Fingerprint Characterization Tyrosine Kinase Inhibitors in Advanced HCC

Terminated

• Conditions: Sorafenib; Hepatocellular Carcinoma

• Registration Number: NCT03958669
• Lead Sponsor: University Hospital Tuebingen

Brief Summary

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.

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 Timeline

• Study First Submitted: 2018-12-16
• Study First Submitted QC: 2019-05-17
• Study First Posted: 2019-05-22
• Study Start: 2019-11-01
• Primary Completion: 2022-12-31
• Study Completion: 2023-05-31
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-28
• Last Update Posted: 2024-04-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University Hospital Eberhard Karls University; 🇩🇪 Tübingen, BW, Germany