Study of Ibrutinib in Subjects With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in Combination With Either Cytarabine or Azacitidine in Subjects With Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Ibrutinib + LD-AraC
* Drug: Ibrutinib+Azacitidine


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

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib Monotherapy Cohort<br>Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis. | Drug: Ibrutinib<br>* Subjects will receive ibrutinib 560 mg once daily on a continuing basis.<br>* Other names: Cohort 1;|
| Experimental: Ibrutinib + LD-AraC Combination Cohort<br>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. | Drug: Ibrutinib + LD-AraC<br>* 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.<br>* Other names: Cohort 2;|
| Experimental: Ibrutinib+Azacitidine Combination Cohort<br>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). | Drug: Ibrutinib+Azacitidine<br>* Subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle (with an option to increase to 100 mg/m2 after 2 cycles).<br>* Other names: Cohort 3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | When the last subject enrolled completes approximately 12 months of treatment. | 
| Safety and Tolerability of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine | 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. | Up to 30 days following the last dose of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS) | To evaluate clinical efficacy by assessing 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) | To evaluate clinical benefit defined as CR, CRi, morphologic leukemia-free state, and partial remission (PR). | When the last subject enrolled completes approximately 12 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, AML, Ibrutinib, Cytarabine, LD-AraC, Azacitidine