The study is to check the duration of response of Capecitabine and Erlotinib combination after the 1st line chemo therapy of sorafenib in advanced Hepatocellular Carcinoma ( Liver Cancer)
- Conditions
- Other specified carcinomas of liver,
- Registration Number
- CTRI/2021/01/030657
- Lead Sponsor
- Tata Memorial Hospital
- Brief Summary
**CAPER HCC Study Brief Summary:**
**Hepatocellular carcinoma (HCC) incidence hasbeen rising worldwide over the last 20 years. In 2012, liver cancer representsthe fifth most common cancer in men and the ninth in women and the second mostcommon cause of cancer-related death worldwide. Incidence is more inunderdeveloped countries of Africa and Asia compared to developed countriescorrelating with the incidence of Hepatitis B (HBV) and Hepatitis C (HCV)infection in most regions.**
**Hepatocellular carcinoma (HCC) usually occurs inthe setting of chronic liver disease and cirrhosis. Potentially curativetreatments include surgical tumor resection/ liver transplantation. However,only a handful (<20%) of patients are able to undergo such treatments due tothe advanced nature of disease at the time of diagnosis.**
**The treatment options available to thesepatients are limited and the prognosis is poor. Loco-regional therapies, suchas percutaneous ablation and radiofrequency ablation (RFA), arterialchemoembolization (TACE), and conventional chemotherapies appear to offerlimited survival benefits in most cases.**
**Increased VEGF signaling leading to increasedtumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, amultikinase inhibitor (including VEGF signaling) has been approved for thefirst line of treatment of HCC based on phase III trials showing significantlyimprovement in progression free and overall survival (approximately by threemonths) compared with placebo in patients with advanced HCC.**
**Recently multiple therapies have been approvedfor second line therapy after sorafenib based on phase III trials, where therewas significant improvement in PFS and OS.**
**Unfortunately, regorafenib or other approvedsecond line therapy are not easily feasible for the majority of the population indeveloping countries like India. There is thus a pressing need for easilyfeasible, e****ff****ective and tolerableoptions to allow patients with advanced HCC to continue treatment after theirdisease progresses on sorafenib.**
**EGFR and its ligands EGF and transforming growthfactor alpha (TGF-α) have been implicated in hepatocarcinogenesis andoverexpression of EGFR and EGF ligands is found in human HCC tissues. Erlotinibis an orally active small-molecule tyrosine kinase inhibitor of EGFR approvedto treat patients with advanced non– small-cell lung and pancreatic cancers.Erlotinib can inhibit invasion, metastasis, and angiogenesis in tumor cellsbesides proliferation. Erlotinib 150 mg daily has demonstrated modest activitybut promising overall survival (OS) benefit in patients with unresectable HCC.There are approximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3trial), showing a disease control rate of 42.5% to 79.6% and a median OS of6.25 to 15.65 months. Also, the tolerance of erlotinib was not associated withsignificant grade 3/4 toxicity in more than 10% of patients. Marie-José et alresults highlight that pathways controlled by EGFR/HER-3 are the driving forcefor HCC cells to maintain proliferation under sorafenib. Therefore, EGFRinhibitors are likely to be useful in the clinic in sorafenib resistantpatients.**
**Metronomic chemotherapy principally inhibitsangiogenesis by directly disrupting endothelial cell proliferation. Metronomicchemotherapy may decrease the mobilization or viability of bone marrow-derivedcirculating endothelial precursors, which contribute Hepatocellular carcinoma(HCC) incidence has been rising worldwide over the last 20 years. In 2012,liver cancer represents the fifth most common cancer in men and the ninth inwomen and the second most common cause of cancer-related death worldwide.Incidence is more in underdeveloped countries of Africa and Asia compared todeveloped countries correlating with the incidence of Hepatitis B (HBV) andHepatitis C (HCV) infection in most regions.**
**Hepatocellular carcinoma (HCC) usually occurs inthe setting of chronic liver disease and cirrhosis. Potentially curativetreatments include surgical tumor resection/ liver transplantation. However,only a handful (<20%) of patients are able to undergo such treatments due tothe advanced nature of disease at the time of diagnosis. The treatment optionsavailable to these patients are limited and the prognosis is poor.Loco-regional therapies, such as percutaneous ablation and radiofrequencyablation (RFA), arterial chemoembolization (TACE), and conventionalchemotherapies appear to offer limited survival benefits in most cases.**
**Increased VEGF signaling leading to increasedtumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, a multikinaseinhibitor (including VEGF signaling) has been approved for the first line oftreatment of HCC based on phase III trials showing significantly improvement inprogression free and overall survival (approximately by three months) comparedwith placebo in patients with advanced HCC.