Clinical Trials /

A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

NCT03760666

Description:

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.

Related Conditions:
  • Acute Bilineal Leukemia
  • Acute Myeloid Leukemia
  • Mixed Phenotype Acute Leukemia
  • T-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
  • 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

Clinical Trial IDs

  • ORG STUDY ID: CCB-01
  • NCT ID: NCT03760666

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
BrequinarBrequinar
Brequinar + RibavirinBrequinar + Ribavirin

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
BrequinarExperimentalBrequinar dosed orally. Multiple doses.
  • Brequinar
Brequinar + RibavirinOtherSubjects in Cohort 2 may roll over to add ribavirin dosing; subjects in Cohort 3 will start with brequinar alone then add ribavirin dosing.
  • Brequinar + Ribavirin

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Treatment-Related Adverse Events
Time Frame:12 months
Safety Issue:
Description:The number of subjects with treatment-related adverse events as assessed by CTCAE v. 4.03.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:12 months
Safety Issue:
Description: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.
Measure:Complete Remission (CR) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The proportion of subjects in the Efficacy Analysis Set with best overall response of CR
Measure:Complete Remission with Incomplete Hematologic Recovery (CRi) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi
Measure:Complete Remission with Partial Hematological Recovery (CRh) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh
Measure:Morphologic Leukemia Free State (MLFS) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS
Measure:Partial Remission (PR) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR
Measure:Event free survival (EFS) rate
Time Frame:Up to approximately 12 months
Safety Issue:
Description:Interval between first dose and relapse (>=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both
Measure:Duration of response
Time Frame:Up to approximately 12 months
Safety Issue:
Description: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.
Measure:Brequinar Pharmacokinetics - Elimination Half-Life (T 1/2)
Time Frame:Up to 14 days after first dose.
Safety Issue:
Description:The period of time required for the concentration of drug in plasma to be reduced by one-half.
Measure:Brequinar Pharmacokinetics - AUC
Time Frame:Up to 14 days after first dose.
Safety Issue:
Description:The plot of drug concentration in blood plasma vs. time.
Measure:DHO Plasma Level
Time Frame:Up to 14 days after first dose. Pre-dose at the beginning of each cycle (every 2 weeks for 3 months then every 4 weeks).
Safety Issue:
Description:Plasma level of DHO

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Clear Creek Bio, Inc.

Trial Keywords

  • DHODH
  • Brequinar
  • Differentiation
  • IMPDH Inhibition

Last Updated

June 17, 2020