A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
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|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
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|Condition or disease||Intervention/treatment||Phase|
|Acute Myeloid Leukemia||Drug: Brequinar/Brequinar + Ribavirin||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||17 participants|
|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)|
|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|
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.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 1. Willing and able to provide written informed consent for the trial.
- 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.
- ECOG Performance Status 0 to 2.
- 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA Class 0 to 2.
Adequate hepatic function (unless deemed to be related to underlying leukemia).
- Direct bilirubin ≤ 2 x ULN
- ALT ≤ 3 x ULN
- AST ≤ 3 x ULN
- Adequate renal function as documented by creatinine clearance ≥ 50 mL/min based on the Cockcroft-Gault equation.
- 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.
- 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.
- Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.
- Patients in need of immediate leukapheresis.
- Any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness that could place the participant at unacceptable risk of study treatment.
- 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.
- Pre-existing liver disease.
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.
- 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).
- Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL).
- Diagnosis of acute promyelocytic leukemia (APL)
- Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
- Severe gastrointestinal or metabolic condition that could interfere with the absorption of oral study medication.
- 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.
- Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
- Documented hemoglobinopathy.
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
|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|
Documents provided by Clear Creek Bio, Inc.:
|Responsible Party:||Clear Creek Bio, Inc.|
|Other Study ID Numbers:||
|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.|
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
|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.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs