Radiation Therapy Followed by Durvalumab (MEDI4736) and Tremelimumab And Surgery Versus Radiation Therapy Followed by Surgery for Resectable Hepatocellular Carcinoma.

NCT07027436 | Not Yet Recruiting Phase 3 DMC

• 2 other identifiers: DARTS ESR-23-22174ESR-23-22174
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

Durvalumab/tremelimumab, SBRT, radiation, HCC; WOO, Window of Opportunity

Outcome Measures

Primary Outcomes (1)

• 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%.

  Baseline and immediately after the intervention

Secondary Outcomes (5)

• Intratumoural immune cells including M2-TAMs measured similarly to the primary outcome measure.

  Baseline and immediately after the intervention

• Intratumoural immune cells

  Baseline and immediately after the intervention

• TMB

  Baseline and immediately after the intervention

• PD-L1 expression

  Baseline and immediately after the intervention

• The percent change in peripheral blood immune repertoire.

  Baseline and immediately after the intervention

Other Outcomes (1)

• Exploratory outcome

  Baseline and immediately after the intervention

Study Arms (2)

SBRT and Chemotherapy

EXPERIMENTAL

Study participants randomized to treatment Group 1, will receive SBRT prior to surgery on Day 1, and receive one infusion of Durvalumab (1500mg IV) / Tremelimumab 300mg IV) on Day 15.

Drug: Chemotherapy/Radiation

SBRT alone

NO INTERVENTION

The patients receive radiation only without chemotherapy SBRT prior to the surgery.

Interventions

Chemotherapy/Radiation DRUG

Combination of radiation and chemotherapy

Also known as: Group 1

SBRT and Chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Tumour less than 12 cm in maximum size on CT or MRI.
• Planned surgical resection of HCC with a life expectancy of at least 12 weeks
• Age \>18 years at time of study entry.
• Child-Pugh Class A within 14 days prior to study enrollment
• Eastern Cooperative Oncology Group (ECOG) of 0 or 1 (see Appendix 3)
• Body weight \>30 kg at time of study enrollment
• Adequate normal organ and marrow function as defined below:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC ≥1.0 × 109 /L)
• Platelet count ≥75 × 109/L
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
• Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine clearance CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
• Males:

You may not qualify if:

• Previous therapy for HCC, including systemic therapy, surgery, radiation therapy, ablation or embolization.
• Participation in another clinical study with an investigational product during the last 4 weeks or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Previous radiation therapy or surgery within 4 weeks of the randomization.
• Previous allogenic organ transplantation
• Previous anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapy
• Previous receipt of durvalumab and / or tremelimumab or allergy to it
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone

Sponsors & Collaborators

• Hamilton Health Sciences Corporation: lead
• McMaster University: collaborator

Study Sites (1)

Juravinski Hospital

Hamilton, Ontario, L8V 1C3, Canada

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Drug Therapy; Radiation

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Local principal Investigator

Study Record Dates

• First Submitted: June 3, 2025
• First Posted: June 18, 2025
• Study Start: July 7, 2025
• Primary Completion (Estimated): October 12, 2027
• Study Completion (Estimated): October 10, 2028
• Last Updated: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)