**
**Recently multiple therapies have been approvedfor second line therapy after sorafenib based on phase III trials, where therewas significant improvement in PFS and OS.**
**Unfortunately, regorafenib or other approvedsecond line therapy are not easily feasible for the majority of the populationin developing countries like India. There is thus a pressing need for easilyfeasible, e****ff****ective and tolerable options to allow patientswith advanced HCC to continue treatment after their disease progresses onsorafenib.**
**EGFR and its ligands EGF and transforming growthfactor alpha (TGF-α) have been implicated in hepatocarcinogenesis andoverexpression of EGFR and EGF ligands is found in human HCC tissues. Erlotinibis an orally active small-molecule tyrosine kinase inhibitor of EGFR approvedto treat patients with advanced non– small-cell lung and pancreatic cancers.Erlotinib can inhibit invasion, metastasis, and angiogenesis in tumor cellsbesides proliferation. Erlotinib 150 mg daily has demonstrated modest activitybut promising overall survival (OS) benefit in patients with unresectable HCC.There are approximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3trial), showing a disease control rate of 42.5% to 79.6% and a median OS of6.25 to 15.65 months. Also, the tolerance of erlotinib was not associated withsignificant grade 3/4 toxicity in more than 10% of patients. Marie-José et alresults highlight that pathways controlled by EGFR/HER-3 are the driving forcefor HCC cells to maintain proliferation under sorafenib. Therefore, EGFRinhibitors are likely to be useful in the clinic in sorafenib resistantpatients.**
**Metronomic chemotherapy principally inhibitsangiogenesis by directly disrupting endothelial cell proliferation. Metronomicchemotherapy may decrease the mobilization or viability of bone marrow-derivedcirculating endothelial precursors, which contribute to tumorneovascularization. Metronomic chemotherapy even upregulates antiangiogenicfactors such as thrombospondin- 1 (TSP-1) and angiostatin, and down-regulatesangiogenic factors such as vascular endothelial growth factor (VEGF), basicfibroblast growth factor (b-FGF), and hypoxia-inducible factor-1 (HIF-1). Inaddition, metronomic chemotherapy reduces regulatory T cells and promotedendritic cell maturation thereby stimulate the immune response. Tumor cellsmay also be directly affected by the metronomic therapy.**
**HCCs are highly vascular tumors. HCC isdependent on preexisting vasculature for its development and onneovascularization and angiogenesis for its growth. Angiogenesis plays animportant role in the progression from cirrhosis to regenerative nodules,dysplastic nodules, and ultimately to HCC. Therefore, antiangiogenic therapy isan attractive approach in the treatment of HCC.**
**The optimal metronomic dose is known for only afew drugs and diseases, Capecitabine 500 mg twice daily has shown to haveactivity and antiangiogenic effectiveness in colorectal cancer, as demonstratedby contrast-enhanced magnetic resonance imaging. Capecitabine, anoral prodrug of 5- fluorouracil (5-FU), is rapidly and almost completelyabsorbed from the gastrointestinal tract and it undergoes hydrolysis in theliver and tissues to form active moiety fluorouracil. Fluorouracil is an antimetabolitethat inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree,RNA synthesis. Multiple studies have shown that mild to moderate liverdysfunction in patients with liver metastatic cancer did not significantlyaffect Capecitabine pharmacokinetics as the predominant route of elimination isvia the kidney. Therefore, patients with liver dysfunction should be monitoredclosely during treatment, but no dose adjustment is required for liverdysfunction solely. Phase I and II studies suggest that Capecitabine 500mg BDis safe and effective in HCC patients.**
**HCC is a complex, highly heterogeneous tumor,which makes it unlikely that targeting any one pathway will achieve optimaldisease control. Also, resistance mechanisms to sorafenib in HCC are stillpoorly understood. Proposed resistance mechanisms include upregulation of VEGFand other growth factors, activation of alternate signaling pathways, co-optionof existing vessels, and transformation of the tumor vasculature to a moremature, less VEGF-dependent phenotype. Thereby making metronomic capecitabinebased anti-angiogenesis a suitable therapy in sorafenib resistant patients.**
**There is preclinical evidence to suggest thatinhibiting EGFR may make tumors more angiogenesis dependent, and therefore moresusceptible to anti-angiogenesis inhibitors. Factors such as fibroblast growthfactors (FGFs), insulin like growth factors (IGFs), angiopoietins, andtumor-stromal interaction also contribute to sorafenib resistance. Hencemetronomic capecitabine based VEGF and other angiogenesis inhibition is worthtrying with anti EGFR inhibitor Erlotinib.**
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|HCC (BCLC B or C stage) progressed or intolerant to sorafenib with CTP <=7
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|Capecitabine 500 mg BD with Erlotinib 100 mg OD continuously
