CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

Determine efficacy of CPX-351 by measuring the response rate as the sum of complete response
(CR) and complete remission with incomplete count recovery (CRi) in older patients (age 60
and older) with: higher risk of myelodysplastic syndrome (MDS) who are refractory/relapsed
after prior hypomethylating (HMA) therapy; subjects greater than 75 years old with higher
risk MDS who are HMA relapsed/refractory who have progressed to acute myeloid leukemia
(AML)); AML with refractory/relapsed disease after prior HMA therapy for AML.

SECONDARY OBJECTIVES:

1. Determine the safety of CPX-351, as the frequency of Grade 3 to 5 SAEs

2. Determine the duration of remission (DOR) following induction therapy with CPX-351.

3. Determine overall survival (OS) at 12 months.

4. Determine the early induction mortality (at 30 and 60 days) following CPX-351 following
induction therapy.

OUTLINE:

Patients receive liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) at a dose of 65
units/m2/day over 90 minutes on days 1, 3, and 5 of each induction cycle.

- 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose
of 65 units/m2/day over 90 minutes on days 1, 3, and 5. Patients achieving a complete
remission (CR) or a CR with incomplete blood count recovery (CRi) at day 14 proceed to
consolidation therapy

- 2nd INDUCTION: Patients with reduced blast count not achieving a morphological leukemia
free state (< 5% blasts) receive the 2nd course of induction therapy. Patients receive
liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes
on days 1 and 3. Patients achieving a complete remission (CR) or a CR with incomplete
blood count recovery (CRi) after the 2nd course of induction therapy proceed to
consolidation therapy.

- CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin
CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.

After completion of study treatment, patients are followed up for up to 1 year.

Inclusion Criteria:

- Ability to understand and voluntarily give informed consent

- Age ≥ 60

- Pathological diagnosis of AML (by WHO criteria) or higher risk MDS (includes int-2 and
high risk MDS by IPSS) along with one of the following:

- Patients with de novo or secondary MDS with progression/refractoriness after HMA
treatment who have not transformed to AML

- Patients with MDS and prior HMA treatment for MDS who transform to AML

- Patients with AML who are refractory/relapsed after HMA therapy for their AML are
eligible

- Life expectancy > 1 month

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

- Able to adhere to the study visit schedule and other protocol requirements

- Laboratory values fulfilling the following:

- Serum creatinine < 2.0 mg/dL

- Serum total bilirubin ≤ 2.5 mg/dL. Note, patients with Gilbert's syndrome may
have elevated bilirubin at baseline prior to diagnosis with AML or MDS. Patients
with Gilbert's syndrome are included if their total bilirubin is ≤ 2 times their
baseline total bilirubin.

- Serum alanine aminotransferase or aspartate aminotransferase < 3 times ULN

- Cardiac ejection fraction ≥ 45% by echocardiography (transthoracic echocardiography)
or MUGA scan

- Patients with second malignancies may be eligible at discretion of PI given acute life
threatening nature of untreated AML or higher risk MDS. Patients maintained on
long-term non-chemotherapy treatment, e.g., hormonal therapy, are also eligible.

Exclusion Criteria:

- Patients who have previously undergone allogeneic hematopoietic stem cell transplant
will be excluded from this study

- Patients who have previously had > 368 mg/m2 cumulative dose of daunorubicin or > 368
mg/m2 daunorubicin-equivalent anthracycline therapy (for example, from prior treatment
of solid tumors). See appendix for anthracycline equivalence table.

- Acute promyelocytic leukemia [t(15;17)]

- Any serious medical condition, laboratory abnormality or psychiatric illness that
would prevent obtaining informed consent

- Patients who have had conventional intensive cytotoxic induction chemotherapy for
treatment of specifically MDS or AML are excluded.

- Patients who have not previously been treated with HMA therapy will be excluded

- Clinical evidence of active CNS leukemia

- Patients with evidence of uncontrolled current myocardial impairment (e.g. unstable
ischemic heart disease, uncontrolled arrhythmia, symptomatic valvular dysfunction not
controlled on medical therapy, uncontrolled hypertensive heart disease, and
uncontrolled congestive heart failure)

- Active and uncontrolled infection. Patients with an active infection receiving
treatment and hemodynamically stable for 48 hours may be entered into the study

- Known active uncontrolled HIV or hepatitis C infection

- Known hypersensitivity to cytarabine, daunorubicin or liposomal products

- Known history of Wilson's disease or other copper-related disorders

- Other medical or psychiatric illness or organ dysfunction or laboratory abnormality
which in the opinion of the investigator would compromise the patient's safety or
interfere with data interpretation

- Laboratory abnormalities:

- Serum creatinine ≥ 2.0 mg/dL

- Serum total bilirubin > 2.5 mg/dL. Note, patients with Gilbert's syndrome may
have elevated bilirubin at baseline prior to diagnosis with AML or MDS. Patients
with Gilbert's syndrome are excluded if their total bilirubin is > 2 times their
baseline total bilirubin.

- Serum alanine aminotransferase or aspartate aminotransferase > 3 times ULN