Clinical trial NCT02351037: Study of Ibrutinib in Subjects With Acute Myeloid Leukemia
Official title: A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in Combination With Either Cytarabine or Azacitidine in Subjects With Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Acute Myeloid Leukemia
AML
Ibrutinib
Cytarabine
LD-AraC
Azacitidine
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2015-01-30
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: 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
timeFrame: When the last subject enrolled completes approximately 12 months of treatment.
measure: Safety and Tolerability of Ibrutinib Monotherapy or in Combination With Either LD-AraC or Azacitidine
timeFrame: Up to 30 days following the last dose of study drug.
Secondary outcomes:
measure: Relapse-free Survival (RFS), Event-free Survival (EFS) and Overall Survival (OS)
timeFrame: When the last subject enrolled completes approximately 12 months of treatment
measure: Clinical Benefit Rate - as Defined as the Proportion of Subjects Who Achieve CR, CRi, Morphologic Leukemia-free State, or Partial Remission (PR)
timeFrame: When the last subject enrolled completes approximately 12 months of treatment
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Bronx
country: United States
facility: Montefiore Einstein Center for Cancer Research
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Jorge Cortes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.