Ignite Creation Date:
2024-05-06 @ 5:41 PM
Last Modification Date:
2024-10-26 @ 2:33 PM
Study NCT ID:
NCT05391867
Status:
UNKNOWN
Last Update Posted:
2022-05-26
First Post:
2020-11-26
Brief Title:
Assessment of the Efficacy of Lenvatinib Versus Sorafenib in the Management of Advanced Hepatocellular Carcinoma
Sponsor:
Sir Salimullah Medical College Mitford Hospital
Organization:
Sir Salimullah Medical College Mitford Hospital
Study Overview
Official Title:
Assessment of the Efficacy of Lenvatinib Versus Sorafenib in the Management of Advanced Hepatocellular Carcinoma - An Open-label Randomized Clinical Control Trial in a Tertiary Care Hospital
Status:
UNKNOWN
Status Verified Date:
2022-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hepatocellular carcinoma is the most common type of liver cancer which is the 3rd leading cause of cancer deaths worldwide The incidence is expected to increase as a consequence of chronic liver disease with its multiple risk factors including chronic hepatitis B virus HBV and hepatitis C virus HCV infections excessive alcohol consumption nonalcoholic fatty liver disease hemochromatosis and aflatoxin B1It is estimated that 70-90 of patients with HCC have chronic liver disease and cirrhosis which limits the feasibility of surgical procedures in advanced cases There are limited treatment options for HCC patients who are ineligible for surgical resection Locoregional therapies such as radiofrequency ablation transarterial chemoembolization TACE transarterial embolization TAE or hepatic arterial infusion chemotherapy HAIC are primarily recommended and if one of those fail then systemic therapy is considered The 2013 Japan Society of Hepatology HCC Guidelines outlined that the factors influencing treatment decisions should be based on the degree of liver damage Child-Pugh presence or absence of extrahepatic spread and macrovascular invasion the number of tumors and tumor diameter Sorafenib has been the standard of care since 2007 when the SHARP trial demonstrated that sorafenib improved median overall survival OS compared to placebo in patients who had not received prior systemic therapy 107 vs 79 months HR 069 P0001 In patients from the Asia-Pacific region taking sorafenib the median improvement in overall survival compared with placebo was 23 months 65 months vs 42 months HR 068 p0014 Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials of sunitinib brivanib linifanib and erlotinib plus sorafenib that did not show non-inferiority Sorafenib an oral multikinase inhibitor has been the only systemic therapy demonstrated to extend overall survibility as a firstline treatment showing a median improvement of 28 months compared with placebo 107 months vs 79 months hazard ratio HR 069 p00016 Inpatients from the Asia-Pacific region taking sorafenib the median OS mOS improvement compared with placebo was 23 months HR 068 p 0014 The use of other molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority to sorafenib thus until the appearance of lenvatinib sorafenib has also been widely used as the first-line treatment for uHCC patients in Japan Recently regorafenib and Nivolumab were approved as a second-line systemic treatment for patients who do not respond to the first-line treatments Otherwise best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines Chemotherapy in combination with sorafenib doxorubicin and radioembolization with SIR Spheres Y-90 resin microspheres failed to demonstrate a survival benefit or showed a worse safety profile compared to sorafenib in the first-line setting Eventually the PhaseIII non-inferiority REFLECT trial showed that lenvatinib was non-inferior compared to sorafenib
Detailed Description:
1 Introduction
Hepatocellular carcinoma is one of the most common type of liver cancer which is the 3rd leading cause of cancer deaths worldwide The incidence is expected to increase as a consequence of chronic liver disease with its multiple risk factors including chronic hepatitis B virus HBV and hepatitis C virus HCV infections excessive alcohol consumption nonalcoholic fatty liver disease hemochromatosis drugs and aflatoxin B1 It is estimated that 70-90 of patients with HCC have chronic liver disease and cirrhosis which limits the feasibility of surgical procedures in advanced cases There are limited treatment options for HCC patients who are ineligible for surgical resection