Ph 1 Study of ADI-PEG 20 Plus Low Dose Cytarabine in Older Patients With AML

Inclusion Criteria:

1. AML diagnosed by morphologic (with \>20% blasts in blood or bone marrow) and histochemical and/or cell surface marker criteria.
2. Patients with AML must fall into one of the following:

   1. Patients with AML (i.e., \> 20% bone marrow blasts) who are deemed unfit\* for intensive chemotherapy with refractory or relapsed disease. The patients must have been refractory to at least one cycle of cytarabine containing regimens or at least two cycles of azacitidine or similar hypomethylating agents.
   2. Patients with untreated AML (i.e., \> 20% bone marrow blasts) with intermediate risk karyotype (MRC risk group) who are deemed unfit for intensive chemotherapy.
   3. Patients with untreated AML with adverse risk karyotype (MRC risk group) who are deemed unfit for intensive chemotherapy and who are intolerant of azacitidine (or other hypomethylating agents) or who are unable to access azacitidine or other hypomethylating agents.

      * Patients unfit for conventional intensive chemotherapy are defined as having at least one of the following based on the conceptual criteria of Ferrara (2013):

        1. Advanced age (over 75 years).
        2. Cardiac impairment with ejection fraction ≤ 50% or heart failure (NYHA class 2) or ischemic heart disease with stable angina.
        3. Pulmonary impairment: chronic obstructive pulmonary disease (COPD) stage 1-2 (forced expiratory volume in one second \[FEV1\] \> 49%) or other comparable respiratory disease with forced vital capacity (FVC) \> 50%.
        4. Hepatic comorbidity with Child-Pugh grade A cirrhosis
        5. Chronic kidney disease stage 3 but with creatinine clearance \> 30 mls/min
        6. Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy.
3. Age \> 17 years.
4. ECOG performance status of 0-2.
5. Bone marrow aspirate and/or biopsy for testing for ASS1-deficiency. This must be a fresh sample obtained after any prior chemotherapy and before enrollment in this study. ASS1-deficiency is not required for study entry, but the fresh bone marrow sample must be processed either before or within 1 week of first study dose (see Section 10 for more details).

Exclusion Criteria:

A subject will not be eligible for study participation if he/she meets any of the exclusion criteria:

1. Patients with uncontrolled infections requiring intravenous (IV) antibiotic/antiviral therapy are not eligible for entry onto the study; patients on prophylactic antibiotics or antivirals are acceptable.
2. Pregnancy or lactation.
3. Expected non-compliance.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina, ventricular cardiac arrhythmia (other than ventricular ectopy), severe pulmonary comorbidity: COPD grade 3-4 (FEV1 \<50%) or other comparable documented pulmonary disease with FVC \<50%, or dyspnea at rest or requiring oxygen at home, cognitive impairment: current mental illness requiring psychiatric hospitalization, institutionalization or intensive outpatient management, or uncontrolled current cognitive status (as confirmed by the specialist; dependence on a caregiver is permitted as long as this is well controlled), severe hepatic comorbidity: liver Child-Pugh grade B-C cirrhosis or acute viral hepatitis, social situations that would limit compliance with study requirements or DIC causing coagulopathy not correctable with factor replacement.
5. Subjects who have had any anti-leukemia treatment prior to entering the study and have not recovered to baseline (except alopecia) or≤ Grade 1 AEs, or deemed irreversible from the effects of prior cancer therapy. AEs \> Grade 1 that are not considered a safety risk by the Sponsor and Investigator may be allowed upon agreement with both.