This phase II trial tests the safety and effectiveness of preoperative immunotherapy with durvalumab and chemotherapy with cisplatin and gemcitabine with or without futibatinib targeted therapy in treating patients with intrahepatic cholangiocarcinoma that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. Futibatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving immunotherapy with durvalumab and chemotherapy with cisplatin and gemcitabine and/or targeted therapy with futibatinib before surgery may make the tumor smaller for resection and may help prevent the cancer from coming back. Patients whose molecular profiling test result show a genetic change called FGFR2 fusion, rearrangement, or activating mutation, receive immunotherapy, chemotherapy and targeted therapy while patients without a FGFR2 fusion, rearrangement, or activating mutation just receive immunotherapy and chemotherapy. Giving targeted therapy based on molecular profile test results prior to attempted resection for patients with intrahepatic cholangiocarcinoma that has a risk for either not being able to be removed or for coming back after it has been removed may help improve treatment outcomes in patients with resectable intrahepatic cholangiocarcinoma.
PRIMARY OBJECTIVE: I. To assess the feasibility and safety of a novel treatment strategy that includes conducting next generation sequencing (NGS) on a preoperative tissue biopsy to administer prior to surgical resection. SECONDARY OBJECTIVES: I. To assess the radiological response rate (RRR) according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and advanced image analysis (radiomics) in patients with resectable intrahepatic cholangiocarcinoma (IHCC). II. To assess the degree of pathologic response in the surgical specimen of patients with resectable intrahepatic cholangiocarcinoma (IHCC). III. To assess response by measuring circulating tumor DNA (CT-DNA) dynamics in the blood samples of patients with resectable intrahepatic cholangiocarcinoma (IHCC). IV. To determine the R0 resection rate post-surgery in patients with resectable intrahepatic cholangiocarcinoma (IHCC). V. To determine progression-free survival (PFS) in patients with resectable intrahepatic cholangiocarcinoma (IHCC). VI. To determine recurrence-free survival (RFS) in patients with resectable intrahepatic cholangiocarcinoma (IHCC). VII. To identify patients' overall survival (OS) rate in patients with resectable intrahepatic cholangiocarcinoma (IHCC). EXPLORATORY OBJECTIVE: I. To assess the circulating and tumor immune microenvironment in tissue and blood samples. OUTLINE: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 and cisplatin IV over 60 minutes and gemcitabine IV over 30 minutes on days 1 and 8 of one 21-day cycle in the absence of disease progression or unacceptable toxicity while awaiting for NGS results. After obtaining NGS molecular results, patients with FGFR2 fusion, rearrangement, or activating mutation are assigned to Arm A, while patients without FGFR2 fusion, rearrangement, or activating mutation are assigned to Arm B. ARM A: Patients receive futibatinib orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) and blood sample collection throughout the trial. ARM B: Patients continue receiving durvalumab IV over 60 minutes on day 1 and cisplatin IV over 60 minutes and gemcitabine IV over 30 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT and blood sample collection throughout the trial. After completion of study treatment, patients are followed up every 3 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
44
Undergo blood and previously collected tissue sample collection
Given IV
Undergo CT
Given IV
Given PO
Given IV
Undergo MRI
Northwestern University
Chicago, Illinois, United States
Completion of all preoperative testing and therapy
Treatment completion is defined as completion of next generation sequencing testing and all preoperative and operative therapy. Will record the completion of all therapy rate, along with the exact 95% binomial confidence interval.
Time frame: Up to 3 years
Incidence of Treatment-Emergent Adverse Events during all preoperative testing and therapy
Unacceptable toxicity is defined as any grade 3 or higher toxicities by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 that result in a treatment delay of \> 28 days.
Time frame: Up to 3 years
Radiological response rate
Will be assessed by according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and defined as the percentage of patients who will have complete response, partial response or stable disease after the neoadjuvant therapy.
Time frame: Up to 3 years
Pathologic response rate (PRR)
Will be defined as the degree of treatment effect to preoperative therapy. Pathologic complete response (pCR) will be defined as no viable tumor cells (0% viable tumor, 100% necrosis or fibrosis). Absent response will be defined as 100% viable tumor cells with no evidence of tumor regression. Partial response will be defined as degree of necrosis or fibrosis in the tumor bed, rounded to the nearest 10% interval. This is an endpoint to assess the pathologic response to futibatinib in those with FGFR2 fusions / rearrangements / activating mutations compared to cytotoxic chemotherapy in those without FGFR2 fusions/alterations. Pathological response will be measured by a three-tier response rate using pathologic (p) complete response = 0% tumor cells, no response = no histologic evidence of tumor regression and partial response = % necrosis and evident tumor regression. PRR will be calculated by Northwestern's pathologists with subspecialty training in gastrointestinal pathology.
Time frame: At the time of surgery
Response by measuring circulating tumor deoxyribonucleic acid in the blood samples of patients with resectable intrahepatic cholangiocarcinoma
Time frame: Up to 3 years
R0 resection rate
Time frame: Up to 7 days after last dose of study drug
Progression-free survival (PFS)
Disease progression is defined as progressive disease per RECIST 1.1, other documented clinical or radiographical progression per physician judgement, or death due to disease. If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the PFS will be censored as the last available disease assessment.
Time frame: From the time of enrollment to either the day of first documented disease progression or death from any cause, assessed up to 3 years
Recurrence-free survival (RFS)
Disease recurrence is defined as documented clinical or radiographical progression per physician judgment, or death due to disease. Disease progression/recurrence, if it occurs, will be noted by the treating clinician. RFS data will be collected from baseline (day of surgery) until the subject experiences disease recurrence, initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause, whichever comes first.
Time frame: Time that elapses between time of surgery and either the day of first documented disease recurrence or death from any cause, assessed up to 3 years
Overall survival
Time frame: From enrollment to the date of any cause death from or to the date of last follow-up if patients are alive, assessed up to 3 years
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