Locoregional therapies such as radiofrequency ablation RFA transarterial chemoembolization TACE transarterial embolization TAE or hepatic arterial infusion chemotherapy HAIC are primarily recommended and if one of those fail then systemic therapy is considered The 2013 Japan Society of Hepatology HCC Guidelines outlined that the factors influencing treatment decisions should be based on the degree of liver damage Child-Pugh presence or absence of extrahepatic spread and macrovascular invasion the number of tumors and tumor diameter Sorafenib has been the standard of care since 2007 when the SHARP trial demonstrated that sorafenib improved median overall survival OS compared to placebo in patients who had not received prior systemic therapy 107 vs 79 months HR 069 P0001 In patients from the Asia-Pacific region taking sorafenib the median improvement in overall survival compared with placebo was 23 months 65 months vs 42 months HR 068 p0014 Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials of sunitinib brivanib linifanib and erlotinib plus sorafenib that did not show non inferiority Sorafenib an oral multikinase inhibitor has been the only systemic therapy demonstrated to extend overall survibility as a firstline treatment showing a median improvement of 28 months compared with placebo 107 months vs 79 months hazard ratio HR 069 p0001 Inpatients from the Asia-Pacific region taking sorafenib the median OS mOS improvement compared with placebo was 23 months HR 068 p 0014 The use of other molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority to sorafenib thus until the appearance of lenvatinib sorafenib has also been widely used as the first-line treatment for HCC patients in Japan Recently regorafenib and Nivolumab were approved as a second-line systemic treatment for patients who do not respond to the first-line treatments Otherwise best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines Chemotherapy in combination with sorafenib doxorubicin and radioembolization with SIR Spheres Y-90 resin microspheres failed to demonstrate a survival benefit or showed a worse safety profile compared to sorafenib in the first-line setting Eventually the PhaseIII non-inferiority REFLECT trial showed that lenvatinib was non-inferior compared to sorafenib
2 Objectives
21 General objectives
To assess and compare the efficacy of Lenvatinib versus Sorafenib in the management of Hepatitis B virus related Hepatocellular Carcinoma
22 Specific objectives
a To assess and compare the overall survibility of hepatocellular carcinoma patients between the groups of Lenvatinib and Sorafenib b To assess and compare the progression free survival outcome between the groups of Lenvatinib and Sorafenib c To assess and compare the improvement of liver function tests between the groups of Lenvatinib and Sorafenib d To assess and compare the improvement of AFP levels between the groups of Lenvatinib and Sorafenib e To assess and compare the improvement of ECOG performance status of the HCC patients between the groups of Lenvatinib and Sorafenib f To assess and compare the improvement of Chil-Pugh scores among the HCC patients between the groups of Lenvatinib and Sorafenib g To assess and compare the size and number of target lesions by mRECIST criteria among the HCC patients between the groups of Lenvatinib and Sorafenib
3 Methodology
The study will be conducted considering the following methodological aspects
31 Study design An open label randomized clinical control trial study
32 Study duration From the date of randomization to next 3 months or till death whichever one will be earlier
33 Study place Department of Hepatology Sir Salimullah Medical College Mitford Hospital
34 Study population Patients diagnosed as advanced Hepatocellular Carcinoma by imaging cytology or histology with no option of resectibility will be selected for the study
35 Sample size calculation
n P1 1-P1 P2 1-P2 P1 -P2 2 ZαZβ2
P1 Proportion of patients developed objective response in one arm Lenvatinib group P2 Proportion of patients developed objective response in another arm Sorafenib group Zα Z-value two tail at a definite level of significance eg 196 at 5 level of significance Zβ Z-value one tail at a definite power eg 084
Here P1 406 objective response with Lenvatinib 0406 P2 124 objective response with Sorafenib 0124 Zα196 and Zβ 08419
n04061-0406 01241-01240406-01242 1960842 343 in each group 35 in each group Total sample number 70 35 in Lenvatinib group and 35 in Sorafenib group
36 Sampling technique and recruitment of study subjects
Participants of the study will be recruited via 11 randomization from patients admitted in the department of Hepatology Sir Salimullah Medical College Mitford Hospital and diagnosed as a case of advanced Hepatocellular Carcinoma with no option of resectibility
37 Eligibility criteria
371 Inclusion criteria
1 Patients with Hepatocellular Carcinoma Diagnosed histologically or cytologically or by imaging criteria with CT or MRI with no option of resectibility BCLC stage B or C
2 Age 18 years
372 Exclusion criteria
1 Patients with very early stage Hepatocellular Carcinoma BCLC stage 0
2 Patients with early stage Hepatocellular Carcinoma BCLC stage A
3 Patients with terminal stage Hepatocellular Carcinoma BCLC stage D
4 Patients with Hepatocellular Carcinoma with obvious invasion to bile duct
5 Patients who received previous systemic therapy for Hepatocellular Carcinoma
7 Patients with jaundice serum bilirubin 3 mgdl 8 Patients with aminotransferases 5ULN 8 Patients with other co-morbid conditions COPD CKD Heart failure IHD pregnancy
373 Primary outcome measure
1 To measure overall survival of the patients from the date of randomization up to 6 months or till death whichever one will be earlier
374 Secondary outcome measure
1 Progression free survival
2 Time to progress
3 Objective response rate
4 Quality of life
5 Assessment of safety
38 Outcome measure
1 Primary endpoint
a Overall survibility From the date of Randomization to next 3 months or till death
2 Secondary endpoint
1 Progression free survival
2 Time to progress
3 Quality of life measurement By ECOG performance status
4 Liver function tests By SBilirubin ALT AST ALP Prothrombin time INR Serum albumin
5 AFP level
6 Child-turcotte-Pugh score
7 Tumor assessment by mRECIST criteria
39 Research instrument
For collection of primary data about patient a semi-structured questionnaire will be developed based on research objective Pre-testing of the questionnaire will be done on other patients admitted at the same facility After the pretesting amendment of the items and question will be done based on study finding In the final questionnaire both structured and open questions will be kept
A check list will be prepared to compile the data from hospital records treatment records outcome of treatment and laboratory investigation reports
310 Data collection procedure
All data will be collected by face-to-face interview of the patients attendant by the researcher at health facility upon their consent and convenience Socio demographic and personal information will be recorded from patient through interview with a semi structured pre-tested questionnaire Information regarding risk factors and risk behavior will be inquired taking effort to minimize the recall bias
311 Data processing
Data processing will include data cleaning and quality control check editing of data coding of data and data entry into computer The edited data will be entered on to the template of SPSS 23
312 Data analysis
The edited data will then be entered on to the template of SPSS 23 For Back ground variables and socio-demographic data descriptive statistics and relative frequency percentage will be generated All data will be presented as mean SD Qualitative data will be analyzed by Chi-square test and quantitative data will be analyzed by students t-test Through univariate analysis the base line characteristics and treatment outcome will be compared The effect of treatment will be identified through Multivariate analysis after adjusting for possible confounders Relative risk with 95 CI will be generated through binary logistic regression adjusting for all possible confounders A statistically significant result will be considered when p value 005
313 Data Presentation
Data will be presented in the form of table and graphs Descriptive statistics will be presented with frequency table Association will be illustrated with cross tables and test statistics will be added in the foot note of the table Bar and pie charts will be generated to illustrate descriptive statistics
4 Ethical considerations
