Introduction Hepatocellular carcinoma (HCC) is a major health problem, accounting for more
      than 626,000 new cases per year worldwide. It is the third highest cause of cancer-related
      death globally. In the west, the disease is diagnosed in 30 to 40% of all patients at early
      stages and is amenable to potentially curative treatments, such as surgical therapies
      (resection and liver transplantation) and locoregional procedures (radio-frequency ablation).
      There are no clear epidemiological studies in the Kingdom of Saudi Arabia that gives the real
      incidence of HCC in Saudi population, however the Saudi Cancer registration have labelled it
      as among the top five cancers in the country. Sorafenib has emerged as the treatment of
      choice in the treatment of advanced HCC and has demonstrated an anti-angiogenic and
      anti-proliferative effect. It is a kinase inhibitor that decreases tumor cell proliferation
      in Vitro. Sorafenib has been shown to inhibit multiple intracellular (CRAF, BRAF, and mutant
      BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-B).
      Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and
      apoptosis. In a phase 3 international, multi-center, randomised, doubleblind,
      placebo-controlled trial in patients with unresectable hepatocellualr carcinoma Sorafenib
      showed a statistically significant advantage over placebo for overall survival (HR: 0.69,
      p=0.00058). Final analysis of time to tumor progression also was significantly longer in the
      Protocol number: 1.0 dated 01Aug2013 Short title: HCC - Sorafenib study Confidential Page 11
      The Long-Term Comprehensive National Plan for Science, Technology and Innovation Sorafenib
      arm. This benefit was calculated in months because of the quick emergence of resistance in
      many patients. Therefore, individualizing the treatment to patients with most expected
      response and avoiding it in patients with resistant cancers has stimulated this research to
      evaluate why some patients develop resistance to this therapy.

      Literature review Epidemiology Hepatocellular carcinoma (HCC) is the sixth most common cause
      of cancer worldwide with an annual incidence of over 711,000 new cases, and the third most
      common cause of cancer death with an annual mortality of 679,000 patients. Most commonly HCC
      develops in cirrhosis, irrespective of the etiology. In the western world, chronic alcohol
      abuse and nonalcoholic stratohepatitis are about the as important etiologic factors for
      cirrhosis as chronic hepatitis c. In chronic hepatitis C it is estimated that about 20% of
      patients will eventually develop cirrhosis after 20-30 years of infection. Once cirrhosis is
      established, the annual risk of developing HCC is estimated to be between 3 and 4 %, largely
      irrespective of the etiology of cirrhosis. Diagnosis of HCC HCC is mostly asymptomatic in
      early stage disease. Without proper surveillance programs of cirrhotic patients, diagnosis is
      only established in advanced stage disease. The efficacy of surveillance by Ultrasound (and
      to a lesser extent by alpha-fetoprotein measurement) has been established in prospective
      trials in the west as well in the east. surveillance by experienced sonographers makes
      curative treatment possible treatment possible in up to 75% of patients,while there is no
      curative treatment without proper surveillance. Surveillance is recommended for the following
      groups of patients: Hepatitis B carriers Asian males > 40 years, Asian females >50 years, All
      cirrhotic hepatitis B carriers, Family history of HCC, Africans over age 20. For
      non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies depending on the
      severity of the underlying liver disease, the Long-Term Comprehensive National Plan for
      Science, Technology and Innovation inflammatory activity. Patients with high HBV DNA
      concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC.
      Non-hepatitis B cirrhosis Hepatitis C, Alcoholic cirrhosis, Genetic hemochromatosis, Primary
      biliary cirrhosis. Although the following groups have an increased risk of HCC no
      recommendations for or against surveillance can be made because a lack of data precludes an
      assessment of whether surveillance would be beneficial - Alpha1-antitrypsin deficiency
      ,Non-alcoholic steatohepatitis, Autoimmune hepatitis. Once a lesion is detected by
      ultrasound, the diagnosis can be established radiologically in lesions with typical
      appearance above 1 cm in diameter. Biopsy is mandated only in cases with atypical
      presentation on imaging. Staging of HCC Staging of HCC can be done using several systems.
      currently, the most widely used staging system is the Barcelona Clinic Liver Cancer (BCLC)
      staging system , which takes the underlying liver disease, tumor characteristics, as well as
      the general performance status into account . This staging system is popular as it is
      directly linked to treatment, making treatment decisions easy. Advanced stage HCC: the
      current role of medical therapies In western countries, about 30 % of patients are identified
      with an HCC in BCLC stage 0 or A, either through surveillance or by chance. For those
      patients curative options can be applied, which currently involve only surgical or
      interventional treatments. However , curatively treated patients , except for those who
      underwent transplantation, will have a tumor recurrence in 70 to 80 % of cases within 5 years
      of therapy and will eventually progress to BCLC B or BCLC C stage disease. Another 20 % of
      patients are diagnosed at very advanced stages BCLC D, being either symptomatic from the
      decompensated cirrhosis (Child-Pugh C) or having an advanced tumor. Those patients have a
      very short survival, which cannot be influenced by any therapeutic intervention and are only
      eligible to receive best supportive care. Currently, the domain of medical therapies for HCC
      is in the setting of advanced stage BCLC C. Conventional chemotherapy of any kind has never
      shown any meaningful therapeutic benefit, particularly in overall survival in randomized
      controlled trials in adult patients and cannot be recommended for the treatment of HCC today.
