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HepatocarcinomaHELPNCT03956940

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

A study testing Intplex test in people with Hepatocarcinoma, run by Institut du Cancer de Montpellier - Val d'Aurelle at 6 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatocarcinoma
What is being tested?
Intplex test
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
6 sitesFrance
Study dates
4 Oct 2019to 31 Dec 2021
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female patients ≥ 18 years of age
  • 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
  • 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
  • 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
  • Liver function status Child-Pugh Class A
  • Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
Show all 22Show fewer
  • 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
  • Life expectancy ≥ 3 months
  • Women of childbearing potential and men must agree to use adequate contraception
  • Patients must be affiliated to a Social Security System
  • 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:
  • Documented progression under treatment with Sorafenib (defined as documented radiological and/or clinical and/or biological progression)

Who cannot join

  • Prior liver transplantation or candidates for liver transplantation
  • Hypersensitivity to the active substance or to any of the excipients
  • Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
  • 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
  • Known history or symptomatic metastatic brain or meningeal tumors
  • Major surgical procedure or significant traumatic injury within 28 days before enrollment
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  • Congestive heart failure New York Heart Association (NYHA) ≥ class 2
  • Unstable angina or myocardial infarction within the past 6 months before enrollment
  • Cardiac arrhythmias requiring anti-arrhythmic therapy
  • Uncontrolled hypertension
  • Patients with phaeochromocytoma
  • Uncontrolled ascites
  • Persistent proteinuria of NCI-CTCAE version 4.0 ≥ Grade 3
  • Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B is allowed if no active replication is required
  • Clinically significant bleeding NCI-CTCAE version 4.0 ≥ Grade 3 within 30 days before enrollment
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before enrollment
  • 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
  • Known history of human immunodeficiency virus (HIV) infection
  • Seizure disorder requiring medication
  • Non-healing wound, ulcer or bone fracture
  • Active autoimmune disease (lupus, sclerodermia, rheumatoid arthritis, …)
  • Any malabsorption condition
  • Breast feeding
  • Pregnancy
  • High performance sport practice
  • 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:
  • Prior discontinuation of prior Sorafenib therapy due to Sorafenib-related toxicity
  • Unresolved toxicity (Sorafenib) ≥ NCI-CTCAE version 4.0 Grade 2

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

France6 sites

  • Hôpital Beaujon

    Clichy, Seine-Saint-Denis, 92210

  • CHU Grenoble - Hôpital Michalon

    Grenoble, Isère, 38043

  • CHRU de Lille - Hôpital Claude Duriez

    Lille, Nord, 59037

  • Hôpital Saint-Eloi

    Montpellier, Hérault, 34295

  • Hôpital Hôtel Dieu

    Nantes, Loire-Atlantique, 44093

  • CHRU Nancy - Hôpital Brabois

    Vandœuvre-lès-Nancy, Meurthe Et Moselle, 54511

Other trials in France

About this study

Official title: A Sorafenib-Regorafenib Sequence Treatment Monitoring Study Using Liquid Biopsy

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.

Read the detailed 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.

Conditions
Hepatocarcinoma
Being tested
Intplex test
Keywords
Hepatocarcinoma, cfDNA, intplex
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Intplex testDevice

    Blood sample at baseline, 15 days, 4-8-16 weeks and then every 12 weeks

Study groups in NCT03956940
Study groupRoleWhat they receive
Intplex testExperimentalIn vitro diagnostic device
Receives: Device: Intplex test

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Baseline

Secondary outcomes (6)

  1. total circulating free deoxyribonucleic acid (cfDNA) fragmentation index

    Fragmentation of cfDNA

    Measured: Baseline

  2. Objective response rate

    From the date of inclusion to the date of death from any cause

    Measured: Approximately 36 months

  3. Disease control rate

    From the date of inclusion to the date of death from any cause

    Measured: Approximately 36 months

  4. Progression-Free Survival

    The time from the date of start of Sorafenib (Regorafenib respectively) to the date of first documented

    Measured: Approximately 36 months

  5. Time-to-progression

    The time from the date of start of Sorafenib (Regorafenib respectively) to the date of first documented progression ( radiological or clinical)

    Measured: Approximately 36 months

  6. Overall Survival

    The time from the date of start of Sorafenib to the date of documented death from any cause

    Measured: Approximately 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 May 2019
  2. Study start4 Oct 2019
  3. Primary completion31 Dec 2021
  4. Study completion31 Dec 2021

Why it stopped: Change of the scientific and medical context that is no longer favorable to our study. This has resulted in the termination of inclusions.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Diagnosis
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03956940
Sponsor's protocol ID
2018-A02911-54
Acronym
HELP
Status last verified
Jun 2022
First submitted
15 May 2019
Last updated
21 Jun 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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. doi: 10.7326/0003-4819-139-1-200307010-00012.

    PubMed 12834318

  • 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.

    PubMed 19805671

  • 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.

    PubMed 19064965

  • 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, Chazouilleres 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 alpha-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.

    PubMed 22750200

  • 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.

    PubMed 22414760

  • 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.

    PubMed 18316609

  • 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.

    PubMed 11406535

  • 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.

    PubMed 24658074

  • 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.

    PubMed 27392603

  • 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.

    PubMed 28210698

  • 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.

    PubMed 25646427

  • 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.

    PubMed 24449238

  • 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.

    PubMed 26847055

  • 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.

    PubMed 24698732

  • 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.

    PubMed 26231488

Questions about this trial

What is this clinical trial studying?

A study testing Intplex test in people with Hepatocarcinoma, run by Institut du Cancer de Montpellier - Val d'Aurelle at 6 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was stopped early (reason given: Change of the scientific and medical context that is no longer favorable to our study. This has resulted in the termination of inclusions.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Detection rate of total circulating free deoxyribonucleic acid (cfDNA) concentration at the baseline. (time frame: Baseline). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03956940, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.

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