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

This study is currently recruiting participants.
Verified November 2017 by Tolero Pharmaceuticals, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03298984
First Posted: October 2, 2017
Last Update Posted: November 29, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.
  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

Condition Intervention Phase
Acute Myeloid Leukemia Drug: Alvocidib Drug: Cytarabine Drug: Daunorubicin Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Tolero Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • Minimal residual disease (MRD) using standardized techniques [ Time Frame: 12 - 18 months ]
    Review MRD in all patients


Estimated Enrollment: 25
Actual Study Start Date: September 25, 2017
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: April 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Alvocidib
IV bolus followed by IV infusion
Drug: Cytarabine
continuous infusion
Drug: Daunorubicin
IV bolus

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

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03298984


Contacts
Contact: Nissa Ashenbramer, BBA 210-931-2533 nashenbramer@toleropharma.com
Contact: Susan Smith, MSN 210-414-7702 su.smith@toleropharma.com

Locations
United States, Maryland
Johns Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Jackie Greer       jgreer6@jhmi.edu   
Principal Investigator: Douglas Smith, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Sarah Leach       sl3971@cumc.columbia.edu   
Principal Investigator: Mark Frattini, MD         
United States, North Carolina
University of North Carolina Not yet recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Jack Zhang       jack_zhang@med.unc.edu   
Principal Investigator: Joshua Zeidner, MD         
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Investigators
Study Director: Steve C Weitman, MD, PhD Tolero Pharmaceuticals
  More Information

Responsible Party: Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03298984     History of Changes
Other Study ID Numbers: TPI-ALV-101
First Submitted: September 27, 2017
First Posted: October 2, 2017
Last Update Posted: November 29, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Alvocidib
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Protein Kinase Inhibitors