Inclusion Criteria:

• Patients with histologically confirmed intra-hepatic, perihilar or extra-hepatic CCA.
• Patients should not have received more than 2 prior treatment lines with systemic anti-neoplastic therapy (chemotherapy, targeted therapy etc.) for advanced or metastatic CCA. Previous adjuvant therapy, neoadjuvant or combined chemoradiotherapy for early stage disease, are not considered as part of the 2 allowed therapy lines for the purpose of this study.
• The tumor is unresectable and not amenable to curative therapy.
• At least 1 measurable lesion on CT scan per RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy of at least 3 months.
• Age ≥ 18 years.
• Signed, written IRB-approved informed consent.
• A negative pregnancy test (if female).
• Serum sodium within normal limits.
• Acceptable liver and renal function:
  • Bilirubin ≤ 1.5 times upper limit of normal (NCI-CTCAE Grade 2 baseline);
  • AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal (ULN);
  • Serum creatinine ≤ 1.5 X ULN (NCI-CTCAE Grade 1 baseline);
  • Albumin > 3.0 g/dL
• Acceptable hematologic status:
  • Absolute neutrophil count ≥1000 cells/mm^3;
  • Platelet count ≥ 75,000 (plt/mm^3) (NCI-CTCAE Grade 1 baseline);
  • Hemoglobin ≥ 9 g/dL.
  • Acceptable blood sugar control:
    • Fasting glucose value ≤ 160 mg/dL (NCI-CTCAE Grade 1 baseline).
  • Urinalysis: No clinically significant abnormalities.
  • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 X ULN after correction of nutritional deficiencies that may have contributed to prolonged PT/PTT.
  • For men and women of child-producing potential, willingness to use of effective contraceptive methods during the study. If female (or female partner of male patient), was either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or hysterectomy]) or practicing one of the following medically acceptable methods of birth control and agreed to continue with the regimen throughout the duration of the study:
    • Oral, implantable or injectable contraceptives for 3 consecutive months before the baseline/randomization visit;
    • Total abstinence from sexual intercourse (≥ 1 complete menstrual cycle before the baseline/randomization visit);
    • Intrauterine device;
    • Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal jellies or cream).

Exclusion Criteria:

• > 2 previous systemic anti-neoplastic regimens for advanced/metastatic CCA.
• Previously having received ABC294640 or HCQ (or chloroquine) for the treatment of a malignancy.
• New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.
• History of psychosis or anxiety disorders.
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
• Pregnant or nursing women.
  • NOTE: If a woman became pregnant or suspects she is pregnant while participating in this study, she must inform her treating physician immediately.
• Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days prior to study entry. Patients who had received any antineoplastic therapy > 28 days prior to starting treatment with ABC294640 must have recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and Grade 1 neuropathy).
• Unwillingness or inability to comply with procedures required in this protocol.
• Known infection with human immunodeficiency virus.
• Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• Patients who were currently receiving any other investigational agent.
• Patients who were receiving drugs that are:
  • Sensitive substrates, or substrates with a narrow therapeutic range, for CYP2C8, CYP2C9, CYP2C19, CYP3A4 should be avoided, when possible, or used with caution because ABC294640 may either increase or decrease patients’ exposure to these drugs. In addition, P-gp and BCRP sensitive and/or narrow therapeutic range substrates for which safety cannot be readily monitored for should be avoided, when possible, or used with caution for the same reasons.
  • Moderate or strong inhibitors of CYP1A2, CYP3A4 or CYP2D6 or moderate to strong inducers of CYP3A4 and CYP1A2 are prohibited
• Patients who are taking warfarin, apixaban, argatroban or rivaroxaban.
• If the patient is to receive HCQ, pre-existing retinopathy.
• Known history of G-6-PD Deficiency, porphyria or psoriasis.
• History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to HCQ.
• Corrected QT (QTc) interval on electrocardiogram (ECG) > 470 ms for females or > 450 ms for males, calculated using Friedericia’s formula (QTcF)
• In cell culture, ABC294640 inhibited hERG potassium current, with a maximum inhibition of 71%. In dog studies, no ECG abnormalities were noted, nor has QTc prolongation been noted in human studies. However, due to the in vitro hERG results, treatment within seven days, or 5 half-lives, whichever is longer, with any medication that causes QT prolongation prior to initiation of study drug, or intention to use them throughout the study is not recommended. These medications include but not limited to: amiodarone, amitriptyline, azithromycin, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilide, pimozide, procainamide, quinidine, quinine, quinolone, ranolazine, risperidone, sotalol and tolterodine.

Eligibility last updated 9/29/21. Questions regarding updates should be directed to the study team contact.