A Randomized Phase II/III Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy
This phase II/III trial studies how well daunorubicin and cytarabine with or without uproleselan works in treating older adult patients with acute myeloid leukemia receiving intensive induction chemotherapy. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Uproleselan may prevent cancer from returning or getting worse. Giving daunorubicin and cytarabine with uproleselan may work better in treating patients with acute myeloid leukemia compared to daunorubicin and cytarabine alone.
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)
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 cycles 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 cycles 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.
60 Years and up
Accepting Healthy Volunteers?
- 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.
- 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.
- Total bilirubin =< 3 x upper limit of normal (ULN)
- Creatinine < 3 x upper limit of normal (ULN) OR creatinine clearance >= 30 mL/min/1.73m^2