      Conventional cisplatin-based chemotherapy, Technology and Innovation without doxorubicine
      only has a place in the treatment of childhood hepatoblastoma, which is a distinctly
      different disease entity. In hepatoblastoma cisplatin-based chemotherapy does improve
      survival and can even provide a cure in over 80% of patients when combined with resection.
      Medical treatment of HCC changed dramatically in 2007 , when the first data from the
      successful use of targeted agents in advanced stage HCC, in particular tyrosine kinase
      inhibitors, were presented. Up-regulated signaling through the mitogen-activated protein
      kinase (MAPK) intracellular signal transduction pathway plays a crucial role in the
      development of hepatocellular carcinoma , as does tumor angiogenesis .The MAPK pathway
      comprises Raf ,MAPK kinase (MEK ) and extracellular signal-regulated Kinase (ERK), and is a
      mediator of tumor proliferation, differentiation and survival. The identification of pivotal
      pathways, such as the MAPK cascade, led to the development of targeted treatments, such as
      Sorafenib. Sorafenib is an orally active multikinase inhibitor that inhibits cell surface
      tyrosine kinases, as well as downstream intracellular Raf kinases in the MAPK cascade.
      Sorafenib is widely available for the use in the treatment of advanced renal cell carcinoma
      and has been reviewed in this indication previously. Recently, Sorafenib was also approved in
      the US and the EU for use in the treatment of hepatocellular carcinoma, the first systemic
      drug to be approved in this indication. Indeed, current US treatment guidelines recommend
      Sorafenib as the first-lone treatment option in patients with unresectable HCC who are
      Child-Pugh class A. Receptor tyrosine Kinases inhibited by Sorafenib include vascular
      endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, Platelet-derived growth
      factor receptor (PDGFR)-B, cKIT, FMS-like tyrosine kinase 3 (FLT-3) and RET. Intracellular
      Raf serine/threonine kinase isoforms inhibited by Sorafenib include Raf-1(or C-Raf), wild
      -type B-Raf and Mutant B-Raf. These kinases are involved in tumor cell proliferation and
      tumor angiogenesis. In vitro, dose-dependent inhibition of cell proliferation was seen with
      Sorafenib in the human hepatocellular carcinoma cell lines PLC/PRF/5 and HepG2. Moreover,
      dose dependent induction of apoptosis was seen after Sorafenib exposure, as assessed by TUNEL
      (terminal deoxynucleotide transferase d-uridine triphosphate nick end labeling) staining.
      Inhibition by Sorafenib of the Raf/MEK/ERK signaling pathway in PCL/PRF/5 and HepG2 cells was
      shown by, among other things, the inhibition of MEK and ERK phosphorylation. Sorafenib
      demonstrated Protocol number: 1.0 dated 01Aug2013 Short title: HCC - Sorafenib study
      Confidential Page 14 The Long-Term Comprehensive National Plan for Science, Technology and
      Innovation dose-dependent antitumor activity in murine xenograft model of PCL/PRF/5 human
      hepatocellular carcinoma. Significant tumor growth inhibition of 49% and 78% was seen in mice
      receiving oral Sorafenib 10 or 30 mg/kg/day for 16 or 21 days ( both P 16 weeks and 48
      (35.0%) had progressive disease (the remaining 32 patients [23.4%] were not available for
      independent review). With Sorafenib, the median time to progression was 4.2 months
      (investigator assessment) or 5.5 months (independent assessment), and the median overall
      survival duration was 9.2 months. Phase III trial The clinical efficacy of oral Sorafenib was
      examined in patients with advanced HCC in a randomized, double-blind, placebo-controlled,
      multi center, phase III trial (the SHARP study) (22). Inclusion criteria were histologically
      proven, advanced hepatocellular carcinoma, with at least one measurable untreated lesion, an
      ECOG performance status of 0-2, Child-Pugh class A and no prior systemic treatment . 902
      patients were screened and 602 were randomized to receive oral Sorafenib 400 mg twice daily
      (n=299) or placebo (n=303). The median duration of treatment was 23 weeks in Sorafenib
      recipients and 19 weeks in placebo recipients. Prior to randomization, patients were
      stratified according to macroscopic vascular invasion and/or extrahepatic spread, ECOG
      performance status and Geographical region. In terms of baseline characteristics, mean
      patient age was 65.5 years; 87% of patients were male; 87.5% of patients were from Europe;
      96.5% of patients were Child-Pugh class A; 54%, 38.5% and 7.5% of patients had an ECOG
      performance status of 0, 1, 2 at baseline; 17.5% and 82.5% of patients had Barcelona Clinic
      Liver Cancer Group stage B and C cancer; and 70% of patients had vascular invasion and/or
      extrahepatic spread . The primary endpoints were overall survival and time to symptomatic
      progression (defined as the time from randomization to a 4-point decline from baseline in
      patient response to the Functional Assessment Of Cancer Treatment Hepatobiliary Symptom index
      [FHSI-8] confirmed at next visit , deterioration to ECOG performance status 4, or death). The
      time to progression (assessed by independent central review) was a pre-specified secondary
      endpoint. Tumor response rates were assessed using Response Evaluation Criteria in Solid
      Tumors (RECIST). Analyses were conducted in the intent-to-treat (ITT) population (22).
