Fingerprint Characterization Tyrosine Kinase Inhibitors in Advanced HCC

University Hospital Tuebingen2 enrolled

Overview

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.

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

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

To prospectively evaluate image fingerprint analysis of HCC tumor tissue to predict therapy responses

MRI and CT scan, including radiomics analysis

Time frame: 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

Time frame: 6 months after therapy initiation

Secondary Outcomes

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

Time frame: Diagnostic procedures at baseline and between week 3 and 6 after treatment initiation

Progression Free Survival

Months

Time frame: Median PFS is expected between 3.5 and 5.5 months

Radiologically determined time to tumor progression (TTP)

Months

Time frame: 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

Time frame: 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

Time frame: Through study completion, up to 18 months

Overall Survival (OS)

Months

Time frame: Current data suggest approximately 12 months

To prospectively assess patient-reported outcome of HCC patients under treatment with sorafenib

EORTC QLQ-C30 questionnaire

Time frame: Through study completion, up to 18 months

Distribution of sorafenib adverse drug reactions

CTCAE criteria

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline and between week 3 and 6 after treatment initiation

Fingerprint Characterization Tyrosine Kinase Inhibitors in Advanced HCC

Overview

Conditions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes