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Trial record 1 of 4 for:    Brequinar
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A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03760666
Recruitment Status : Terminated (No efficacy observed, COVID-19 caused sites to shut down)
First Posted : November 30, 2018
Results First Posted : August 8, 2022
Last Update Posted : August 8, 2022
Sponsor:
Information provided by (Responsible Party):
Clear Creek Bio, Inc.

Brief Summary:
A Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid leukemia (AML). Ribavirin BID may be added to brequinar twice weekly in eligible subjects.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Brequinar/Brequinar + Ribavirin Phase 1 Phase 2

Detailed Description:
Up to 27 subjects will be entered in this Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid leukemia (AML). Active Cohort 2 subjects on brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID. Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses may be adjusted based on safety, tolerability, and enzyme inhibition levels.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: Subjects start dosing with brequinar alone; Cohort 2 subjects may roll over into ribavirin dosing; Cohort 3 subjects started with brequinar monotherapy then added ribavirin dosing.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a Open-label, Multi-center Study to Assess the Safety, Efficacy and Pharmacokinetics of Intrapatient Dose-adjusted Brequinar and Inhibition of Dihydroorotate Dehydrogenase (DHODH) in Adult Subjects With AML
Actual Study Start Date : December 20, 2018
Actual Primary Completion Date : December 31, 2020
Actual Study Completion Date : February 9, 2021


Arm Intervention/treatment
Experimental: Brequinar/Brequinar + Ribavirin
Brequinar and ribavirin were dosed orally; brequinar starting doses ranged from 200 mg/m2 to 500 mg/m2. Brequinar doses were adjusted by cohort for starting dose and regimen (either twice-weekly or once-weekly). In addition, the dose for each participant was also adjusted (either escalated or decreased) based on safety, brequinar PK and levels of dihydroorotate (DHO). Ribavirin 1000 mg twice a day (bid) was added in combination with brequinar for the final 3 study participants.
Drug: Brequinar/Brequinar + Ribavirin
The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.




Primary Outcome Measures :
  1. Number of Participants With Treatment-Related Adverse Events [ Time Frame: 12 months ]
    The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 12 months ]
    The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS. No participant met the efficacy endpoint to be included in this analysis

  2. Complete Remission (CR) Rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.

  3. Complete Remission With Incomplete Hematologic Recovery (CRi) Rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.

  4. Complete Remission With Partial Hematological Recovery (CRh) Rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.

  5. Morphologic Leukemia Free State (MLFS) Rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.

  6. Partial Remission (PR) Rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.

  7. Event Free Survival (EFS) Rate [ Time Frame: Up to approximately 12 months ]
    Interval between first dose and relapse (>=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.

  8. Duration of Response [ Time Frame: Up to approximately 12 months ]
    The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation. No participant met this efficacy endpoint to be included in this analysis.

  9. Brequinar Pharmacokinetics - Area Under the Curve (AUC) [ Time Frame: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours. ]
    The plot of drug concentration in blood plasma vs. time.



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. 1. Willing and able to provide written informed consent for the trial.
  2. Patients 18 years of age or older, with relapsed/refractory AML by World Health Organization classification, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL) and who have exhausted available therapy.
  3. ECOG Performance Status 0 to 2.
  4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA Class 0 to 2.
  5. Adequate hepatic function (unless deemed to be related to underlying leukemia).

    1. Direct bilirubin ≤ 2 x ULN
    2. ALT ≤ 3 x ULN
    3. AST ≤ 3 x ULN
  6. Adequate renal function as documented by creatinine clearance ≥ 50 mL/min based on the Cockcroft-Gault equation.
  7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed therapy to first dose of study drug will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents. Use of supportive care measures per institution's standard of care is permitted at any time.
  8. The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 90 days after completion of brequinar administration.
  9. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.

Exclusion Criteria:

  1. Patients in need of immediate leukapheresis.
  2. Any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness that could place the participant at unacceptable risk of study treatment.
  3. QTc interval using Fridericia's formula (QTcF) ≥ 470 msec. Participants with a bundle branch block and prolonged QTc interval may be eligible after discussion with the medical monitor.
  4. Pre-existing liver disease.
  5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions:

    a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia.

  6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥ 0.5 mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine or other calcineurin inhibitors or other immunosuppressive agents used for GVHD).
  7. Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL).
  8. Diagnosis of acute promyelocytic leukemia (APL)
  9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
  10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of oral study medication.
  11. Prior malignancy, unless it has not been active or has remained stable for at least 2 years. Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if at the active surveillance stage, hormonal therapy has been initiated, or the malignancy has been surgically removed or treated with definitive radiotherapy.
  12. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
  13. Documented hemoglobinopathy.

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): NCT03760666


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth-Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Ohio
Cleveland Clinic Lerner College of Medicine
Cleveland, Ohio, United States, 44195
United States, Texas
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Clear Creek Bio, Inc.
  Study Documents (Full-Text)

Documents provided by Clear Creek Bio, Inc.:
Study Protocol  [PDF] March 9, 2020
Statistical Analysis Plan  [PDF] September 11, 2019

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Responsible Party: Clear Creek Bio, Inc.
ClinicalTrials.gov Identifier: NCT03760666    
Other Study ID Numbers: CCB-01
First Posted: November 30, 2018    Key Record Dates
Results First Posted: August 8, 2022
Last Update Posted: August 8, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Clear Creek Bio is committed to responsible data sharing regarding the clinical trials we sponsor. Data that may be shared include access to anonymized participant and trial level data (analysis data sets), as well as other information (e.g., protocol) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Requests for data can be submitted at any time and if the below conditions are met data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Requests for data may be made by qualified researchers who plan to engage in rigorous, independent scientific research. Data will be provided following review and approval of a research proposal including a formal statistical analysis plan and execution of a Data Sharing Agreement.

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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 Clear Creek Bio, Inc.:
DHODH
Brequinar
Differentiation
IMPDH Inhibition
Additional relevant MeSH terms:
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Brequinar
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Ribavirin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs