Clinical trial NCT06050252: Durvalumab With Gemcitabine and Cisplatin for the Treatment of High-Risk Resectable Liver Cancer Before Surgery
Official title: A Phase II Trial of Durvalumab With Gemcitabine and Cisplatin as Neoadjuvant Therapy for High-Risk Resectable Intrahepatic Cholangiocarcinoma
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Resectable Intrahepatic Cholangiocarcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2023-09-22
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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: 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.
* 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.

Primary outcomes:
measure: Proportion of patients who complete 4 cycles of neoadjuvant therapy followed by surgical resection
timeFrame: After surgical resection, up to week 18 after starting neoadjuvant therapy
Secondary outcomes:
measure: Major pathologic response (MPR) rate
timeFrame: After surgical resection, up to week 18 after starting neoadjuvant therapy
measure: Proportion of patients who attain an R0 margin status after surgical resection
timeFrame: After surgical resection, up to week 18 after starting neoadjuvant therapy
measure: Radiological response rate
timeFrame: After 2 and 4 cycles of neoadjuvant therapy (cycle length=21 days)
measure: Overall survival (OS)
timeFrame: From randomization to death, assessed up to 2 years
measure: Relapse free survival (RFS)
timeFrame: From surgery to recurrence of intrahepatic cholangiocarcinoma (iCCa), assessed up to 2 years
measure: Incidence of adverse events
timeFrame: Up to recurrence of iCCA
measure: Proportion of patients who are able to start adjuvant therapy
timeFrame: Up to 10 weeks after surgical resection
measure: Proportion of patients who complete 4 cycles of adjuvant therapy
timeFrame: Up to week 12 after starting adjuvant therapy
Other outcomes:
measure: Tissue and blood based immune biomarkers
timeFrame: Up to week 12 after starting adjuvant therapy
measure: Tumor genomics, transcriptional profile and multiplex immunohistochemistry and multiplex immunofluorescence
timeFrame: Up to week 12 after starting adjuvant therapy
measure: Changes in circulating immune phenotypic profiles in the neoadjuvant phase
timeFrame: Up to week 12 after starting adjuvant therapy
measure: Circulating tumor deoxyribonucleic acid-based minimal residual disease correlated with pathological response and RFS
timeFrame: Up to week 12 after starting adjuvant therapy
measure: Measures of body composition and fatty liver from imaging
timeFrame: Up to week 12 after starting adjuvant therapy
Locations:
city: Irvine
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
state: California
city: Los Angeles
country: United States
facility: Los Angeles General Medical Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Derby
country: United States
facility: Smilow Cancer Hospital-Derby Care Center
state: Connecticut
city: Fairfield
country: United States
facility: Smilow Cancer Hospital Care Center-Fairfield
state: Connecticut
city: Glastonbury
country: United States
facility: Smilow Cancer Hospital Care Center at Glastonbury
state: Connecticut
city: Greenwich
country: United States
facility: Smilow Cancer Hospital Care Center at Greenwich
state: Connecticut
city: Guilford
country: United States
facility: Smilow Cancer Hospital Care Center - Guilford
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: North Haven
country: United States
facility: Yale-New Haven Hospital North Haven Medical Center
state: Connecticut
city: Stamford
country: United States
facility: Smilow Cancer Hospital Care Center at Long Ridge
state: Connecticut
city: Torrington
country: United States
facility: Smilow Cancer Hospital-Torrington Care Center
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care Center-Trumbull
state: Connecticut
city: Waterbury
country: United States
facility: Smilow Cancer Hospital-Waterbury Care Center
state: Connecticut
city: Waterford
country: United States
facility: Smilow Cancer Hospital Care Center - Waterford
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: West Chester
country: United States
facility: University of Cincinnati Cancer Center-West Chester
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Westerly
country: United States
facility: Smilow Cancer Hospital Care Center - Westerly
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Conroe
country: United States
facility: MD Anderson in The Woodlands
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center LAO
state: Texas
city: Houston
country: United States
facility: MD Anderson West Houston
state: Texas
city: League City
country: United States
facility: MD Anderson League City
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Sugar Land
country: United States
facility: MD Anderson in Sugar Land
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
Study officials:
affiliation: University of Texas MD Anderson Cancer Center LAO
name: Hop S Tran Cao
role: PRINCIPAL_INVESTIGATOR
References: