Analysis of cfDNA in Patients With Hepatocarcinoma and Treated by Sorafenib or Regorafenib

Hepatocarcinoma Clinical Trial

— HELP  

Official title:

A Sorafenib-Regorafenib Sequence Treatment Monitoring Study Using Liquid Biopsy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03956940
• Other study ID #: 2018-A02911-54
• Status: Terminated
• Phase: N/A
• Start date: October 4, 2019
• Est. completion date: December 31, 2021

Study information

• Verified date: June 2022
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this trial is to investigate whether quantitative analysis of the total concentration of circulating free deoxyribonucleic acid (cfDNA) and of the cfDNA integrity index (DII) (Intplex®) may reflect hepatocellular carcinoma (HCC) tumor dynamics or response for patients treated by Sorafenib or Regorafenib and if it could be used as a tool for patient management under targeted therapy.

Description:

Circulating free deoxyribonucleic acid (cfDNA) is increasingly used in oncology with the aiml of early diagnosis of the disease, its therapeutic management and monitoring the evolution of the disease. Numerous publications have shown that the cfDNA concentration is correlated with the pathology of cancer. Larger amounts of cfDNA are detected in metastatic patients or patients with advanced cancer. However, the cfDNA concentrations have not yet shown their clinical interest mainly because of the variations in the same individual during the effort or the moment of collection of the blood sample. The concept of the integrity of cfDNA has also been studied as a biomarker in oncology and seems to show an interesting clinical value. The cfDNA is essentially released by cell apoptosis generating 170 bp fragments, corresponding to the size of a nucleosome. Many studies have shown that the integrity of cfDNA increases with the pathology of cancer. Thus, tumor-derived cfDNA is more fragmented than healthy cells with fragments smaller than the size nucleosome. To date, no predictive biomarker is available for the management of treatment with Sorafenib which is a targeted therapy with a marketing authorization in first-line treatment of HCC (hepatocellular carcinoma) or second line with Regorafenib, treatment having shown a benefit positive on overall survival in the Resorce study. AFP (alpha-foetoprotein) is the only serum marker available with an inconstant increase in patients with HCC in fact only 30 to 40% of patients have abnormal values. In liver cancer, Ono et al showed that serum cfDNA is positively correlated with a larger tumor size. This study shows that the rate of tumor cfDNA reflects the progression of the disease. Jiang et al showed that cfDNA derived from HCC is more fragmented than that derived from healthy cells, with fragments smaller than the size nucleosome. These data demonstrate the potential utility of cfDNA amount and integrity as a biomarker for individualized management of hepatocellular carcinoma. This new marker is expected to be an effective tool to overcome the lack of specificity of the AFP (alpha foetoprotein) assay in this pathology. The investigator's team developed an Intplex® test that showed significant discrimination between healthy individuals and cancer patients. The aim of this trial is to investigate whether quantitative analysis of the total concentration of cfDNA and of the cfDNA integrity index (DII) (Intplex®) may reflect HCC tumor dynamics or response for patients treated by Sorafenib or Regorafenib and if it could be used as a tool for patient management under targeted therapy.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 18
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female patients = 18 years of age

2. Histological or cytological documentation of hepatocellular carcinoma (HCC) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis

3. Patient treated for stage B hepatocellular carcinoma (multifocal disease) or stage C (metastatic disease) according to Barcelona Clinic liver cancer, regardless of treatment line, and that cannot benefit from local treatments such as resection, local ablation, chemoembolization

4. At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST criteria 1.1 and modified RECIST for HCC

5. Liver function status Child-Pugh Class A

6. Eastern Cooperative Oncology Group (ECOG) Performance Status = 1

7. Adequate bone marrow, liver and renal function as assessed by the following laboratory

tests:

• Hemoglobin > 8.5 g/dL
• Absolute neutrophil count = 1500/mm3
• Platelet count = 60,000/ mm3
• Total bilirubin = 2 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 5 x upper limit of normal (ULN)
• Serum creatinine = 1.5 x Upper limit normal (ULN)
• Lipase = 2 x ULN
• Prothrombin time-international normalized ratio (PT-INR) < 2.3 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN
• Glomerular Filtration Rate (GFR) = 30 mL/min/1.73 m2

