.0%) the best overall response was missing. The DCR (defined as the proportion of patients with confirmed CR, confirmed PR or SD for at least 6 weeks) was 56.3% in the total population based on both independent and investigator assessments according to mrecist. Both assessments with respective to RECIST v. 1.1 resulted in DCR of 62.5%. As no objective responses were observed during the study, analyses were not performed for DOR and time to objective response. Analysis of OS resulted in the median survival time of 177 days with 95% CI [58; upper bound could not be estimated due to censored data] (range between 15 and 182 days). Overall, a total of 8 patients (50%) died. The OS rate was at month 2, 95% CI [0.521; 0.960]; at month 4, 95% CI [0.391;0.904] and at month 6, 95% CI [0.000;0.583]. Analysis of TTP resulted in median time to radiological progression of 84 days (range between 42 and 84 days) based on independent assessment according to mrecist. The 95% CI was [42; upper bound could not be estimated due to censored data]. A total of 4 patients (25.0%) had radiological progression. The TTP rate was at month 1, 95% CI [1.000;1.000] and at month 2, 95% CI [0.205;0.938]. Later time points (month 3 and month 4) could not be estimated due to censored data. Of the 16 patients in the FAS, a best percent change in target lesions from baseline could be determined for 12 patients. Based on independent assessment (mrecist) by reader 1 and 2, increase in tumor size was observed in 9 and 8 patients, while tumor shrinkage in target lesions was observed in 3 and 4 patients, respectively. Based on investigator s assessment, (mrecist) 7 patients had increase in tumor size, 4 patients had observed tumor shrinkage in target lesions and in 1 patient there was no change in target lesions. Median PFS time was 58 days (range between 15 and 133 days) in the total population based on independent assessment according to mrecist. The 95% CI was [42;133]. A total of 9 patients (56.3%) were observed with disease progression or had died. The PFS rate was at month 1, 95%

9 15-MAY-2017 Study no Page: 9 of 13 CI [1.000;1.000]; at month 2, 95% CI [0.117;0.709]; at month 3, 95% CI [0.000;0.528] and at month 4, 95% CI [0.000;0.528]. Exploratory efficacy variables The analysis of radiographically assessed PFS based on independent assessment according to mrecist resulted in median PFS time of 58 days, 95% CI [42;133], which is identical to the results on median PFS which takes into account both radiographic as well as clinical progression. Safety evaluation Extent of exposure The median overall duration of study treatment (including interruptions) was 7.14 weeks in the total population, 6.29 weeks in the Asia population and 8.29 weeks in the RoW population. The median actual duration (excluding interruptions) was 6.29 weeks in the total population, 4.29 weeks in the Asia population and 7.14 weeks in the RoW population. The mean actual refametinib dose (excluding interruptions) per day was ± mg in the total population, ± mg in the Asia population and ± mg in the RoW population. The majority of patients (75.0%) received actual daily refametinib dose between 81 and 100 mg. In average, the patients took ± 18.52% of the planned dose in the total population. Overall, the mean total dose given to patients was ± mg, in the Asia population the mean total dose ( ± mg) was lower compared to the mean total dose of the RoW population ( ± mg) correlating with shorter duration of treatment in the Asia population. Dose modifications Study treatment was interrupted or delayed in 8 patients (50.0%), 4 patients in both groups. The total number of interruptions or delays was 18, 7 patients had 2 or more interruptions. The mean duration of interruption or delay per event was 5.1 ± 4.0 days in the Asia population and 4.9 ± 3.9 days in the RoW population. The primary reason for dose interruption or delay was AE in 94.4% of the events. Study drug dose was reduced in 6 patients (37.5%) including 2 patients in the Asia population and 4 patients in the RoW population. There was only one dose reduction per patient. The mean duration of reduction per event was 38.5 ± 34.6 days in the Asia population and 64.3 ± 39.4 days in the RoW population. The reason for dose reduction was AE in all (100.0%) events. Treatment-emergent adverse events (TEAE) At least one TEAE was reported in all 16 patients (100%). Overall, the most common TEAEs in >20% of the study population included edema limbs (43.8%), fatigue (37.5%, all in RoW population), nausea (37.5%), vomiting (37.5%), Creatine phosphokinase (CPK) increased (31.3%) diarrhea (31.3%), rash acneiform (31.3%), aspartate aminotransferase increased (25.0%), hypertension (25.0%) and rash maculo-papular (25.0%). Of these, the following AEs were more common in the RoW population compared to the Asia population: edema limbs (55.6% vs. 28.6%), fatigue (66.7% vs. 0%), nausea (55.6% vs. 14.3%), vomiting (44.4% vs. 28.6%); CPK increased, diarrhea and rash acneiform (each 33.3% vs. 28.6% in the RoW vs. Asia populations, respectively). The following AEs (>20% in the total

