Dexrazoxane Hydrochloride in Preventing Heart-Related Side Effects of Chemotherapy in Participants With Blood Cancers

PRIMARY OBJECTIVES:

I. To estimate the percentage of patients experiencing a decrease in left ventricular
ejection fraction (LVEF) of 10 percent from baseline or decrease in LVEF below the normal
limit of 50% during treatment with dexrazoxane (dexrazoxane hydrochloride) combined with
cladribine, idarubicin, cytarabine, and Mylotarg (gemtuzumab ozogamicin) within the first
6-months of treatment.

SECONDARY OBJECTIVES:

I. To estimate the incidence of these cardiac symptoms while on dexrazoxane combined with
idarubicin-based treatment: clinical heart failure, exertional dyspnea, orthopnea, S3 gallop,
acute coronary syndrome, acute pulmonary edema and life-threatening arrhythmias.

II. To assess and monitor the change of troponin I (while still standard of care at MD
Anderson) and high-sensitivity troponin T during treatment.

III. Collect safety/toxicity profile. IV. To assess rates of complete remission (CR)/complete
remission with incomplete blood count recovery (CRi). (Cohorts 1-3) V. Other efficacy
endpoints of interest include overall response, overall survival, event-free survival and
remission duration. (Cohorts 1-3) VI. To assess the recurrence-free survival rate at 6
months. (Cohort 4)

EXPLORATORY OBJECTIVES:

I. To assess the metal chelation effects of dexrazoxane combined with chemotherapy (Mylotarg,
cladribine, idarubicin, and cytarabine) by quantifying concentrations of toxic and essential
metals and isotopic abundance ratios of blood and bone marrow before and during treatment.

II. To study and describe the relationship between pretreatment patient / disease
characteristics (including cytogenetic and molecular abnormalities) and clinical outcomes.

III. To identify molecular biomarkers predictive of response to therapy. IV. To study and
describe the relationship between patient / disease characteristics, use of intrathecal
prophylaxis, and incidence of leptomeningeal disease.

V. To observe rates of fungal and other infections on the regimen. VI. To study environmental
exposure data based on an environmental health assessment survey.

VII. To explore the impact of minimal residual disease (MRD) on relapse.

OUTLINE:

INDUCTION PHASE: Participants receive gemtuzumab ozogamicin intravenously (IV) over 2 hours
on days 1, 4, and 7, cladribine IV over 1-2 hours on days 1-5, dexrazoxane hydrochloride IV
over 15 minutes on days 1-3, idarubicin IV over 30 minutes on days 1-3, and cytarabine IV
over 2 hours on days 1-5. Treatment repeats every 3-7 weeks for up to 2 courses in the
absence of disease progression or unacceptable toxicity.

CONSOLIDATION PHASE: After induction phase, participants receive gemtuzumab ozogamicin IV
over 2 hours on day 1, cladribine IV over 1-2 hours on days 1-3, dexrazoxane hydrochloride IV
over 15 minutes on days 1-2, idarubicin IV over 30 minutes on days 1-2, and cytarabine IV
over 2 hours on days 1-3. Treatment repeats every 3-7 weeks for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Participants who go into remission or who are already in remission receive
gemtuzumab ozogamicin IV over 2 hours on day 1 of course 1 and then every 2-3 months as
needed. Participants also receive dexrazoxane hydrochloride IV over 15 minutes and idarubicin
IV over 30 minutes on day 1, and cytarabine subcutaneously (SC) on days 1-7. Courses repeat
every 3-7 weeks for 32 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 6-12 months.

Inclusion Criteria:

- Baseline left ventricular ejection fraction (LVEF) is greater than or equal to 50% by
echocardiography (echo) or multigated acquisition (MUGA) scan.

- Patients of child bearing potential should use contraception.

- Patients with a diagnosis of acute myeloid leukemia (AML), or high risk
myelodysplastic syndrome (MDS) (>= 10% blasts or International Prognostic Scoring
System [IPSS] >= intermediate-2) or high-risk myeloproliferative neoplasm will be
eligible.

- Patients with untreated or previously untreated chronic myeloid leukemia (CML) in
myeloid blast phase or (Philadelphia chromosome-positive (Ph+) AML are also eligible.

- Patients with myeloproliferative neoplasms in blast phase will be eligible.

- Patients with isolated extramedullary myeloid neoplasm will be eligible.

- Patients with active CNS (central nervous system) disease are eligible.

- Bilirubin < 2mg/dL.

- AST (aspartate aminotransferase) and/or ALT (alanine aminotransferase) < 3 x ULN
(upper limit of normal) - or < 5 x ULN if related to leukemic involvement.

- Creatinine < 1.5 x ULN.

- Hyperbilirubinemia is allowed if due to Gilbert's hyperbilirubinemia.

- A negative urine pregnancy test is required within 1 week for all women of
childbearing potential prior to enrolling on this trial.

- Women of childbearing potential and men must agree to use contraception prior to study
entry and for the duration of study participation.

- Patient must have the ability to understand the requirements of the study and signed
informed consent. A signed informed consent by the patient or his legally authorized
representative is required prior to their enrollment on the protocol.

- Prior therapy for any of the cohorts may include with hydroxyurea, rescue doses of
cytarabine, various combination-chemotherapy regimens, hematopoietic growth factors,
azacytidine, decitabine, ATRA (all-trans retinoic acid).

- Cohort 1: Frontline cohort patients are eligible in the frontline cohort if they are
untreated or previously treated already in CR if they received 3 or fewer cycles of
previous chemotherapy (including either 1 induction and 2 consolidations or 2
inductions and 1 consolidation).

- Cohort 2: Salvage cohort in 1st and 2nd salvage patients are eligible in the salvage
cohort 2 if they have active disease after first or second relapse or if they are in
CR after previously documented first or second relapse as long as they if they have
received 3 or fewer cycles of chemotherapy to achieve the most current CR.

- Cohort 3: Salvage cohort in 3rd salvage and beyond patients may be eligible in salvage
cohort 3 if they have active disease after 3rd or greater relapse or if they are in CR
after a previously documented relapse (3rd or greater), but may have only received 3
or fewer cycles of chemotherapy to achieve the most current CR.

- Cohort 4: Maintenance cohort: Patients in CR who are considered by treating physician
to benefit from maintenance therapy are eligible for maintenance therapy with
dexrazoxane combined with idarubicin plus cytarabine.

Exclusion Criteria:

- Any condition, including the presence of laboratory abnormalities, which judged by the
investigator, places the patient at unacceptable risk.

- Active heart disease defined as: Unstable coronary syndromes, unstable or severe
angina, recent myocardial infarction (MI) within 6 months.

- Decompensated heart failure (HF).

- Clinically significant arrhythmias.

- Severe valvular disease.

- History of coronary artery disease (CAD).

- Pregnant women are excluded from this study because the agents used in this study have
the potential for teratogenic or abortifacient effects. Because there is a potential
risk for adverse events in nursing infants secondary to treatment of the mother with
the chemotherapy agents, breastfeeding should also be avoided.

- Psychiatric illness/social situations that would limit compliance with study
requirements per the judgment of the investigator.

- Patient with documented hypersensitivity to any of the components of the chemotherapy
program.

- Men and women of childbearing potential who do not practice contraception.