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

A Phase 1, Open-label, Dose-escalation, Safety and Biomarker Prediction of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

The purpose of this Phase I study is to determine the safety and tolerability including the maximum 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

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:

  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 prior to study entry, for the duration of study participation, and for at least 6 months after the last dose of study drug.
  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 >200 mg/m2 equivalents of daunorubicin
  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