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

Primary Purpose

Acute Myeloid Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Alvocidib
Cytarabine
Daunorubicin
Sponsored by
Sumitomo Pharma America, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Sidney Kimmel Cancer Center at Johns Hopkins
  • Columbia University
  • University of North Carolina

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Alvocidib and Cytarabine/Daunorubicin

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Alvocidib
Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib
Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Secondary Outcome Measures

Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria
CR: Measurable residual disease is positive or unknown; BM blasts (bls) <5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC >1.0 x 109/L; platelets >100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls <5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by >50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (>15% point inc required in cases w/ <30% bls at baseline or persistent BM bls % of >70% over at least 3 months; without at least 100% improvement in ANC to absolute level [>0.5 x 109/L and/or platelet count to >50 x 109/L non-transfused); or >50% inc in peripheral bls to >25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease.
Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3
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

Full Information

First Posted
September 27, 2017
Last Updated
April 4, 2022
Sponsor
Sumitomo Pharma America, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03298984
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)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
September 25, 2017 (Actual)
Primary Completion Date
March 20, 2020 (Actual)
Study Completion Date
March 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sumitomo Pharma America, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alvocidib and Cytarabine/Daunorubicin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Alvocidib
Intervention Description
IV bolus followed by IV infusion
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
continuous infusion
Intervention Type
Drug
Intervention Name(s)
Daunorubicin
Intervention Description
IV bolus
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of Alvocidib
Description
Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time Frame
During the first cycle
Title
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib
Description
Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML
Time Frame
During the first cycle
Secondary Outcome Measure Information:
Title
Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria
Description
CR: Measurable residual disease is positive or unknown; BM blasts (bls) <5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC >1.0 x 109/L; platelets >100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls <5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by >50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (>15% point inc required in cases w/ <30% bls at baseline or persistent BM bls % of >70% over at least 3 months; without at least 100% improvement in ANC to absolute level [>0.5 x 109/L and/or platelet count to >50 x 109/L non-transfused); or >50% inc in peripheral bls to >25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease.
Time Frame
Best response during duration of study
Title
Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3
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
Time Frame
During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days
Other Pre-specified Outcome Measures:
Title
Minimal Residual Disease (MRD) Using Standardized Techniques
Description
Percentage of participants with a CRMRD- response at the end of Cycle 1
Time Frame
During duration of study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: To be eligible for participation in the study, patients must meet all of the following inclusion criteria: Be between the ages of ≥18 and ≤65 years 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 Be newly diagnosed and previously untreated Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 Have a serum creatinine level ≤1.8 mg/dL Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN) Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia) Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 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. Be able to comply with the requirements of the entire study. 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. Received any previous treatment for AML Diagnosed with APL-M3 or CBF-AML 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. Received >200 mg/m2 equivalents of daunorubicin Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above) Have active central nervous system (CNS) leukemia Have evidence of uncontrolled disseminated intravascular coagulation Have an active, uncontrolled infection Have other life-threatening illness Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. Are pregnant and/or nursing
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Anthony, DO
Organizational Affiliation
Sumitomo Pharma America, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Sidney Kimmel Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32998965
Citation
Zeidner JF, Lee DJ, Frattini M, Fine GD, Costas J, Kolibaba K, Anthony SP, Bearss D, Smith BD. Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia. Clin Cancer Res. 2021 Jan 1;27(1):60-69. doi: 10.1158/1078-0432.CCR-20-2649. Epub 2020 Sep 30.
Results Reference
derived

Learn more about this trial

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

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