Radiation Therapy Followed by Durvalumab (MEDI4736) and Tremelimumab And Surgery Versus Radiation Therapy Followed by Surgery for Resectable Hepatocellular Carcinoma. A Randomized Window of Opportunity Trial (DARTS)
Overview
- Phase
- Phase 3
- Status
- Not yet recruiting
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Intratumoral immune cells (regulatory T lymphocytes or Tregs).
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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)
Exclusion Criteria
- •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
- •Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy except for alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- •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.
Arms & Interventions
SBRT and Chemotherapy
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.
Intervention: Chemotherapy/Radiation (Drug)
Outcomes
Primary Outcomes
Intratumoral immune cells (regulatory T lymphocytes or Tregs).
Time Frame: Baseline and immediately after the intervention
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%.
Secondary Outcomes
- 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)
Investigators
Pablo Serrano
Local principal Investigator
Hamilton Health Sciences Corporation