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|**Primary endpoint**
PFS
**Secondary endpoint**
OS
Response rate
Toxicity
**Patients of advanced HCC failing first linesorafenib will be treated with Capecitabine and erlotinib combination asfollows**
**Tab Erlotinib 100 mg PO OD to continue**
**Tab Capecitabine 500mg PO BD to continue**
**Start of next cycle on D 28**
**(=1 cycle)**
**Treatment will be continued until unacceptabletoxicity, death, or consent withdrawal.**
**Study design:**
**Patients with unresectable or metastatic HCC whohave progression or are intolerant to sorafenib will be taken into study aftersigning informed consent. Patient will be given capecitabine - erlotinib dailyuntil progression, unacceptable toxicity, consent withdrawal, death or lost tofollow up.**
**Sample size and statistical methods**
**Based on phase III second line regorafenibtrial, patients on placebo arm had a PFS of 10% at 6months. The hypothesis ofthe study is based on the assumption that the PFS at 6 months would improvefrom 10 to 30% by combination of metronomic capecitabine with erlotinib for thetreatment of advanced HCC post sorafenib failure, with a power of****80****% and alpha of 0.1, aPhase II study will require 29 patients with study accrual period of 2 years.Follow up duration of the study will be 1-year post accrual of last patient.Assuming an attrition rate of 10% per arm, a total of 32 patients will berequired to complete the study.**
**Duration of study**
**2.5 years (2years of recruitment; 6 months offollow up)**
**Overview of advanced Hepatocellular carcinoma.**
**Hepatocellular carcinoma (HCC) incidence hasbeen rising worldwide over the last 20 years and is expected to increase until2030.([[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1),[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2),[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)) In 2012, liver cancer represents thefifth most common cancer in men and the ninth in women and the second mostcommon cause of cancer-related death worldwide.(3) Incidence is morein underdeveloped countries of Africa and Asia compared to developed countriescorrelating with the incidence of Hepatitis B (HBV) and Hepatitis C (HCV)infection in most regions.([[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn4))**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Petrick JL, KellySP, Altekruse SF et al. Future of hepatocellular carcinoma incidence in theUnited States forecast through 2030. J Clin Oncol 2016; 34: 1787–1794.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****White DL, ThriftAP, Kanwal F et al. Incidence of hepatocellular carcinoma in all 50 UnitedStates, from 2000 through 2012. Gastroenterology 2017; 152: 812–820.e5.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Globoscan.http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.asp**
**[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref4)****Ferlay J,Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide:sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:e359–e386.**
**Hepatocellular carcinoma (HCC) usually occurs inthe setting of chronic liver disease and cirrhosis. Potentially curativetreatments include surgical tumor resection/ livertransplantation. However, only a handful (<20%) of patients are able toundergo such treatments due to the**
**advanced nature of disease at the time ofdiagnosis. The treatment options available to these patients are limited andthe prognosis is poor. Loco-regional therapies, such as percutaneous ablationand radiofrequency ablation (RFA), arterial chemoembolization (TACE), andconventional chemotherapies appear to offer limited survival benefits in mostcases. (****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****)**
**As the understanding of molecular alterations incancer is growing, more specific targeted therapies are taking shape and arethe future of cancer medicine. Increased VEGF signaling leading to increasedtumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, amultikinase inhibitor (including VEGF signaling) has been approved for thefirst line of treatment of HCC based on phase III trials showing significantlyimprovement in progression free and overall survival (approximately by threemonths) compared with placebo in patients with advanced HCC.(****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****,****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****)**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Rimassa, Lorenzaet al. The present and the future landscape of treatment of advanced hepatocellularcarcinoma. Digestive and Liver Disease, Volume 42, S273 - S280.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Pinter M, SieghartW, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma frommild to advanced stage liver cirrhosis. Oncologist 2009;14:70–6.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Wörns MA, WeinmannA, Pfingst K, et al. Safety and efficacy of sorafenib in patients with advancedhepatocellular carcinoma in consideration of concomitant stage of livercirrhosis. J Clin Gastroenterol 2009; 43:489–95.