A Phase II Trial of Durvalumab With Gemcitabine and Cisplatin as Neoadjuvant Therapy for High-Risk Resectable Intrahepatic Cholangiocarcinoma
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.
Detailed description
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.
Arms & interventions
- ProcedureBiopsy Procedure
Undergo tissue biopsy
- ProcedureBiospecimen Collection
Undergo blood sample collection
- DrugCisplatin
Given IV
- ProcedureComputed Tomography
Undergo CT scan
- BiologicalDurvalumab
Given IV
- DrugGemcitabine
Given IV
- ProcedureMagnetic Resonance Imaging
Undergo MRI scan
- ProcedureResection
Undergo surgical resection
Outcome measures
Primary
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
Secondary
Major pathologic response (MPR) rate
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
Time frame: After surgical resection, up to week 18 after starting neoadjuvant therapy
Radiological response rate
Time frame: After 2 and 4 cycles of neoadjuvant therapy (cycle length=21 days)
Overall survival (OS)
Time frame: From randomization to death, assessed up to 2 years
Relapse free survival (RFS)
Time frame: From surgery to recurrence of intrahepatic cholangiocarcinoma (iCCa), assessed up to 2 years
Incidence of adverse events
Time frame: Up to recurrence of iCCA
Proportion of patients who are able to start adjuvant therapy
Time frame: Up to 10 weeks after surgical resection
Proportion of patients who complete 4 cycles of adjuvant therapy
Time frame: Up to week 12 after starting adjuvant therapy
Eligibility criteria
Study locations (58)
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
Los Angeles General Medical Center
Los Angeles, California, 90033
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut, 06418
Smilow Cancer Hospital Care Center-Fairfield
Fairfield, Connecticut, 06824
Smilow Cancer Hospital Care Center at Glastonbury
Glastonbury, Connecticut, 06033
Smilow Cancer Hospital Care Center at Greenwich
Greenwich, Connecticut, 06830
Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut, 06437
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, 06105
Yale University
New Haven, Connecticut, 06520
Yale-New Haven Hospital North Haven Medical Center
North Haven, Connecticut, 06473
Smilow Cancer Hospital Care Center at Long Ridge
Stamford, Connecticut, 06902
Smilow Cancer Hospital-Torrington Care Center
Torrington, Connecticut, 06790
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, 06611
Smilow Cancer Hospital-Waterbury Care Center
Waterbury, Connecticut, 06708
Smilow Cancer Hospital Care Center - Waterford
Waterford, Connecticut, 06385
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Northwestern University
Chicago, Illinois, 60611
Memorial Hospital East
Shiloh, Illinois, 62269
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
Boston Medical Center
Boston, Massachusetts, 02118
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri, 64116
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
NYP/Weill Cornell Medical Center
New York, New York, 10065
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
University of Cincinnati Cancer Center-UC Medical Center
Cincinnati, Ohio, 45219
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
University of Cincinnati Cancer Center-West Chester
West Chester, Ohio, 45069
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
Smilow Cancer Hospital Care Center - Westerly
Westerly, Rhode Island, 02891
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
MD Anderson in The Woodlands
Conroe, Texas, 77384
M D Anderson Cancer Center
Houston, Texas, 77030
MD Anderson West Houston
Houston, Texas, 77079
MD Anderson League City
League City, Texas, 77573
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229
MD Anderson in Sugar Land
Sugar Land, Texas, 77478
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792