Clinical trial NCT03958669: Fingerprint Characterization Tyrosine Kinase Inhibitors in Advanced HCC
Official title: Prospective Evaluation of Image and Molecular Fingerprint Characterization to Guide Treatment With Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Hepatocellular Carcinoma
Sorafenib
Keywords: Liver Cancer
Imaging
Molecular Charakterization
Tyrosine Kinase Inhibitor
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
First posted: 2019-05-22
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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 .

Eligibility criteria: 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.

Primary outcomes:
measure: To prospectively evaluate image fingerprint analysis of HCC tumor tissue to predict therapy responses
timeFrame: 6 months after therapy initiation
measure: To prospectively evaluate molecular fingerprint analysis of HCC tumor tissue to predict therapy responses
timeFrame: 6 months after therapy initiation
Secondary outcomes:
measure: Time needed to determine parameter based prediction of therapy outcome for single parameters and for multiscale modelling
timeFrame: Diagnostic procedures at baseline and between week 3 and 6 after treatment initiation
measure: Progression Free Survival
timeFrame: Median PFS is expected between 3.5 and 5.5 months
measure: Radiologically determined time to tumor progression (TTP)
timeFrame: Median TTP is expected between 3.5 and 5.5 months
measure: Objective response rate (ORR) as measured by the sum of partial and complete responders.
timeFrame: Within 6 months after treatment initiation
measure: Duration of tumor stabilization (CR, PR, SD)
timeFrame: Through study completion, up to 18 months
measure: Overall Survival (OS)
timeFrame: Current data suggest approximately 12 months
measure: To prospectively assess patient-reported outcome of HCC patients under treatment with sorafenib
timeFrame: Through study completion, up to 18 months
measure: Distribution of sorafenib adverse drug reactions
timeFrame: Through study completion during sorafenib treatment, up to 18 months
measure: Feasibility of detection of circulating miRNA
timeFrame: Baseline and between week 3 and 6 after treatment initiation
measure: Changes of Radiomics analysis under treatment with Sorafenib
timeFrame: Baseline and between week 3 and 6 after treatment initiation
measure: Changes of ultrasound elastography under treatment with Sorafenib
timeFrame: Baseline and between week 3 and 6 after treatment initiation
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: University Hospital Eberhard Karls University
state: BW
Study officials:
affiliation: University Hospital, Eberhard Kars University Tübingen
name: Michael Bitzer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Eberhard Kars University Tübingen
name: Nisar P Malek, MD
role: PRINCIPAL_INVESTIGATOR
References: