Pevonedistat, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of
pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
myeloid leukemia. (Phase Ib) II. To determine the composite complete response rate (complete
remission [CR] or complete remission with incomplete blood count recovery [CRi]) of
pevonedistat in combination with cytarabine and idarubicin in newly diagnosed high-risk acute
myeloid leukemia. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate plasma pharmacokinetic (PK) profiles of pevonedistat when used in combination
with cytarabine and idarubicin in the phase Ib part of the study.

II. To evaluate the relapse free (RFS), overall survival (OS), safety and tolerability of
pevonedistat in combination with cytarabine and idarubicin in the phase II part of the study.

TERTIARY OBJECTIVES:

I. To evaluate the pharmacodynamics (PD) effects of pevonedistat in combination with
cytarabine and idarubicin in acute myelogenous leukemia (AML) blasts.

II. To evaluate potential predictive biomarkers of response to pevonedistat in combination
with cytarabine and idarubicin in AML.

III. To determine the CR without minimal residual disease rate (CR MRD-) of pevonedistat in
combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia.

OUTLINE: This is a phase Ib, dose escalation study of pevonedistat followed by a phase II
study.

INDUCTION: Patients receive idarubicin intravenously (IV) over 10-15 minutes on days 1-3,
cytarabine IV over 1-3 hours on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3,
and 5. Patients with gross residual disease on day 14 bone marrow may receive a second course
of induction chemotherapy.

CONSOLIDATION: Patients who achieve CR and will not undergo bone marrow transplant receive
cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats every 28-35
days for 4 courses in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up for at least 30 days, and then
every 3 months for 2 years.

Inclusion Criteria:

- Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care

- Female patients who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 1 highly effective
method and 1 additional (barrier) of contraception, at the same time, from the
time of signing the informed consent through 4 months after the last dose of
study drug (female and male condoms should not be used together), or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods] withdrawal, spermicides only and
lactational amenorrhea are not acceptable methods of contraception)

- Male patients, even if surgically sterilized (ie, status postvasectomy), who:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 4 months after the last dose of study drug (female
and male condoms should not be used together), or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods for the female partner] withdrawal,
spermicides only and lactational amenorrhea are not acceptable methods of
contraception)

- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0-2

- Expected survival > 3 months from study enrollment

- Within 3 days before the first dose of study drug: albumin > 2.7 g/dL

- Within 3 days before the first dose of study drug: total bilirubin < upper limit of
normal (ULN)

- Within 3 days before the first dose of study drug: alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) < 2.5 x ULN

- Within 3 days before the first dose of study drug: creatinine clearance > 50 mL/min

- Within 3 days before the first dose of study drug: hemoglobin > 8 g/dL (prior red
blood cell [RBC] transfusion allowed); patients may be transfused to achieve this
value; elevated indirect bilirubin due to post-transfusion hemolysis is allowed

- Patients with previously untreated AML (except acute promyelocytic leukemia [APL]) who
have at least one of the following:

- Adverse genetic features as per the European Leukemia Net guidelines

- Treatment related AML or AML with antecedent myelodysplastic syndrome (MDS);
(patient who have received treatment with hypomethylating agents for MDS and have
now transformed to AML are eligible)

- Are over the age of 55 years and considered fit for chemotherapy

- Patients with AML with MDS-related changes

- Patients must be considered candidates for intensive chemotherapy treatment with
standard doses of cytarabine and anthracycline regimen (?7+3 regimen?)

- White blood cell (WBC) count < 50,000/uL before administration of pevonedistat on
cycle 1 day 1; Note: hydroxyurea may be used to control the level of circulating
leukemic blast cell counts to not lower than 10,000/uL during the study

Exclusion Criteria:

- Known cardiopulmonary disease defined as one of the following:

- Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg,
diastolic blood pressure > 95 mm Hg)

- Cardiomyopathy or history of ischemic heart disease

- Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de
pointes); however, patients with < grade 3 atrial fibrillation (a fib) for a
period of at least 6 months may enroll; grade 3 a fib is symptomatic and
incompletely controlled medically, or controlled with device (e.g., pacemaker),
or ablation; patients with paroxysmal a fib are permitted to enroll

- Implantable cardioverter defibrillator

- Congestive heart failure (New York Heart Association [NYHA] class III or IV; or
class II with a recent decompensation requiring hospitalization or referral to a
heart failure clinic within 4 weeks before screening), myocardial infarction
and/or revascularization (eg, coronary artery bypass graft, stent) within 6
months of first dose of study drug

- Patients who had ischemic heart disease who have had acute coronary syndrome
(ACS), myocardial infarction (MI), and/or revascularization greater than 6 months
before screening and who are without cardiac symptoms may enroll

- Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)

- Pulmonary hypertension

- Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to
institutional guidelines

- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
radionuclide angiography

- Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial
lung disease, and pulmonary fibrosis

- Any serious medical or psychiatric illness that could, in the investigator?s opinion,
potentially interfere with the completion of study procedures

- Treatment with any investigational products within 14 days before the first dose of
any study drug

- Patients receiving any other investigational or commercial agents or therapies
administered with the intention to treat their malignancy within 14 days of first
receipt of study drug with the exception of: hydroxyurea (HU) in patients who need to
continue this agent to maintain WBC count =< 50,000/mm^3

- Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, septicemia, or methicillin resistant staphylococcus aureus infection

- Major surgery within 14 days before the first dose of any study drug or a scheduled
surgery during study period

- Diagnosed or treated for another malignancy within 2 years before randomization or
previously diagnosed with another malignancy and have any evidence of residual
disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone resection

- Life-threatening illness unrelated to cancer

- Patients with uncontrolled coagulopathy or bleeding disorder

- Known central nervous system (CNS) involvement

- Known human immunodeficiency virus (HIV) seropositive

- Known hepatitis B surface antigen seropositive or known or suspected active hepatitis
C infection

- Note: patients who have isolated positive hepatitis B core antibody (ie, in the
setting of negative hepatitis B surface antigen and negative hepatitis B surface
antibody) must have an undetectable hepatitis B viral load

- Known hepatic cirrhosis or severe pre-existing hepatic impairment

- Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose
of any study drug, except for hydroxyurea

- Treatment with clinically significant metabolic enzyme inducers within 14 days before
the first dose of the study drug; clinically significant metabolic enzyme inducers are
not permitted during this study

- Patients who refuse to potentially receive blood products and/or have a
hypersensitivity to blood products

- Patients with history of allergic or toxic reactions attributed to cytarabine or a
history of allergic reactions to components of the formulated product

- Patients with history of allergic or toxic reactions attributed to anthracyclines or a
history of allergic reactions to components of the formulated product

- Patients who have had prior chemotherapy for AML

- Female patients who intend to donate eggs (ova) during the course of this study or 4
months after receiving their last dose of study drug(s)

- Female patients who are both lactating and breastfeeding or have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on day 1
before first dose of study drug (if applicable)

- Male patients who intend to donate sperm during the course of this study or 4 months
after receiving their last dose of study drug(s)