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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 6
- 主要终点
- Number of Participants With Treatment-Related Adverse Events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA Class 0 to
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Brequinar/Brequinar + Ribavirin (Drug)
结局指标
主要结局
Number of Participants With Treatment-Related Adverse Events
时间窗: 12 months
The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.
次要结局
- Morphologic Leukemia Free State (MLFS) Rate(Up to approximately 12 months)
- Partial Remission (PR) Rate(Up to approximately 12 months)
- Overall Response Rate (ORR)(12 months)
- Complete Remission (CR) Rate(Up to approximately 12 months)
- Complete Remission With Incomplete Hematologic Recovery (CRi) Rate(Up to approximately 12 months)
- Complete Remission With Partial Hematological Recovery (CRh) Rate(Up to approximately 12 months)
- Event Free Survival (EFS) Rate(Up to approximately 12 months)
- Duration of Response(Up to approximately 12 months)
- Brequinar Pharmacokinetics - Area Under the Curve (AUC)(First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.)