Phase II Study of the Combination of Mitoxantrone, Etoposide and Gemtuzumab Ozogamicin (MEGO) for Patients With Acute Myeloid Leukemia Refractory to Initial Standard Induction Therapy

Eligible patients will be treated inpatient. Patients will receive mitoxantrone 10mg/m2
administered intravenous piggyback (IVPB) in 50ml 0.9% normal saline over 15 minutes on days
1-5 and etoposide 100 mg/m2 administered intravenously in 500 ml of 0.9% sodium chloride over
2 hours on days 1-5.

On day 6, patients will receive a single dose of GO 3mg/m2 (maximum dose 4.5mg). Patients
will be pre-medicated 1 hour prior to the GO infusion with diphenhydramine 50mg administered
orally or intravenously, acetaminophen 650 mg administered orally or intravenously and 1mg/kg
methylprednisolone or an equivalent dose of alternative corticosteroid administered IV within
30 minutes prior to infusion of GO. GO will be administered intravenously in 50 ml (or other
suitable volume resulting in a final GO concentration between 0.075 mg/mL to 0.234 mg/mL) of
0.9% sodium chloride over 2 hours. Doses of GO will be based on BSA calculated using actual
body weight with a cap of 4.5mg. Vital signs will be recorded within one hour prior to the
infusion and then every 30 minutes during the infusion and 30 minutes and one hour after
completion of infusion. An additional dose of methylprednisolone 1 mg/kg IV may be given for
any sign of infusion reaction, such as fever, chills, hypotension, or dyspnea occurring
during the GO infusion or within 4 hours after the GO infusion.

For dose modifications based on kidney and liver function please see the treatment schema at
the end of the study.

Supportive care including blood product transfusions, antiemetic medications, antiviral and
antifungal medications, growth factor support, tumor lysis syndrome prophylaxis, or empiric
antibiotics may be used at the clinical discretion of the provider.

Inclusion Criteria:

1. Able to understand and have the ability to provide written consent.

2. Age: 18 - 75 years-old.

3. Patients with newly diagnosed AML based on the World Health Organization
classification who have persistent disease after their first course treatment with an
anthracycline and cytarabine (the diagnosis of persistent disease, which is defined as
>10% blasts by morphology for this trial, will be based on their assessment after bone
marrow aspiration and/or biopsy after initial treatment).

4. CD33 expression in ≥ 30% of leukemic blasts on the bone marrow.

5. Eastern Cooperative Oncology Group Performance Status of 0 -2 (see Appendix I).

6. Patients must have the following laboratory values prior to beginning protocol
treatment:

- Calculated creatinine clearance ≥ 30 mL/min (using the Cockcroft-Gault equation
CL creatinine = ((140-age) x body mass X 0.85 if female)/72 x creatinine where
age is given in years, body mass is given in Kg and creatinine is given in
mg/dl).

- Aspartate aminotransferase (AST) ≤ 2.5 x upper normal limit.

- Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit.

- Total bilirubin ≤ 2 x upper normal limit. Note: As many eligible patients will be
pancytopenic secondary to their disease or prior treatments, hematologic
abnormalities will not be used as criteria for entry or exclusion.

7. Left ventricular ejection fraction (LVEF) ≥50 %.

8. Females of child-bearing potential must have a negative pregnancy test during
screening and all subjects must agree to use an effective method of contraception. A
woman is eligible to enter and participate in the study if she is of:

1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant)
including any female who has had a hysterectomy or has had a bilateral
oophorectomy (ovariectomy).

2. Childbearing potential, has a negative serum pregnancy test during the screening
period and agrees to avoid sexual activity or use contraception from screening
through follow-up (method of birth control if the patient is not neutropenic
include the use of a diaphragm, intrauterine device, contraceptive sponge and/or
usage of male condom with a spermicide from the partner). A man with a female
partner of childbearing potential is eligible to enter and participate in the
study if he has either had a prior vasectomy or agrees to avoid sexual activity
or use adequate contraception (as described above) from screening through
follow-up.

Exclusion Criteria:

1. Patients with a diagnosis of Acute Promyelocytic Leukemia (APL) as defined by the
World Health Organization.

2. Relapsed acute leukemia.

3. Bi-lineage or bi-phenotypic leukemia.

4. Prior use of mitoxantrone or etoposide or GO.

5. Previous allogeneic or autologous hematopoietic cell transplantation or solid organ
transplantation.

6. First induction course of acute myeloid leukemia with CPX-351.

7. Prior use of a FLT3 inhibitor.

8. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of treating investigator.

9. Has known history of active Hepatitis B (HBsAg reactive) or Hepatitis C (detectable
HCV RNA).

10. Uncontrolled, life-threatening infection that is not responding to antimicrobial
therapy.

11. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

12. Patient may have not received any other investigational anti-neoplastic agents within
4 weeks from the start of therapy.

13. Concurrent active malignancy; exceptions include patients who have been disease free
for 5 years, patients with a history of completely resected non-melanoma skin cancer
or successfully treated in situ carcinoma, or patients with another malignancy that is
indolent or definitively treated.

14. Women who are pregnant or breastfeeding.

15. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
respiratory or cardiac disease).