Approval from the ethical review committee of Sir Salimullah Medical College and Mitford Hospital will be taken prior to commencement of the study Informed written consent will be taken from the participants after explaining about the details of the study The participants will be assured that the information acquired will be used for academic purpose They will be assured of confidentiality and for the purpose of data analysis no individual data were reported rather de identified data will be preceded for analysis
5 Facilities Resources Equipments Chemicals Subjects etc required for the study
Principal investigator has full-fledged Department of Hepatology at Sir Salimullah Medical College Mitford Hospital Dhaka
Sir Salimullah Medical College Mitford Hospital Dhaka has adequate facilities to carry out all the investigations required for this study
Sir Salimullah Medical College Mitford Hospital Dhaka has adequate facility to deal with the adverse effect of the drug under trial as well as management of the subjects of the current study
6 Material methods
The study will be conducted in the department of Hepatology Sir Salimullah Medical College Mitford Hospital It will be an open label randomized clinical control trial study Patients admitted in the department of Hepatology diagnosed as a case of Hepatocellular Carcinoma by imaging or cytopathology or histopathology will be primarily targeted for the study Initial assessment of each patient will be done by Chil-pugh score ECOG performance status Tumor assessment by mRECIST criteria and BCLC staging According to initial assessment the patients who will fulfill the inclusion criteria BCLC stage C will be informed about the study procedure Patients who will give informed written consent will be randomly assigned 11 ratio to receive either Lenvatinib or Sorafenib Macroscopic portal vein invasion extrahepatic spread or both yes or no Eastern Cooperative Oncology Group performance status 0 or 1 will be considered as stratification factors As the study will be open labeled the treatment will not be masked to the patients or investigators After randomization there will be two groups Lenvatinib group Group A and Sorafenib group Group B Group A patients will receive Cap Lenvatinib 8 mgday in two divided doses and group B patients will receive tab Sorafenib 400 mgday in two divided doses Tumor evaluation will be done in each treatment arm in accordance with mRECIST criteria Liver will be examined with CT or MRI by using a triphasic scanning technique Patient follow-up and tumor assessment will be done in every 6 weeks interval by liver function tests S Bilirubin ALT AST ALP Prothrombin time S Albumin AFP and imaging triphasic CT or MRI Quality of life will be assessed by ECOG performance status on follow-up Patients will followed up for next 3 months or till death whichever one will be earlier After 3 months of treatment the two groups Group A and Group B will be compared of overall survibility improvement of patients clinical and biochemical status reduction of tumor size as well as the tumor marker
7 Statistical Analysis
The result of the study will be collected in a separate questionnaire sheet After collection of data it will be compiled and analyzed using SPSS software version 23
References
1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D Bray F Cancer incidence and mortality worldwide sources methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 Mar 1 136 5359-86 2 Forner A Reig M Bruix J Hepatocellular carcinoma Lancet 2018 Mar 31 391101271301-1314 3 Kudo M Finn RS Qin S Han KH Ikeda K Piscaglia F Baron A Park JW Han G Jassem J Blanc JF Vogel A Komov D Evans TRJ Lopez C Dutcus C Guo M Saito K Kraljevic S Tamai T Ren M Cheng AL Lenvatinib versus sorafenib in first- line treatment of patients with unresectable hepatocellular carcinoma A randomised phase 3 non-inferiority trial Lancet 2018 Mar 24 391101261163-1173 4 Snayal AJ Yoon SK Lencioni R The etiology of hepatocellular carcinoma and consequences for treatment The Oncologist 2010 15414-22 5 Kokudo N Hasegawa K Akahane M Igaki H Izumi N Ichida T Uemoto S Kaneko S Kawasaki S Ku Y Kudo M Kubo S Takayama T Tateishi R Fukuda T Matsui O Matsuyama Y Murakami T Arii S Okazaki M Makuuchi M Evidence-based clinical practice guidelines for hepatocellular carcinoma The Japan society of Hepatology 2013 update 3rd JHS-HCC guidelines Hepatol RES 2015 Jan 27 452 123-127 6 Llovet JM Ricci S Mazzaferro V Hilgard P Gane E Blanc JF de Oliveira AC Santoro A Raoul JL Forner A Schwartz M Porta C Zeuzem S Bolondi L Greten TF Galle PR Seitz JF Borbath I Häussinger D Giannaris T Shan M Moscovici M Voliotis D Bruix J Sorafenib in advanced hepatocellular carcinoma N Engl J Med
2008 Jul 24 3594378-390 7 Cheng AL Kang YK Chen Z Tsao CJ Qin S Kim JS Luo R Feng J Ye S Yang TS Xu J Sun Y Liang H Liu J Wang J Tak WY Pan H Burock K Zou J Voliotis D Guan Z Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma a phase III randomised double-blindplacebo- controlled trial Lancet Oncol 2009 Jan 101 25-34 8 Cheng AL Kang YK Lin DY Park JW Kudo M Qin S Chung HC Song X Xu J Poggi G Omata M Pitman Lowenthal S Lanzalone S Yang L Lechuga MJ Raymond E Sunitinib versus sorafenib in advanced hepatocellular cancer results of a randomized phase III trial J Clin Oncol 2013 Nov 10 3132 4067-75 9 Johnson PJ Qin S Park JW Poon RT Raoul JL Philip PA Hsu CH Hu TH Heo J Xu J Lu L Chao Y Boucher E Han KH Paik SW Robles-Aviña J Kudo M Yan L Sobhonslidsuk A Komov D Decaens T Tak WY Jeng LB Liu D Ezzeddine R Walters I Cheng AL Brivanib versus sorafenib as first-line therapy in patients with unresectable advanced hepatocellular carcinoma results from the randomizedphase III BRISK-FL study J Clin Oncol 2013 Oct 1 3128 3517-24 10 Cainap C Qin S Huang WT Chung IJ Pan H Cheng Y Kudo M Kang YK Chen PJ Toh HC Gorbunova V Eskens FA Qian J McKee MD Ricker JL Carlson DM El-Nowiem S Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma results of a randomized phase III trial J Clin Oncol 2015 Jan 10 332 172-79 11 Zhu AX Rosmorduc O Evans TR Ross PJ Santoro A Carrilho FJ Bruix J Qin S Thuluvath PJ Llovet JM Leberre MA Jensen M Meinhardt G Kang YK SEARCH a phase III randomized double-blind placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma J Clin Oncol 2015 Feb 20336559-66 12 Kaneko S Ikeda K Matsuzaki Y Furuse J Minami H Okayama Y Sunaya T Ito Y Inuyama L Okita K Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice interim analysis of a prospective post marketing all-patient surveillance study J Gastroenterol 2016 Oct51101011- 21 13 Kudo M Ikeda M Takayama T Numata K Izumi N Furuse J Okusaka T Kadoya M Yamashita S Ito Y Kokudo N Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice a subgroup analysis of GIDEON J Gastroenterol 2016 Dec51121150-60 14 Bruix J Qin S Merle P Granito A Huang YH Bodoky G Pracht M Yokosuka O Rosmorduc O Breder V Gerolami R Masi G Ross PJ Song T Bronowicki JP Ollivier-Hourmand I Kudo M Cheng AL Llovet JM Finn RS LeBerre MA Baumhauer A Meinhardt G Han G RESORCE Investigators Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment RESORCE a randomised double-blind placebo-controlled phase 3 trial Lancet
2017 Jan 73891006455-66 15 NCCN evidence blocks Hepatobiliary cancers NCCN clinical practice guidelines in oncology 2017 Available from httpswwwnccnorgprofessionalsphysician_glsdefaultaspx 16 Abou-Alfa GK Niedzwieski D Knox JJ Kaubisch A Posey J Kavan BRT Goel R Murray JJ Bekaii-Saab TS Tam VC Rajdev L Kelley RK Siegel A Balletti J Harding JJ Schwartz LH Goldberg RM Bertagnolli MM Venook AP Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma HCC CALGB 80802 Alliance J Clin Oncol 2016 Feb 1344192-192 17 Vilgrain V Pereira H Assenat E Guiu B Ilonca AD Pageaux GP Sibert A Bouattour M Lebtahi R Allaham W Barraud H Laurent V Mathias E Bronowicki JP Tasu JP Perdrisot R Silvain C Gerolami R Mundler O Seitz JF Vidal V Aubé C Oberti F Couturier O Brenot-Rossi I Raoul JL Sarran A Costentin C Itti E Luciani A Adam R Lewin M Samuel D Ronot M Dinut A Castera L Chatellier G SARAH Trial Group Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma SARAH an open-label randomised controlled Phase 3 trial Lancet Oncol 2017 Dec18121624-1636 18 Chow PKH Gandhi M Tan SB Khin MW Khasbazar A Ong J Choo SP Cheow PC Chotipanich C Lim K Lesmana LA Manuaba TW Yoong BK Raj A Law CS Cua IHY Lobo RR Teh CSC Kim YH Jong YW Han HS Bae SH Yoon HK Lee RC Hung CF Peng CY Liang PC Bartlett A Kok KYY Thng CH Low AS Goh ASW Tay KH Lo RHG Goh BKP Ng DCE Lekurwale G Liew WM Gebski V Mak KSW Soo KC Asia-Pacific Hepatocellular Carcinoma Trials Group SIRveNIB selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma J Clin Oncol 2018 Jul 136191913-1921 19 Nicola P Tiziana P Lorenza R Lenvatinib for the treatment of unresectable hepatocellular carcinoma Evidence to date Journal of hepatocellular carcinoma
2019 Jan 31 6 31-39 20 Reig M Bruix J Hepatocellular Carcinoma The Lancet2018 Mar 31 39110127 1301-1314 21 Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Carbone PP Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group AM J Clin Oncol 1982 Dec 56 649-655 22 Lencioni R Liovet JM Modified RECIST mRECIST Assessment for Hepatocellular Carcinoma Semin Liver Dis 2010 Feb 30 1 52-60 23 Attia KA Mahassadi AK Messou E Kissi YH Child-Pugh-Turcott versus Meld score for predicting survival in a retrospective cohort of black African cirrhotic patients
World Gastroenterol 2008 Jan142 286-291
Hepatocellular carcinoma is one of the most common type of liver cancer which is the 3rd leading cause of cancer deaths worldwide The incidence is expected to increase as a consequence of chronic liver disease with its multiple risk factors including chronic hepatitis B virus HBV and hepatitis C virus HCV infections excessive alcohol consumption nonalcoholic fatty liver disease hemochromatosis drugs and aflatoxin B1 It is estimated that 70-90 of patients with HCC have chronic liver disease and cirrhosis which limits the feasibility of surgical procedures in advanced cases There are limited treatment options for HCC patients who are ineligible for surgical resection Locoregional therapies such as radiofrequency ablation RFA transarterial chemoembolization TACE transarterial embolization TAE or hepatic arterial infusion chemotherapy HAIC are primarily recommended and if one of those fail then systemic therapy is considered The 2013 Japan Society of Hepatology HCC Guidelines outlined that the factors influencing treatment decisions should be based on the degree of liver damage Child-Pugh presence or absence of extrahepatic spread and macrovascular invasion the number of tumors and tumor diameter Sorafenib has been the standard of care since 2007 when the SHARP trial demonstrated that sorafenib improved median overall survival OS compared to placebo in patients who had not received prior systemic therapy 107 vs 79 months HR 069 P0001 In patients from the Asia-Pacific region taking sorafenib the median improvement in overall survival compared with placebo was 23 months 65 months vs 42 months HR 068 p0014 Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials of sunitinib brivanib linifanib and erlotinib plus sorafenib that did not show non inferiority Sorafenib an oral multikinase inhibitor has been the only systemic therapy demonstrated to extend overall survibility as a firstline treatment showing a median improvement of 28 months compared with placebo 107 months vs 79 months hazard ratio HR 069 p0001 Inpatients from the Asia-Pacific region taking sorafenib the median OS mOS improvement compared with placebo was 23 months HR 068 p 0014 The use of other molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority to sorafenib thus until the appearance of lenvatinib sorafenib has also been widely used as the first-line treatment for HCC patients in Japan Recently regorafenib and Nivolumab were approved as a second-line systemic treatment for patients who do not respond to the first-line treatments Otherwise best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines Chemotherapy in combination with sorafenib doxorubicin and radioembolization with SIR Spheres Y-90 resin microspheres failed to demonstrate a survival benefit or showed a worse safety profile compared to sorafenib in the first-line setting Eventually the PhaseIII non-inferiority REFLECT trial showed that lenvatinib was non-inferior compared to sorafenib
2 Objectives
21 General objectives
To assess and compare the efficacy of Lenvatinib versus Sorafenib in the management of Hepatitis B virus related Hepatocellular Carcinoma
22 Specific objectives
a To assess and compare the overall survibility of hepatocellular carcinoma patients between the groups of Lenvatinib and Sorafenib b To assess and compare the progression free survival outcome between the groups of Lenvatinib and Sorafenib c To assess and compare the improvement of liver function tests between the groups of Lenvatinib and Sorafenib d To assess and compare the improvement of AFP levels between the groups of Lenvatinib and Sorafenib e To assess and compare the improvement of ECOG performance status of the HCC patients between the groups of Lenvatinib and Sorafenib f To assess and compare the improvement of Chil-Pugh scores among the HCC patients between the groups of Lenvatinib and Sorafenib g To assess and compare the size and number of target lesions by mRECIST criteria among the HCC patients between the groups of Lenvatinib and Sorafenib
