Daunorubicin and Cytarabine With or Without Uproleselan in Treating Older Adult Patients With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

PRIMARY OBJECTIVES:

I. Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus
daunorubicin and cytarabine in subjects >= age 60 with previously untreated acute myeloid
leukemia. (Phase II) II. Compare the overall survival (OS) of the daunorubicin, cytarabine
plus uproleselan to daunorubicin and cytarabine in this patient population. (Phase III)

SECONDARY OBJECTIVES:

I. Determine the rates of complete remission (CR), complete remission with incomplete count
recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) and
cytogenetic complete remission (CCyR) for each chemotherapy regimen.

II. Determine the overall survival (OS), and remission duration of patients for each
chemotherapy regimen.

III. Describe the frequency and severity of adverse events for patients for each chemotherapy
regimen.

IV. Describe the interaction of pretreatment disease and patient characteristics including
morphology, cytogenetics, molecular genetic features, white blood cell (WBC) count and
hemogram, and performance status on clinical outcomes.

CORRELATIVE SCIENCE OBJECTIVES:

I. Correlate specific karyotype groups (normal or various primary and secondary chromosomal
abnormalities) with clinical and laboratory parameters and with response rates, response
duration, survival and cure in patients treated with various induction and post-induction
regimens.

II. Correlate specific karyotype groups with selected molecular abnormalities and with
measurable residual disease.

III. To determine karyotype changes at end of consolidation and the influence of the type of
change (or no change) in karyotype at the end of consolidation on subsequent clinical course.

IV. To determine karyotype changes at relapse and the influence of the type of change (or no
change) in karyotype at relapse on subsequent clinical course.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP 1: INDUCTION: Patients receive daunorubicin intravenously (IV) on days 1-3 and
cytarabine via continuous intravenous infusion (CIVI) over 168 hours on days 1-7. Patients
with residual disease indicated by bone marrow examination receive a second induction
including daunorubicin IV on days 1-3 and cytarabine CIVI over 12 hours on days 1-5.

CONSOLIDATION: Patients receive cytarabine IV over 3 hours on days 1-5. Treatment repeats
every 28 days for up to 3 courses in the absence of disease progression or unacceptable
toxicity.

GROUP 2: INDUCTION: Patients receive uproleselan IV QD on day 1 and then every 12 hours on
days 2-10. Patients also receive daunorubicin IV on days 2-4 and cytrarabine CIVI over 168
hours on days 2-8 over 168 hours. Patients with residual disease indicated by bone marrow
examination receive a second induction including uprleselan IV QD on day 1 and then every 12
hours on days 2-10, daunorubicin IV on days 2-3, and cytarabine CIVI over 120 hours on days
2-6.

CONSOLIDATION: Patients who achieve a CR or CRi receive uproleselan IV QD on day 1 and every
12 hours on days 2-8 and cytarabine IV over 3 hours on days 2-6. Treatment repeats every 28
days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year,
every 3 months in year 2, and then every 6 months for up to 5 years.

Inclusion Criteria:

- Diagnosis of acute myeloid leukemia (AML) based on 2017 World Health Organization
(WHO) criteria excluding acute promyelocytic leukemia with PML-RARA.

- Note: Patients with myeloid sarcoma without bone marrow involvement, acute
leukemia of ambiguous lineage or blast transformation of chronic myelogenous
leukemia (CML) are not eligible.

- No activating mutation in the Fms-like tyrosine kinase-3 (FLT3) defined as a ratio of
mutant to wild-type allele >= 0.05 by capillary electrophoresis or a variant allele
fraction of >= 5% by next generation sequencing from either bone marrow or peripheral
blood.

- No evidence of CNS involvement of AML.

- No prior chemotherapy for myelodysplastic syndrome (MDS) or AML including
hypomethylating agents (e.g. azacitidine and decitabine) or lenalidomide with the
following exceptions:

- Emergency leukapheresis.

- Hydroxyurea.

- Growth factor/cytokine support.

- All-trans retinoic acid (ATRA).

- Single dose of intrathecal cytarabine and/or methotrexate for patients undergoing
lumbar puncture to evaluate for CNS involvement.