Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement

PRIMARY OBJECTIVES:

I. Determine a safe and tolerable schedule of DOT1L inhibitor EPZ-5676 (pinometostat)
continuous intravenous infusion in combination with daunorubicin hydrochloride (daunorubicin)
and cytarabine in patients with untreated, newly diagnosed acute myeloid leukemia harboring
MLL rearrangement.

II. Determine the rate of complete remission (complete remission [CR], CR with incomplete
hematologic recovery [CRi]) in patients with newly diagnosed acute myeloid leukemia harboring
MLL rearrangement after treatment with pinometostat in combination with daunorubicin and
cytarabine.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Estimate biologic activity of 7 day window
treatment of pinometostat monotherapy.

III. Estimate the toxicity profile of pinometostat alone (week 1) and in combination with
daunorubicin and cytarabine.

IV. Estimate event free and overall survival of patients with MLL rearranged acute myeloid
leukemia after combination treatment with pinometostat, daunorubicin, and cytarabine.

V. Estimate the early death rate (death =< 30 days) of pinometostat, daunorubicin, and
cytarabine.

VI. Determine the rate of minimal residual disease (MRD) negativity by clinical flow
cytometry on post-treatment recovery bone marrow.

OUTLINE: This is a phase I, dose-escalation study of DOT1L inhibitor EPZ-5676 followed by a
phase II study.

Patients receive DOT1L inhibitor EPZ-5676 intravenously (IV) continuously on days 1-35,
daunorubicin hydrochloride IV over 10-30 minutes on days 8-10 and cytarabine IV continuously
on days 8-14 in the absence of disease progression or unacceptable toxicity.

Patients who do not achieve CR/CRi after treatment receive DOT1L inhibitor EPZ-5676 IV
continuously on days 1-28, daunorubicin hydrochloride IV over 10-30 minutes on days 1 and 2
and cytarabine IV continuously on days 1-5 in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year, then every
3 months for up to 4 years.

Inclusion Criteria:

- Patients must have histologically confirmed acute myeloid leukemia by World Health
Organization (WHO) criteria

- Presence of a cytogenetic rearrangement of KMT2A (MLL) by interphase fluorescent
in-situ hybridization (FISH)

- Patients must have previously untreated (with exception of hydroxyurea for count
control or all-trans retinoic acid [ATRA] for acute promyelocytic leukemia [APML] that
was initially suspected but later ruled out) AML by World Health Organization (WHO)
criteria

- Age >=14 years at time of screening, although individual sites may further restrict
age eligibility in accordance with local Institutional Review Board (IRB) and hospital
policy.

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), unless elevated
due to Gilbert syndrome, hemolysis, or leukemia (at the time of eligibility screening)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN, unless due to leukemia in which case < 5 x ULN (at the
time of eligibility screening)

- Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (at the
time of eligibility screening)

- Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN
(both) (at the time of eligibility screening)

- Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial (at
the time of eligibility screening)

- If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated (at the time of eligibility
screening)

- If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load (at the time of eligibility screening)

- Be medically fit, in the opinion of the investigator, for intensive (7+3) induction
chemotherapy

- Left ventricular ejection fraction (LVEF) >= 45% confirmed by echocardiogram or
multi-gated acquisition scan (MUGA), AND no symptoms of congestive heart failure
exceeding New York Heart Association (NYHA) class II

- Willingness to comply with all study procedures, including scheduled visits,
investigational and standard of care drug administration plans, imaging studies,
laboratory tests (including all biomarkers), procedures, and study- and
disease-related restrictions

- The effects of pinometostat on the developing human fetus are unknown. For this reason
and because other small molecule inhibitors as well as other therapeutic agents used
in this trial are known to be teratogenic, women of child-bearing potential must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry for the duration of study participation, and for 4
weeks after the last dose of study treatment. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate barrier contraception prior to the study, for
the duration of study participation, and for 90 days after completion of pinometostat
administration

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

Exclusion Criteria:

- Acute promyelocytic leukemia with t(15;17)(q22;q12) and/or PML-RARA molecular
rearrangement, or other atypical RARA translocation partner

- Patients who have received prior chemotherapy for AML, excluding hydroxyurea for count
control, or ATRA for APML that was initially suspected but later ruled out

- Patients who have received any prior investigational agent for acute myeloid leukemia

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia, or
peripheral neuropathy (up to grade 2 is permitted)

- Patients who are receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pinometostat or other agents used in study

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible unless the offending medication can be safely
stopped prior to enrollment. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated medical reference.
As part of the enrollment/informed consent procedures, the patient will be counseled
on the risk of interactions with other agents, and what to do if new medications need
to be prescribed or if the patient is considering a new over-the-counter medicine or
herbal product

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring antibiotics (with exception), symptomatic congestive heart
failure, unstable angina pectoris, unstable cardiac arrhythmia not controllable with
medications, electrocardiographic evidence of ischemia, or psychiatric illness/social
situations that would limit compliance with study requirements. Patients receiving an
anti-microbial agent may be eligible if the patient remains afebrile and
hemodynamically stable for 72 hours

- Patients with an active bleeding diathesis

- Pregnant women are excluded from this study because pinometostat is a small molecule
inhibitor with the potential for teratogenic or abortifacient effects. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with pinometostat, breastfeeding should be discontinued if the
mother is treated with pinometostat. These potential risks may also apply to other
agents used in this study

- Subjects with known symptomatic leukemia of the central nervous system including
leptomeningeal leukemic involvement

- History of active other malignancy that limits survival to less than 1 year

- Ongoing viral or drug induced liver injury, including active chronic hepatitis C virus
(HCV), chronic active hepatitis B, clinically known alcoholic liver disease,
non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, primary biliary
cirrhosis, other cirrhosis of the liver, history of hepatic encephalopathy, or portal
hypertension

- Any other prior condition that could, in the opinion of the investigator, compromise
patient safety or evaluation of the primary outcome