**
**Treatment of advanced HCC post sorafenib.**
**Recently multiple therapies have been approvedfor second line therapy after sorafenib based on phase III trials, where therewas significant improvement in PFS and OS.**
**Regorafenib, oral multikinase inhibitor is thefirst drug approved as second line treatment in HCC patients who havetolerated sorafenib but progressed on sorafenib based on survivalbenefit in a phase III RESORCE study. (****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****) Points to noteare median time on treatment being 3.5 months, 51% patient required dosereductions and 10% required treatment discontinuation due to AEs. Regorafenibis not suitable for the treatment of patients intolerant to sorafenibor CTP -B, and a second-line treatment for this subgroup of patients remains anunmet need.**
**Cabozantinib, another multikinase inhibitor isapproved in second line and beyond in patients with well-preserved liverfunction and ECOG PS 0–1 based on CELESTIAL trial (again 62%**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Bruix J, Qin S,Merle P, Granito A, Huang YH, Bodoky G, et al: Regorafenib for patients withhepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): arandomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389:56–66.**
**patients required dose reductions and 16%treatment discontinuation).(****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****) Cabozantinib is stillnot available in many countries (including India).**
**Ramucirumab, a human immunoglobulin G1 (IgG1)monoclonal antibody that inhibits ligand activation of VEGFR2, is approved as asecond line therapy in a specific subset of HCC with baseline AFP >= 400ng/mL, well preserved liver function and ECOG PS 0–1 based on survival benefitin phase III REACH 2 trial. (****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****) However, cost oframucirumab is around 1.6 lakh rupees per month in developing countries likeIndia.**
**Nivolumab, a fully human molecular antibodyanti-PD-1 has been approved in second line based on impressive result ofCheckmate 040 study in patients with intermediate or advanced HCC and preservedliver function (CP-A). (****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****) However, the cost oftherapy is around Rs 2 lakh per month in India.**
**Unfortunately, regorafenib or other approvedsecond line therapy are not easily feasible for the majority of the populationin developing countries like India. There is thus a pressing need for easilyfeasible, e****ff****ective and tolerableoptions to allow patients with advanced HCC to continue treatment after theirdisease progresses on sorafenib.**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Abou-Alfa GK,Meyer T, Cheng AL et al. Cabozantinib (C) versus placebo (P) in patients (pts)with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib:results from the randomized phase III CELESTIAL trial. J Clin Oncol 2018;36(Suppl 4): 207.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Zhu AX, Kang Y-K,Yen C-J et al. REACH-2: a randomized, doubleblind, placebo-controlled phase 3study of ramucirumab versus placebo as second-line treatment in patients withadvanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein(AFP) following first-line sorafenib. J Clin Oncol 2018; 36: 4003–4003.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****El-Khoueiry AB,Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellularcarcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 doseescalation and expansion trial. Lancet 2017;389:2492-502.**
**Role of anti EGFR therapy in HCC.**
**EGFR and its ligands EGF and transforming growthfactor alpha (TGF-α) have been implicated in many malignancies including HCC;overexpression of EGFR and EGF ligands is found in human HCC tissues. (****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****,****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****). Erlotinib is anorally active small-molecule tyrosine kinase inhibitor of EGFR approved totreat patients with advanced non– small-cell lung and pancreatic cancers.(****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****) Erlotinib can inhibitinvasion, metastasis, and angiogenesis in tumor cells besides proliferation.(****[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn4)****) Erlotinib 150 mg dailyhas demonstrated modest activity but promising overall**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Hisaka T, Yano H,Haramaki M et al (1999) Expressions of epidermal growth factor family and itsreceptor in hepatocellular carcinoma cell lines: relationship to cellproliferation. Int J Oncol 14:453–460.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Ito Y, Takeda T,Higashiyama S et al (2001) Expression of heparin binding epidermal growthfactor-like growth factor in hepatocellular carcinoma: an immunohistochemicalstudy. Oncol Rep 8:903–907.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Astellas PharmaUS, Genentech: Tarceva (erlotinib tablets, oral): Prescribing information.Farmingdale,NY, Astellas Pharma US, Genentech, 2012.