Durvalumab and SNDX-6352 with Chemoembolization or Radioembolization for the Treatment of Intrahepatic Cholangiocarcinoma

Inclusion Criteria

• Have cytologically confirmed intrahepatic cholangiocarcinoma
• All disease must be localized to the liver (locally advanced)
• Be a candidate for conventional transarterial chemoembolization or yttrium-90 radioembolization, the two most common modalities of IAT
• Have measurable disease by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Measurable disease will be confirmed by radiological imaging (magnetic resonance imaging [MRI], computed tomography [CT])
• Age >= 18 years at time of study entry
• Body weight > 30 kg
• Eastern Cooperative Oncology Group (ECOG) (World Health Organization) performance status 0-1
• Life expectancy >= 12 weeks
• Absolute neutrophil count >= 1,500 cells/mm^3
• Hemoglobin >= 8 g/dL
• Platelets >= 100,000 cells/mm^3
• Serum creatinine < 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 x ULN
• Total bilirubin =< 1.5 x ULN * Subjects with Gilbert’s syndrome should have direct bilirubin within normal institutional limits
• Prothrombin time (PT) or international normalized ratio (INR) =< 1.5 x ULN
• Albumin >= 2.8 g/dL
• Child Pugh class A
• Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine clearance CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
• Evidence of either 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, bilateral salpingectomy, hysterectomy, or tubal ligation) * 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, hysterectomy, or tubal ligation) If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required for the patient to be eligible. If patient has a positive serum pregnancy test, then an ultrasound must be done to rule out pregnancy in order to enroll on trial
• Men and women of child bearing potential must be willing to use an adequate method of contraception starting with visit 1 through 120 days after the last dose of study therapy. Note: Complete abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form
• Patient is willing and able to comply with the protocol for the duration of the study including treatment, scheduled visits and examinations, and follow up

Exclusion Criteria

• Candidate for surgical resection
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up of an interventional study
• Patients who have had major surgery 28 days prior to first dose of the study drug excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) =< 28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca, MedImmune, Syndax, and the investigator
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, neuropathy and the laboratory values defined in the inclusion criteria * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or SNDX-6352 may be included only after consultation with the study physician
• Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable
• 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, checkpoint inhibitor-induced immune mediated reaction 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 adverse events (AEs) or compromise the ability of the patient to give written informed consent
• History of another primary malignancy except for * Malignancy treated with curative intent and with no known active disease >= 5 years before the first dose of IP and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
• History of leptomeningeal carcinomatosis
• Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry
• History of active primary immunodeficiency
• 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 hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 ribonucleic acid (RNA)
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or SNDX-6352. 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 expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Prior randomization or treatment in a previous durvalumab and/or SNDX-6352 clinical study regardless of treatment arm assignment
• Patients with prolonged heart rate-controlled corrected QT (QTc) measurements (using Fridericia’s formula), defined as >= 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (family history of long QT interval syndrome). Bundle branch block and prolonged QTcF interval may be permitted with approval of the medical monitor