A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in Combination With Either Cytarabine or Azacitidine in Subjects With Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 36
- 试验地点
- 9
- 主要终点
- Efficacy of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine Using the Overall Remission Rate (Defined as Proportion of Subjects Achieving a CR or CRi) According to the LeukemiaNet Guidelines
研究概览
简要总结
The purpose of this study is to evaluate the efficacy, safety and tolerability of ibrutinib alone or in combination with either cytarabine or azacitidine in the treatment of subjects with Acute Myeloid Leukemia (AML) who have failed standard treatment, or subjects without prior therapy who refuse standard chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Male and female ≥ 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Subjects with pathologically documented AML that has failed standard treatment, or subjects without prior therapy who refuse standard treatment options
- •Bone marrow aspirate/biopsy results showing >5% blasts
- •WBC count <25,000 cells/mm3 (25 x 109/L)
- •Platelet count >10,000 cells/mm3 (10 x 109/L)
- •Adequate hepatic and renal function defined as:
- •For Cohorts 1 and 2: serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper limit of normal (ULN); for Cohort 3: ALT ≤2.5 or AST ≤2.5 ULN.
- •Serum creatinine ≤2 mg/dL or Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault).
- •Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
- •PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (When treated with warfarin or other vitamin K antagonists, then INR ≤3.0).
- •Female subjects who are of non-reproductive potential (Female subjects of reproductive potential must have a negative serum pregnancy test upon study entry).
- •Male and female subjects of reproductive potential agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug.
排除标准
- •Acute promyelocytic leukemia (French-American-British Class M3 AML).
- •Known active central nervous system (CNS) leukemia.
- •Known active systemic infection (Grade ≥2).
- •Active bleeding disorders or clinical signs of bleeding (Grade ≥2).
- •Prior bone marrow transplant that requires immunosuppressant therapy or presents with graft vs host disease (GVHD).
- •History of other malignancies, except:
- •Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and with low risk of recurrence by treating physician.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated carcinoma in situ without evidence of disease.
- •Prior treatment with a BTK inhibitor.
- •For Cohort 3 subjects, prior treatment with hypomethylating agents (eg, azacitidine, decitabine)
- •Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose of study drug.
- •Subject has received a monoclonal antibody for anticancer intent within 8 weeks prior to the first dose of study drug.
- •Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
- •Recent infection requiring intravenous (IV) systemic treatment that was completed ≤14 days before the first dose of study drug.
- •Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, unless otherwise defined in the inclusion/exclusion criteria with the exception of alopecia.
- •Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.
- •History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
- •Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
- •Major surgery within 4 weeks of first dose of study drug.
- •Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
- •Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
- •Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
- •Concomitant use of warfarin or other Vitamin K antagonists.
- •Requires treatment or prophylaxis with a strong cytochrome P450 (CYP) 3A inhibitor
- •Currently active, clinically significant hepatic impairment (≥ moderate hepatic impairment according to the Child Pugh classification).
- •Lactating or pregnant.
- •Unwilling or unable to participate in all required study evaluations and procedures.
- •Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
研究组 & 干预措施
Ibrutinib Monotherapy Cohort
Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis.
干预措施: Ibrutinib (Drug)
Ibrutinib + LD-AraC Combination Cohort
Up to 25-28 additional response evaluable subjects (for a total of 34 subjects) will receive ibrutinib 560 mg once daily on a continuous basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 10 days of a 28-day cycle.
干预措施: Ibrutinib + LD-AraC (Drug)
Ibrutinib+Azacitidine Combination Cohort
Up to 34 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75mg/m2 IV once daily Days 1-7 of a 28-day cycle (with an option to increase to 100mg/m2 after 2 cycles).
干预措施: Ibrutinib+Azacitidine (Drug)
结局指标
主要结局
Efficacy of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine Using the Overall Remission Rate (Defined as Proportion of Subjects Achieving a CR or CRi) According to the LeukemiaNet Guidelines
时间窗: When the last subject enrolled completes approximately 12 months of treatment.
Dohner's 2000 Criteria for AML: Complete Response (CR), Bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \> 1.0 x 109/L (1000/µL); platelet count \>100 x 109/L (100 000/µL); independence of red cell transfusions; CR with Incomplete Recovery (CRi), All CR criteria except for residual neutropenia (\< 1.0 x 109/L \[1000/µL\]) or thrombocytopenia (\<100 x 109/L \[100 000/µL\]) ; Morphologic leukemia-free state, Bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; Partial Remission (PR), All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%; Relapse, Bone marrow blasts \> 5%; or reappearance of blasts in the blood; or development of extramedullary disease.
Safety and Tolerability of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine
时间窗: Up to 30 days following the last dose of study drug.
Number of Participants with Adverse Events and number of patients with lab abnormalities.The safety profile of ibrutinib was evaluated based on the incidence of adverse events (AEs) as well as clinically significant laboratory abnormalities and vital signs, and other malignancies. The safety evaluations performed in this study were standard and/or were required based on the safety data available from other clinical and preclinical settings.
次要结局
- Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS)(When the last subject enrolled completes approximately 12 months of treatment)
- Clinical Benefit Rate - as Defined as the Proportion of Subjects Who Achieve CR, CRi, Morphologic Leukemia-free State, or Partial Remission (PR)(When the last subject enrolled completes approximately 12 months of treatment)