The objectives of this study is to estimate the biological activity of combination chemotherapy and radiation versus radiation alone in patients with Hepato Cellular Carcinoma (HCC).
The study hypothesizes is that combination chemotherapy and radiation is superior to radiation alone in inducing a biological response. The study hypothesizes that combination chemotherapy and radiation is superior to radiation alone in inducing a biological response. A biological response, or change in the tumor microenvironment (TME), is defined by reduced infiltration of intra-tumoral regulatory T cells (Tregs), a decrease in tumour-associated macrophages (TAMs) of the M2 phenotype, and an increase in immune cells such as effector CD8+ T-cells. An increased rate of biological response is therefore expected in participants receiving the combination of Durvalumab, Tremelimumab, and stereotactic body radiation therapy (SBRT), compared to those receiving SBRT alone. Additionally, biological response is hypothesized to correlate with pathological response.
The study has been conducted within a WOO window of opportunity randomized clinical trial in order to obtain data in the quickest and safest manner. Patients undergoing surgery are very healthy by definition and will be able to tolerate treatment without any major complications, leading to adequate tissue samples before and after treatment.
Radiologically or biopsy proven solitary HCC without biliary invasion or metastases, Liver Imaging Reporting and Data Systems (LI- RADS) 4 or 5 only. Participants with satellite tumour nodules are eligible. Satellitosis or a satellite nodule is defined as a tumour (LI-RADS 4 or 5 only) less than or equal to 2 cm and located less than or equal to 2 cm from the main tumour.
Previous therapy for HCC, including systemic therapy, surgery, radiation therapy, ablation or embolization.
Parallel
Chemotherapy/Radiation
DrugCombination of radiation and chemotherapy
Intratumoral immune cells (regulatory T lymphocytes or Tregs).
This will be measured pre and post treatment through proteomic analysis with digital spatial profiling (DSP) technology. This will determine with high resolution the area of infiltration (tumour versus stroma), to assess the relative immune status of the tumor (i.e., hot or cold). The primary endpoint is the percentage change in Tregs in the TME. The percentage change in Tregs is defined as the: (number of Tregs at surgery) / (number of Tregs at baseline) \*100%.
Intratumoural immune cells including M2-TAMs measured similarly to the primary outcome measure.
measured similarly to the primary outcome measure.
Intratumoural immune cells
Intratumoural immune cells (such as B cells, CD8+ T cells)
TMB
which will be defined as the number of somatic nonsynonymous mutations or variants present in the coding region expressed as mutations per megabase (muts/Mb) of sequence. TMB will be measured using DNA/RNA seq, which will be analysed in the specimen pre- treatment. RNA seq will be analysed post treatment using ThermoFisher's Oncomine Comprehensive Assay Plus Assay (DNA-seq) and ThermoFisher's Ion AmpliSeqTM Transcriptome Human Gene Expression Kit (RNA-seq).
PD-L1 expression
PD-L1 expression before and after treatment will be performed using immunohistochemistry in the specimen
Exploratory outcome
Pathologic response
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Hamilton Health Sciences Corporation
Lead sponsor
McMaster University
Collaborator
London Health Sciences Centre
Collaborator
