A Study of ABC294640 (Yeliva ®) Alone and in Combination With Hydroxychloroquine Sulfate in Treatment of Patients With Advanced Cholangiocarcinoma

ABC-108 is a single-arm Phase IIA clinical study of ABC294640 (Yeliva ®, opaganib) alone and in combination with hydroxychloroquine sulfate (HCQ) in the treatment of cholangiocarcinoma (CCA). In Part 1 of this clinical study, all participants will be receiving ABC294640 and in Part 2 all participants will be receiving ABC294640 and HCQ to explore the drugs activity signal in CCA. The study drug, ABC294640 is an orally available inhibitor of the enzyme sphingosine kinase-2 (SK2). SK2 is an innovative target for anti-cancer therapy because of its critical role in sphingolipid metabolism, which is known to regulate tumor cell death and proliferation. ABC294640 also inhibits proliferation and induces apoptosis of cholangiocarcinoma cell lines. Furthermore, in a recent Phase I trial, ABC294640 demonstrated clinical activity in CCA patients. HCQ, is an orally available, FDA approved therapy for the treatment of malaria as well as discoid and systemic lupus erythematosus and rheumatoid arthritis. It is also known as an inhibitor of autophagy, a pro-survival mechanism utilized by many cancers. Evidence indicates that inhibition of autophagy can increase the therapeutic activity of ABC294640 in CCA. In Part 1 of this study, ABC294640 will be continuously administrated orally, twice a day, in 28 day cycles. In Part 2, ABC294640 and HCQ will be continuously administrated orally (the safe and tolerable will be determined in the study) in 28 day cycles. Administration of drug/s in both parts of the study will continue until disease progression, unacceptable toxicity or voluntary withdrawal initiated by the participants or physician.

This is an open-label clinical study to explore the activity signal of ABC294640 and of ABC294640 and HCQ in adult subjects who have been diagnosed with unresectable cholangiocarcinoma either intra- perhilar or extra-hepatic. The study will be conducted at 5 sites in the USA.

For Part 1, a maximum of 39 participants evaluable for efficacy will be enrolled in the study. Eligible participants will receive ABC294640, 500 mg twice a day, continuously administered in 28 day cycles.

Part 2 will be a single-arm Phase IIA study identical to Part 1 but treatment will consist of both ABC294640 together with HCQ. Additionally, Part 2, will consist of two phases: Phase I: accelerate HCQ dose-escalation run-in starting with a HCQ dose of 200 mg QD (once a day). Based on safety results, patient cohorts will be expanded, and dosing will continue to 200 mg BID (twice a day), 400 mg BID and 600 BID. At the end of Part2, Phase I, it will be determined what is the safe and tolerable HCQ dose for Phase II.

For Part 2, up to 15 patients evaluable for safety and tolerability will be enrolled in Phase I component of Part 2; and 20 patients evaluable for efficacy in the Phase II component of Part 2. All eligible participants will receive ABC294640, 500 mg BID in addition to the determined HCQ dose, continuously administered in 28 day cycles.

In addition to physical, neurological and eye exams (eye exams only for participants receiving HCQ), blood and urine samples will be routinely collected for safety and to determine response to the study drugs. Participants will be radiographically assessed for disease status every 2 cycles of treatment.

Tumor biopsies, when accessible, will be obtained within 21 days prior to the beginning of treatment and again on the beginning of the second treatment cycle.

All participants will be followed every 2 months for progression and survival for a maximum of 24 months after the last patient has been entered to the study. Follow up procedures may include physical examination, laboratory work and radiographic tumor assessment.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically confirmed intrahepatic, perihilar or extra-hepatic CCA.
2. Patients with no more than 2 prior treatments with systemic anti-neoplastic therapy for CCA.
3. The tumor is unresectable and not amenable to curative therapy.
4. One or more tumors measurable on CT scan per RECIST 1.1.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0- 1.
6. Life expectancy of at least 3 months.
7. Age ≥18 years.
8. Signed, written IRB-approved informed consent.
9. A negative pregnancy test (if female).
10. Acceptable liver and renal function:

    * Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 2 baseline)
    * AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal (ULN),
    * Serum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 baseline)
    * Albumin \> 3.0 g/dL
11. Acceptable hematologic status:

    * Absolute neutrophil count ≥1000 cells/mm3
    * Platelet count ≥75,000 (plt/mm3) (CTCAE Grade 1 baseline)
    * Hemoglobin ≥ 9 g/dL
12. Acceptable blood sugar control:

    - Fasting glucose value ≤ 160 mg/dL (CTCAE Grade 1 baseline)
13. Urinalysis: No clinically significant abnormalities.
14. 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.
15. For men and women of child-producing potential, willingness to use 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:

1. \>2 previous systemic anti-neoplastic regimens for CCA.
2. Previously having received ABC294640 or HCQ (or chloroquine) for the treatment of a malignancy.
3. 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.
4. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
5. 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.
6. 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 and HCQ must have recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and Grade 1 neuropathy).
7. Unwillingness or inability to comply with procedures required in this protocol.
8. Known infection with human immunodeficiency virus.
9. 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.
10. Patients who were currently receiving any other investigational agent.
11. Patients who were receiving drugs that were sensitive substrates of CYP450 1A2, 3A4, 2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes that could not have been stopped at least 7 days or 5 half-lives (whichever was longer) before starting treatment with ABC294640, could not have been replaced with another appropriate medication or not given for the duration of the clinical study must be discussed with the Medical Monitor in order to determine eligibility for the study.
12. Patients who are taking warfarin, apixaban, argatroban or rivaroxaban.
13. If the patient is to receive HCQ, pre-existing retinopathy.
14. Known history of G-6-PD Deficiency, porphyria or psoriasis.
15. History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations.
16. History of allergic reactions attributed to compounds of similar chemical or biologic composition to HCQ.