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

NCT03298984

Description:

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

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: TPI-ALV-101
  • NCT ID: NCT03298984

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
AlvocidibAlvocidib and Cytarabine/Daunorubicin
CytarabineAlvocidib and Cytarabine/Daunorubicin
DaunorubicinAlvocidib and Cytarabine/Daunorubicin

Purpose

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

Detailed Description

      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
    

Trial Arms

NameTypeDescriptionInterventions
Alvocidib and Cytarabine/DaunorubicinExperimentalThe starting dose of alvocidib will be 20 mg/m2 as a 30-minute intravenous (IV) bolus followed by 30 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3 of Induction. Patients will have a one day drug holiday (Day 4) before initiation of the 7+3 regimen. Beginning on Day 5, cytarabine will be administered as a 100 mg/m2/day continuous IV infusion for seven consecutive days (Days 5-11) plus daunorubicin administered at a dosage of 60 mg/m2 IV on Days 5-7.
  • Alvocidib
  • Cytarabine
  • Daunorubicin

Eligibility Criteria

        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
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) and dose-limiting toxicities (DLTs)
Time Frame:12 - 18 months
Safety Issue:
Description:The dose at which ≤1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1.

Secondary Outcome Measures

Measure:Antileukemic activity of alvocidib plus 7+3
Time Frame:3 months
Safety Issue:
Description:Review response using 2017 ELN Response criteria
Measure:Correlation between the benefit from alvocidib and sequential 7+3 therapy and BH3 profiling for MCL-1 dependency and other potential biomarkers
Time Frame:6 months
Safety Issue:
Description:Review of biomarkers
Measure:Recommended Phase 2 Dose (RP2D) of alvocidib in combination with 7+3
Time Frame:12 - 18 months
Safety Issue:
Description:Review MTD data to determine RP2D

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tolero Pharmaceuticals, Inc.

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