Ibrutinib, Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

Identify the safety and recommended phase 2 dose of ibrutinib in combination with
idarubicin/cytarabine in relapsed/refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

- Assess the induction response rate (complete remission [CR]/complete remission with
incomplete count [CRi]) of ibrutinib in combination with idarubicin/cytarabine in
relapsed/refractory AML.

- Assess overall survival of ibrutinib in combination with idarubicin/cytarabine in
relapsed/refractory AML.

OUTLINE: This is a dose-escalation study of ibrutinib.

INDUCTION: Patients receive ibrutinib orally (PO) once daily (QD) on days 1 to 21, idarubicin
intravenously (IV) over 15 minutes on days 1 to 3 and cytarabine IV continuously on days 1 to
4.

CONSOLIDATION: Patients achieving CR or CRi may receive ibrutinib PO QD on days 1 to 21,
idarubicin IV over 15 minutes on Days 1and 2 and cytarabine IV continuously on days 1-3.
Treatment repeats every 28 days for 2 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Patients maintaining a CR/CRi may receive ibrutinib PO QD on days 1 to 28.
Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 6 months.

INCLUSION CRITERIA

- Previous morphologically-confirmed diagnosis of acute myeloid leukemia (AML) based on
World Health Organization (WHO) Criteria

- At least one prior chemotherapy regimen to treat AML

- Disease relapse or refractory disease as shown by > 5% blasts in the bone marrow (not
attributable to another cause). Administration of hydrea to control high WBC count is
permitted.

- Age ≥ 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, or Karnofsky
Performance Status (KPS) ≥ 60%

- Life expectancy > 4 weeks

- Platelet count ≥ 10,000/mm3 within 72 hours of initiating the Induction Cycle
(platelet transfusion support is allowed)

- Serum creatinine ≤ 2.0 mg/dL within 72 hours of initiating the Induction Cycle

- Total bilirubin ≤ 2.1 mg/dL within within 72 hours of initiating the Induction Cycle
(EXCEPTION: If elevation is not due to liver dysfunction, and is due primarily to
elevated unconjugated hyperbilirubinemia secondary to Gilbert's syndrome, or hemolysis
of non-hepatic origin)

- Serum glutamic oxaloacetic transaminase (SGOT) [aspartate aminotransferase (AST) ] ≤
3.0 X upper limit of normal (ULN) within 72 hours of initiating the Induction Cycle

- Serum glutamic pyruvic transaminase (SGPT) [alanine aminotransferase (ALT)] ≤ 3.0 X
ULN within 72 hours of initiating the Induction Cycle

- Baseline prothrombin time (PT)/international normalized ratio (INR) ratio < 3 X ULN
within 7 days of initiating the Induction Cycle (for subjects with correctable
coagulation abnormalities, coagulation factor support per institutional standard of
care for AML is allowed)

- Partial thromboplastin time (PTT) < 3 X ULN within 7 days of initiating the Induction
Cycle (for subjects with correctable coagulation abnormalities, coagulation factor
support per institutional standard of care for AML is allowed)

- Negative pregnancy test within 14 days prior to study treatment (for Women of
reproductive potential only)

- Women of child-bearing potential and men must agree (in ICF) to use adequate
contraception (eg, hormonal or barrier methods of birth control; abstinence;
sterilized partner) for the duration of study participation

- Ability to understand and the willingness to sign the written informed consent
document

EXCLUSION CRITERIA

- Received anticancer therapy (chemotherapy, immunotherapy, radiotherapy, or
investigational therapy) within 2 weeks prior to starting study treatment [EXCEPTION:
Hydroxyurea (hydrea) to control high white blood cell count is permitted]

- Receiving any other investigational agents within 14 days or 5 effective half lives
(whichever is shorter) prior to 1st dose of ibrutinib

- Prior treatment with ibrutinib

- Known unresolved toxicities due to prior anticancer therapy [≥ Grade 2, by Common
Terminology Criteria for Adverse Events (CTCAE) v4.03] unless otherwise defined in the
inclusion/exclusion criteria (EXCEPTION: alopecia)

- Known acute promyelocytic leukemia (French-American-British Class M3-AML)

- Known active central nervous system (CNS) leukemia

- Prior bone marrow transplant presenting with active uncontrolled graft vs host disease
(GvHD)

- Known congenital bleeding disorders, such as hemophilia

- Known history of stroke or intracranial hemorrhage within 6 months prior to study
treatment

- Concomitant use of warfarin or other vitamin K antagonists

- Requires treatment with strong CYP3A inhibitors at the time of study enrollment.
Washout period is 5 effective half-lives is required prior to 1st dose of ibrutinib

- Requires treatment with strong CYP3A inducers at the time of study enrollment. Washout
period is 5 effective half-lives is required prior to 1st dose of ibrutinib

- Known active uncontrolled systemic infection

- Major surgery within 4 weeks of 1st dose of ibrutinib

- Unable to swallow capsules

- Known Malabsorption syndrome

- Known Disease significantly affecting gastrointestinal function

- Resection of the stomach or small bowel

- Uncontrolled symptomatic inflammatory bowel disease

- Ulcerative colitis

- Bowel obstruction, partial or complete

- Congestive heart failure with ejection fraction (EF) < 45%

- Uncontrolled cardiac disease, including uncontrolled cardiac arrhythmia or coronary
artery disease (CAD) with active symptoms due to CAD defined as unstable angina

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ibrutinib; idarubicin; or cytarabine

- Uncontrolled intercurrent illness including, but not limited to:

- Active infection

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Pregnant

- Lactating

- Known positive HIV

- Known active hepatitis C

- 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)