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

Determine the maximum tolerated dose (MTD) and toxicity profile of the combination of cyclophosphamide and ATO (Arsenic Trioxide) in subjects with relapsed refractory AML.

Determine the efficacy of ATO and cyclophosphamide in this population, as defined by response rate, response duration, event-free survival (EFS) and overall survival (OS).

Determine the number of transplant-eligible subjects who are successfully bridged to stem cell transplantation or donor lymphocyte infusion.

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.

Eligibility Criteria:
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 criteria

   * 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.