A Phase Ib Study of Durvalumab (Medi4736) and Tremelimumab Following Radioembolization in Patients With Unresectable Locally Advanced Hepatocellular Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Tremelimumab
- Conditions
- BCLC Stage B Hepatocellular Carcinoma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 25
- Locations
- 2
- Primary Endpoint
- Overall response
- Status
- Active, not recruiting
- Last Updated
- 12 days ago
Overview
Brief Summary
This phase Ib trial investigates the side effects of durvalumab and tremelimumab after radioembolization (radiation particles against liver tumors) and to see how well they work in treating patients with liver cancer that cannot be removed by surgery (unresectable) and has spread to nearby tissues and lymph nodes (locally advanced). Durvalumab and tremelimumab are antibodies (proteins produced by the defense system of the body [immune system]) that have been made in the laboratory and may improve the ability of the immune system to detect and fight cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To establish the safety of durvalumab and tremelimumab following radioembolization with Yttrium-90 selective internal radiation (SIR)-spheres in patients with locally advanced hepatocellular carcinoma without extra-hepatic disease. II. If the combination of durvalumab and tremelimumab is deemed unsafe, to establish the safety of single agent durvalumab and explore all endpoints with durvalumab alone. III. To evaluate the overall response rate in patients treated with durvalumab and tremelimumab following radioembolization with Yttrium-90 SIR-Spheres using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, modified (m) RECIST and immune modified RECIST criteria. SECONDARY OBJECTIVES: I. To evaluate the rate of 6-month progression-free survival in patients treated with durvalumab and tremelimumab following radioembolization with Yttrium-90 SIR-spheres. II. To evaluate median progression-free survival and overall survival in patients treated with durvalumab and tremelimumab following radioembolization with Yttrium-90 SIR-spheres. EXPLORATORY OBJECTIVES: I. To explore the association of response and survival outcomes with PD-L1 expression of baseline tumor biopsies. II. To explore the association of response and survival outcomes with next generation sequencing results including tumor mutational burden of baseline tumor biopsies. III. To explore genomic alterations/evolutions in tumor tissue following Yttrium-90 SIR-spheres and durvalumab plus tremelimumab through comparison of baseline and post-combination immunotherapy treatment tumor biopsies. IV. To explore the association of response and survival outcomes with gene expression signatures. OUTLINE: Patients undergo standard of care radioembolization with Yttrium-90 SIR-spheres intra-arterially over 60-90 minutes on day -14. Patients then receive durvalumab intravenously (IV) over 1 hour and tremelimumab IV over 1 hour on day 1. Cycles with durvalumab repeat every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 90 days, and then every 12 weeks thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically or cytologically confirmed unresectable, locally advanced hepatocellular carcinoma as defined by Barcelona Clinic Liver Cancer (BCLC) (B) intermediate stage or BCLC (C) advanced stage without extra-hepatic disease (only with branch portal vein thrombosis)
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the United States \[US\]) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- •Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- •Eastern Cooperative Oncology Group (ECOG) 0-1
- •Must have a life expectancy of at least 12 weeks
- •Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- •Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
- •Women \>= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \> 1 year ago, had chemotherapy-induced menopause with last menses \> 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
- •Male patients must be surgically sterile, or if sexually active and having a pre-menopausal female partner then must be using an acceptable form of contraception
- •Have a Child-Pugh class A liver score within 7 days of radioembolization
Exclusion Criteria
- •Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac involvement of hepatocellular carcinoma (HCC) based on imaging. Vascular invasion to portal vein side branches are eligible for study
- •Evidence of diffuse HCC (tumor burden occupying \> 50% of liver)
- •Any evidence of known metastatic disease
- •Major surgical procedure (as defined by the investigator) within 28 days prior to radioembolization
- •Note: Local surgery of isolated lesions for palliative intent is acceptable
- •Participation in another clinical study with an investigational product during the last 4 weeks
- •Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
- •Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) =\< 28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator
- •Prior exposure to anti-PD-1/PD-L1 inhibitor or anti-CTLA4 inhibitor, including durvalumab or tremelimumab
- •Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade \>= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Arms & Interventions
Treatment (durvalumab, tremelimumab)
Patients undergo standard of care radioembolization with Yttrium-90 SIR-spheres intra-arterially over 60-90 minutes on day -14. Patients then receive durvalumab IV over 1 hour and tremelimumab IV over 1 hour on day 1. Cycles with durvalumab repeat every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Tremelimumab
Treatment (durvalumab, tremelimumab)
Patients undergo standard of care radioembolization with Yttrium-90 SIR-spheres intra-arterially over 60-90 minutes on day -14. Patients then receive durvalumab IV over 1 hour and tremelimumab IV over 1 hour on day 1. Cycles with durvalumab repeat every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.
Intervention: Durvalumab
Outcomes
Primary Outcomes
Overall response
Time Frame: From the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started), assessed up to 2 years
Will be evaluated using the new updated international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) committee version 1.1, modified RECIST (mRECIST), and immune modified RECIST (imRECIST) criteria.
Incidence of adverse events
Time Frame: Up to 90 days post-last dose of durvalumab
Will be assessed per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Dose-limiting toxicity
Time Frame: From the time of first administration of durvalumab or tremelimumab until 4 weeks (one cycle) after the first administration
Will be assessed per NCI CTCAE version 5.0.
Secondary Outcomes
- Overall survival(From study enrollment until death, assessed up to 2 years)
- Progression-free survival(From study enrollment to when objective evidence of disease progression is documented, assessed at 6 months)
- Median progression-free survival(Up to 2 years)