3 Methodology
The study will be conducted considering the following methodological aspects
31 Study design An open label randomized clinical control trial study
32 Study duration From the date of randomization to next 3 months or till death whichever one will be earlier
33 Study place Department of Hepatology Sir Salimullah Medical College Mitford Hospital
34 Study population Patients diagnosed as advanced Hepatocellular Carcinoma by imaging cytology or histology with no option of resectibility will be selected for the study
35 Sample size calculation
n P1 1-P1 P2 1-P2 P1 -P2 2 ZαZβ2
P1 Proportion of patients developed objective response in one arm Lenvatinib group P2 Proportion of patients developed objective response in another arm Sorafenib group Zα Z-value two tail at a definite level of significance eg 196 at 5 level of significance Zβ Z-value one tail at a definite power eg 084
Here P1 406 objective response with Lenvatinib 0406 P2 124 objective response with Sorafenib 0124 Zα196 and Zβ 08419
n04061-0406 01241-01240406-01242 1960842 343 in each group 35 in each group Total sample number 70 35 in Lenvatinib group and 35 in Sorafenib group
36 Sampling technique and recruitment of study subjects
Participants of the study will be recruited via 11 randomization from patients admitted in the department of Hepatology Sir Salimullah Medical College Mitford Hospital and diagnosed as a case of advanced Hepatocellular Carcinoma with no option of resectibility
37 Eligibility criteria
371 Inclusion criteria
1 Patients with Hepatocellular Carcinoma Diagnosed histologically or cytologically or by imaging criteria with CT or MRI with no option of resectibility BCLC stage B or C
2 Age 18 years
372 Exclusion criteria
1 Patients with very early stage Hepatocellular Carcinoma BCLC stage 0
2 Patients with early stage Hepatocellular Carcinoma BCLC stage A
3 Patients with terminal stage Hepatocellular Carcinoma BCLC stage D
4 Patients with Hepatocellular Carcinoma with obvious invasion to bile duct
5 Patients who received previous systemic therapy for Hepatocellular Carcinoma
7 Patients with jaundice serum bilirubin 3 mgdl 8 Patients with aminotransferases 5ULN 8 Patients with other co-morbid conditions COPD CKD Heart failure IHD pregnancy
373 Primary outcome measure
1 To measure overall survival of the patients from the date of randomization up to 6 months or till death whichever one will be earlier
374 Secondary outcome measure
1 Progression free survival
2 Time to progress
3 Objective response rate
4 Quality of life
5 Assessment of safety
38 Outcome measure
1 Primary endpoint
a Overall survibility From the date of Randomization to next 3 months or till death
2 Secondary endpoint
1 Progression free survival
2 Time to progress
3 Quality of life measurement By ECOG performance status
4 Liver function tests By SBilirubin ALT AST ALP Prothrombin time INR Serum albumin
5 AFP level
6 Child-turcotte-Pugh score
7 Tumor assessment by mRECIST criteria
39 Research instrument
For collection of primary data about patient a semi-structured questionnaire will be developed based on research objective Pre-testing of the questionnaire will be done on other patients admitted at the same facility After the pretesting amendment of the items and question will be done based on study finding In the final questionnaire both structured and open questions will be kept
A check list will be prepared to compile the data from hospital records treatment records outcome of treatment and laboratory investigation reports
310 Data collection procedure
All data will be collected by face-to-face interview of the patients attendant by the researcher at health facility upon their consent and convenience Socio demographic and personal information will be recorded from patient through interview with a semi structured pre-tested questionnaire Information regarding risk factors and risk behavior will be inquired taking effort to minimize the recall bias
311 Data processing
Data processing will include data cleaning and quality control check editing of data coding of data and data entry into computer The edited data will be entered on to the template of SPSS 23
312 Data analysis
