Fingerprint Characterization Tyrosine Kinase Inhibitors in Advanced HCC (e:Med-HCC-2)

Prospective Evaluation of Image and Molecular Fingerprint Characterization to Guide Treatment With Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma

This study is a prospective evaluation of a multiscale prediction model for the treatment with tyrosine kinase inhibitors (TKI) in HCC. Patients with HCC that qualify for systemic treatment with TKIs will be included. At baseline, prior to treatment, molecular and image fingerprints are collected (fingerprint #1). Further fingerprint investigations will be performed after a short treatment period at week 4 (fingerprint #2) and optional at tumor progression (Fingerprint #3). Based on previous findings from a preceding trial the fingerprint diagnostics #1 and #2 will be used to determine a prediction for treatment outcome at the earliest possible point in time ("therapy prediction"). This prediction will be compared to the prospectively determined outcome of the treated patients in this study (validation cohort; primary study endpoint). Fingerprint #3 will be optional to generate hypothesis for treatment failure.

Study Overview

• Status: Terminated
• Conditions: Hepatocellular Carcinoma; Sorafenib

Detailed Description

The aim of this prospective observational clinical study is to validate prognostic parameters for the treatment with tyrosine kinase inhibitors (TKI) that have been identified in a separate patient cohort with HCC (Study title "Fingerprint characterization of advanced HCC to optimize treatment decisions and enable an early prediction of therapy resistance", ClinicalTrials.gov Identifier NCT02372162). Based on these previous findings, predefined parameters that have been found to correlate with therapy responses will be determined for the patients in this observational trial. Diagnostic procedures include an image fingerprint (MRI and multi-phase CT scan of tumor manifestations, radiomics analysis of defined tumor areas, ultrasound elastography and a molecular fingerprint with exome and transcriptome sequencing from tumor tissue, single cell sequencing of PBMCs, MR spectroscopy for metabolomics analysis of blood and urine. These parameters at baseline will be used to predict therapy outcome, which will be prospectively compared to the clinical outcome under treatment with sorafenib. A second fingerprint will be collected at 4 weeks treatment and optional at tumor progression. New hypothesis generating parameters will be investigated in this patient cohort .

• Study Type: Observational
• Enrollment (Actual): 2

Contacts and Locations

• Study Contact: Name: Ursula Koppenhöfer, Dipl. biol.; Phone Number: 2984457 +497071; Email: ursula.koppenhoefer@med.uni-tuebingen.de

Study Locations

• Germany
  • BW
    • Tübingen, BW, Germany, 72076
      • University Hospital Eberhard Karls University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

We will prospectively enrol all patients with HCC at our institution that qualify for a systemic treatment with sorafenib that fulfil the inclusion and exclusion criteria.

Description

Inclusion Criteria:

1. HCC patients with indication for the treatment with an approved tyrosine kinase inhibitor, irrespective of previous systemic therapies.
2. If prior systemic therapies had been applied, progression has to be documented prior to the start of treatment.
3. Male or female ≥ 18 years and written informed consent.
4. Histologically confirmed advanced stage hepatocellular carcinoma, BCLC class B or C.
5. Child-Pugh class A or B. Only patients with Child-Pugh index class B of not more than 7 will be included. Patients with untreatable ascites or hepatic encephalopathy > Grade 1 are excluded (see exclusion criteria).
6. ECOG performance status 0, 1 or 2.
7. Life expectancy of 12 weeks or more.
8. At least one measurable lesion without previous local therapy and that is suitable for accurate repeated measurements as per mRECIST guidelines.
9. Adequate hematological parameters, as demonstrated by:
10. Hemoglobin ≥ 9.0 g/dl (SI units: 5.6 mmol/l);
11. WBC ≥ 2.5 x 109/l;
12. Platelets ≥ 60 x 109/l;
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 times upper limit of normal range (ULNR);
14. Bilirubin ≤ 3 mg/dl;
15. Serum creatinine ≤ 1.5 mg/dl (SI units: 132 µmol/l);
16. Prothrombin Time (PT) International Normalized Ratio (INR) ≤ 1.5.

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for study participation:

1. Renal failure requiring hemo- or peritoneal dialysis.
2. Patients with no adequate treatment for gastrointestinal bleeding and esophagus varices within 14 days prior to study entry.
3. Child-Pugh index class B in combination with more than slight ascites or hepatic encephalopathy > Grade I.
4. Altered mental status precluding understanding of the informed consent process.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Sorafenib treated HCC patients; No intervention is performed. This is an observational study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To prospectively evaluate image fingerprint analysis of HCC tumor tissue to predict therapy responses	MRI and CT scan, including radiomics analysis	6 months after therapy initiation
To prospectively evaluate molecular fingerprint analysis of HCC tumor tissue to predict therapy responses	Multiscale analysis of exome, transcriptome and metabolic Tumor characteristics	6 months after therapy initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time needed to determine parameter based prediction of therapy outcome for single parameters and for multiscale modelling	Days needed for prediction of therapy outcome by image, molecular and metabolic analysis	Diagnostic procedures at baseline and between week 3 and 6 after treatment initiation
Progression Free Survival	Months	Median PFS is expected between 3.5 and 5.5 months
Radiologically determined time to tumor progression (TTP)	Months	Median TTP is expected between 3.5 and 5.5 months
Objective response rate (ORR) as measured by the sum of partial and complete responders.	% of all treated patients	Within 6 months after treatment initiation
Duration of tumor stabilization (CR, PR, SD)	Days of duration of CR, PR or SD after diagnosis of best response	Through study completion, up to 18 months
Overall Survival (OS)	Months	Current data suggest approximately 12 months
To prospectively assess patient-reported outcome of HCC patients under treatment with sorafenib	EORTC QLQ-C30 questionnaire	Through study completion, up to 18 months
Distribution of sorafenib adverse drug reactions	CTCAE criteria	Through study completion during sorafenib treatment, up to 18 months
Feasibility of detection of circulating miRNA	Change of miRNA detection in peripheral blood sample between baseline and after treatment initiation	Baseline and between week 3 and 6 after treatment initiation
Changes of Radiomics analysis under treatment with Sorafenib	Collection of radiomics features of tumor tissue at baseline and after treatment initiation	Baseline and between week 3 and 6 after treatment initiation
Changes of ultrasound elastography under treatment with Sorafenib	Determination of ultrasound elastography of tumor tissue at baseline and after treatment initiation	Baseline and between week 3 and 6 after treatment initiation

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: German Federal Ministry of Education and Research
• Investigators: Principal Investigator: Michael Bitzer, MD, University Hospital, Eberhard Kars University Tübingen; Principal Investigator: Nisar P Malek, MD, University Hospital, Eberhard Kars University Tübingen

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2019
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: December 16, 2018
• First Submitted That Met QC Criteria: May 17, 2019
• First Posted (Actual): May 22, 2019

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Imaging; Liver Cancer; Tyrosine Kinase Inhibitor; Molecular Charakterization
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: e:Med-HCC-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No