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

Conditions:Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology
Age Range:18 - Any
Start Date:November 26, 2018
End Date:June 30, 2020
Contact:Barbara L Powers, MSN, PhD
Phone:(617) 765-2252

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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

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).

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).

Inclusion Criteria:

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 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 ≥ 30 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. Hydrea is allowed up to 48 hours
prior to the first dose for patients with rapidly proliferative disease.

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

6. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed during the
first 2 weeks of therapy if in the best interest of the participant and is approved by
the medical monitor. Hydroxyurea can be used to treat leukocytosis if concurrent with
and thought to be associated with presumed differentiation syndrome.

7. 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).

8. Active cerebrospinal involvement of AML.

9. Diagnosis of acute promyelocytic leukemia (APL)

10. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.

11. Severe gastrointestinal or metabolic condition that could interfere with the
absorption of oral study medication.

12. 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

13. Nursing women or women of childbearing potential (WOCBP) with a positive urine
pregnancy test.
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