A Study of ABC294640 (Yeliva ®) in the Treatment of Patients With Advanced Cholangiocarcinoma

Overview

ABC-108 is a single-arm Phase IIA clinical study of ABC294640 (Yeliva ®) in the treatment of cholangiocarcinoma (CCA). In this clinical study, all participants will be receiving ABC294640 to explore the drug's 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. In this study, ABC294640 will be continuously administrated orally, twice a day, in 28 day cycles, until disease progression, unacceptable toxicity or voluntary withdrawal initiated by the participants or physician.

Full Title of Study: “A Phase IIA Study of ABC294640 in the Treatment of Patients With Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic Cholangiocarcinoma”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 2020

Detailed Description

This is an open label clinical study to explore the activity signal of ABC294640 in adult subjects who have been diagnosed with unresectable cholangiocarcinoma either intra- perhilar or extra-hepatic.

A maximum of 39 participants evaluable for efficacy will be enrolled in the study which will be conducted at up to 5 sites in the USA. Eligible participants will receive ABC294640, 500 mg twice a day, continuously administered in 28 day cycles.

In addition to physical and neurological exams, blood and urine samples will be routinely collected for safety and to determine response to the study drug. 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.

Interventions

  • Drug: ABC294640
    • Two 250 mg capsules of ABC294640 will be taken twice daily

Arms, Groups and Cohorts

  • Experimental: ABC294640 treatment
    • All participants will be receiving ABC294640, 500 mg twice a day (BID), continuously in 28 day cycles

Clinical Trial Outcome Measures

Primary Measures

  • Determine Response Rate
    • Time Frame: At least 4 months
    • 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.

Secondary Measures

  • Physical exam to measure safety and tolerability of ABC294640
    • Time Frame: 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 physical exam which will include weight measurment in kilograms will be performed in screening and on the beginning of each cycle of treatment till 30 day post treatment.
  • A general neurological exam to measure safety and tolerability of ABC294640
    • Time Frame: 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 will be performed in screening and on the beginning of each cycle of treatment till 30 day post treatment.
  • HADS score for depression and anxiety to measure safety and tolerability of ABC294640
    • Time Frame: 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.
    • HADS (Hospital Anxiety and Depression Scale) questionnaire will be utilized to monitor any alterations in the participant’s anxiety and depression levels.
  • ECOG performance score to measure safety and tolerability of ABC294640
    • Time Frame: 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 (Eastern Cooperative Oncology Group) performance score to the participant’s performance status and how it is impacting the daily living abilities.
  • MMSE score to measure safety and tolerability of ABC294640
    • Time Frame: 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 (Mini-Mental State Examination) questionnaire will be utilized for evaluating the mental state of the participants.
  • Daily diary entries to aid in asessing safety and tolerability of ABC294640
    • Time Frame: 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.
    • Participants will be asked to fill a daily diary to record the drug administration and any side effects that they may experience.
  • Number of treatment-related Adverse Events
    • Time Frame: From screening till the 30 days after the end of treatment (an estimated median of 5 months)
    • Adverse events will be graded according to the revised NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.03) to measure the safety and tolerability of treatment with ABC294640 in patients with unresectable CCA.
  • The Maximum Plasma Concentration (Cmax) of ABC294640
    • Time Frame: From the first day of treatment until the beginning of second cycle of treatment (on day 1, 15, 28 approximately)
    • To determine the pharmacokinetics of ABC294640 in the first 12 patients by measuring Maximum Plasma Concentration (Cmax) of ABC294640
  • The Area Under the Curve (AUC) of ABC294640
    • Time Frame: From the first day of treatment until the beginning of second cycle of treatment (on day 1, 15, 28 approximately)
    • To determine the pharmacokinetics of ABC294640 in the first 12 patients by measuring the Area Under the Curve (AUC) of ABC294640 which reflects the body exposure to drug after administration of a dose of the drug.
  • Determine the progression free survival (PFS)
    • Time Frame: Every 2 months for a maximum of 24 months after the last participant has been entered to the study
  • Determine Disease Control Rate (DCR=CR+PR+SD)
    • Time Frame: Every 2 months for a maximum of 24 months after the last participant has been entered to the study
    • Determine Disease Control Rate (DCR) = complete response (CR)+ partial response (PR) + stable disease (SD)
  • Determine the overall survival (OS)
    • Time Frame: Every 2 months for a maximum of 24 months after the last participant has been entered to the study

Participating in This Clinical Trial

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. 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.

3. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.

4. 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.

5. Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days prior to study entry.

6. Patients who have received any antineoplastic therapy > 28 days prior to starting treatment with ABC294640 and have not adequately recovered from side effects and toxicities of previous antineoplastic therapy.

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. (A list of commonly used drugs that are sensitive substrates of CYP450 1A2, 3A4, 2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes with the half-life of each drug identified, is included in Appendix 3)

12. Patients who are taking Coumadin or Coumadin derivatives.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • RedHill Biopharma Limited
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Mitesh Borad, MD, Principal Investigator, Mayo Clinic
  • Overall Contact(s)
    • Mark L Levitt, MD, PhD, +972-3-541-3131, mark@redhillbio.com

References

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.

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.

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.

Citations Reporting on Results

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.

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