A Phase I/IIA Study of ABC294640 Alone and in Combination With Hydroxychloroquine Sulfate in the Treatment of Patients With Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic 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.
• Patients with histologically confirmed intrahepatic, perihilar or extra-hepatic CCA.
• Patients with no more than 2 prior treatments with systemic anti-neoplastic therapy for CCA.
• The tumor is unresectable and not amenable to curative therapy.
• One or more tumors measurable 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).
⁃ 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
⁃ Acceptable hematologic status:
∙ Absolute neutrophil count ≥1000 cells/mm3
‣ Platelet count ≥75,000 (plt/mm3) (CTCAE Grade 1 baseline)
‣ Hemoglobin ≥ 9 g/dL
⁃ Acceptable blood sugar control:
∙ Fasting glucose value ≤ 160 mg/dL (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 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