Inclusion Criteria:
* Participant diagnosed with histologically confirmed intrahepatic cholangiocarcinoma
* Participant demonstrates disease control following 18 weeks of chemotherapy (gemcitabine and/or cisplatin) and immunotherapy (durvalumab) as part of standard of care first line regimen.
* Participants are allowed to be on maintenance durvalumab therapy following disease control at 18 weeks prior to enrollment into the study.
* All participants must have prior biopsy confirming diagnosis of cholangiocarcinoma.
* Participant has iCCA tumor burden appropriate for biopsy and histotripsy treatment
* Participant able to undergo liver biopsy of Index Tumor.
* Index Tumor will be a predetermined non-histotripsy tumor in patients with multifocal disease, or a predetermined region of intentionally untreated tumor in patients with solitary disease.
* Participant to have iCCA deemed targetable for histotripsy.
* Participants with solitary tumor must have longest dimension ≥ 2.0 cm to allow for planned region of intentionally untreated Target Tumor for Index Tumor.
* Participants' iCCA is considered unresectable or patient is a non-surgical candidate
* Participant can undergo general anesthesia.
* Participant has a Child-Pugh Score of A or B (up to B8).
* Participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade 0-2 at baseline screening.
* Participant meets the following functional criteria, ≤7 days prior to the planned histotripsy procedure date
* Liver function: Alanine transaminase (ALT) and Aspartate transaminase (AST) \<2.5x upper limit of normal (ULN) and/or bilirubin \<2.5 ULN.
* Renal function: serum creatinine \<2x ULN.
* Hematologic function: Absolute neutrophil count \>1,000/uL and platelet \>50,000/uL, hemoglobin \>8.0 g/dL.
* Participant has an International Normalized Ratio (INR) score of \<3.0, ≤7 days prior to the planned histotripsy procedure date.
* Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to registration.
* Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual vaginal intercourse or use an effective method(s) of contraception from the time of informed consent, during the study and for up to 14 months after the last dose of study drug(s). Males able to father a child must be willing to abstain from heterosexual vaginal intercourse or to use an effective method(s) of contraception from initiation of treatment, during the study and for up to 11 months after the last dose of study drug(s).
* Ability of the participant to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee.
Exclusion Criteria:
* Participant is pregnant or planning to become pregnant or nursing (lactating) during the trial period.
* Participant is enrolled in another investigational trial and/or is taking investigational medication or treated with an investigational device ≤30-days prior to planned histotripsy procedure date.
* In the Investigator's opinion, the subject has co-morbid disease(s) or condition(s) that would cause undue risk and preclude safe histotripsy treatment, including but not limited to interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis.
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. .
* Participant has major surgical procedure or significant traumatic injury ≤2 weeks prior to the planned treatment or not fully recovered (CTCAE grade 1 or better) from side effects/complications of such procedure or trauma.
* Participant has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or better from any adverse effects (exceptions for alopecia, grade 2 neuropathy, grade 2 hypothyroidism, grade 2 hypoadrenalism) related to previous anti-cancer therapy. Please refer to inclusion criteria for lab-based enrollment parameters.
* Participant has a history of bleeding disorders (e.g. von Willebrand disease) or subject is suspected to have a bleeding disorder.
* Participant has uncorrectable coagulopathy.
* In the opinion of the Investigator, histotripsy is not a treatment option for the subject.
* Participant has a concurrent condition that, in the investigator's opinion, could jeopardize the safety of the subject or compliance with the protocol.
* Participants' tumor(s) is not targetable per discretion of radiologist.
* Participant has a known sensitivity to contrast media and cannot be adequately pre-medicated.
* Participants' Target Tumor(s) has/have had prior locoregional therapy (e.g. ablation, embolization, radiation).
* History of solid organ or allogeneic bone marrow 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 not eligible for this trial.
* Significant dementia or other mental condition that precludes the participant's ability to consent to the study.
* Untreated central nervous system (CNS) metastasis. Screening of asymptomatic patients for CNS metastasis is not required for enrollment.
* Live vaccine administration within 28 days of planned initial dose of durvalumab.
