CPX-351 and Enasidenib in Treating Patients With Relapsed Acute Myeloid Leukemia Characterized by IDH2 Mutation

PRIMARY OBJECTIVES:

I. To estimate the remission rate (defined as complete remission [CR]/ CR with incomplete
hematologic recovery [CRi]) of the combination of liposome-encapsulated
daunorubicin-cytarabine (CPX-351) plus enasidenib mesylate (enasidenib) in adults with
relapsed acute myeloid leukemia (AML) characterized by a 2-hydroxyglutarate (2-HG) producing
IDH2 mutations that include IDH2^R172 and IDH2^R140.

SECONDARY OBJECTIVES:

I. To evaluate persistent severe hematologic toxicity at induction day 60 in patients with a
morphologic leukemia-free state (bone marrow blasts < 5%).

II. To evaluate delayed CR/CRi with enasidenib maintenance in participants with stable
disease after induction with CPX-351.

IV. To evaluate 30- and 60-day survival. V. To evaluate CPX-351 plus enasidenib as a bridge
to allogeneic hematopoietic stem cell transplantation (HSCT).

EXPLORATORY OBJECTIVES:

I. To determine the co-existing mutations that are present with the IDH2 mutation and
describe those that are present in patients who achieve CR/CRi.

II. To determine the depth of molecular response to induction by minimal residual disease
(MRD) using next generation sequencing.

III. To estimate the subclinical cardiotoxicity of CPX-351 as measured by troponin I,
electrocardiography (ECG), and echocardiography.

OUTLINE:

INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV)
over 90 minutes on days 1, 3, and 5, and enasidenib mesylate orally (PO) on days 10-60 in the
absence of disease progression or unacceptable toxicity. Patients whose bone marrow is not
hypoplastic with no excess blasts receive re-induction including liposome-encapsulated
daunorubicin-cytarabine IV on days 1 and 3, and enasidenib mesylate PO on days 8-60 in the
absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients < 60 years receive cytarabine twice daily (BID) on days 1, 3, and 5,
and patients >= 60 years receive cytarabine IV once daily on days 1-5. Patients also receive
enasidenib mesylate PO on days 6-55. Treatment repeats every 28-55 days for up to 4 cycles in
the absence of disease progression or unacceptable toxicity. Patients who maintain CR/CRi
after completion of consolidation therapy undergo allogeneic HSCT at the discretion of the
treating physician.

MAINTENANCE: Patients receive enasidenib mesylate PO daily in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, then periodically
thereafter.

Inclusion Criteria:

- Bone marrow blasts >= 5% that develops after CR/CRi in patient with prior history of
AML, no restriction on prior number of relapses or regimens

- AML characterized by the IDH2 gene mutation, without requirement for a particular
allelic frequency

- Patients previously treated with IDH2 inhibitor can be enrolled

- At least a 3-month duration of CR/CRi prior to relapse

- Relapses after allogeneic HSCT are included with a minimum of 3 from the date of
allogeneic HSCT

- Up to 1 cycle of hypomethylating agent monotherapy at time of relapse is allowed, must
be discontinued at least 14 days prior to start of salvage induction

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert?s disease or
leukemic involvement

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 3 times the upper
limit of normal, unless considered due to leukemic involvement

- Alkaline phosphatase < 3 times the upper limit of normal, unless considered due to
leukemic involvement

- Serum creatinine =< 2.0 mg/dL, or creatinine clearance > 40 mL/min based on
Cockcroft-Gault glomerular filtration rate (GFR)

- Females of reproductive potential as well as fertile men and their partners who are
female of reproductive potential must agree to abstain from sexual intercourse or to
use two highly effective forms of contraception from the time of giving informed
consent, during the study, and for four months (females and males) following the last
dose of IDH inhibitor. A highly effective form of contraception is defined as hormonal
oral contraceptives, injectables, patches, intrauterine devices, double-barrier method
(eg, synthetic condoms, diaphragm or cervical cap with spermicidal foam, cream, or
gel) or male partner sterilization

Exclusion Criteria:

- Concurrent FLT3 mutation that the treating physician deems necessary to treat with
FLT3-targeted therapy; whereas, patients with FLT3-mutated AML not treated with
FLT3-targeted therapy can be enrolled

- Inability to swallow medications or history of gastrointestinal (GI) malabsorptive
disease

- Active malignancy that would limit survival by less than two years

- New York Heart Association class III or VI

- Left ventricular ejection fraction < 40%

- History of coronary stent placement that require mandatory continuation of
dual-antiplatelet therapy

- Baseline QT corrected interval based on Fridericia?s formula (QTcF) interval > 450 ms

- History of Wilson?s disease or other copper handling disorders

- Hypersensitivity to cytarabine, daunorubicin, or liposomal products

- Active hepatitis B with surface antibody positivity (participants with hepatitis B
core antibody positivity can be enrolled if given concurrent entecavir)

- Hepatitis C immnuoglobulin (Ig)G antibody positivity, unless received curative
hepatitis C therapy and now with hepatitis C ribonucleic acid (RNA) undetectable

- Active invasive fungal infection

- Active bacterial or viral infection manifesting as fevers or hemodynamic instability
within the past 72 hours

- Lifetime cumulative daunorubicin-equivalent anthracycline dose > 368 mg/m^2

- Pregnant or breast feeding