Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma

Cytarabine in combination with an anthracycline is a frequently used chemotherapy platform
for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) and other
hematologic malignancies. Synergistic antitumor activity has been demonstrated between
cytarabine and daunorubicin that is dependent upon the ratio of the drugs with the best
therapeutic effect observed with a cytarabine to daunorubicin ratio of 5:1 in in vitro and in
vivo models. CPX-351 is a liposomal preparation of cytarabine and daunorubicin that maintains
this therapeutic drug ratio 24 hours post infusion. The altered biodistribution from
encapsulation may result in a greater therapeutic effect in patients with relapsed
hematologic malignancies and demonstrate greater tolerability than non-liposomal cytarabine
and daunorubicin.

This is a single institution phase-I pilot study that aims to assess the pharmacokinetics,
toxicity and tolerability of CPX-351 in pediatric and young adults with relapsed/refractory
hematologic malignancies. Subjects will receive a single course of CPX-351 administered on
Days 1, 3, and 5. The study will first open to children in a dose exploration phase, and then
be available to an expanded cohort, which will be open to children and young adults once a
tolerable dose has been determined.

Inclusion Criteria:

- Age

1. 12 months to 21 years at time of enrollment into dose exploration phase

2. 12 months to 30 years at time of enrollment into expanded phase

- Diagnosis: Patients must have a diagnosis of a hematologic malignancy (acute myeloid
leukemia (AML), acute lymphoblastic leukemia (ALL), or aggressive lymphoma.

- Disease Status

1. Acute myeloid leukemia - patients with non-therapy related AML must be in first
or greater relapse or have refractory disease to at least two courses of
induction therapy.

2. Acute lymphoid leukemia - patients with ALL must be in second or greater relapse
or have relapsed disease refractory to re-induction therapy.

3. Aggressive Lymphoma - patients must have relapsed or refractory disease for which
there is no known curative therapy available. Patients must have measurable
disease by CT scan.

- Performance status: Karnofsky > or = to 50% or Lansky > or = to 50.

- Prior therapy: Patients must have fully recovered from acute toxicities of prior
therapy.

1. Hematopoetic Stem cell transplant (HSCT): Patients who relapsed after HSCT, are
eligible provided they have no evidence of active graft versus host disease
(GVHD) and are at least 2 months post-transplant.

2. Anthracycline exposure: Patients who have not previously had TBI (total body
irradiation) must have a total previous cumulative anthracycline exposure ≤ 450
mg/m2 daunorubicin equivalents. Patients who have had prior TBI or radiation to
the mediastinum must have a previous cumulative anthracycline exposure e ≤ 300
mg/m2 daunorubicin equivalents.

3. Cytotoxic therapy:

1. AML and Lymphoma: at least 14 days must have elapsed since the completion of
systemic cytotoxic therapy, with the exception of hydroxyurea.

2. ALL: patients who relapsed while receiving standard maintenance therapy do
not have a waiting period. At least 14 days must have elapsed since
receiving systemic cytarabine or an anthracycline/anthracenedione.

3. Intrathecal cytotoxic therapy: no waiting period is required for patients
receiving intrathecal cytarabine, methotrexate and/or hydrocortisone. At
least 14 days must have elapsed since receiving liposomal cytarabine in
intrathecal injection.

- Organ function requirements

1. Adequate bone marrow function - platelet count >/= 20,000/uL (may receive
platelet transfusions; Hemoglobin >/= 8 g/dL (may receive red blood cell
transfusions)

2. Adequate Renal function - a maximum serum creatinine is based on age/gender.
Subjects that do not meet eligibility criteria based upon serum creatinine may
meet eligibility criteria based upon a 24 hour creatinine clearance or
radioisotope determined GFR >/= 70 mL/min/1.73 m2.

3. Adequate liver function - Direct bilirubin for age and SGPT (ALT) < 5.0 x upper limit of normal (ULN) for age and
institution (unless elevation is related to leukemia involvement).

4. Adequate cardiac function - Shortening fraction of >/= 27% by echocardiogram, or
Ejection fraction of >/= 50% by gated radionuclide study or echocardiogram.

5. Central Nervous system function - patients with seizure disorder may be enrolled
if on anticonvulsants and well controlled and CNS toxicity
Exclusion Criteria:

- Patients with the following diagnosis are not eligible: acute promyelocytic leukemia
(APML), Down Syndrome, Fanconi Anemia, acute lymphoblastic leukemia with central
nervous system leukemia (CNS status 3), Wilson's disease

- Pregnant or breast-feeding women. Males and females of reproductive potential may not
participate unless they have agreed to use an effective method of contraception.

- Concomitant medications

1. Growth factors- growth factors that support platelet or white cell number or
function must not be administered within 7 days prior to enrollment.

2. Investigational drugs - patients currently receiving another investigational drug
are not eligible.

3. Anti-cancer agents- patients who are currently receiving other anti-cancer agents
are not eligible with the exception of intrathecal cytarabine and oral
hydroxyurea. Hydroxyurea must be discontinued 24 hours prior to initiation of
protocol therapy.

- Infection: Patients who have an uncontrolled infection are not eligible.

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.

- History of Wilson's disease or other copper-metabolism disorder

- Major surgery within 4 weeks of enrollment.

- Greater than 13.6 Gy prior radiation to the mediastinum