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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Brequinar/Brequinar + Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brequinar/Brequinar + Ribavirin<br>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<br>* The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events | The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | 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 | 12 months | 
| Complete Remission (CR) Rate | 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. | Up to approximately 12 months | 
| Complete Remission With Incomplete Hematologic Recovery (CRi) Rate | 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. | Up to approximately 12 months | 
| Complete Remission With Partial Hematological Recovery (CRh) Rate | 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. | Up to approximately 12 months | 
| Morphologic Leukemia Free State (MLFS) Rate | 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. | Up to approximately 12 months | 
| Partial Remission (PR) Rate | 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. | Up to approximately 12 months | 
| Event Free Survival (EFS) Rate | 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. | Up to approximately 12 months | 
| Duration of Response | 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. | Up to approximately 12 months | 
| Brequinar Pharmacokinetics - Area Under the Curve (AUC) | The plot of drug concentration in blood plasma vs. time. | First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DHODH, Brequinar, Differentiation, IMPDH Inhibition