8. Life expectancy = 3 months

9. Women of childbearing potential and men must agree to use adequate contraception

10. Patients must be affiliated to a Social Security System

11. Written informed consent signed Patients initially treated with Sorafenib, will be switched to Regorafenib if all the

above conditions are still met and, in addition:

12. Documented progression under treatment with Sorafenib (defined as documented radiological and/or clinical and/or biological progression)

Exclusion Criteria:

1. Prior liver transplantation or candidates for liver transplantation

2. Hypersensitivity to the active substance or to any of the excipients

3. Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention

4. Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated > 3 years prior to study entry is permitted

5. Known history or symptomatic metastatic brain or meningeal tumors

6. Major surgical procedure or significant traumatic injury within 28 days before enrollment

7. Congestive heart failure New York Heart Association (NYHA) = class 2

8. Unstable angina or myocardial infarction within the past 6 months before enrollment

9. Cardiac arrhythmias requiring anti-arrhythmic therapy

10. Uncontrolled hypertension

11. Patients with phaeochromocytoma

12. Uncontrolled ascites

13. Persistent proteinuria of NCI-CTCAE version 4.0 = Grade 3

14. Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B is allowed if no active replication is required

15. Clinically significant bleeding NCI-CTCAE version 4.0 = Grade 3 within 30 days before enrollment

16. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before enrollment

17. Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure

18. Known history of human immunodeficiency virus (HIV) infection

19. Seizure disorder requiring medication

20. Non-healing wound, ulcer or bone fracture

21. Active autoimmune disease (lupus, sclerodermia, rheumatoid arthritis, …)

22. Any malabsorption condition

23. Breast feeding

24. Pregnancy

25. High performance sport practice

26. Patient unable to swallow oral medication Patients who discontinue sorafenib will not be switched to regorafenib if any of the

condition listed above occurs and/or the following criteria are met:

27. Prior discontinuation of prior Sorafenib therapy due to Sorafenib-related toxicity

28. Unresolved toxicity (Sorafenib) = NCI-CTCAE version 4.0 Grade 2

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Hepatocarcinoma

Intervention

Device:
• Intplex test
Blood sample at baseline, 15 days, 4-8-16 weeks and then every 12 weeks

Locations

Country	Name	City	State
France	Hôpital Beaujon	Clichy	Seine-Saint-Denis
France	CHU Grenoble - Hôpital Michalon	Grenoble	Isère
France	CHRU de Lille - Hôpital Claude Duriez	Lille	Nord
France	Hôpital Saint-Eloi	Montpellier	Hérault
France	Hôpital Hôtel Dieu	Nantes	Loire-Atlantique
France	CHRU Nancy - Hôpital Brabois	Vandœuvre-lès-Nancy	Meurthe Et Moselle

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

References & Publications (15)

Chan SL, Mo FK, Johnson PJ, Hui EP, Ma BB, Ho WM, Lam KC, Chan AT, Mok TS, Yeo W. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol. 2009 Jan 20;27(3):446-52. doi: 10.1200/JCO.2008.18.8151. Epub 2008 Dec 8. — View Citation

Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014 Feb 20;32(6):579-86. doi: 10.1200/JCO.2012.45.2011. Epub 2014 Jan 21. Review. — View Citation

Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, Francoz C, Compagnon P, Vanlemmens C, Dumortier J, Dharancy S, Gugenheim J, Bernard PH, Adam R, Radenne S, Muscari F, Conti F, Hardwigsen J, Pageaux GP, Chazouillères O, Salame E, Hilleret MN, Lebray P, Abergel A, Debette-Gratien M, Kluger MD, Mallat A, Azoulay D, Cherqui D; Liver Transplantation French Study Group. Liver transplantation for hepatocellular carcinoma: a model including a-fetoprotein improves the performance of Milan criteria. Gastroenterology. 2012 Oct;143(4):986-94.e3; quiz e14-5. doi: 10.1053/j.gastro.2012.05.052. Epub 2012 Jun 29. — View Citation

El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, Fiess C, Crapez E, Bibeau F, Theillet C, Mazard T, Pezet D, Mathonnet M, Ychou M, Thierry AR. Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care. Clin Cancer Res. 2016 Jun 15;22(12):3067-77. doi: 10.1158/1078-0432.CCR-15-0297. Epub 2016 Feb 4. — View Citation

Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med. 2003 Jul 1;139(1):46-50. Review. — View Citation

Jiang P, Chan CW, Chan KC, Cheng SH, Wong J, Wong VW, Wong GL, Chan SL, Mok TS, Chan HL, Lai PB, Chiu RW, Lo YM. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1317-25. doi: 10.1073/pnas.1500076112. Epub 2015 Feb 2. — View Citation

Mouliere F, El Messaoudi S, Pang D, Dritschilo A, Thierry AR. Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer. Mol Oncol. 2014 Jul;8(5):927-41. doi: 10.1016/j.molonc.2014.02.005. Epub 2014 Mar 24. — View Citation

Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga N, Imamura M, Kawaoka T, Tsuge M, Abe H, Hayes CN, Miki D, Furuta M, Tsunoda T, Miyano S, Kubo M, Aikata H, Ochi H, Kawakami YI, Arihiro K, Ohdan H, Nakagawa H, Chayama K. Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy. Cell Mol Gastroenterol Hepatol. 2015 Jun 17;1(5):516-534. doi: 10.1016/j.jcmgh.2015.06.009. eCollection 2015 Sep. — View Citation

Personeni N, Bozzarelli S, Pressiani T, Rimassa L, Tronconi MC, Sclafani F, Carnaghi C, Pedicini V, Giordano L, Santoro A. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2012 Jul;57(1):101-7. doi: 10.1016/j.jhep.2012.02.016. Epub 2012 Mar 10. — View Citation

Riaz A, Ryu RK, Kulik LM, Mulcahy MF, Lewandowski RJ, Minocha J, Ibrahim SM, Sato KT, Baker T, Miller FH, Newman S, Omary R, Abecassis M, Benson AB 3rd, Salem R. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol. 2009 Dec 1;27(34):5734-42. doi: 10.1200/JCO.2009.23.1282. Epub 2009 Oct 5. — View Citation

Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C, Pierotti MA, Tavecchio L. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res. 2001 Jun 15;61(12):4675-8. — View Citation

Thierry AR, El Messaoudi S, Gahan PB, Anker P, Stroun M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016 Sep;35(3):347-76. doi: 10.1007/s10555-016-9629-x. Review. — View Citation

Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, Gillet B, Gongora C, Dechelotte P, Robert B, Del Rio M, Lamy PJ, Bibeau F, Nouaille M, Loriot V, Jarrousse AS, Molina F, Mathonnet M, Pezet D, Ychou M. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014 Apr;20(4):430-5. doi: 10.1038/nm.3511. Epub 2014 Mar 23. — View Citation

Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008 Mar 1;68(5):1451-61. doi: 10.1158/0008-5472.CAN-07-6013. — View Citation

Zonta E, Nizard P, Taly V. Assessment of DNA Integrity, Applications for Cancer Research. Adv Clin Chem. 2015;70:197-246. doi: 10.1016/bs.acc.2015.03.002. Epub 2015 Apr 11. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Detection rate of total circulating free deoxyribonucleic acid (cfDNA) concentration at the baseline.	Total cfDNA concentration is considered as detected if total cfDNA concentration = 5 ng/mL and not detected if total cfDNA concentration < 5 ng/mL	Baseline
Secondary	total circulating free deoxyribonucleic acid (cfDNA) fragmentation index	Fragmentation of cfDNA	Baseline
Secondary	Objective response rate	From the date of inclusion to the date of death from any cause	Approximately 36 months
Secondary	Disease control rate	From the date of inclusion to the date of death from any cause	Approximately 36 months
Secondary	Progression-Free Survival	The time from the date of start of Sorafenib (Regorafenib respectively) to the date of first documented	Approximately 36 months
Secondary	Time-to-progression	The time from the date of start of Sorafenib (Regorafenib respectively) to the date of first documented progression ( radiological or clinical)	Approximately 36 months
Secondary	Overall Survival	The time from the date of start of Sorafenib to the date of documented death from any cause	Approximately 36 months