10 15-MAY-2017 Study no Page: 10 of 13 population) were more common in the Asia population compared to the RoW population: aspartate aminotransferase increased (42.9% vs. 11.1%), hypertension and rash maculo-papular (each 28.6% vs. 22.2% in the Asia vs. RoW populations, respectively). In the majority of the patients (68.8%) the worst grade of TEAEs was assessed as CTCAE grade 3. The most commonly reported worst grade 3 TEAEs were fatigue, CPK increased, aspartate aminotransferase increased, hypertension, rash acneiform, vomiting, ascites and general disorders and administration site conditions (other, specify). None of the patients had grade 4 assessed as worst grade TEAE while worst grade 5 TEAEs occurred in 5 patients (31.3%). Drug-related adverse events A total of 14 patients (87.5%) experienced at least one TEAE that was considered as related to the study drug. Generally, the events were distributed equally with 7 patients (100%) from Asia and 7 patients (77.8%) from RoW. The most common study drug-related TEAEs in >20% of the study population included fatigue (31.3%), rash acneiform (31.3%), aspartate aminotransferase increased (25.0%), CPK increased (25.0%), edema limbs (25.0%), hypertension (25.0%) and rash maculo-papular (25.0%). In most of the patients (75.0%), the worst grade of study drug-related TEAEs was grade 3. The reported grade 3 TEAEs were fatigue, CPK increased, anemia, aspartate aminotransferase increased, edema limbs, generalized muscle weakness, hypertension, vomiting and rash acneiform. CTCAE grade 4 was the worst grade of study drug-related TEAEs occurring in 1 patient (serum amylase increased). Of note, no grade 5 study drug-related events were reported. Evaluation of cardiac, ophthalmic and neurologic AEs Treatment-emergent cardiac disorders were experienced by a total of 3 patients (18.8%), all of these events were reported in the RoW population. Two of the events (atrial flutter, heart failure) were considered as SAEs. However, these events were assessed as not related to the study medication. One event, left ventricular systolic dysfunction of grade 3 was assessed as study drug-related, the same patient experienced SAE heart failure of grade 5 which was assessed as not related to study drug. The direct cause of death was heart failure (AE Heart failure) specified as severe sclerosis of coronary arteries with cicatrization of myocardium. A total of 2 patients (12.5%) experienced treatment-emergent eye disorders, both of them were in the Asia population. These ophthalmic events (grade 2 blurred vision, grade 1 dry eye) were assessed as related to refametinib and were not regarded as serious. Nervous system disorders were reported in a total of 7 patients (43.8%). TEAEs dizziness, encephalopathy and syncope were experienced by 2 patients (12.5%) each, the rest of the events were reported in 1 patient (6.3%) each. Most of the neurologic events were of grade 1 (18.8%) or grade 2 (12.5%), 2 patients (12.5%) were reported with grade 3 events. Neurologic disorders were assessed as related to refametinib for 3 patients: dizziness and encephalopathy (one patient), somnolence (one patient) and syncope (one patient). A total of 3 (18.8%) patients experienced neurologic events which were regarded as serious (syncope of grade 3, encephalopathy: 2 events of grade 1 and 1 of grade 3 and transient ischemic attacks of grade 2). None of these SAEs were assessed as related to study drug.

11 15-MAY-2017 Study no Page: 11 of 13 Psychiatric disorders were reported in a total of 5 patients (31.3%). Psychiatric events were assessed as related to refametinib for 2 (12.5%) patients; hallucinations (one patient), and personality change (one patient). 1 patient experienced a psychiatric event which was regarded as serious: delirium of grade 3, which was assessed as not related to refametinib. Deaths Overall, a total of 8 patients died (50.0%), of which 5 (31.3%) up to 30 days after the last dose of study medication and 3 (18.8%) later than 30 days after the last dose of study medication. No patients died during the study treatment. Of the 8 deaths, 3 (42.9%) were reported in the Asia population and 5 (55.6%) in the RoW population. One patient died before completion of the screening. However, this was not captured in the database as AEs during pre-screening were not recorded according to protocol. The cause of death was progression of the underlying disease. None of the deaths were caused by drug-related TEAEs. The cause of death was reported as AE associated with clinical disease progression for 2 patients (sepsis and heart failure), AE not associated with clinical disease progression for 2 patients (lung infection and multi-organ failure), and progressive disease for 4 patients (1 patient died within 30 days after the last dose of study medication, 3 patients died later than 30 days after the last dose). Serious adverse events SAEs were reported in a total of 12 patients (75.0%). SAEs were experienced by 4 patients (57.1%) in the Asia population and by 8 patients (88.9%) in the RoW population. The worst grade for SAEs was most commonly grade 3 (43.8%). No patient had an SAE with worst grade 4. However, of note, 1 patient experienced 2 grade 4 SAEs, but grade 4 was not the worst grade SAE experienced by this patient as the patient experienced also a grade 5 SAE. Grade 5 SAEs were reported in 5 patients (31.3%). The most common SAEs occurring in 2 patients were CPK increased (3 patients) and general disorders and administration site conditions - other, specify (2 patients). Drug-related SAEs were experienced by 7 patients (43.8%), of which 2 (28.6%) were reported in the Asia population and 5 (55.6%) in the RoW population. Most of the study drug-related SAEs were of worst grade 3 in severity with an overall incidence rate of 37.5%. Study drug-related SAEs of worst grade 1, 4 and 5 were not reported. Overall, CPK increase was the most commonly reported drugrelated SAE (3 patients). Per protocol, CPK increase of grade 3 was considered as an AE of special interest and was to be reported as an SAE. All other drug-related SAEs were reported in 1 patient (6.3%) each: anemia, acute kidney injury, dyspnea and hypertension. Other significant adverse events A total of 4 patients (25.0%) in the SAF population experienced one or more TEAEs causing discontinuation from the study drug. All these TEAEs were reported in the RoW population. TEAEs that led to drug discontinuation were assessed as drug-related in 3 patients (18.8%). One patient discontinued the study drug due to generalized muscle weakness and fatigue (both AEs of grade 3 and assessed as related to study drug), one patient due to rash acneiform (grade 2, related) and one patient due to heart failure (grade 5, not related). For one patient the following AEs were reported as cause of study drug discontinuation: rash maculo-papular (grade 1, related), skin infection (two events of grade

12 15-MAY-2017 Study no Page: 12 of 13 2, one related, one not related), flu like symptoms (grade 1, not related) and epistaxis (grade 1, not related). TEAEs led to dose interruption in 14 patients (87.5%) of which 6 were in the Asia population and 8 in the RoW population. The most common TEAEs leading to dose interruption, occurring in 2 patients, were CPK increased, syncope, rash acneiform, and hypertension. Investigator considered the TEAEs resulting in dose interruption as study drug-related in a total of 13 patients (81.3%). CPK increased, rash acneiform and hypertension were the most common drug-related TEAEs that led to dose interruption. Study drug dose was reduced due to TEAEs in a total of 6 patients (37.5%) of which 2 patients were in the Asia population and 4 patients in the RoW population. All events leading to dose reduction occurred in 1 patient each: left ventricular systolic dysfunction, mucositis oral, fatigue, CPK increased, dizziness, hallucinations, rash acneiform. All of these TEAEs were assessed as study drug-related. Adverse events of special interest AE of special interest, CPK increase grade 3, was experienced by 3 patients. All these events were of grade 3 in severity, reported as serious as required per the protocol, and considered as related to the study drug. Laboratory abnormalities The most common pre-treatment laboratory abnormalities were Gamma-glutamyltransferase (GGT) increased in 14 patients (87.5%), anemia in 12 patients (75.0%), and Aspartate aminotransferase (AST) increased in 9 patients (56.3%). The most common laboratory abnormality observed after the start of treatment was anemia that was reported in all 16 patients (100.0%). The other common laboratory abnormalities after the start of treatment (occurred in 80% of the patients) were AST increased, GGT increased, hyperglycemia, hypoalbuminemia, CPK increased, and lymphocyte count decreased. The reported worst grade 3 laboratory abnormalities which occurred in more than 1 patient were AST increased, CPK increased, Alanine aminotransferase (ALT) increased, GGT increased, anemia and hyponatremia. The worst grade 4 laboratory abnormalities were hyperuricemia (5 patients), serum amylase increased, AST increased, creatinine increased, GGT increased and platelet count decreased (1 patient each). For CPK increase no abnormal laboratory values were observed in any of the patients before the start of the treatment. During the treatment CPK increase was observed in 12/15 patients (80.0%). In general, the laboratory abnormalities of the liver function parameters of interest, ALT increased, AST increased, and blood bilirubin increased, were more common after the start of the treatment compared to the pre-treatment. Before the start of the treatment, AST increase was reported in 9 patients (56.3%), ALT increase in 4 patients (25.0%), and blood bilirubin increase in 5 patients (31.3%). After the start of the treatment AST increase was reported in 15 patients (93.8%), ALT increase in 10 patients (62.5%), and blood bilirubin increase in 9 patients (56.3%) consistent with deterioration in patient s underlying liver disease.

13 15-MAY-2017 Study no Page: 13 of 13 Other safety evaluations No clinically relevant changes were observed in vital signs. Regarding electrocardiogram findings abnormal interpretations (not clinically significant) were reported in all cycles, 1 patient at EOT visit had clinically significant ECG result containing summary (mean) ventricular rate 60 bpm, summary (mean) PR duration 120 msec, summary (mean) QRS duration 151 msec, sinus rhythm and right bundle branch block. Evaluation of ECOG and Child-Pugh scores during the study are consistent with deterioration in patient s health status mainly due to progression of the underlying disease. Overall conclusions In this trial using refametinib monotherapy in a selected RAS mutant HCC population the following results were observed: Prospective testing for RAS mutation using circulating cell free tumor DNA was feasible The incidence of RAS mutation was 6.5% (n=32) in the overall HCC population tested No patient achieved a confirmed CR or PR (as assessed by central review) using mrecist; the target of the trial (at least 5 out of 15 patients with a confirmed CR or PR) was not reached Median progression free survival (PFS) was 58 days. Time to radiological progression (TTP) was 84 days Overall survival data show a median survival time of 177 days. Refametinib monotherapy was tolerated but did not show sufficient efficacy to warrant further development in this highly selected patient population.