Study of Ibrutinib in Subjects With Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Ibrutinib; Ibrutinib + LD-AraC; Ibrutinib+Azacitidine
Intervention description: Subjects will receive ibrutinib 560 mg once daily on a continuing basis.; 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.; 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).
Intervention MeSH terms: Azacitidine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia; AML; Ibrutinib; Cytarabine; LD-AraC; Azacitidine

Summary:

      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.
    

Eligibility criteria:

        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).