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Trial record 6 of 12 for:    RedHill Biopharma

A Study of ABC294640 (Yeliva ®) Alone and in Combination With Hydroxychloroquine Sulfate in Treatment of Patients With Advanced Cholangiocarcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03377179
Recruitment Status : Recruiting
First Posted : December 19, 2017
Last Update Posted : January 27, 2020
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

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.

Condition or disease Intervention/treatment Phase
Cholangiocarcinoma Cholangiocarcinoma Non-resectable Cholangiocarcinoma, Perihilar Cholangiocarcinoma, Extrahepatic Cholangiocarcinoma, Intrahepatic Drug: ABC294640 Drug: Hydroxychloroquine Sulfate 200 MG Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

This is an open-label clinical study to explore the activity signal of ABC294640 and of ABC294640 and HCQ in adult subjects who have been diagnosed with unresectable cholangiocarcinoma either intra- perhilar or extra-hepatic. The study will be conducted at 5 sites in the USA.

For Part 1, a maximum of 39 participants evaluable for efficacy will be enrolled in the study. Eligible participants will receive ABC294640, 500 mg twice a day, continuously administered in 28 day cycles.

Part 2 will be a single-arm Phase IIA study identical to Part 1 but treatment will consist of both ABC294640 together with HCQ. Additionally, Part 2, will consist of two phases: Phase I: accelerate HCQ dose-escalation run-in starting with a HCQ dose of 200 mg QD (once a day). Based on safety results, patient cohorts will be expanded, and dosing will continue to 200 mg BID (twice a day), 400 mg BID and 600 BID. At the end of Part2, Phase I, it will be determined what is the safe and tolerable HCQ dose for Phase II.

For Part 2, up to 15 patients evaluable for safety and tolerability will be enrolled in Phase I component of Part 2; and 20 patients evaluable for efficacy in the Phase II component of Part 2. All eligible participants will receive ABC294640, 500 mg BID in addition to the determined HCQ dose, continuously administered in 28 day cycles.

In addition to physical, neurological and eye exams (eye exams only for participants receiving HCQ), blood and urine samples will be routinely collected for safety and to determine response to the study drugs. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/IIA Study of ABC294640 Alone and in Combination With Hydroxychloroquine Sulfate 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 : December 2022
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: ABC294640 +/- HCQ treatment
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
Two 250 mg capsules of ABC294640 will be taken twice daily
Other Names:
  • yeliva
  • opaganib

Drug: Hydroxychloroquine Sulfate 200 MG
HCQ tablets will be taken at a dose that will be determined
Other Name: HCQ




Primary Outcome Measures :
  1. Part1 - 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.

  2. Part 2 - Determine the Durable Disease Control Rate [ Time Frame: At least 4 months ]
    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


Secondary Outcome Measures :
  1. 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 [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ [ 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 alone and in combination with HCQ in patients with unresectable CCA.

  8. The Maximum Plasma Concentration (Cmax) of ABC294640 and of HCQ [ 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 (Part 1) and of ABC294640 and HCQ (Part 2) in the first 12 patients by measuring Maximum Plasma Concentration (Cmax) of ABC294640 and HCQ

  9. The Area Under the Curve (AUC) of ABC294640 (Part 1) and of ABC294640 and HCQ (Part 2) [ 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 (Part 1) and of ABC294640 and HCQ (Part 2) in the first 12 patients by measuring the Area Under the Curve (AUC) of ABC294640 and of HCQ 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 with ABC294640 alone or in combination with HCQ 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

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.


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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. Previously having received ABC294640 or HCQ (or chloroquine) for the treatment of a malignancy.
  3. 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.
  4. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
  5. 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.
  6. 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).

  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 must be discussed with the Medical Monitor in order to determine eligibility for the study.
  12. Patients who are taking warfarin, apixaban, argatroban or rivaroxaban.
  13. If the patient is to receive HCQ, pre-existing retinopathy.
  14. Known history of G-6-PD Deficiency, porphyria or psoriasis.
  15. History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations.
  16. History of allergic reactions attributed to compounds of similar chemical or biologic composition to HCQ.

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
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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
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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
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Principal Investigator: Mitesh Borad, MD Mayo Clinic
Publications of Results:
Other Publications:
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Responsible Party: RedHill Biopharma Limited
ClinicalTrials.gov Identifier: NCT03377179    
Other Study ID Numbers: ABC-108
First Posted: December 19, 2017    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 ®
opaganib
Hydroxychloroquine Sulfate
HCQ
Autophagy
Additional relevant MeSH terms:
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Cholangiocarcinoma
Klatskin Tumor
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents