Testing the Combination of the Anticancer Drug Durvalumab With Chemotherapy (Gemcitabine and Cisplatin) at Improving Outcomes for High-Risk Resectable Liver Cancer Before Surgery
Purpose
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.
Condition
- Resectable Intrahepatic Cholangiocarcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy 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 Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- N/A
- Intervention Model
- Single Group Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Treatment (durvalumab, gemcitabine, cisplatin) |
Patients receive durvalumab 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 CT scans and/or MRI scans and blood sample collection throughout study, as well as tissue biopsies during screening and on study. |
|
Recruiting Locations
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California 92612
Irvine, California 92612
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California 92868
Orange, California 92868
UCHealth University of Colorado Hospital
Aurora, Colorado 80045
Aurora, Colorado 80045
Contact:
Site Public Contact
720-848-0650
Site Public Contact
720-848-0650
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut 06418
Derby, Connecticut 06418
Smilow Cancer Hospital Care Center-Fairfield
Fairfield, Connecticut 06824
Fairfield, Connecticut 06824
Smilow Cancer Hospital Care Center at Glastonbury
Glastonbury, Connecticut 06033
Glastonbury, Connecticut 06033
Smilow Cancer Hospital Care Center at Greenwich
Greenwich, Connecticut 06830
Greenwich, Connecticut 06830
Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut 06437
Guilford, Connecticut 06437
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut 06105
Hartford, Connecticut 06105
Yale University
New Haven, Connecticut 06520
New Haven, Connecticut 06520
Yale-New Haven Hospital North Haven Medical Center
North Haven, Connecticut 06473
North Haven, Connecticut 06473
Smilow Cancer Hospital Care Center at Long Ridge
Stamford, Connecticut 06902
Stamford, Connecticut 06902
Smilow Cancer Hospital-Torrington Care Center
Torrington, Connecticut 06790
Torrington, Connecticut 06790
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut 06611
Trumbull, Connecticut 06611
Smilow Cancer Hospital-Waterbury Care Center
Waterbury, Connecticut 06708
Waterbury, Connecticut 06708
Smilow Cancer Hospital Care Center - Waterford
Waterford, Connecticut 06385
Waterford, Connecticut 06385
UF Health Cancer Institute - Gainesville
Gainesville, Florida 32610
Gainesville, Florida 32610
Contact:
Site Public Contact
352-273-8010
Site Public Contact
352-273-8010
Emory University Hospital Midtown
Atlanta, Georgia 30308
Atlanta, Georgia 30308
Contact:
Site Public Contact
888-946-7447
Site Public Contact
888-946-7447
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia 30322
Atlanta, Georgia 30322
Contact:
Site Public Contact
404-778-1868
Site Public Contact
404-778-1868
Emory Saint Joseph's Hospital
Atlanta, Georgia 30342
Atlanta, Georgia 30342
Contact:
Site Public Contact
404-851-7115
Site Public Contact
404-851-7115
Northwestern University
Chicago, Illinois 60611
Chicago, Illinois 60611
Memorial Hospital East
Shiloh, Illinois 62269
Shiloh, Illinois 62269
University of Kansas Clinical Research Center
Fairway, Kansas 66205
Fairway, Kansas 66205
University of Kansas Cancer Center
Kansas City, Kansas 66160
Kansas City, Kansas 66160
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas 66210
Overland Park, Kansas 66210
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205
Westwood, Kansas 66205
Ochsner Medical Center Jefferson
New Orleans, Louisiana 70121
New Orleans, Louisiana 70121
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland 21201
Baltimore, Maryland 21201
Contact:
Site Public Contact
800-888-8823
Site Public Contact
800-888-8823
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri 63376
City of Saint Peters, Missouri 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri 63141
Creve Coeur, Missouri 63141
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri 64116
Kansas City, Missouri 64116
Contact:
Site Public Contact
913-588-3671
Site Public Contact
913-588-3671
University of Kansas Cancer Center - North
Kansas City, Missouri 64154
Kansas City, Missouri 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri 64064
Lee's Summit, Missouri 64064
Washington University School of Medicine
St Louis, Missouri 63110
St Louis, Missouri 63110
Siteman Cancer Center-South County
St Louis, Missouri 63129
St Louis, Missouri 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri 63136
St Louis, Missouri 63136
NYP/Weill Cornell Medical Center
New York, New York 10065
New York, New York 10065
Contact:
Site Public Contact
212-746-1848
Site Public Contact
212-746-1848
Wake Forest University Health Sciences
Winston-Salem, North Carolina 27157
Winston-Salem, North Carolina 27157
Contact:
Site Public Contact
336-713-6771
Site Public Contact
336-713-6771
University of Cincinnati Cancer Center-UC Medical Center
Cincinnati, Ohio 45219
Cincinnati, Ohio 45219
Ohio State University Comprehensive Cancer Center
Columbus, Ohio 43210
Columbus, Ohio 43210
University of Cincinnati Cancer Center-West Chester
West Chester, Ohio 45069
West Chester, Ohio 45069
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104
Oklahoma City, Oklahoma 73104
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania 15232
Pittsburgh, Pennsylvania 15232
Contact:
Site Public Contact
412-647-8073
Site Public Contact
412-647-8073
Smilow Cancer Hospital Care Center - Westerly
Westerly, Rhode Island 02891
Westerly, Rhode Island 02891
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee 37232
Nashville, Tennessee 37232
Contact:
Site Public Contact
800-811-8480
Site Public Contact
800-811-8480
UT MD Anderson - The Woodlands
Conroe, Texas 77384
Conroe, Texas 77384
UT MD Anderson Cancer Center
Houston, Texas 77030
Houston, Texas 77030
UT MD Anderson - West Houston
Houston, Texas 77079
Houston, Texas 77079
UT MD Anderson - League City
League City, Texas 77573
League City, Texas 77573
UT MD Anderson - Sugar Land
Sugar Land, Texas 77478
Sugar Land, Texas 77478
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah 84112
Salt Lake City, Utah 84112
University of Virginia Cancer Center
Charlottesville, Virginia 22908
Charlottesville, Virginia 22908
VCU Massey Comprehensive Cancer Center
Richmond, Virginia 23298
Richmond, Virginia 23298
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin 53718
Madison, Wisconsin 53718
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin 53792
Madison, Wisconsin 53792
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
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.