Summary

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.

Objectives

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.

Eligibility

1. Patients must have histologically or cytologically confirmed intrahepatic cholangiocarcinoma (iCCA) that is resectable by imaging evaluation. Choice of staging modality is left up to the discretion of the treatment team; we favor high-quality CT scan of the chest/abdomen/pelvis with liver or biliary protocol. Eligibility will be confirmed through central imaging review.
2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam.
3. Patients must be an acceptable risk surgical candidate at the time of enrollment, as determined by a board-certified surgeon with expertise in hepatobiliary surgery.
4. High-risk iCCA is defined as the presence of any of these factors: * Tumor size > 5 cm. * Multifocality or satellitosis limited to the same lobe. * Vascular invasion. * Suspected or confirmed (via biopsy) regional lymph node metastases. ** Suspected is defined as lymph nodes that are deemed suspicious for metastasis based on large size (criteria vary per anatomical location; 6-10 mm for abdominal and 8-10 mm for pelvic), enhancement pattern, and shape. These may also include lymph nodes that display fludeoxyglucose F 18 (FDG)-avidity on positron emission tomography (PET) scan, if obtained, in the course of disease work-up (not mandatory). * CA 19-9 > 200 U/mL.
5. Patients are treatment naïve for iCCA.
6. Age >= 18 years. Because no dosing or adverse event data are currently available on the use of durvalumab (MEDI4736) in combination with cisplatin and gemcitabine in patients < 18 years of age, children are excluded from this study.
7. Body weight > 30 kg.
8. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%).
9. Leukocytes >= 3,000/mcL.
10. Hemoglobin >= 9.0 g/dL.
11. Absolute neutrophil count >= 1,500/mcL.
12. Platelets >= 100,000/mcL.
13. Neuropathy grade =< 1 by CTCAE.
14. Albumin >= 2.8 g/dL.
15. Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN).
16. Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 3 × institutional ULN.
17. Serum creatinine =< 1.5 x institutional ULN.
18. Measured creatinine clearance > 60 mL/min or glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (by the Cockcroft-Gault equation).
19. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
20. Life expectancy >= 12 weeks.
21. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
22. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
23. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
24. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
25. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. If non-protocol anticancer agents for non-study indications is required concurrently with the protocol therapy, the case should be discussed and approved by the study chair and the sponsor (Cancer Therapy Evaluation Program [CTEP]).
26. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
27. Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Treatment Sites in Georgia