Low-Dose Daunorubicin in Relapsed/Refractory Acute Leukemia

Disease relapse remains the primary challenge in the treatment of acute myeloid leukemia
(AML) and acute lymphocytic leukemia (ALL). There is no standard of care treatment option for
relapsed acute leukemia, and investigational therapies are recommended. Clinically targeting
the leukemia stem cell (LSC) remains an unmet need in both AML and ALL. Therefore, a primary
objective of this trial is to determine the molecular pharmacodynamic effects of low dose
daunorubicin (DNR) on beta-catenin phosphorylation in serial bone marrow samples of patients
with relapsed leukemia.

Prior to studying low-dose DNR in complex, multi-agent regimens, it is essential to confirm
that it inhibits p-beta-catenin S552 in humans. This pilot study is designed to assess the
feasibility and tolerability of low dose DNR administration to patients with
relapsed/refractory AML and ALL, and obtain preliminary data regarding target engagement. A
second objective is to demonstrate the safety and feasibility of low-dose daunorubicin
administration in patients with relapsed/refractory acute leukemia.

Beta-catenin phosphorylation will be measured by immunohistochemistry assay in bone marrow
samples taken from patients at study entry and at Day 8 following study therapy with low-dose
DNR. The investigators will also measure the pharmacokinetics of low dose DNR in these
patients, to enable preliminary PK-PD analyses and because there are essentially no PK data
for DNR at comparable doses using modern analytical methodologies.

Following participation on this brief pharmacodynamic proof-of-concept trial, patients can
then proceed to other conventional or investigational therapies, as clinically indicated.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent or have
parental consent.

- Age ≥ 18 years

- Pathological confirmation by bone marrow documenting the following:

1. AML which has relapsed after Complete Remission

2. AML which has been refractory to two prior induction attempts

3. ALL which has relapsed after Complete Remission

4. ALL which has been refractory to two prior induction attempts

- Disease status allows delay of additional anti-leukemia therapy for the duration of
the study (hydroxyurea is allowed for control of WBC throughout study)

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3

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

- Cardiac ejection fraction ≥45% by ECHO

- Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN

- Women of child-bearing potential and men with partners of child-bearing potential must
agree to use adequate contraception prior to study entry, for the duration of study
participation, and for 90 days following completion of therapy.

Exclusion Criteria:

- Concurrent use of conventional or investigational anticancer agents, except
hydroxyurea (Standard prophylactic anti-infectives and medications to prevent/treat
tumor lysis syndrome are allowed. Hydroxyurea may be used to keep the WBC<25,000.
Additional anti-leukemia therapy is prohibited during the study.).

- Patient has received chemotherapy or radiotherapy within 2 weeks prior to entering the
study or has not recovered from adverse events due to agents administered more than 2
weeks earlier, with the exception of hydroxyurea.

- Patients with known active uncontrolled central nervous system (CNS) leukemia

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to daunorubicin

- Patients with a total lifetime anthracycline exposure exceeding the equivalent of 900
mg/m2 of daunorubicin

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Unwilling or unable to undergo serial bone marrow aspirate/biopsy

- Pregnant or nursing