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

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ClinicalTrials.gov Identifier: NCT03377179
Recruitment Status : Recruiting
First Posted : December 19, 2017
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

Tracking Information
First Submitted Date  ICMJE December 1, 2017
First Posted Date  ICMJE December 19, 2017
Last Update Posted Date March 12, 2019
Actual Study Start Date  ICMJE March 7, 2018
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 13, 2017)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03377179 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 13, 2017)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 13, 2017)
  • Determine the effect of treatment withABC294640 on pharmacodynamic markers that are associated with the mechanism of action of the drug. [ Time Frame: Within 21 days prior to treatment and on the beginning of the second cycle of treatment (approximately a month) ]
    Tumor biopsies, when accessible, will be obtained and will be assessed for tumor signaling proteins (c-Myc, pAKT, SK2). Peripheral Blood Mononuclear Cells (PBMC) for c-Myc will be collected within 1 hour prior to the pre- and posttreatment biopsies (or at the scheduled time of biopsy if not performed).
  • Serial measurement of circulating tumor DNA (ctDNA) [ Time Frame: 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) ]
    Serum ctDNA be assessed for mutational status and development of new mutations.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Study of ABC294640 (Yeliva ®) in the Treatment of Patients With Advanced Cholangiocarcinoma
Official Title  ICMJE A Phase IIA Study of ABC294640 in the Treatment of Patients With Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic Cholangiocarcinoma
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
This will be a single-arm Phase IIA study with all participants receiving ABC294640, continuously administered in 28 day cycles, until disease progression, unacceptable toxicity or voluntary withdrawal initiated by the participant or physician. A maximum of 39 participants evaluable for efficacy will be enrolled in a two-stage design. In the first stage, 12 participants will be accrued. If none of the first 12 patients respond, the registration will be halted. If one or more patients respond, an additional 27 patients will be enrolled.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cholangiocarcinoma
  • Cholangiocarcinoma Non-resectable
  • Cholangiocarcinoma, Perihilar
  • Cholangiocarcinoma, Extrahepatic
  • Cholangiocarcinoma, Intrahepatic
Intervention  ICMJE Drug: ABC294640
Two 250 mg capsules of ABC294640 will be taken twice daily
Study Arms  ICMJE Experimental: ABC294640 treatment
All participants will be receiving ABC294640, 500 mg twice a day (BID), continuously in 28 day cycles
Intervention: Drug: ABC294640
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 28, 2018)
70
Original Estimated Enrollment  ICMJE
 (submitted: December 13, 2017)
39
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mark L Levitt, MD, PhD +972-3-541-3131 mark@redhillbio.com
Contact: Vered Katz Ben-Yair, MSc +972-3-541-3131 vered@redhillbio.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03377179
Other Study ID Numbers  ICMJE ABC-108
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party RedHill Biopharma Limited
Study Sponsor  ICMJE RedHill Biopharma Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mitesh Borad, MD Mayo Clinic
PRS Account RedHill Biopharma Limited
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP