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RecruitingInterventionalPhase 2

A Phase II Trial of Durvalumab With Gemcitabine and Cisplatin as Neoadjuvant Therapy for High-Risk Resectable Intrahepatic Cholangiocarcinoma

NCT ID: NCT06050252Sponsor: National Cancer Institute (NCI)Last updated: 2026-05-22

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

Sex: AllAge: 18 Years and olderHealthy volunteers: No
Inclusion Criteria: * 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. * 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. * 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. * 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. * Patients are treatment naïve for iCCA. * 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. * Body weight \> 30 kg. * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%). * Leukocytes \>= 3,000/mcL. * Hemoglobin \>= 9.0 g/dL. * Absolute neutrophil count \>= 1,500/mcL. * Platelets \>= 100,000/mcL. * Neuropathy grade =\< 1 by CTCAE. * Albumin \>= 2.8 g/dL. * Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN). * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) / alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 × institutional ULN. * Serum creatinine =\< 1.5 x institutional ULN. * Measured creatinine clearance \> 60 mL/min or glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 (by the Cockcroft-Gault equation). * 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). * Life expectancy \>= 12 weeks. * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * 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. * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. * 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 \[CTEP\]). * 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. * 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. Exclusion Criteria: * Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment. * Major surgical procedure (as defined by the Investigator) within 14 days prior to the first dose of durvalumab. Note: Local surgery of isolated lesions for palliative intent or biliary stents is acceptable. * Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection). * Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent. * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). * Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab. * Patients who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab, gemcitabine, cisplatin, or other platinum-containing compounds. * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make this protocol unreasonably hazardous. * Pregnant women are excluded from this study because durvalumab (MEDI4736) is an anti-PD-L1 monoclonal antibody agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab, breastfeeding should be discontinued if the mother is treated with durvalumab. These potential risks may also apply to other agents used in this study. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after durvalumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of durvalumab. * Patients with active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia. * Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement. * Any chronic skin condition that does not require systemic therapy. * Patients without active disease in the last 5 years may be included but only after consultation with the study physician. * Patients with celiac disease controlled by diet alone. * Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis \[TB\] testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. * History of allogenic organ transplantation. * Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Study locations (58)

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California, 92612

Recruiting
Site Public Contact · Contact
Zeljka Jutric · Principal Investigator

Los Angeles General Medical Center

Los Angeles, California, 90033

Active Not Recruiting

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868

Recruiting
Site Public Contact · Contact
Zeljka Jutric · Principal Investigator

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045

Recruiting
Site Public Contact · Contact
Sarah L. Davis · Principal Investigator

Smilow Cancer Hospital-Derby Care Center

Derby, Connecticut, 06418

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center-Fairfield

Fairfield, Connecticut, 06824

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center at Glastonbury

Glastonbury, Connecticut, 06033

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center at Greenwich

Greenwich, Connecticut, 06830

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center - Guilford

Guilford, Connecticut, 06437

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center at Saint Francis

Hartford, Connecticut, 06105

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Yale University

New Haven, Connecticut, 06520

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Yale-New Haven Hospital North Haven Medical Center

North Haven, Connecticut, 06473

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center at Long Ridge

Stamford, Connecticut, 06902

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital-Torrington Care Center

Torrington, Connecticut, 06790

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center-Trumbull

Trumbull, Connecticut, 06611

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital-Waterbury Care Center

Waterbury, Connecticut, 06708

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Smilow Cancer Hospital Care Center - Waterford

Waterford, Connecticut, 06385

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

UF Health Cancer Institute - Gainesville

Gainesville, Florida, 32610

Recruiting
Site Public Contact · Contact
Ali Zarrinpar · Principal Investigator

Emory University Hospital Midtown

Atlanta, Georgia, 30308

Recruiting
Site Public Contact · Contact
Seth Concors · Principal Investigator

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322

Recruiting
Site Public Contact · Contact
Seth Concors · Principal Investigator

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342

Recruiting
Site Public Contact · Contact
Seth Concors · Principal Investigator

Northwestern University

Chicago, Illinois, 60611

Recruiting
Site Public Contact · Contact
Aparna Kalyan · Principal Investigator

Memorial Hospital East

Shiloh, Illinois, 62269

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

University of Kansas Clinical Research Center

Fairway, Kansas, 66205

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

University of Kansas Cancer Center

Kansas City, Kansas, 66160

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

Ochsner Medical Center Jefferson

New Orleans, Louisiana, 70121

Recruiting
Site Public Contact · Contact
Jonathan D. Mizrahi · Principal Investigator

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201

Recruiting
Site Public Contact · Contact
Daniel Shu · Principal Investigator

Boston Medical Center

Boston, Massachusetts, 02118

Active Not Recruiting

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri, 63376

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

University of Kansas Cancer Center - Briarcliff

Kansas City, Missouri, 64116

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064

Recruiting
Site Public Contact · Contact
Raed Al-Rajabi · Principal Investigator

Washington University School of Medicine

St Louis, Missouri, 63110

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

Siteman Cancer Center-South County

St Louis, Missouri, 63129

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

Siteman Cancer Center at Christian Hospital

St Louis, Missouri, 63136

Recruiting
Site Public Contact · Contact
Olivia Aranha · Principal Investigator

NYP/Weill Cornell Medical Center

New York, New York, 10065

Recruiting
Site Public Contact · Contact
Rutika Mehta · Principal Investigator

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157

Recruiting
Site Public Contact · Contact
Michael McCormack · Principal Investigator

University of Cincinnati Cancer Center-UC Medical Center

Cincinnati, Ohio, 45219

Recruiting
Site Public Contact · Contact
Davendra P. Sohal · Principal Investigator

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210

Recruiting
Site Public Contact · Contact
Jordan M. Cloyd · Principal Investigator

University of Cincinnati Cancer Center-West Chester

West Chester, Ohio, 45069

Recruiting
Site Public Contact · Contact
Davendra P. Sohal · Principal Investigator

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104

Recruiting
Site Public Contact · Contact
Hassan Hatoum · Principal Investigator

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232

Recruiting
Site Public Contact · Contact
Anwaar Saeed · Principal Investigator

Smilow Cancer Hospital Care Center - Westerly

Westerly, Rhode Island, 02891

Recruiting
Site Public Contact · Contact
Raghav Sundar · Principal Investigator

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232

Recruiting
Site Public Contact · Contact
Kristen K. Ciombor · Principal Investigator

MD Anderson in The Woodlands

Conroe, Texas, 77384

Recruiting
Site Public Contact · Contact
Hop S. Tran Cao · Principal Investigator

M D Anderson Cancer Center

Houston, Texas, 77030

Recruiting
Site Public Contact · Contact
Hop S. Tran Cao · Principal Investigator

MD Anderson West Houston

Houston, Texas, 77079

Recruiting
Site Public Contact · Contact
Hop S. Tran Cao · Principal Investigator

MD Anderson League City

League City, Texas, 77573

Recruiting
Site Public Contact · Contact
Hop S. Tran Cao · Principal Investigator

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229

Withdrawn

MD Anderson in Sugar Land

Sugar Land, Texas, 77478

Recruiting
Site Public Contact · Contact
Hop S. Tran Cao · Principal Investigator

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112

Recruiting
Site Public Contact · Contact
Glynn W. Gilcrease · Principal Investigator

University of Virginia Cancer Center

Charlottesville, Virginia, 22908

Recruiting
Matthew J. Reilley · Principal Investigator

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, 23298

Recruiting
Site Public Contact · Contact
Emily N. Kinsey · Principal Investigator

University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Madison, Wisconsin, 53718

Recruiting
Site Public Contact · Contact
Jeremy Kratz · Principal Investigator

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, 53792

Recruiting
Site Public Contact · Contact
Jeremy Kratz · Principal Investigator