      Sorafenib significantly improved survival in patients with advanced hepatocellular carcinoma
      in the SHARP trial (22). The median duration of survival was 10.7 months with Sorafenib and
      7.9 months with placebo, yielding a hazard ratio (HR) of 0.69 (95% CI 0.55, 0.88; P =
      0.00058). Following the second planned interim analysis, the SHARP study was terminated early
      on the basis of this survival result. At the time of study termination, there was no
      significant difference between Sorafenib and placebo recipients in the time to symptomatic
      progression (assessed using FHSI-8 criteria). The median time to progression (assessed by
      independent central review) was significantly longer in patients receiving Sorafenib than
      those receiving placebo (5.5 vs. 2.8 months), with an HR of 0.58(95% CI 0.44, 0.74; P Overall
      study design Screening and Pre-Treatment Period Investigator/ Co-Investigator/Study
      Coordinator • Medical history • Biopsy and review of pathology • Physical examination and
      vital signs • Review of previous or concurrent medications and procedures • Child-Pugh
      assessment • ECOG assessment • Lesion(s) measurement • Determination of study eligibility •
      Written, signed and date informed consent Laboratory investigations • Hematology: CBC,
      Differential • Serology: HBV, HCV, and HIV • The levels of the Bimarkers: c-KIT, Soluble
      VEGFR-2,-3. • Coagulation: platelets, PT, PTT, INR • Liver function tests • Serum pregnancy
      test (as appropriate) Radiological investigations • CT scan (or MRI) of the chest • CT scan
      (or MRI) of the abdomen • PET Scan Patient • Review of patient information leaflet Treatment
      period Baseline Visit - Day 1 Investigator/ Co-Investigator/Study Coordinator • Review of
      concomitant medications and therapies • Review of ECOG • Prescription of Sorafenib Patient •
      Start of the Sorafenib 6-8 weeks cycle Sorafenib Cycle Week 0-6/8 Laboratory investigations
      to be done on a weekly basis • Hematology: CBC, Differential • Serology: HBV, HCV, and HIV •
      Coagulation: platelets, PT, PTT, INR results of laboratory investigations on a weekly basis •
      See patients every other week Patient • Takes the appropriate dose of Sorafenib • Goes for
      blood test every week • Consult with the investigator/co-investigator every other week Visit
      after first Sorafenib cycle (Week 5 + 1 week) Investigator/ Co-Investigator/Study Coordinator
      • Physical examination • Review of concomitant medications and therapies • Child-Pugh
      re-assessment • ECOG re-assessment • Lesion(s) measurement • Recording of Adverse events
      Laboratory investigations • Hematology: CBC, Differential • Coagulation: platelets, PT, PTT,
      INR • Liver function tests Radiological investigations • CT scan (or MRI) of the abdomen
      Follow-up Visits (Every 3 months)* Investigator/ Co-Investigator/Study Coordinator • Physical
      examination • Review of concomitant medications and therapies • Child-Pugh re-assessment •
      ECOG re-assessment • Lesion(s) measurement • Recording of Adverse events Laboratory
      investigations • Hematology: CBC, Differential • Coagulation: platelets, PT, PTT, INR • The
      Bio-markers: c-KIT, VEGFR -2,-3 at week 12. • Liver function tests Radiological
      investigations • CT scan (or MRI) of the abdomen *The patient is going to be followed up in
      the basis of either stable disease or partial response or progression this based on
      radiological profession (which is assessed by RECIST). For those with progression other
      Biopsy will be taken and the tissue to be evaluated further.

