Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine and Mitoxantrone in Treating Participants With Previously Untreated Acute Myeloid Leukemia or High-Grade Myeloid Neoplasm

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of gemtuzumab ozogamicin (GO) when added to
GCLAM in patients with newly-diagnosed AML requiring induction chemotherapy. (Phase I) II. To
evaluate the 6-month event-free survival (EFS) rate with GO + GCLAM treated at the MTD.
(Phase II)

SECONDARY OBJECTIVES:

I. Describe, within the limits of a phase 1/2 study, the toxicity profile of the study
regimen.

II. Compare, within the limits of a phase 1/2 study, measurable residual disease (MRD) rates
with GO + GCLAM at the MTD to patients treated previously with GCLAM alone.

III. Estimate, within the limits of a phase 1/2 study, the relationship between MRD status
after induction therapy and relapse risk/time to relapse as well as relapse-free and overall
survival.

IV. Compare, within the limits of a phase 1/2 study, complete remission rates with GO + GCLAM
at the MTD to patients treated previously with GCLAM alone.

V. Compare, within the limits of a phase 1/2 study, overall survival rates with GO + GCLAM at
the MTD to patients treated previously with GCLAM alone VI. Evaluate, within the limits of a
phase 1/2 study, the impact of GO dosing regimens on the duration of cytopenias.

VII. Collect biological specimens for use for the future laboratory investigation of
biomarkers for response to GO.

OUTLINE: This is a phase I dose escalation study of gemtuzumab ozogamicin followed by a phase
II study.

INDUCTION THERAPY: Participants receive gemtuzumab ozogamicin intravenously (IV) either as a
single dose on day 1, or as three doses on days 1, 4, and 7. Participants also receive G-CSF
subcutaneously (SC) on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2
hours on days 1-5, and mitoxantrone hydrochloride IV on days 1-3. Patients who do not achieve
a CR or CRi following the first course of induction are eligible for a second course, which
is given without gemtuzumab ozogamicin. Participants with a complete remission (CR) or
complete remission with incomplete count recovery (CRi) may then proceed to Post-Remission
Therapy.

POST-REMISSION THERAPY: Participants receive G-CSF, cladribine, and cytarabine as in
Induction Therapy during course 1, and cytarabine IV every 12 hours on days 1-6 of courses
2-3. Treatment repeats every month for up to 3 courses in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 months for 5 years.

Inclusion Criteria:

- Diagnosis of untreated "high-grade" myeloid neoplasm (≥ 10% blasts in blood or bone
marrow) or acute myeloid leukemia (AML) other than acute promyelocytic leukemia (APL)
with t(15;17)(q22;q12) or variants according to the 2016 World Health Organization
(WHO) classification; outside diagnostic material is acceptable to establish
diagnosis; submission of peripheral blood specimen for flow cytometry performed at the
study institution should be considered; diagnostic material must have been submitted
for cytogenetic and/or molecular testing as clinically appropriate

- Medically fit, as defined by treatment-related mortality (TRM) score ≤13.1 calculated
with simplified model

- The use of hydroxyurea prior to study registration is allowed; patients with
symptoms/signs of hyperleukocytosis or white blood cells (WBC) > 100,000/uL can be
treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500
mg/m^2/dose) prior to enrollment

- Patients may have received low-intensity treatment (e.g. azacitidine/decitabine,
lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10%
blasts in blood and bone marrow)

- Bilirubin ≤ 2.5 x institutional upper limit of normal (IULN) unless elevation is
thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
(assessed within 14 days prior to study day 0)

- Serum creatinine ≤ 2.0 mg/dL (assessed within 14 days prior to study day 0)

- Left ventricular ejection fraction ≥ 45%, assessed within 12 months prior to study day
0, e.g. by multigated acquisition (MUGA) scan or echocardiography, or other
appropriate diagnostic modality and no clinical evidence of congestive heart failure

- Women of childbearing potential and men must agree to use adequate contraception

- Provide written informed consent

Exclusion Criteria:

- Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
considered candidate for tyrosine kinase inhibitor treatment

- Concomitant illness associated with a likely survival of < 1 year

- Active systemic fungal, bacterial, viral, or other infection, unless disease is under
treatment with anti-microbials, and/or controlled or stable (e.g. if specific,
effective therapy is not available/feasible or desired [e.g. known chronic viral
hepatitis, human immunodeficiency virus (HIV)]); patient needs to be clinically stable
as defined as being afebrile and hemodynamically stable for 24 hours; patients with
fever thought to be likely secondary to leukemia are eligible

- Known hypersensitivity to any study drug

- Confirmed or suspected pregnancy or lactation

- Treatment with any other investigational anti-leukemia agent