Ph I Study of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML).

Primary Objective:

• To determine the safety and tolerability including the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Secondary Objectives:

• To observe patients for any evidence of antileukemic activity of alvocidib plus 7+3 using the 2017 ELN response criteria
• To establish the Recommended Phase 2 Dose (RP2D) for future studies with alvocidib in combination with 7+3

Exploratory Objective:

• To assess levels of minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry [MPFC] and next generation sequencing [NGS] and evaluate other potential biomarkers including, but not limited to, MCL-1 dependency.

Inclusion criteria

• To be eligible for participation in the study, patients must meet all of the following inclusion criteria:

• Be between the ages of ≥18 and ≤65 years
• Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria with ≥20% bone marrow blasts based on histology or flow cytometry
• Be newly diagnosed and previously untreated
• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
• Have a serum creatinine level ≤1.8 mg/dL
• Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN)
• Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
• Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
• Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry, for the duration of study participation, and for at least 6 months after the last dose of study drug.
• Be able to comply with the requirements of the entire study.
• Provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)

Exclusion criteria

• Patients meeting any one of these exclusion criteria will be prohibited from participating in this study.

• Received any previous treatment for AML
• Diagnosed with APL-M3 or CBF-AML
• Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting Induction therapy.
• Received >200 mg/m2 equivalents of daunorubicin
• Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above)
• Have active central nervous system (CNS) leukemia
• Have evidence of uncontrolled disseminated intravascular coagulation
• Have an active, uncontrolled infection
• Have other life-threatening illness
• Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
• Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
• Are pregnant and/or nursing