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Study of Ibrutinib in Subjects With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT02351037
Recruitment Status : Terminated (Study data do not support development in AML.)
First Posted : January 30, 2015
Results First Posted : August 14, 2018
Last Update Posted : August 14, 2018
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

Tracking Information
First Submitted Date  ICMJE January 16, 2015
First Posted Date  ICMJE January 30, 2015
Results First Submitted Date  ICMJE April 4, 2018
Results First Posted Date  ICMJE August 14, 2018
Last Update Posted Date August 14, 2018
Actual Study Start Date  ICMJE February 2015
Actual Primary Completion Date April 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2018)
  • 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 [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 29, 2015)
  • Efficacy of ibrutinib, with or without LD-AraC measured by overall remission rate, defined as proportion of subjects achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi). [ Time Frame: When the last subject enrolled completes approximately 12 months of treatment. ]
  • Number of participants with adverse events as a measure of safety and tolerability of ibrutinib, with or without LD-AraC. [ Time Frame: Up to 30 days following the last dose of study drug. ]
Change History Complete list of historical versions of study NCT02351037 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2018)
  • Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS) [ Time Frame: When the last subject enrolled completes approximately 12 months of treatment ]
    To evaluate clinical efficacy by assessing relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS).
  • Clinical Benefit Rate - as Defined as the Proportion of Subjects Who Achieve CR, CRi, Morphologic Leukemia-free State, or Partial Remission (PR) [ Time Frame: When the last subject enrolled completes approximately 12 months of treatment ]
    To evaluate clinical benefit defined as CR, CRi, morphologic leukemia-free state, and partial remission (PR).
Original Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2015)
  • Relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) [ Time Frame: 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) as best response. [ Time Frame: When the last subject enrolled completes approximately 12 months of treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Ibrutinib in Subjects With Acute Myeloid Leukemia
Official Title  ICMJE A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in Combination With Either Cytarabine or Azacitidine in Subjects With Acute Myeloid Leukemia
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: Ibrutinib
    Subjects will receive ibrutinib 560 mg once daily on a continuing basis.
    Other Name: Cohort 1
  • Drug: Ibrutinib + LD-AraC
    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.
    Other Name: Cohort 2
  • Drug: Ibrutinib+Azacitidine
    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).
    Other Name: Cohort 3
Study Arms  ICMJE
  • Experimental: Ibrutinib Monotherapy Cohort
    Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis.
    Intervention: Drug: Ibrutinib
  • Experimental: 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.
    Intervention: Drug: Ibrutinib + LD-AraC
  • Experimental: 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).
    Intervention: Drug: Ibrutinib+Azacitidine
Publications * Wilken R, Li CS, Sharon VR, Kim K, Patel FB, Patel F, Maverakis E. Topical clobetasol for the treatment of toxic epidermal necrolysis: study protocol for a randomized controlled trial. Trials. 2015 Aug 22;16:374. doi: 10.1186/s13063-015-0879-7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 18, 2017)
36
Original Estimated Enrollment  ICMJE
 (submitted: January 29, 2015)
67
Actual Study Completion Date  ICMJE April 2017
Actual Primary Completion Date April 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02351037
Other Study ID Numbers  ICMJE PCYC-1131-CA
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Pharmacyclics LLC.
Study Sponsor  ICMJE Pharmacyclics LLC.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jorge Cortes, MD M.D. Anderson Cancer Center
PRS Account Pharmacyclics LLC.
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP