Arsenic Trioxide With Cyclophosphamide in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This is an open label phase 1 study of fixed dose ATO (Arsenic Trioxide) and escalating doses
of cyclophosphamide using a standard 3+3 dose escalation design. All subjects will be treated
with sequential cycles of 3 days of ATO at 0.15 mg/kg/d IV followed by Cyclophosphamide as a
single IV dose on day 4 along with mesna at a dose equal to the cyclophosphamide (for doses
≥1000 mg/m2) and hydration for a maximum of 6 cycles. ATO and Cyclophosphamide will be
repeated every 28-42 days. Treatment will be given inpatient for the first cycle, with the
option of outpatient treatment for subsequent cycles. Subjects may remain on study in the
absence of disease progression or unacceptable toxicity for a maximum six cycles. Toxicity
assessments will be performed continuously; DLT determination will be made based on adverse
events (AEs) that occur during cycle 1 (day 1-28). An expansion cohort of ten subjects at the
maximum tolerated dose will occur at the conclusion of dose escalation.

Inclusion Criteria:

1. WHO-confirmed AML, other than APL, with no standard treatment options available

2. Age 18 years or older

3. Relapsed or refractory (resistant) disease, as defined by standard criteria7

- Relapsed: Bone marrow blasts ≥5%, reappearance of blasts in the blood, or
development of extramedullary disease following achievement of CR/CRi/CRp/MLFS

- Refractory (resistant): Failure to achieve CR/CRi/MLFS in subjects who survive ≥7
days following completion of initial treatment, with evidence of persistent
leukemia by blood and/or bone marrow examination

4. >14 days since any prior therapy for AML excluding hydroxyurea

5. Willing and able to understand and voluntarily sign a written informed consent

6. Able to adhere to the study visit schedule and other protocol requirements

7. Women of childbearing potential must use an acceptable form of birth control for 28
days prior to beginning study treatment, through the duration of study treatment, and
for 3 months after discontinuing study treatment.

Exclusion Criteria:

1. New York Heart Association Class III or IV heart failure

2. Unstable angina pectoris

3. Significant uncontrolled cardiac arrhythmias, including ventricular arrhythmias,
congenital long QT syndrome, symptomatic atrial fibrillation, symptomatic bradycardia,
right bundle branch block plus left anterior hemiblock or bifasicular block

4. QTc >500 ms, uncorrectable by managing electrolytes and medications, using the QTcF
formula in Appendix D.

5. Active acute graft vs. host disease ≥ grade 2 or active extensive chronic GVHD

6. Relapse after allogeneic stem cell transplantation prior to post-transplant day 30

7. Active central nervous system (CNS) involvement of leukemia (lumbar puncture not
required to rule out CNS involvement if not suspected)

8. Uncontrolled psychiatric illness that would limit compliance with requirements

9. Pregnant or breast feeding females

10. Laboratory abnormalities:

1. Either creatinine >2.0 mg/dL or creatinine clearance <30 mL/min

2. Total bilirubin > 3 x institutional upper limit of normal (ULN) (unless
documented Gilbert's syndrome)

3. AST or ALT > 3 x institutional ULN, unless felt to be due to disease involvement

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