Neoplasms

All Conditions

Rare Diseases

Cholangiocarcinoma

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

Intrahepatic Cholangiocarcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Tremelimumab

Ipilimumab

Antineoplastic Agents, Immunological

Immunologic Factors

Immune Checkpoint Inhibitors

Patients receive transarterial Y90 radioembolization and tremelimumab 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 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.

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.

Angiography

Biopsy

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Positron Emission Tomography

Receive transarterial Y90 radioembolization

Yttrium-90 Microsphere Radioembolization

Clinical Trials Referral Office

Umair Majeed, M.D.

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.

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.

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

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)

Dose-limiting toxicities (DLTs) will be defined as an adverse event (AE) attributed as definitely, probably, or possibility related to the study treatment in the first cycle. All the relevant results pertaining to toxicity will be examined in an exploratory and hypothesis-generating fashion. The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ AEs will also be described and summarized in a similar fashion. Toxicity is defined as AEs that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity will be explored and summarized.

DLTs will be defined as an AE attributed as definitely, probably, or possibility related to the study treatment in the first cycle. All the relevant results pertaining to toxicity will be examined in an exploratory and hypothesis-generating fashion. The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ AEs will also be described and summarized in a similar fashion. Toxicity is defined as AEs that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity will be explored and summarized.

Will be assessed by response rate modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Positron Emission Tomography (PET) (PERCIST).

Timed endpoints and will be examined in an exploratory and hypothesis-generating fashion.

Best response is defined to be the best objective status. The modified RECIST version 1.1, mRECIST and PERCIST criteria will be used for tumor evaluation and patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).

The modified RECIST version 1.1, mRECIST and PERCIST criteria will be used for tumor evaluation and patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).

Assessed using Guardant 360 at baseline and throughout treatment

Assessed by reviewing pre- and post-biopsies for predictive biomarkers

Personalized ctDNA assay recorded and assessed using Signatera bespoke multiplex PCR (mPCR) Next-Generation Sequencing (NGS) assay by Natera, specific to each patient's tumor mutational signatures

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Radioembolization With Tremelimumab and Durvalumab for Locally Advanced Unresectable or Oligo-Metastatic Intrahepatic Cholangiocarcinoma	NCT06058663	Locally Advance... Oligometastatic... Stage III Intra... Stage IV Intrah... Unresectable In...	Angiography Biopsy Biospecimen Col... Computed Tomogr... Durvalumab Magnetic Resona... Positron Emissi... Tremelimumab Yttrium-90 Micr...	18 Years -	Mayo Clinic
Radioembolization With Tremelimumab and Durvalumab for Locally Advanced Unresectable or Oligo-Metastatic Intrahepatic Cholangiocarcinoma	NCT06058663	Locally Advance... Oligometastatic... Stage III Intra... Stage IV Intrah... Unresectable In...	Angiography Biopsy Biospecimen Col... Computed Tomogr... Durvalumab Magnetic Resona... Positron Emissi... Tremelimumab Yttrium-90 Micr...	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for oligometastatic intrahepatic cholangiocarcinoma