The edited data will then be entered on to the template of SPSS 23 For Back ground variables and socio-demographic data descriptive statistics and relative frequency percentage will be generated All data will be presented as mean SD Qualitative data will be analyzed by Chi-square test and quantitative data will be analyzed by students t-test Through univariate analysis the base line characteristics and treatment outcome will be compared The effect of treatment will be identified through Multivariate analysis after adjusting for possible confounders Relative risk with 95 CI will be generated through binary logistic regression adjusting for all possible confounders A statistically significant result will be considered when p value 005
313 Data Presentation
Data will be presented in the form of table and graphs Descriptive statistics will be presented with frequency table Association will be illustrated with cross tables and test statistics will be added in the foot note of the table Bar and pie charts will be generated to illustrate descriptive statistics
4 Ethical considerations
Approval from the ethical review committee of Sir Salimullah Medical College and Mitford Hospital will be taken prior to commencement of the study Informed written consent will be taken from the participants after explaining about the details of the study The participants will be assured that the information acquired will be used for academic purpose They will be assured of confidentiality and for the purpose of data analysis no individual data were reported rather de identified data will be preceded for analysis
5 Facilities Resources Equipments Chemicals Subjects etc required for the study
Principal investigator has full-fledged Department of Hepatology at Sir Salimullah Medical College Mitford Hospital Dhaka
Sir Salimullah Medical College Mitford Hospital Dhaka has adequate facilities to carry out all the investigations required for this study
Sir Salimullah Medical College Mitford Hospital Dhaka has adequate facility to deal with the adverse effect of the drug under trial as well as management of the subjects of the current study
6 Material methods
The study will be conducted in the department of Hepatology Sir Salimullah Medical College Mitford Hospital It will be an open label randomized clinical control trial study Patients admitted in the department of Hepatology diagnosed as a case of Hepatocellular Carcinoma by imaging or cytopathology or histopathology will be primarily targeted for the study Initial assessment of each patient will be done by Chil-pugh score ECOG performance status Tumor assessment by mRECIST criteria and BCLC staging According to initial assessment the patients who will fulfill the inclusion criteria BCLC stage C will be informed about the study procedure Patients who will give informed written consent will be randomly assigned 11 ratio to receive either Lenvatinib or Sorafenib Macroscopic portal vein invasion extrahepatic spread or both yes or no Eastern Cooperative Oncology Group performance status 0 or 1 will be considered as stratification factors As the study will be open labeled the treatment will not be masked to the patients or investigators After randomization there will be two groups Lenvatinib group Group A and Sorafenib group Group B Group A patients will receive Cap Lenvatinib 8 mgday in two divided doses and group B patients will receive tab Sorafenib 400 mgday in two divided doses Tumor evaluation will be done in each treatment arm in accordance with mRECIST criteria Liver will be examined with CT or MRI by using a triphasic scanning technique Patient follow-up and tumor assessment will be done in every 6 weeks interval by liver function tests S Bilirubin ALT AST ALP Prothrombin time S Albumin AFP and imaging triphasic CT or MRI Quality of life will be assessed by ECOG performance status on follow-up Patients will followed up for next 3 months or till death whichever one will be earlier After 3 months of treatment the two groups Group A and Group B will be compared of overall survibility improvement of patients clinical and biochemical status reduction of tumor size as well as the tumor marker
7 Statistical Analysis
The result of the study will be collected in a separate questionnaire sheet After collection of data it will be compiled and analyzed using SPSS software version 23
References
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World Gastroenterol 2008 Jan142 286-291
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None