A Study of ABC294640 in the Treatment of Patients With Advanced Cholangiocarcino

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    gavin
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    A Study of ABC294640 in the Treatment of Patients With Advanced Cholangiocarcinoma

    Please note that information regarding clinical trials is being rovided for informational purposes only.The Cholangiocarcinoma Foundation does not endorse any specific clinical trial. Please discuss any questions you may have about clinical trials with your healthcare provider.

    https://clinicaltrials.gov/ct2/show/NCT03377179

    Study Description

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    Brief Summary:
    ABC-108 is a single-arm Phase IIA clinical study of ABC294640 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
    CholangiocarcinomaCholangiocarcinoma Non-resectableCholangiocarcinoma, PerihilarCholangiocarcinoma, ExtrahepaticCholangiocarcinoma, 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 Design

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    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
    Anticipated Study Start Date  :
    January 2018
    Estimated Primary Completion Date  :
    January 2020
    Estimated Study Completion Date  :
    January 2021
    Resource links provided by the National Library of Medicine

     

    Genetics Home Reference related topics: Cholangiocarcinoma
    Genetic and Rare Diseases Information Center resources: Bile Duct Cancer Klatskin Tumor
    U.S. FDA Resources

     

    Arms and Interventions

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    Arm
    Intervention/treatment
    Experimental: ABC294640 treatmentAll participants will be receiving ABC294640, 500 mg twice a day (BID), continuously in 28 day cycles
    Drug: ABC294640Two 250 mg capsules of ABC294640 will be taken twice daily

     

    Outcome Measures

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    Primary Outcome 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 Outcome 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 ]

     

    Other Outcome Measures: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.

     

     

    Eligibility Criteria

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    Information from the National Library of Medicine

    Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

     

    Ages Eligible for Study:
    18 Years and older   (Adult, Senior)
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Criteria
    Inclusion Criteria:

    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
    Exclusion Criteria:

    >2 previous systemic anti-neoplastic regimens for CCA.
    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 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.
    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. (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)
    Patients who are taking Coumadin or Coumadin derivatives.
    Contacts and Locations

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    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
    Sponsors and Collaborators
    RedHill Biopharma Limited
    Investigators

    Principal Investigator:
    Mitesh Borad, MD
    Mayo Clinic
    More Information

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    Publications: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.
    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.

     

    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:
    December 19, 2017
    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

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