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NCT06050252PHASE2Recruiting

Testing the Combination of the Anticancer Drug Durvalumab With Chemotherapy (Gemcitabine and Cisplatin) at Improving Outcomes for High-Risk Resectable Liver Cancer Before Surgery

National Cancer Institute (NCI)

Start Date

7/10/2024

Completion Date

2/12/2027

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.

Eligibility Criteria

Age Range: 18 years to No maximum

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.

Interventions

PROCEDURE

Biopsy Procedure

PROCEDURE

Biospecimen Collection

DRUG

Cisplatin

PROCEDURE

Computed Tomography

BIOLOGICAL

Durvalumab

DRUG

Gemcitabine

PROCEDURE

Magnetic Resonance Imaging

PROCEDURE

Resection

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Conditions

Resectable Intrahepatic Cholangiocarcinoma

Locations

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California 92612

United States

Los Angeles General Medical Center

Los Angeles, California 90033

United States

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California 92868

United States

UCHealth University of Colorado Hospital

Aurora, Colorado 80045

United States

Smilow Cancer Hospital-Derby Care Center

Derby, Connecticut 06418

United States

Smilow Cancer Hospital Care Center-Fairfield

Fairfield, Connecticut 06824

United States

Smilow Cancer Hospital Care Center at Glastonbury

Glastonbury, Connecticut 06033

United States

Smilow Cancer Hospital Care Center at Greenwich

Greenwich, Connecticut 06830

United States

Smilow Cancer Hospital Care Center - Guilford

Guilford, Connecticut 06437

United States

Smilow Cancer Hospital Care Center at Saint Francis

Hartford, Connecticut 06105

United States

Yale University

New Haven, Connecticut 06520

United States

Yale-New Haven Hospital North Haven Medical Center

North Haven, Connecticut 06473

United States

Smilow Cancer Hospital Care Center at Long Ridge

Stamford, Connecticut 06902

United States

Smilow Cancer Hospital-Torrington Care Center

Torrington, Connecticut 06790

United States

Smilow Cancer Hospital Care Center-Trumbull

Trumbull, Connecticut 06611

United States

Smilow Cancer Hospital-Waterbury Care Center

Waterbury, Connecticut 06708

United States

Smilow Cancer Hospital Care Center - Waterford

Waterford, Connecticut 06385

United States

UF Health Cancer Institute - Gainesville

Gainesville, Florida 32610

United States

Emory University Hospital Midtown

Atlanta, Georgia 30308

United States

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia 30322

United States

Emory Saint Joseph's Hospital

Atlanta, Georgia 30342

United States

Northwestern University

Chicago, Illinois 60611

United States

Memorial Hospital East

Shiloh, Illinois 62269

United States

University of Kansas Clinical Research Center

Fairway, Kansas 66205

United States

University of Kansas Cancer Center

Kansas City, Kansas 66160

United States

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas 66210

United States

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas 66205

United States

Ochsner Medical Center Jefferson

New Orleans, Louisiana 70121

United States

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland 21201

United States

Boston Medical Center

Boston, Massachusetts 02118

United States

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri 63376

United States

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri 63141

United States

University of Kansas Cancer Center - Briarcliff

Kansas City, Missouri 64116

United States

University of Kansas Cancer Center - North

Kansas City, Missouri 64154

United States

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri 64064

United States

Washington University School of Medicine

St Louis, Missouri 63110

United States

Siteman Cancer Center-South County

St Louis, Missouri 63129

United States

Siteman Cancer Center at Christian Hospital

St Louis, Missouri 63136

United States

NYP/Weill Cornell Medical Center

New York, New York 10065

United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina 27157

United States

University of Cincinnati Cancer Center-UC Medical Center

Cincinnati, Ohio 45219

United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio 43210

United States

University of Cincinnati Cancer Center-West Chester

West Chester, Ohio 45069

United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73104

United States

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania 15232

United States

Smilow Cancer Hospital Care Center - Westerly

Westerly, Rhode Island 02891

United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee 37232

United States

UT MD Anderson - The Woodlands

Conroe, Texas 77384

United States

UT MD Anderson Cancer Center

Houston, Texas 77030

United States

UT MD Anderson - West Houston

Houston, Texas 77079

United States

UT MD Anderson - League City

League City, Texas 77573

United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas 78229

United States

UT MD Anderson - Sugar Land

Sugar Land, Texas 77478

United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah 84112

United States

University of Virginia Cancer Center

Charlottesville, Virginia 22908

United States

VCU Massey Comprehensive Cancer Center

Richmond, Virginia 23298

United States

University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Madison, Wisconsin 53718

United States

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin 53792

United States