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 study the correlation between the benefit from alvocidib and sequential 7+3 therapy
and BH3 profiling for MCL-1 dependency and other potential biomarkers including, but not
limited to, NOXA, MS1, or TMS1 using bone marrow aspirates and peripheral blood samples

- 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

Inclusion Criteria:

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

1. Be between the ages of ≥18 and ≤65 years

2. 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

3. Be newly diagnosed and previously untreated

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2

5. Have a serum creatinine level ≤1.8 mg/dL

6. Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level
≤5 times upper limit of normal (ULN)

7. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome,
hemolysis, or leukemia)

8. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or
multigated acquisition (MUGA) scan

9. 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 during and for 6 months after completion of
study therapy (see Section 4.5.3).

10. Be able to comply with the requirements of the entire study.

11. 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.

1. Received any previous treatment for AML

2. Diagnosed with APL-M3 or CBF-AML

3. 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.

4. Received >100 mg/m2 equivalents of daunorubicin (see Appendix G for conversion
table)

5. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above)

6. Have active central nervous system (CNS) leukemia

7. Have evidence of uncontrolled disseminated intravascular coagulation

8. Have an active, uncontrolled infection

9. Have other life-threatening illness

10. Have other active malignancies or diagnosed with other malignancies within the
last 6 months, except nonmelanoma skin cancer or cervical intraepithelial
neoplasia

11. Have mental deficits and/or psychiatric history that may compromise the ability
to give written informed consent or to comply with the study protocol.

12. Are pregnant and/or nursing