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

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ClinicalTrials.gov Identifier: NCT03298984
Recruitment Status : Recruiting
First Posted : October 2, 2017
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.

September 27, 2017
October 2, 2017
October 16, 2018
September 25, 2017
April 2019   (Final data collection date for primary outcome measure)
Maximum Tolerated Dose (MTD) and dose-limiting toxicities (DLTs) [ Time Frame: 12 - 18 months ]
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.
Determine the safety and tolerability including the Maximum Tolerated Dose (MTD) and dose-limiting toxicities (DLTs) [ Time Frame: 12 - 18 months ]
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.
Complete list of historical versions of study NCT03298984 on ClinicalTrials.gov Archive Site
  • Antileukemic activity of alvocidib plus 7+3 [ Time Frame: 3 months ]
    Review response using 2017 ELN Response criteria
  • 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 ]
    Review of biomarkers
  • Recommended Phase 2 Dose (RP2D) of alvocidib in combination with 7+3 [ Time Frame: 12 - 18 months ]
    Review MTD data to determine RP2D
  • Observe patients for any evidence of antileukemic activity of alvocidib plus 7+3 [ Time Frame: 3 months ]
    Review response using 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 [ Time Frame: 6 months ]
    Review of biomarkers
  • To establish the Recommended Phase 2 Dose (RP2D) for future studies with alvocidib in combination with 7+3 [ Time Frame: 12 - 18 months ]
    Review MTD data to determine RP2D
Minimal residual disease (MRD) using standardized techniques [ Time Frame: 12 - 18 months ]
Review MRD in all patients
To assess levels of minimal residual disease (MRD) using standardized techniques [ Time Frame: 12 - 18 months ]
Review MRD in all patients
 
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 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

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Acute Myeloid Leukemia
  • Drug: Alvocidib
    IV bolus followed by IV infusion
  • Drug: Cytarabine
    continuous infusion
  • Drug: Daunorubicin
    IV bolus
Experimental: Alvocidib and Cytarabine/Daunorubicin
The 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.
Interventions:
  • Drug: Alvocidib
  • Drug: Cytarabine
  • Drug: Daunorubicin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
25
Same as current
October 2019
April 2019   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult, Older Adult)
No
Contact: Nissa Ashenbramer, BBA 210-931-2533 nashenbramer@toleropharma.com
Contact: Susan Smith, MSN 210-414-7702 su.smith@toleropharma.com
United States
 
 
NCT03298984
TPI-ALV-101
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Tolero Pharmaceuticals, Inc.
Tolero Pharmaceuticals, Inc.
Not Provided
Study Director: Stephen Anthony, DO Tolero Pharmaceuticals
Tolero Pharmaceuticals, Inc.
October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP