Durvalumab With Gemcitabine and Cisplatin for the Treatment of High-Risk Resectable Liver Cancer Before Surgery

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed intrahepaticcholangiocarcinoma (iCCA) that is resectable by imaging evaluation. Choice ofstaging modality is left up to the discretion of the treatment team; we favorhigh-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 beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with CTscan, MRI, or calipers by clinical exam.

• Patients must be an acceptable risk surgical candidate at the time of enrollment, asdetermined 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 formetastasis based on large size (criteria vary per anatomical location; 6-10 mm for abdominal and 8-10 mm for pelvic), enhancement pattern, andshape. 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 onthe use of durvalumab (MEDI4736) in combination with cisplatin and gemcitabine inpatients < 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) >= 60mL/min/1.73 m^2 (by the Cockcroft-Gault equation).

• Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if theyhave been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women >= 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

• Life expectancy >= 12 weeks.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants.

Exclusion Criteria:

• Potential trial participants should have recovered from clinically significantadverse events of their most recent therapy/intervention prior to enrollment.

• Major surgical procedure (as defined by the Investigator) within 14 days prior tothe first dose of durvalumab. Note: Local surgery of isolated lesions for palliativeintent or biliary stents is acceptable.

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection).

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent.

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication).

• Receipt of live attenuated vaccine within 30 days prior to the first dose ofdurvalumab. Note: Patients, if enrolled, should not receive live vaccine whilstreceiving 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 orbiologic composition to durvalumab, gemcitabine, cisplatin, or otherplatinum-containing compounds.

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make this protocol unreasonably hazardous.

• Pregnant women are excluded from this study because durvalumab (MEDI4736) is ananti-PD-L1 monoclonal antibody agent with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with durvalumab,breastfeeding should be discontinued if the mother is treated with durvalumab. Thesepotential risks may also apply to other agents used in this study. Women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for 6 months after durvalumab administration.Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate 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 areexceptions to this criterion:

• Patients with vitiligo or alopecia.

• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable onhormone replacement.

• Any chronic skin condition that does not require systemic therapy.

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

• Patients with celiac disease controlled by diet alone.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis [TB]testing in line with local practice), hepatitis B (known positive HBV surfaceantigen (HBsAg) result), or hepatitis C. Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody areeligible 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 treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen are eligible for this trial.