**
**[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref4)****Van den Eynde M,Baurain JF, Mazzeo F, Machiels JP. Epidermal growth factor receptor targetedtherapies for solid tumours. Acta Clin Belg 2011; 66: 10-17, Hirte HW. Profileof erlotinib and its potential in the treatment of advanced ovarian carcinoma.Onco Targets Ther 2013; 6: 427-435.**
**survival (OS) benefit in patients withunresectable HCC.(****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****,****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****) There areapproximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3 trial),showing a disease control rate of 42.5% to 79.6% and a median OS of 6.25 to15.65 months. Also the tolerance of erlotinib was not associated withsignificant grade 3/4 toxicity in more than 10% of patients.(****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****) Marie-José et alresults highlight that pathways controlled by EGFR/HER-3 are the driving forcefor HCC cells to maintain proliferation under sorafenib.(****[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn4)****) Therefore, EGFRinhibitors are likely to be useful in the clinic in sorafenib resistantpatients.**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Philip PA, MahoneyMR, Allmer C, et al: Phase II study of erlotinib (OSI-774) in patients withadvanced hepatocellular cancer. J Clin Oncol 23:6657-6663, 2005.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Thomas MB, ChadhaR, Glover K, et al: Phase 2 study of erlotinib in patients with unresectablehepatocellular carcinoma. Cancer 110:1059-1067, 2007.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Zhang J, Zong Y,Xu GZ, et al. Erlotinib for advanced hepatocellular carcinoma. A systematicreview of phase II/III clinical trials. Saudi Med J.2016;37(11):1184-1190.**
**[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref4)****Blivet-VanEggelpoël, Marie-José et al. Epidermal growth factor receptor and HER-3restrict cell response to sorafenib in hepatocellular carcinoma cells. Journalof Hepatology, Volume 57, Issue 1, 108 – 115.**
**Rationale of Metronomic capecitabine**
**Metronomic chemotherapy principally inhibitsangiogenesis by directly disrupting endothelial cell proliferation. Metronomicchemotherapy may decrease the mobilization or viability of bone marrow-derivedcirculating endothelial precursors, which contribute to tumorneovascularization. (****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****) Metronomicchemotherapy even upregulates antiangiogenic factors such as thrombospondin- 1(TSP-1) and angiostatin, and down-regulates angiogenic factors such as vascularendothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), andhypoxia-inducible factor-1 (HIF-1). (****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****) In addition,metronomic chemotherapy reduces regulatory T cells and promote dendritic cellmaturation thereby stimulate the immune response. (****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****,****[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn4)****) Tumor cells mayalso be directly affected by the metronomic therapy. (****[[v]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn5)****)**
**HCCs are highly vascular tumors. HCC isdependent on preexisting vasculature for its development and onneovascularization and angiogenesis for its growth. Angiogenesis plays animportant role in the progression from cirrhosis to regenerative nodules,dysplastic nodules, and ultimately to HCC. (****[[vi]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn6)****) Therefore,antiangiogenic therapy is an attractive approach in the treatment of HCC.**
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**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Bertolini F, Paul S,Mancuso P, Monestiroli S, Gobbi A, Shaked Y, et al. Maximum tolerable dose andlow-dose metronomic chemotherapy have opposite effects on the mobilization andviability of circulating endothelial progenitor cells. Cancer Res.2003;63:4342–6.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Torimura T,Iwamoto H, Nakamura T, Koga H, Ueno T, Kerbel RS, et al. Metronomicchemotherapy: possible clinical application in advanced hepatocellularcarcinoma. Transl Oncol. 2013;6:511–9.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Lutsiak MEC,Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition ofCD4(+)25+T regulatory cell function implicated in enhanced immune response bylow-dose cyclophosphamide. Blood. 2005;105:2862–8.**
