A Phase 1 Neoadjuvant Trial of Selective Internal Yttrium-90 Radioembolization (SIRT) With Tremelimumab and Durvalumab (MEDI4736) for Resectable Hepatocellular Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Resectable Hepatocellular Carcinoma
- Sponsor
- Jiping Wang, MD, PhD
- Enrollment
- 20
- Locations
- 3
- Primary Endpoint
- Number of Participants with Adverse Events
- Status
- Recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
The goal of this research study is to evaluate the safety and tolerability of tremelimumab and durvalumab with or without Selective Internal Yttrium-90 Radioembolization (SIRT) in participants with resectable hepatocellular carcinoma (HCC) who will undergo liver surgery.
The names of the interventions involved in this study are:
- Durvalumab (a type of immunotherapy)
- Tremelimumab (a type of immunotherapy)
- Selective Internal Yttrium-90 Radioembolization (SIRT) (a type of radiation microsphere bead)
Detailed Description
This is a Phase 1, open-label, randomized research study to evaluate the safety and tolerability of tremelimumab and durvalumab with or without Selective Internal Yttrium-90 Radioembolization (SIRT) in participants with resectable hepatocellular carcinoma (HCC) who will undergo liver surgery. Participants will be randomized into one of two treatment groups: Durvalumab + Tremelimumab versus Durvalumab + Tremelimumab + SIRT. Randomization means that a participant is put into a group by chance. Radioembolization is a combination of radiation therapy and a procedure called embolization to treat cancer. SIRT blocks tumor blood supply by injecting radioactive particles into the hepatic artery and delivers internal radiotherapy on the tumor. The U.S. Food and Drug Administration (FDA) has not approved Durvalumab as treatment for HCC but it has been approved for other uses. The U.S. FDA has not approved tremelimumab as a treatment option for HCC. The research study procedures include screening for eligibility, study treatment including evaluations, radiology scans of the liver, blood tests, electrocardiograms, and follow up visits. Participation in this study is expected to last about 18 months with long-term follow up for a maximum of 3 years. It is expected that about 20 people will take part in this research study. AstraZeneca, a pharmaceutical company, is supplying the study drugs, tremelimumab and durvalumab. Sirtex Medical Inc., a medical device company, is supplying the Yttrium-90 resin Microsphere beads.
Investigators
Jiping Wang, MD, PhD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed HCC (documentation of original biopsy for diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic subjects (presence of arterial hypervascularity with venous washout). For subjects without cirrhosis, histological confirmation is mandatory.
- •Participants must have resectable disease. Those patients must have preserved liver function (Child A) and with either AJCC stage IA, IB, II, and IIIA or BCLC stage 0 or stage A disease. The determination of resectability will ultimately lie in the clinical judgment of the treating investigator and surgical oncologist involved in the care of the patient.
- •Participants must be treatment naïve for HCC.
- •Age ≥18 years. Because no dosing or adverse event data are currently available on the use of tremelimumab, durvalumab, and SIRT in participants \<18 years of age, children are excluded from this study.
- •Measurable disease per RECIST 1.1 criteria.
- •ECOG performance status ≤ 1 (see Appendix A).
- •Body weight \>30 kg.
- •Participants must have adequate organ and marrow function as defined below:
- •Hemoglobin ≥ 9.0 g/dL
- •Absolute Neutrophil Count (ANC) ≥ 1,000 /mcL
Exclusion Criteria
- •Participants who have received any prior treatment for HCC.
- •Patients who have had a major surgical procedure, open biopsy, or significant traumatic injury with poorly healed wound within 6 weeks prior to first dose of study drug.
- •History of allogenic organ transplantation.
- •Participants who are receiving any other investigational agents.
- •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 with celiac disease controlled by diet alone
- •Patients without active disease in the last 5 years may be included but only after consultation with the sponsor-investigator
Arms & Interventions
Durvalumab + Tremelimumab (Arm A)
-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 28 of 28 Day cycle: Pre-determined dose of Durvalumab * Participants will undergo surgery on day 49 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab
Intervention: Durvalumab
Durvalumab + Tremelimumab (Arm A)
-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 28 of 28 Day cycle: Pre-determined dose of Durvalumab * Participants will undergo surgery on day 49 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab
Intervention: Tremelimumab
Durvalumab + Tremelimumab + SIRT (Arm B)
-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 3 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 31 of 28 Day Cycle: Pre-determined dose of Durvalumab * Day 1 of 28 Day Cycle: Yttrium-90 * Participants will undergo surgery on Day 52 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab
Intervention: Durvalumab
Durvalumab + Tremelimumab + SIRT (Arm B)
-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 3 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 31 of 28 Day Cycle: Pre-determined dose of Durvalumab * Day 1 of 28 Day Cycle: Yttrium-90 * Participants will undergo surgery on Day 52 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab
Intervention: Tremelimumab
Durvalumab + Tremelimumab + SIRT (Arm B)
-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 3 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 31 of 28 Day Cycle: Pre-determined dose of Durvalumab * Day 1 of 28 Day Cycle: Yttrium-90 * Participants will undergo surgery on Day 52 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab
Intervention: SIRT
Outcomes
Primary Outcomes
Number of Participants with Adverse Events
Time Frame: up to 18 months
Defined as All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv5 as reported on case report forms were counted. Rate is the proportion of treated participants experiencing at least one treatment-related grade 3-5 AE of any type during the time of observation.
Secondary Outcomes
- Best Pathological Response(up to 65 days)
- Median Progression-Free Survival (PFS)(up to 3 years)
- Median Overall Survival (OS)(up to 3 years)
- Best Radiologic Response(up to 15 months)
- Cytokines Level(up to 3 years)
- CD8+/CD4+T Cells Level(up to 3 years)
- Dendritic Cells Level(up to 3 years)
- Number of Participants with Surgical Complications(up to 30 days)