Liposome-encapsulated Daunorubicin-Cytarabine and Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To determine the safety of liposome -encapsulated daunorubicin-cytarabine (liposomal
cytarabine and daunorubicin [CPX-351]) in combination with gemtuzumab ozogamicin (GO) in
relapsed refractory (R-R) patients with acute myeloid leukemia (AML) and post-hypomethylating
agent (post-HMA) failure high-risk myelodysplastic syndrome (HR-MDS).

II. To determine the efficacy of liposomal cytarabine and daunorubicin (CPX-351) in
combination with gemtuzumab ozogamicin (GO) in relapsed refractory patients with acute
myeloid leukemia (AML) and post-hypomethylating agent (post-HMA) failure high-risk
myelodysplastic syndrome (HR-MDS).

SECONDARY OBJECTIVES:

I. To determine the preliminary assessment of efficacy by response to revised International
Working Group (IWG) criteria and time to response variables including overall survival (OS),
event-free survival (EFS) and duration of response (DOR) of patients treated with this
combination.

EXPLORATORY OBJECTIVES:

I. To determine the minimal residual disease (MRD) after treatment with this combination and
its impact in long-term outcome.

II. To determine the effect of the level of pre-treatment expression of CD33 with response to
this combination.

III. To determine the effect of this treatment combination on responding patients
transitioning to hematopoietic stem cell transplantation (HSCT).

IV. To evaluate the effect of the treatment combination on Health Related Quality of Life
(HRQoL) parameters.

OUTLINE:

INDUCTION CYCLE: Participants receive liposome-encapsulated daunorubicin-cytarabine
intravenously (IV) over 90 minutes on days 1, 3, and 5 or course and days 1 and 3 of course 2
and gemtuzumab ozogamicin IV over 120 minutes on day 1. Treatment repeats every 28 days for
up to 2 courses in the absence of unacceptable toxicity.

CONSOLIDATION CYCLE: Participants receive liposome-encapsulated daunorubicin-cytarabine IV
over 90 minutes on days 1 and 3 and gemtuzumab ozogamicin over 120 minutes on day 1.
Treatment repeats every 28 days for up to 2 courses in the absence of unacceptable toxicity.

MAINTENANCE CYCLE: Participants receive gemtuzumab ozogamicin IV over 120 minutes on day 1.
Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up for 14 months.

Inclusion Criteria:

- Diagnosis of CD33 positive (>= 3%), relapsed refractory acute myeloid leukemia by
World Health Organization (WHO) criteria. Patients with post-hypomethylating agent
(post-HMA) failure high-risk myelodysplastic syndrome (MDS), as defined by the
presence of > 10% blasts, are also eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2.

- Total serum bilirubin =< 2 x upper limit of normal (ULN). Patients with known
Gilbert's syndrome may have a total bilirubin up to =< 3 x ULN.

- Serum creatinine =< 2.0 mg/dl.

- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x ULN; =<
5 x ULN in case of suspected leukemic liver involvement.

- Females of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (b-HCG) pregnancy test result within 14 days prior to the first
dose of study drugs and must agree to use one of the following effective contraception
methods during the study and for 30 days following the last dose of study drug.
Effective methods of birth control include: Birth control pills, shots, implants
(placed under the skin by a health care provider) or patches (placed on the skin);
Intrauterine devices (IUDs); Condom or occlusive cap (diaphragm or cervical/vault
caps) used with spermicide; Abstinence.

- Females of non-childbearing potential are those who are postmenopausal greater than 1
year or who have had a bilateral tubal ligation, oophorectomy, and/or hysterectomy.

- Males who have partners of childbearing potential must agree to use an effective
contraceptive method during the study and for 30 days following the last dose of study
drug.

- Patients or their legally authorized representative must provide written informed
consent.

Exclusion Criteria:

- History of another primary invasive malignancy that has not been definitively treated
and in remission. Patients with non-melanoma skin cancers or with carcinomas in situ
are eligible regardless of the time from diagnosis (including concomitant diagnoses).

- Presence of clinically significant uncontrolled central nervous system (CNS) pathology
such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain
injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
or psychosis.

- Evidence of active cerebral/meningeal disease. Patients may have history of CNS
leukemic involvement if definitively treated with prior therapy and no evidence of
active disease at the time of consent with at least 2 consecutive spinal fluid
negative assessments for residual leukemia and negative imaging (imaging required only
if previously showing evidence of CNS leukemia not otherwise documented by spinal
fluid assessment).

- Patients with active unstable angina, concomitant clinically significant active
arrhythmias, myocardial infarction within 6 months, or congestive heart failure New
York Heart Association class III-IV. Patients with a cardiac ejection fraction (as
measured by either multigated acquisition scan [MUGA] or echocardiogram) < 50% are
excluded.

- Patients with total cumulative doses of non-liposomal daunorubicin, or other
anthracycline equivalent, greater than 200 mg/m^2.

- Patients with uncontrolled, active infections (viral, bacterial, or fungal).

- Known active hepatitis B or C infection, or known seropositivity for human
immunodeficiency virus (HIV).

- Patients with liver cirrhosis or other serious active liver disease or with suspected
active alcohol abuse.

- Allogeneic hematopoietic stem cell transplantation (HSCT) within 6 months before the
start of protocol-specified therapy, or with active acute/chronic graft-versus-host
disease (GvHD) requiring systemic treatment; or receiving immunosuppression for GvHD
prophylaxis within 2 weeks from the start of study therapy.

- Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the
start of study drugs with the following exception: To reduce the circulating blast
count or palliation; Single dose intravenous cytarabine or hydroxyurea. No washout
necessary for these agents

- Patients must have recovered from acute non hematologic toxicity (to =< grade 1) of
all previous therapy prior to enrollment.

- Females who are pregnant or lactating.

- Male or female subjects of childbearing potential, unwilling to use an approved,
effective means of contraception in accordance with institution's standards.

- Other severe, uncontrolled acute or chronic medical or psychiatric condition or
laboratory abnormality that in the opinion of the investigator may increase the risk
associated with study participation or investigational product administration or may
interfere with the interpretation of study results and/or would make the patient
inappropriate for enrollment into this study.