Slow recruitment due to COVID-19 pandemic and several newly approved treatment options

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 .

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.

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.