      Study procedures All laboratory tests will be conducted as normal with additional specific
      tests to be performed in Liver Disease Research Center (LDRC), or the Proteomics Lab,
      KSU-Riyadh. Blood will be collected in three 7ml tubes with each biopsy. cDNA microarray
      analysis will be done on the pathways acted on by Sorafenib, namely the MAP kinase pathway.
      The analysis will be done at LDRC, KSU-Riyadh. • Tissue samples will be obtained in all
      patients from the tumor under imaging guidance • Tumor tissue biopsies will be performed at
      baseline and at end-of-study/when study endpoint is met o A minimum of 3 cm of tumor tissue
      will be obtained (2-3 needle passes). o Transportation of samples to the LDRC will be done on
      dry ice. o Tissue obtained will be snap frozen at -800C until processing. o Tissue will be
      tested for genes involved in the RAF pathway. o Genetic expression from the fresh tumor
      tissue will be quantified using RT-PCR for mRNA quantification. Once upregulated genes are
      identified, their corresponding proteomic expression will be tested in the serum for
      potential serum markers. Proteomic testing will be performed using Mass Spectroscopy.
      Additional specific blood tests will be performed in LDRC. Blood will be collected in two 7
      ml EDTA tubes (purple top) and one plain tube (red top). Blood samples will be collected at
      the same time with the liver biopsy. Blood once collected will be transported immediately to
      LDRC on dry ice and stored at -80oC. Samples will be thawed and data analysed when the
      individual patient has met study end-point or at study completion, as relevant. Liver biopsy
      samples will also be transported on dry ice to LDRC and snap-frozen at -80oC for subsequent
      analysis. Blood and tissue will be collected and transported by pre-arrangement with LDRC
      staff, and will be coordinated by the SOLID registrar (Nouf Alanezi) and/or the study CRC in
      KAMC-Riyadh. All patient-related data, including demographic, clinical, laboratory, and
      radiological data will be collected in the comprehensive HCC eCRF of the SOLID registry where
      appropriate. As a feature of the registry, all patient-related data is encoded in order to
      remove any patient identifiers. All blood samples stored for end-of-study investigations will
      be barcoded and the stickers tagged to the SOLID registry identifiers for easy retrieval.

      Study subjects The study is expected to run for about 3 years and patients will be followed
      for a period of 24 months. All consecutive patients presenting with HCC satisfying study
      inclusion and exclusion criteria will be approached for participation. At an average, about
      200 patients with HCC are evaluated annually in the multi study centres. We anticipate that
      60 patients would be eligible for the study of whom 40 would be recruited for the study. A
      total of 40 patients will be recruited from 2 - 3 centers in KSA (KSU, LDRC; KAMC-Riyadh). Of
      these 15 patients will be recruited from King Abdulaziz Medical City, Riyadh. Recruitment is
      planned to be completed in the first year of the study.

      Duration of treatment and removal of subjects Patients will be followed for a period of 24
      months. Patients removed from study for unacceptable adverse events will be followed until
      resolution or stabilization of the adverse event. Patients are to continue therapy with
      Sorafenib until • Disease progression • Until a criterion is met for stopping therapy like o
      Concurrent illness that prevents further administration of treatment o Unacceptable adverse
      events(s) o Patient decides to withdraw from the study o General or specific changes in the
      patient's condition render the patient unacceptable for further treatment in the judgment of
      the investigator. In the event of radiologic progression, patients may continue to receive
      the study drug. Decisions about continuing study medication will be made at the discretion of
      the investigator, based on the investigator's judgment about the patient's clinical status.
      In general, it is suggested that patients remain on Sorafenib if, in the opinion of the
      investigator, the patient may be benefiting from continuing on study drug Removal of subjects
      and the reason of the removal will be documented.

      Treatment description No investigational or commercial agents or therapies other than
      Sorafenib may be administered with the intent to treat the patient's malignancy. Sorafenib
      will be given at the dose of 2 tablets of 200mg (400 mg) to be taken twice a day in the
      morning and in the evening without food (at least 1 hour before or 2 hours after a meal). If
      a dose reduction is necessary, the Sorafenib dose may be reduced to 200 mg twice a day. If
      additional dose reduction is required, the dose may be reduced to a single 400 mg dose every
      other day. Reported adverse events, potential risks, and appropriate dose modifications for
      are described below. Informed Consent: If a patient is found to meet the eligibility criteria
      and expresses an interest in participation, Other treatment options will also be discussed
      with the patient prior to completing informed consent. No study related procedures will be
      conducted prior to the patient signing the informed consent. The subject will be provided
      with a copy of the Patient Information Sheet and will be given the opportunity to ask any
      question or seek clarification.