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)
Overview
- Phase
- Phase 1
- Intervention
- Angiography
- Conditions
- Not specified
- Sponsor
- Mayo Clinic
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Cohort 2)
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
Brief 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.
Detailed 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 (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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>= 18 years with body weight \> 30 kg
- •Histologically or cytologically confirmed, locally advanced intrahepatic cholangiocarcinoma that is not amenable to resection, transplantation, or thermal ablation. Oligometastatic intrahepatic cholangiocarcinoma is also eligible. Specifically, such patients must have EITHER =\< 3 malignant extrahepatic lymph nodes (short axis diameter \>= 3cm) OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be \< 3cm, if up to 3 lesions in one organ each lesion MUST be =\< 1cm)
- •Measurable disease
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- •Hemoglobin \>= 9.0 g/dL (=\< 14 days prior to registration)
- •Absolute neutrophil count (ANC) \>= 1000/mm\^3 (=\< 14 days prior to registration)
- •Platelet count \>= 75,000/mm\^3 (=\< 14 days prior to registration)
- •Total bilirubin =\< 1.5 x upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level 3 x ULN may be enrolled) (=\< 14 days prior to registration)
- •Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 5 x ULN (=\< 14 days prior to registration)
- •Calculated creatinine clearance \>= 40 ml/min using the Cockcroft- Gault formula or measured creatinine clearance \> 40 ml/min (=\< 14 days prior to registration)
Exclusion Criteria
- •Concurrent enrollment in another clinical study, unless it is an observational clinical study or during the follow up period of an interventional study
- •Surgery =\< 28 days prior to registration
- •Chemotherapy =\< 4 weeks prior to registration
- •History of \> 1 prior systemic therapy for cholangiocarcinoma not including that in the adjuvant setting. Patients who progressed during or =\< 6 months from completion of adjuvant therapy are excluded
- •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
- •Patients with grade \>= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
- •Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician
- •History of previous locoregional therapy
- •Previous use of therapeutic cancer vaccines
- •Unstable liver function and/ or a change in Child Pugh score during screening
Arms & Interventions
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Angiography
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Biopsy
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Biospecimen Collection
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Computed Tomography
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Durvalumab
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Magnetic Resonance Imaging
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Positron Emission Tomography
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Tremelimumab
Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab)
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.
Intervention: Yttrium-90 Microsphere Radioembolization
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Angiography
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Biopsy
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Biospecimen Collection
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Computed Tomography
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Durvalumab
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Magnetic Resonance Imaging
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Positron Emission Tomography
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Tremelimumab
Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab )
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.
Intervention: Yttrium-90 Microsphere Radioembolization
Outcomes
Primary Outcomes
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Cohort 2)
Time Frame: Day 14 to day 42
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.
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) (Cohort 1)
Time Frame: Day 0 to day 28
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.
Secondary Outcomes
- Change in absolute neutrophil count (ANC)(Up to 24 months)
- Overall efficacy(Up to 24 months)
- Change in white blood cell count (WBC)(Up to 24 months)
- Median overall survival(Up to 24 months)
- Change in absolute monocyte count (AMC)(Up to 24 months)
- Change in absolute neutrophil count to absolute lymphocyte count (ANC:ALC) ratio(Up to 24 months)
- Change in myeloid to lymphoid lineage (M:L)(Up to 24 months)
- Objective response rate (complete response and partial response)(From the start of the treatment until disease progression/recurrence, assessed up to 24 months)
- Duration of response(Up to 24 months)
- Change in tumor biopsy(Up to 24 months)
- Median progression free survival(Up to 24 months)
- Change in circulating tumor DNA (ctDNA)(Up to 24 months)
- Change in personalized ctDNA assay(Up to 24 months)