Radioembolization With Tremelimumab and Durvalumab for Locally Advanced Unresectable or Oligo-Metastatic Intrahepatic Cholangiocarcinoma

Stage III Intrahepatic Cholangiocarcinoma AJCC v8 Clinical Trial

Official title: Phase 1 Trial of Safety and Preliminary Efficacy of Segmental Ablative Radioembolization in Combination With Tremelimumab Plus Durvalumab (MEDI4736) in Patients With Unresectable, or Oligo-Metastatic Cholangiocarcinoma Who Are Not Candidates for Curative Therapy (RAIDEN Trial)

Status Recruiting

Clinical Trial Summary

This phase I trial tests the safety and side effects of yttrium-90 (Y90) radioembolization combined with immunotherapy drugs tremelimumab and durvalumab in treating patients with intrahepatic cholangiocarcinoma (cancer of the bile ducts in the liver) that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable) who are not candidates for curative therapy or that has spread from where it first started (primary side) to multiple other places in the body (oligo-metastatic). Cholangiocarcinoma is a rare but aggressive cancer with limited curative options outside of surgery. Immunotherapy has shown modest benefit in hepatobiliary (liver, bile ducts, and gallbladder) cancers including cholangiocarcinoma. Radioembolization is a type of radiation therapy used to treat liver cancer that is advanced or has come back where tiny beads that hold the radioactive substance (radioisotope) yttrium Y90 are injected into or near the hepatic artery (the main blood vessel that carries blood to the liver). The beads collect in the tumor and the Y90 gives off radiation. This destroys the blood vessels that the tumor needs to grow and kills the tumor cells. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving Y90 radioembolization in combination with tremelimumab and durvalumab immunotherapy may be safe and beneficial in treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy.

Clinical Trial Description

PRIMARY OBJECTIVE:

I. Characterize the safety of the combination of Y90 transarterial radioembolization (TARE), durvalumab and tremelimumab.

SECONDARY OBJECTIVES:

I. Overall efficacy of Y90 + tremelimumab + durvalumab as gauged by response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1, modified [m]RECIST and Positron Emission Tomography [PET] [PERCIST]).

II. Median progression free survival (PFS) and overall survival (OS). III. Infield and out of field objective response rate (complete response and partial response) rate (RECIST v1.1, mRECIST and PERCIST). In-field and out of- field duration of response.

IV. Correlatives:

IVa. Studies pertaining to serial circulating tumor deoxyribonucleic acid (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment; IVb. Post-treatment dose volume histograms will be obtained using Simplicity software; IVi. Tissue immunohistochemistry and Tissue Digital Spatial Profiling - list of biomarkers: CD68, CD 86, CD163, CSF1R - macrophage, M1/M2 markers, CD3 - T-cell differentiator, FoxP3, CD25, CD4 and 8

• T-cell lineage, PD-1, PD-L1, etc. - checkpoints, granzyme B - cytotoxic T lymphocytes (CTL) activity. Next generation (Gen) profiling and ribonucleic acid (RNA) sequencing. Microsatellite instability (MSI)/ mismatch repair (MMR) status, tumor mutational burden (TMB); IVii. Peripheral blood: white blood cell count (WBC); absolute neutrophil count (ANC); absolute lymphocyte count (ALC); absolute monocyte count (AMC); ANC to ALC (ANC:ALC) ratio and myeloid to lymphoid lineage (M:L); IViii. Guardant 360 to assess ctDNA at baseline and evolution throughout treatment; IViv. Personalized ctDNA assay (Signatera bespoke multiplex polymerase chain reaction [mPCR] next generation sequencing [NGS] assay by Natera) specific to each patient's tumor mutational signatures.

EXPLORATORY OBJECTIVES:

I. Tissue and blood for predictive biomarkers.

OUTLINE: Patients are assigned to 1 of 2 arms.

Arm I (COHORT I): Patients receive transarterial Y90 radioembolization and tremelimumab intravenously (IV) over 1 hour on day 1 of cycle 1 and durvalumab IV over 1 hour on day 1 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo mapping angiography during screening as well as computerized tomography (CT) and magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT during screening and on study. Patients also undergo blood sample collection throughout the trial and may undergo tumor biopsy during screening and on study.

Arm II (COHORT II): Patients receive transarterial Y90 radioembolization on day 1 of cycle 1 and receive tremelimumab IV over 1 hour on day 14 of cycle 1 and durvalumab IV over 1 hour on day 14 of each cycle. Cycles repeat every 42 days for cycle 1 and then every 28 days for cycles 2-24 in the absence of disease progression or unacceptable toxicity. Patients also undergo mapping angiography during screening, as well as CT and MRI or PET/CT during screening and on study. Patients also undergo blood sample collection throughout the trial and may undergo tumor biopsy during screening and on study.

Cohort III: This is a dose expansion cohort where patients are enrolled based on the efficacy and safety results from Cohorts I and II.

After completion of study treatment, patients are followed up every 3 months for 2 years. ;

Related Conditions & MeSH terms

• Cholangiocarcinoma
• Locally Advanced Intrahepatic Cholangiocarcinoma
• Stage III Intrahepatic Cholangiocarcinoma AJCC v8
• Stage IV Intrahepatic Cholangiocarcinoma AJCC v8
• Unresectable Intrahepatic Cholangiocarcinoma

• NCT number: NCT06058663
• Study type: Interventional
• Source: Mayo Clinic
• Status: Recruiting
• Phase: Phase 1
• Start date: June 6, 2024
• Completion date: November 30, 2025