Y-90 With Durvalumab/Gem/Cis in Intrahepatic Cholangio

Inclusion Criteria:

* Ability to comprehend and willingness to sign a written ICF for the study
* Male and female participants at least 18 years of age at the time of signing the ICF
* Histologically or cytologically confirmed locally advanced unresectable or metastatic intrahepatic cholangiocarcinoma; at least one intrahepatic lesion must be present
* Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1 criteria
* ECOG performance status ≤1
* Body weight \>30 kg
* Must have a life expectancy of at least 12 weeks
* Participants must have adequate marrow function as defined below:

  * Hemoglobin ≥9.0 g/dL
  * Absolute neutrophil count (ANC) ≥1.0 × 109 /L
  * Platelet count ≥75 × 109/L
* Participants must have adequate renal function as defined below:

  * Serum creatinine ≤ 1.5 mg/dL OR
  * Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
* Participants must have adequate hepatic function as defined below:

  * Bilirubin ≤1.5 x ULN
  * ALT ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤5x ULN
  * AST ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤5x ULN
  * This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
  * No known history of active HBV or HCV infection.

    * Note: Participants with Hepatitis C who have been clinically cured, defined as persistent absence of Hepatitis C RNA detected by polymerase chain reaction (PCR) test in serum 12 weeks after completing antiviral treatment, are eligible for this study
    * Note: Participants with a history of Hepatitis B infection that are currently on viral suppressive therapy are eligible for enrollment
* Adequate coagulation studies as demonstrated by prothrombin (PT) and partial thromboplastin (PTT) time within normal limits (\</= 1.5 x ULN) in the absence of anticoagulation medication. Participants receiving anticoagulation may be approved by sponsor
* Participants with known human immunodeficiency virus (HIV) on effective highly-active antiretroviral therapy (HAART) with undetectable viral load within 6 months are eligible for this trial, so long as the following criteria are met:

  * HAART does not interact with or have overlapping toxicities with study medication, per discretion of the treating provider
  * CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications
  * Probable long-term survival with HIV if cancer were not present
  * Stable on a HAART regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study
  * HIV is not multi-drug resistant
  * Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication

Exclusion Criteria:

* Surgically resectable disease at enrollment
* Histologically or cytologically confirmed diagnosis of primary hepatocellular carcinoma or mixed adenocarcinoma/hepatocellular carcinoma
* Received prior systemic chemotherapy and/or radiotherapy for intrahepatic cholangiocarcinoma. Prior surgical resection and adjuvant chemotherapy or chemoradiotherapy is allowed if more than 6 months have elapsed since last dose of treatment, and if the tumor is amenable to Y-90 SIRT
* Prior treatment with anti-PD-1, anti-PD-L, including durvalumab antibody, or any other drug treatment specifically targeting T-cell co-stimulation or checkpoint pathways
* Any of the following within 6 months of screening:

  * New York Heart Association (NYHA) Class III or IV heart failure
  * Myocardial infarction, unstable angina pectoris, or symptomatic coronary artery disease
  * Unstable arrhythmia
  * Stroke to transient ischemic attack
* Previous malignancies, except for adequately treated non-melanoma skin cancer, in-situ cancer, or any other cancer from which the subject has been disease-free for at least 3 years
* Severe chronic obstructive or other pulmonary disease with chronic baseline hypoxemia due to potential for gemcitabine-induced bronchospasm and/or durvalumab-induced pneumonitis
* Major surgery (other than diagnostic) within 4 weeks of study treatment day 1
* Active, uncontrolled or untreated bacterial, viral, or fungal infection that requires systemic therapy
* Active, untreated HIV, HBV, or HCV
* Subjects who have participated in another investigational drug or device study within 4 weeks prior to study registration.

Pregnant women are excluded from this study because cisplatin is a class D agent with the potential for teratogenic or abortifacient effects. Because cisplatin is present in breast milk and there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cisplatin, breastfeeding should be discontinued prior to entry into the study. Subjects and their sexual partners entered into the study must agree to contraception. The following restrictions apply while the patient is receiving study treatment and for the specified times before and after:

* Female patients of child-bearing potential Female patients of childbearing potential who are not abstinent and intend to be sexually active with a non sterilized male partner must use at least 1 highly effective method of contraception (Table 2) from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy). Non-sterilised male partners of a female patient of childbearing potential must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period.
* Male patients with a female partner of childbearing potential Non-sterilized male patients who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy). However, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period.

Female partners (of childbearing potential) of male patients must also use a highly effective method of contraception throughout this period (Table 2).

Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.

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.
* 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.

Highly effective methods of contraception, defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly are described in Table 2. Note that some contraception methods are not considered highly effective (e.g. male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action \[excluding Cerazette/desogestrel which is considered highly effective\]; and triphasic combined oral contraceptive pills).

* Copper T intrauterine device
* Levonorgestrel-releasing intrauterine system (e.g., Mirena®)a
* Implants: Etonogestrel-releasing implants: e.g. Implanon® or Norplant®
* Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal devices: e.g. NuvaRing®
* Injection: Medroxyprogesterone injection: e.g. Depo-Provera®
* Combined Pill: Normal and low dose combined oral contraceptive pill
* Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g. Ortho Evra® Minipillc: Progesterone based oral contraceptive pill using desogestrel: Cerazette® is currently the only highly effective progesterone-based

  * Any concomitant disease or condition that could interfere with the conduct of the study, or that would in the option of the investigator pose an unacceptable risk to the subject in the study
  * Contraindications to Y-90 SIRT per assessment by treating Interventional Radiologist (eg significant vascular drainage of the tumor to the lung that increases the potential for pulmonary toxicity)
  * Unwillingness or inability to comply with the study protocol
  * History of allogenic organ transplantation.
  * 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
  * Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  * History of active primary immunodeficiency
  * Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice
  * 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 IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
  * Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.