Mechanism of Sorafenib Resistance in Patients With Advanced Hepatocellular Carcinoma

NCT02733809 | Unknown Phase 4 DMC

• 1 other identifier: KSULDRCSSMH001
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hepatocellular Carcinoma

Keywords

Hepatocellular Carcinoma; Sorafenib

Outcome Measures

Primary Outcomes (1)

• Overall and disease-free survival genes.

  Survival analysis

  10 years

Secondary Outcomes (2)

• The predictors of survival ( response to Sorafenib )

  10 years

• Potential genetic targets for resistance.

  10 years

Study Arms (1)

Sorafenib

EXPERIMENTAL

Group under the treatment ( sorafenib ) Maximum dose of 400 mg BID If subjects devolves adverse events, dose can be reduced.

Drug: Sorafenib

Interventions

Sorafenib DRUG

Liver lesion biopsy (HCC) and blood samples will be taken from the subjects before starting the treatment course, and another biopsy and blood samples when they devolve a resistance.

Also known as: Nexavar

Sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• King Saud University: lead
• King Faisal Specialist Hospital & Research Center: collaborator

Study Sites (1)

King Saud University Medical City

Riyadh, 7805, Saudi Arabia

RECRUITING

Related Publications (13)

• Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004 Jul;130(7):417-22. doi: 10.1007/s00432-004-0552-0.

  PMID: 15042359 BACKGROUND

• Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, Morabito A, De Franchis R, Colombo M. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004 Apr;126(4):1005-14. doi: 10.1053/j.gastro.2003.12.049.

  PMID: 15057740 BACKGROUND

• Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet. 2009 Feb 21;373(9664):614-6. doi: 10.1016/S0140-6736(09)60381-0. No abstract available.

  PMID: 19231618 BACKGROUND

• Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008 Jan;47(1):82-9. doi: 10.1002/hep.21933.

  PMID: 18008357 BACKGROUND

• Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25(2):181-200. doi: 10.1055/s-2005-871198.

  PMID: 15918147 BACKGROUND

• Thomas MB, O'Beirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P. Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy. Ann Surg Oncol. 2008 Apr;15(4):1008-14. doi: 10.1245/s10434-007-9705-0. Epub 2008 Jan 31.

  PMID: 18236117 BACKGROUND

• Mathurin P, Rixe O, Carbonell N, Bernard B, Cluzel P, Bellin MF, Khayat D, Opolon P, Poynard T. Review article: Overview of medical treatments in unresectable hepatocellular carcinoma--an impossible meta-analysis? Aliment Pharmacol Ther. 1998 Feb;12(2):111-26. doi: 10.1046/j.1365-2036.1998.00286.x.

  PMID: 9692685 BACKGROUND

• Perilongo G, Maibach R, Shafford E, Brugieres L, Brock P, Morland B, de Camargo B, Zsiros J, Roebuck D, Zimmermann A, Aronson D, Childs M, Widing E, Laithier V, Plaschkes J, Pritchard J, Scopinaro M, MacKinlay G, Czauderna P. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med. 2009 Oct 22;361(17):1662-70. doi: 10.1056/NEJMoa0810613.

  PMID: 19846851 BACKGROUND

• Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006 Dec 15;66(24):11851-8. doi: 10.1158/0008-5472.CAN-06-1377.

  PMID: 17178882 BACKGROUND

• Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. doi: 10.1016/S0076-6879(05)07047-3.

  PMID: 16757355 BACKGROUND

• McKeage K, Wagstaff AJ. Sorafenib: in advanced renal cancer. Drugs. 2007;67(3):475-83; discussion 484-5. doi: 10.2165/00003495-200767030-00009.

  PMID: 17335301 BACKGROUND

• Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. doi: 10.1158/0008-5472.CAN-04-1443.

  PMID: 15466206 BACKGROUND

• Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-300. doi: 10.1200/JCO.2005.01.3441. Epub 2006 Aug 14.

  PMID: 16908937 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Mazen M Hassanain, MBBS FRCSC PhD

  King Saud University Medical City, Riyadh,KSA.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weam S Hussein, MBBS FRCSC PhD

CONTACT

+966 541480459; wshussain@ksu.edu.sa

Mazen M Hassanain

CONTACT

+966 50 514 1090; mhassanain@ksu.edu.sa

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assocaite Professor of Surgery and Consultant HPB and Transplant Surgery

Study Record Dates

• First Submitted: February 15, 2016
• First Posted: April 12, 2016
• Study Start: January 1, 2014
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: August 20, 2019

Record last verified: 2019-08

Locations

SA (1)