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 (Modified Response Evaluation Criteria in Solid Tumors (mRECIST). 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 (mRECIST and) in-field and out-of- field duration of response. IV. Resectability rate. V. Time to respond in treated and non treated lesions. VI. Correlatives: VIa. Circulating tumor deoxyribonucleic acid (ctDNA) monitoring per investigator discretion; VIb. Post-treatment dose volume histograms will be obtained using Simplicity software; VIbi. Tissue and blood banking for testing such as 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). EXPLORATORY OBJECTIVES: I. Tissue and blood for predictive and prognostic biomarkers will be collected. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Undergo mapping angiography
Undergo biopsy
Undergo blood sample collection
Undergo CT
Given IV
Undergo MRI
Undergo PET/CT
Given IV
Receive transarterial Y90 radioembolization
Mayo Clinic in Florida
Jacksonville, Florida, United States
RECRUITINGIncidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Cohort 1)
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.
Time frame: Day 0 to day 28
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Cohort 2)
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.
Time frame: Day 14 to day 42
Overall efficacy
Will be assessed by response rate modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Positron Emission Tomography (PET) (PERCIST).
Time frame: Up to 24 months
Median progression free survival
Timed endpoints and will be examined in an exploratory and hypothesis-generating fashion.
Time frame: Up to 24 months
Median overall survival
Timed endpoints and will be examined in an exploratory and hypothesis-generating fashion.
Time frame: Up to 24 months
Objective response rate (complete response and partial response)
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).
Time frame: From the start of the treatment until disease progression/recurrence, assessed up to 24 months
Duration of response
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).
Time frame: Up to 24 months
Change in white blood cell count (WBC)
Assessed by blood test
Time frame: Up to 24 months
Change in absolute neutrophil count (ANC)
Assessed by blood test
Time frame: Up to 24 months
Change in absolute monocyte count (AMC)
Assessed by blood test
Time frame: Up to 24 months
Change in absolute neutrophil count to absolute lymphocyte count (ANC:ALC) ratio
Assessed by blood test
Time frame: Up to 24 months
Change in myeloid to lymphoid lineage (M:L)
Assessed by blood test
Time frame: Up to 24 months
Change in circulating tumor DNA (ctDNA)
Assessed using Guardant 360 at baseline and throughout treatment
Time frame: Up to 24 months
Change in tumor biopsy
Assessed by reviewing pre- and post-biopsies for predictive biomarkers
Time frame: Up to 24 months
Change in personalized ctDNA assay
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
Time frame: Up to 24 months
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