Clinical trial NCT03760666: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: DHODH
Brequinar
Differentiation
IMPDH Inhibition
Lead sponsor: Clear Creek Bio, Inc.
Sponsor class: INDUSTRY
First posted: 2018-11-30
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Number of Participants With Treatment-Related Adverse Events
timeFrame: 12 months
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 12 months
measure: Complete Remission (CR) Rate
timeFrame: Up to approximately 12 months
measure: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate
timeFrame: Up to approximately 12 months
measure: Complete Remission With Partial Hematological Recovery (CRh) Rate
timeFrame: Up to approximately 12 months
measure: Morphologic Leukemia Free State (MLFS) Rate
timeFrame: Up to approximately 12 months
measure: Partial Remission (PR) Rate
timeFrame: Up to approximately 12 months
measure: Event Free Survival (EFS) Rate
timeFrame: Up to approximately 12 months
measure: Duration of Response
timeFrame: Up to approximately 12 months
measure: Brequinar Pharmacokinetics - Area Under the Curve (AUC)
timeFrame: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth-Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Cleveland
country: United States
facility: Cleveland Clinic Lerner College of Medicine
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
References: