A Study of ABC294640 Alone and in Combination With HCQ Sulfate in the Treatment of Advanced Cholangiocarcinoma

NCT03377179 | Completed Phase 2 FDA Drug

• 1 other identifier: ABC-108
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Cholangiocarcinoma; Cholangiocarcinoma Non-resectable; Cholangiocarcinoma, Perihilar; Cholangiocarcinoma, Extrahepatic; Cholangiocarcinoma, Intrahepatic

Keywords

Clinical Trial, Phase II; Multicenter Trials; Clinical Study; Clinical Trials, Non-Randomized; Oral capsule; Single arm; Anti-cancer; Anti-inflammatory; ABC294640; Yeliva ®; opaganib; Hydroxychloroquine Sulfate; HCQ; Autophagy

Outcome Measures

Primary Outcomes (2)

• Part1 - Determine Response Rate

  To determine the response rate (RR) of CCA defined as objective responses (OR), i.e. complete and partial responses (CR, PR) plus stable disease (SD) of at least 4 months to treatment with ABC294640.

  At least 4 months

• Part 2 - Determine the Durable Disease Control Rate

  To determine the Durable Disease Control Rate (DDCR) of CCA defined as Disease Control Rate (DCR) of at least 4 months duration to treatment with ABC294640 and HCQ

  At least 4 months

Secondary Outcomes (12)

• Physical exam to include eye exams (the latter only for patients enrolled in Part 2) to measure safety and tolerability of ABC294640 alone and in combination with HCQ

  From screening phase, during beginning of each cycle of treatment, till 30 days after the end of treatment (an estimated median of 5 months)

• A general neurological exam to measure safety and tolerability of ABC294640 alone and in combination with HCQ

  From screening phase, during beginning of each cycle of treatment, till 30 days after the end of treatment (an estimated median of 5 months)

• HADS score for depression and anxiety to measure safety and tolerability of ABC294640 alone and in combination with HCQ

  From screening, during each cycle of treatment, till the end of treatment (an estimated median of 4 months). Patient diaries will be filled on a daily basis during treatment.

• ECOG performance score to measure safety and tolerability of ABC294640 alone and in combination with HCQ

  From screening, during each cycle of treatment, till the end of treatment (an estimated median of 4 months). Patient diaries will be filled on a daily basis during treatment.

• MMSE score to measure safety and tolerability of ABC294640 alone and in combination with HCQ

  From screening, during each cycle of treatment, till the end of treatment (an estimated median of 4 months). Patient diaries will be filled on a daily basis during treatment.

Other Outcomes (2)

• Determine the effect of treatment with ABC294640 alone or in combination with HCQ on pharmacodynamic markers that are associated with the mechanism of action of the drug.

  Within 21 days prior to treatment and on the beginning of the second cycle of treatment (approximately a month)

• Serial measurement of circulating tumor DNA (ctDNA)

  Prior to treatment till the end of study (assessed at screening, beginning of cycle three of treatment and every 8 weeks thereafter, up to 24 months)

Study Arms (1)

ABC294640 +/- HCQ treatment

EXPERIMENTAL

Part 1: All participants will be receiving ABC294640, 500 mg twice a day (BID), continuously in 28 day cycles Part 2: All participants will be receiving ABC294640, 500 mg twice a day (BID) and HCQ at a determined level, continuously in 28 day cycles

Drug: ABC294640; Drug: Hydroxychloroquine Sulfate 200 MG

Interventions

ABC294640 DRUG

Two 250 mg capsules of ABC294640 will be taken twice daily

Also known as: yeliva, opaganib

ABC294640 +/- HCQ treatment

Hydroxychloroquine Sulfate 200 MG DRUG

HCQ tablets will be taken at a dose that will be determined

Also known as: HCQ

ABC294640 +/- HCQ treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• \>2 previous systemic anti-neoplastic regimens for 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.
• 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 and HCQ 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 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.
• 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.

Sponsors & Collaborators

• RedHill Biopharma Limited: lead

Study Sites (5)

Mayo Clinic Cancer Center

Phoenix, Arizona, 85054, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84103, United States

Location

Related Publications (4)

• Ding X, Chaiteerakij R, Moser CD, Shaleh H, Boakye J, Chen G, Ndzengue A, Li Y, Zhou Y, Huang S, Sinicrope FA, Zou X, Thomas MB, Smith CD, Roberts LR. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. Oncotarget. 2016 Apr 12;7(15):20080-92. doi: 10.18632/oncotarget.7914.

  PMID: 26956050 BACKGROUND

• Beljanski V, Knaak C, Smith CD. A novel sphingosine kinase inhibitor induces autophagy in tumor cells. J Pharmacol Exp Ther. 2010 May;333(2):454-64. doi: 10.1124/jpet.109.163337. Epub 2010 Feb 23.

  PMID: 20179157 BACKGROUND

• French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub 2010 Jan 8.

  PMID: 20061445 BACKGROUND

• Britten CD, Garrett-Mayer E, Chin SH, Shirai K, Ogretmen B, Bentz TA, Brisendine A, Anderton K, Cusack SL, Maines LW, Zhuang Y, Smith CD, Thomas MB. A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4642-4650. doi: 10.1158/1078-0432.CCR-16-2363. Epub 2017 Apr 18.

  PMID: 28420720 RESULT

MeSH Terms

Conditions

Cholangiocarcinoma; Klatskin Tumor

Interventions

3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Mitesh Borad, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: Part 1- single-arm Phase IIA study, all participants receiving ABC294640, continuously administered in 28 day cycles, until disease progression, unacceptable toxicity or voluntary withdrawal Enrollment in a two-stage design: 12 participants will be accrued, if none of those patients respond, registration will halt. If one or more patients respond, additional 27 patients evaluable for efficacy will be enrolled. Part 2- identical to Part 1 with the exceptions: co-treatment of both ABC294640 and HCQ and study will consist of two phases: Phase I, a hybrid accelerate dose escalation run-in starting at HCQ dose of 200 mg QD. Based on safety results, patient cohorts will be expanded and dosing will escalate up to 600 mg BID. Phase II, treatment with ABC294640 and HCQ at the Phase I determined dose. Up to 15 participants evaluable for safety and tolerability will be accrued in Phase I and 20 participants evaluable for efficacy in Phase II, Part 2.

Study Record Dates

• First Submitted: December 1, 2017
• First Posted: December 19, 2017
• Study Start: March 7, 2018
• Primary Completion: June 21, 2022
• Study Completion: June 21, 2022
• Last Updated: July 23, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)