Cholangiocarcinoma (Bile Duct Cancer) Clinical Trials

• Participants are eligible to be included in the study only if all of the following criteria apply:

• Provision of signed Informed Consent prior to any screening procedures being performed.

• Age ≥ 18 years at the time of informed consent.

• Histologically (or cytologically) confirmed diagnosis of intrahepatic cholangiocarcinoma or adenocarcinoma of suspected biliary origin/ cholangiocarcinoma that is measurable according to RECIST 1.1 criteria.

• a) Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• Has high-risk, but resectable, ICC confined to the liver, bile duct, and /or regional lymph nodes. Tumors will be considered high-risk if the high-quality, contrast-enhanced CT and/or MRI +/- positron emission tomography (PET) scan done within 6 weeks of screening show at least one of the following (a-e):

∙ T-stage ≥ Ib (Ib - IIIb)

‣ Solitary lesion \> 5 cm

‣ Multifocal tumors or satellite lesions present confined to the same lobe of the liver as the dominant lesion but still technically resectable

‣ Presence of major vascular invasion but still technically resectable

‣ Suspicious or involved regional lymph nodes (N1)

‣ Serum CA 19-9 \> 200 U/mL

• ECOG performance status of 0-1.

• Adequate hematologic status: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Hemoglobin (Hgb) ≥ 9 g/dL with or without transfusions; Platelets (PLT) ≥ 100 x 109/L without transfusions.

• Adequate liver function:

∙ ALT and AST ≤2.5 × ULN, or ≤5 × ULN in the presence of liver metastases

‣ Total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL i. Note: Patients who have a total bilirubin level \> 1.5 x ULN will be allowed if their indirect bilirubin level is ≤ 1.5 x ULN ii. Note: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the principle investigator

‣ International normalized ratio (INR), prothrombin time (PT), Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

• Adequate renal function: Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50mL/min at screening.

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

⁃ Participants who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests are not required unless: known history of HBV infection, or as mandated by local health authority.

⁃ Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization. Hepatitis C screening tests are not required unless: known history of HCV infection, or as mandated by local health authority.

⁃ Willing and able to participate in the trial and comply with all trial requirements.

⁃ 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 agent may be included after consultation with the medical monitor.

⁃ The effects of pembrolizumab in combination with gemcitabine and cisplatin on the developing human fetus are unknown. For this reason and because gemcitabine and cisplatin used in this trial are known to be teratogenic, 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 and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

∙ Postmenopausal (no menses in greater than or equal to 12 consecutive months).

‣ History of hysterectomy or bilateral salpingo-oophorectomy.

‣ Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

‣ History of bilateral tubal ligation or another surgical sterilization procedure.

‣ Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 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 4 months after completion of treatment administration.

⁃ Ability to understand and the willingness to sign a written informed consent document.

⁃ English and non-English-speaking patients.

⁃ HIV-infected participants must have well-controlled HIV on ART, defined as:

∙ Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening

‣ Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening

‣ It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.

‣ Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study

‣ \[Include if pembrolizumab or IO/IO combination includes ART that affects CYP\] The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)