**[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref4)****Tanaka H,Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeuticagents based on their differential in vitro effects on dendritic cells. CancerRes. 2009;69:6978–86.**
**[[v]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref5)****Shaked Y,Emmenegger U,Man S, Cervi D, Bertolini F, Ben- David Y, Kerbel RS: Optimalbiologic dose of metronomic chemotherapy regimens is associated with maximumantiangiogenic activity. Blood, 106: 3058-3061, 2005.**
**[[vi]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref6)****Theise ND.Macroregenerative (dysplastic) nodules and hepatocarcinogenesis: theoreticaland clinical considerations. Semin Liver Dis. 1995;15:360–371.**
**The optimal metronomic dose is known for only afew drugs and diseases, Capecitabine 500 mg twice daily has shown to haveactivity and antiangiogenic effectiveness in colorectal cancer, as demonstratedby contrast-enhanced magnetic resonance imaging.(****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****) Capecitabine, an oralprodrug of 5- fluorouracil (5-FU), is rapidly and almost completely absorbedfrom the gastrointestinal tract and it undergoes hydrolysis in the liver andtissues to form active moiety fluorouracil. Fluorouracil is an antimetabolitethat inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree,RNA synthesis. (****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****) Multiple studies haveshown that mild to moderate liver dysfunction in patients with liver metastaticcancer did not significantly affect Capecitabine pharmacokinetics as thepredominant route of elimination is via the kidney. Therefore, patients withliver dysfunction should be monitored closely during treatment, but no doseadjustment is required for liver dysfunction solely. (****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****) Phase I and II studiessuggest that Capecitabine 500mg BD is safe and effective in HCC patients. (****[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn4)****,****[[v]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn5)****)**
**---**
**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Steinbild S,Arends J,MedingerM, Häring B, Frost A, Drevs J, Unger C, Strecker R, Hennig J,Mross K: Metronomic antiangiogenic therapy with capecitabine and celecoxib inadvanced tumor patients -- results of a phase II study. Onkologie, 30: 629-635,2007**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Walko CM, LindleyC. Capecitabine: a review. Clinical Therapeutics 2005;27:23–44.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Twelves C,Glynne-Jones R, Cassidy J, Schuller J, Goggin T, Roos B, Banken L,Utoh M,Weidekamm E, Reigner B. Effect of hepatic dysfunction due to liver metastaseson the pharmacokinetics of Capecitabine and its metabolites. ClinCancerRes. 1999 Jul;5(7):1696-702.**
**[[iv]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref4)****Omar Abdel-Rahman.Sorafenib versus Capecitabine in the management of advanced hepatocellularcarcinoma.**
**[[v]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref5)****MetronomicCapecitabine as second-line treatment in hepatocellular carcinoma aftersorafenib failure Alessandro Granitoa.**
**Rationale of proposed study combination**
**HCC is a complex, highly heterogeneous tumour,which makes it unlikely that targeting any one pathway will achieve optimaldisease control. Also, resistance mechanisms to sorafenib in HCC are stillpoorly understood. Proposed resistance mechanisms include upregulation of VEGFand other growth factors, activation of alternate signaling pathways, co-optionof existing vessels, and transformation of the tumor vasculature to a moremature, less VEGF-dependent phenotype.(****[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn1)****,****[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn2)****) Thereby makingmetronomic capecitabine based anti-angiogenesis a suitable therapy in sorafenibresistant patients.**
**There are preclinical evidence to suggest thatinhibiting EGFR may make tumors more angiogenesis dependent, and thereforemore susceptible to anti-angiogenesis inhibitors15 Factors such asfibroblast growth factors (FGFs), insulin like growth factors (IGFs),angiopoietins, and tumor-stromal interaction also contribute to sorafenibresistance.(****[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_edn3)****) Hence metronomiccapecitabine based VEGF and other angiogenesis inhibition is worth trying withanti EGFR inhibitor Erlotinib.**
**5. Hypothesis**
**The combination of Capecitabine and Erlotinib inadvanced HCC patients after sorafenib failure would lead to an increase in PFSfrom 10% to 30% at 6 months.**
**---**
**[[i]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref1)****Glade Bender J,Cooney EM, Kandel JJ, Yamashiro DJ. Vascular remodeling and clinical resistanceto antiangiogenic cancer therapy. Drug Resist Updat. 2004 Aug-Oct;7(4-5)289-300.**
**[[ii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref2)****Casanovas O, Hicklin DJ,Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting ofVEGF signaling in late-stage pancreatic islet tumors. *Cancer Cell*.2005;8(4):299–309.**
**[[iii]](file:///C:/Users/105630/Downloads/Study_Protocol_Study_Protocol_CAPER%20protocol%20version%201.115812703461582011209%20(1).docx#_ednref3)****Bergers G, HanahanD. Modes of resistance to antiangiogenic therapy. Nat Rev Cancer.2008;8:592–603.**
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Open to Recruitment
- Sex
- All
- Target Recruitment
- 29
- 1.Subjects must provide written informed consent prior to the performance of study specific procedures or assessments, and must be willing to comply with treatment and follow up assessments and procedures.
- 2.Histological or cytological confirmation of HCC (hepatocellular carcinoma) or radiologically confirmed diagnosis of HCC as per American Association for the Study of Liver Diseases criteria in patients with a confirmed diagnosis of cirrhosis.
- 3.Failure to prior treatment with Sorafenib (defined as clinical or radiological progression) or experiencing grade 3/4 toxicities on Sorafenib.
- 4.Barcelona Clinic Liver Cancer stage Category B or C that cannot benefit from treatments of established efficacy with higher priority such as resection, local ablation or chemoembolization.
- 5.Liver function status Child-Pugh (CTP) score ≤7.
- (Child Pugh status will be calculated based on clinical findings and laboratory results during the screening period).
- 6.Local or loco-regional therapy of intrahepatic tumour lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeks before first dose of study medication.
- 7.Age18 years or older with Eastern Cooperative Oncology Group Performance Status of 0 to 2.
- 8.Participants must have normal organ and marrow function as defined below within 15 days before starting study medication: ○Neutrophils≥1,500/mcL ○Platelets≥60,000/mcL ○Haemoglobin ≥8.0 g/dl ○Total bilirubin≤3 × institutional upper limit of normal ○AST(SGOT)/ALT(SGPT) ≤ 3 × institutional upper limit of normal ○Albumin levels of ≥ 2.5 mg/dl ○Calculated Creatinine clearance ≥ 30 ml/min 9.At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to modified RECIST for HCC.
- Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion.
- 10.Life expectancy of at least 3 months.
- 11.Negative serum pregnancy test (if applicable) and willing for adequate contraception.
- 1.Ongoing infection > Grade 2 according to NCI-CTCAE (National Cancer Institute.
- Common Terminology Criteria for Adverse Events) v. 5.0. Hepatitis B and Hepatitis C will be allowed. 2.Fibrolamellar hepatocellular carcinoma. 3.Patients unable to swallow oral medications. 4.Patients has pulmonary fibrosis, or pulmonary interstitial disease. 5.Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix. 6.History or clinical evidence of central nervous system metastases or leptomeningeal carcinomatosis. Screening with CNS imaging studies computed tomography or magnetic resonance imaging is required only if clinically indicated. 7.Known hypersensitivity or contraindications against erlotinib or capecitabine. 8.Patients with a history of liver transplant; gastric varices not amenable to ablative therapy; ascites or encephalopathy refractory to medical management; bleeding from esophageal or gastric varices during the 3 months before study participation or other poorly controlled medical conditions.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Progression-free survival (PFS) will be defined as the time from enrollment to the time of disease progression or death, or to the date of last tumor assessment without any such event (censored observation). 36 months
- Secondary Outcome Measures
Name Time Method 1)Overall survival (OS) 2)Quality of Life (QOL)
Trial Locations
- Locations (1)
Tata Memorial Center
🇮🇳Mumbai, MAHARASHTRA, India
Tata Memorial Center🇮🇳Mumbai, MAHARASHTRA, IndiaDr Prabhat BhargavaPrincipal investigator7276174221bhargava611@gmail.com