Mechanism of Sorafenib Resistance in Patients With Advanced Hepatocellular Carcinoma

It has been shown previously that gene expression profiling signature (a set of dysregulated genes) can be used for molecular classification, diagnosis, and prognosis of several types of cancers. In This study the hypothesise that resistant tumor may be due to genetic mutations and/or other alternative pathways that could be the reason to overcome the Sorafenib and still proliferate. Primary objectives To evaluate the primary and secondary potential mechanisms by which HCC patients on Sorafenib treatment would be resistant to therapy and also identify the favorable genetic makeup of patients responding to treatment. Measures of primary outcome: * cDNA microarray analysis on the MAP kinase pathway. * mRNA quantification of genetic expression (RT-PCR) for identification of upregulated genes, and confirmed by corresponding proteomic testing (by Mass Spectroscopy) in the serum for potential serum markers. Secondary Objectives Progression free survival: Time to disease progression in patients in Saudi Arabia with HCC receiving Sorafenib: \[defined as time, in weeks, from the baseline visit to progression of the disease or death from any cause\] will be diagnosed using the RECIST criteria based on a trimestrial abdominal CT evaluation. * Survival rates and Predictors of survival: * Survival defined as the time from baseline visit to death from any cause \[in weeks\]. * Variables identified in multivariate regression analysis from overall treated patients independently associated with survival till study completion or death. Justification and Value to the Kingdom Sorafenib in the treatment of advanced HCC is a recent development. Since the only current effective treatment for advanced HCC is resection or transplantation and the list for these procedures are ever-growing due to the confounding effect of the lack of infrastructure in the Kingdom, selecting treatment for patients who are more likely to respond to Sorafenib treatment The Long-Term Comprehensive National Plan for Science, Technology and Innovation will help to reduce costs of managing HCC. Among Saudi Arabia population, there are a unique set of patients here (e.g. non-alcohol related HCC, genotype 4 HCV patients and genotype D HBV patients, high percentage of obese patients i.e. NASH) which is different from other parts of the world. There is increasing incidence of HCC in Saudi Arabia. Due to available expertise in management of HCC patients in the participating institutions in the study, this project will represent a bridge for the transfer of technology so that our research staff and doctors will have more expertise in carrying out these techniques independently. This study will also run in parallel to the on-going initiative to start a HCC biobanking establishment which will provide the samples needed to carry out our genetic studies in future. Finally, since the use of Sorafenib (at present, the only approved treatment for advanced HCC) in the treatment of advanced HCC is a new field, the findings of our study will have important implications in the management of HCC, both locally and internationally. HCC is the third most common cancer in Saudi Arabia. In 2001, HCC was the second most common cancer affecting Saudi males and the eighth most common cancer affecting females. Most of patients (90%) present at a more advanced stage when symptoms prevail. Given the high prevalence of HCC in the Kingdom, it is pertinent to study why some patients are resistant to Sorafenib compared to others. Elucidation of the differences in mechanisms among responders and non-responders to Sorafenib therapy will enable physicians to make better decisions in terms of treating Saudi HCC patients.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

Male or female patient over 18 years of age

* Patient who have a life expectancy of at least 12 weeks
* Biopsy proven diagnosis of hepatocellular carcinoma
* Liver lesions are visible and measurable of at least 3 cm in size
* Advanced HCC, defined by the presence of one of the followings:

  * Vascular invasion
  * HCC with cancer-related symptoms with ECOG Score of 0, 1 or 2
  * Progression after resection or local ablation and not for further curative therapies
* Cirrhotic status of Child-Pugh class A and B (score ≤ 8)
* The following laboratory parameters:

  * Platelet count \> 50 X 109 /L
  * Hemoglobin \> 85 g/L
  * Total bilirubin \< 51.3 umol/L
  * ALT and AST \< 5X upper limit of normal
  * Amylase and lipase \< 1.5 X the upper limit of normal
  * Serum creatinine \< 1.5 X the upper limit of normal
  * Prothrombin time (PT) international normalized ratio (INR) \< 2.3 or PT \< 6 seconds above control. Patients who are being therapeutically anticoagulated with an agent such as Coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.
* Able to give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
* Any institution/centre specific criteria that must be adhered to for the patient to be eligible.

Exclusion Criteria:

Previous or concurrent cancer that is distinct in primary site or histology from HCC.

Except:

* Cervical carcinoma in situ
* Prostate cancer with good prognosis
* Treated basal cell carcinoma
* Superficial bladder tumors (Ta, Tis \& T1)
* Any cancer curatively treated 3 years prior to entry is permitted.

  * A Child-Pugh rating of C at entry
  * An ECOG performance score of 3 or 4 at entry
  * Extensive extra-hepatic disease
  * Tumor volume \> 50% of liver volume
  * Contraindication to angiography or selective visceral catheterization
  * Any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agent
  * Severe peripheral vascular disease precluding catheterization
  * History of severe allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically
  * Platelet count \< 30,000 or \< 50% prothrombin activity
  * Renal failure requiring hemo-or peritoneal dialysis
  * Pulmonary insufficiency (clinically evident history of chronic obstructive pulmonary disease)
  * History of cardiac disease:

    * Congestive heart failure \> New York Heart Association (NYHA) class2
    * Active coronary artery disease
    * Uncontrolled hypertension
  * Active clinically serious infection(s)
  * Known history of human immunodeficiency virus (HIV) infection
  * Patient with clinically significant gastrointestinal bleeding within 30 days prior to study entry
  * History of organ allograft/transplantation
  * 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 allergy to the investigational agent or any agent given in association with this trial
  * Patients unable to swallow oral medications
  * Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study
  * Pregnant or breast-feeding patients
  * Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug.
  * Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial.

Excluded therapies and medications - previous and concomitant:

* Prior use of any systemic anti-cancer chemotherapy for HCC
* Prior use of systemic investigational agents for HCC
* Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, EMK inhibitors or Farnesyl transferase inhibitors
* Major surgery within 4 weeks of start of the study drug
* Use of biologic response modifiers, such as granulocytes colony-stimulating factor (G-CSF) within 3 weeks prior to study entry (G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction)
* Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 1 month prior to the study or during the study.
* Autologous bone marrow transplant or stem cell rescues within four months of start of study drug
* Concomitant treatment with rifampin and St John's wort

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