This phase II trial tests how well giving durvalumab with standard chemotherapy, gemcitabine and cisplatin, before surgery works in treating patients with high risk liver cancer (cholangiocarcinoma) that can be removed by surgery (resectable). Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving durvalumab with gemcitabine and cisplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed in patients with high risk resectable cholangiocarcinoma.
PRIMARY OBJECTIVE: I. To examine the proportion of patients who complete neoadjuvant therapy followed by curative intent surgical resection. SECONDARY OBJECTIVES: I. To determine the major pathologic response (MPR) rate. (Efficacy) II. To determine the proportion of patients who attain an R0 resection following neoadjuvant therapy. (Efficacy) III. To determine the radiological response rate after 2 and 4 cycles of neoadjuvant therapy. (Efficacy) IV. To determine the overall survival of patients receiving neoadjuvant therapy prior to curative intent surgical resection. (Efficacy) V. To determine the relapse free survival (RFS) of patients receiving neoadjuvant therapy prior to curative intent surgical resection. (Efficacy) VI. To estimate the incidence of adverse events during neoadjuvant therapy which would preclude completion of the neoadjuvant chemotherapy regiment as defined by grade 4 or above adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. (Feasibility) VII. To determine the proportion of patients who are able to start adjuvant therapy within 10 weeks of surgical resection. (Feasibility) VIII. To determine the proportion of patients who can complete 4 cycles of adjuvant therapy. (Feasibility) IX. To determine the efficacy of therapy in different molecular subtypes (by deoxyribonucleic acid \[DNA\] profiling, ribonucleic acid \[RNA\] profiling, and circulating tumor \[ct\]DNA-based minimal residual disease \[MRD\]). (Toxicity Profiles and Biomarkers) X. To compare pre- and post-neoadjuvant therapy changes in the phenotypic profiles of circulating immune cells. (Toxicity Profiles and Biomarkers) XI. To correlate ctDNA-based MRD, tissue and blood based immune biomarkers, and body composition with the primary/secondary endpoints. (Toxicity Profiles and Biomarkers) EXPLORATORY OBJECTIVES: I. Quantitative European Association for the Study of the Liver (qEASL)-based 3 dimensional (3D) enhancement measurement will be used as a surrogate marker of pathological response. II. The primary and secondary outcomes will be associated with the visceral abdominal fat, subcutaneous abdominal fat, and muscle at the level of L2/L3. OUTLINE: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 with gemcitabine IV over 30 minutes and cisplatin IV over 60 minutes on days 1 and 8 for 4 cycles and then undergo surgical resection on study. Following surgery, patients may continue the durvalumab, gemcitabine and cisplatin regimen for up to 4 additional cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) scans and/or magnetic resonance imaging (MRI) scans and blood sample collection throughout study, as well as tissue biopsies during screening and on study. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 5 years and then yearly.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Undergo tissue biopsy
Undergo blood sample collection
Given IV
Undergo CT scan
Given IV
Given IV
Undergo MRI scan
Undergo surgical resection
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
SUSPENDEDLos Angeles General Medical Center
Los Angeles, California, United States
SUSPENDEDUC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
SUSPENDEDUCHealth University of Colorado Hospital
Aurora, Colorado, United States
Proportion of patients who complete 4 cycles of neoadjuvant therapy followed by surgical resection
Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% confidence interval \[CI\]) will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: After surgical resection, up to week 18 after starting neoadjuvant therapy
Major pathologic response (MPR) rate
MPR will be calculated based on the patients who can successfully undergo surgical resection. Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: After surgical resection, up to week 18 after starting neoadjuvant therapy
Proportion of patients who attain an R0 margin status after surgical resection
Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: After surgical resection, up to week 18 after starting neoadjuvant therapy
Radiological response rate
Defined as the percentage of patients with complete response, partial response, stable disease or progressive disease after neoadjuvant therapy by Response Evaluation Criteria in Solid Tumor (RECIST), modified RECIST and quantitative European Association for the Study of the Liver after completing 4 cycles of neoadjuvant therapy. Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: After 2 and 4 cycles of neoadjuvant therapy (cycle length=21 days)
Overall survival (OS)
OS, including treatment-related, and disease-related death will be assessed using immune RECIST. Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Kaplan-Meier method will be used to estimate the survival curves. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: From randomization to death, assessed up to 2 years
Relapse free survival (RFS)
Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% confidence interval (CI) will be reported. Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Kaplan-Meier method will be used to estimate the survival curves. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: From surgery to recurrence of intrahepatic cholangiocarcinoma (iCCa), assessed up to 2 years
Incidence of adverse events
Adverse events will be defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI) will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: Up to recurrence of iCCA
Proportion of patients who are able to start adjuvant therapy
Defined as the proportion of patients with Eastern Cooperative Oncology Group \> 2, immunotherapy related adverse event \> 3, any CTCAE \> grade 3 that prevent from starting adjuvant therapy. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: Up to 10 weeks after surgical resection
Proportion of patients who complete 4 cycles of adjuvant therapy
Descriptive analysis will be used. Summary statistics (such as mean, median, range, proportion, as well as the associated 95% CI will be reported. Regression models (such as the logistic regression for binary endpoints and the Cox regression for survival endpoints) will be constructed to assess the association between the primary/secondary endpoints and the prognostic or biomarker variables.
Time frame: Up to week 12 after starting adjuvant therapy
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