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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 : June 12, 2018
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

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. 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.

Condition or disease Intervention/treatment Phase
Cholangiocarcinoma Cholangiocarcinoma Non-resectable Cholangiocarcinoma, Perihilar Cholangiocarcinoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Drug: ABC294640 Phase 2

Detailed Description:

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

A maximum of 39 participants 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 : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
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 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
Official Title: A Phase IIA Study of ABC294640 in the Treatment of Patients With Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic Cholangiocarcinoma
Actual Study Start Date : March 7, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ABC294640 treatment
All participants will be receiving ABC294640, 500 mg twice a day (BID), continuously in 28 day cycles
Drug: ABC294640
Two 250 mg capsules of ABC294640 will be taken twice daily




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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 ]
  11. 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)

  12. 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 ]

Other Outcome Measures:
  1. 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).

  2. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03377179


Contacts
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

Locations
United States, Arizona
Mayo Clinic Cancer Center Recruiting
Phoenix, Arizona, United States, 85054
Contact: Clinical Trials Office    855-776-0015      
Principal Investigator: Daniel Ahn, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Tyra Gaines    404-712-3308    tgaine3@emory.edu   
United States, Minnesota
Mayo Clinic Cancer Center Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Office    855-776-0015      
Principal Investigator: Amit Mahipal, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Michelle Escano    713-794-1776    MEscano@mdanderson.org   
Principal Investigator: Shubham Pant, MD         
United States, Utah
Huntsman Cancer Institute, University of Utah Recruiting
Salt Lake City, Utah, United States, 84103
Contact: Cherie Peterson    801-587-5598    Cherie.peterson@hci.utah.edu   
Contact: Ignacio Garrido-Laguna, MD    801-585-0255    Ignacio.garrido-laguna@hci.utah.edu   
Principal Investigator: Ignacio Garrido-Laguna, MD         
Sponsors and Collaborators
RedHill Biopharma Limited
Investigators
Principal Investigator: Mitesh Borad, MD Mayo Clinic

Publications of Results:
Other Publications:
Responsible Party: RedHill Biopharma Limited
ClinicalTrials.gov Identifier: NCT03377179     History of Changes
Other Study ID Numbers: ABC-108
First Posted: December 19, 2017    Key Record Dates
Last Update Posted: June 12, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by RedHill Biopharma Limited:
Clinical Trial, Phase II
Multicenter Trials
Clinical Study
Clinical Trials, Non-Randomized
Oral capsule
Single arm
Anti-cancer
Anti-inflammatory
ABC294640
Yeliva ®

Additional relevant MeSH terms:
Cholangiocarcinoma
Klatskin Tumor
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms