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ASTX727 and Dasatinib for the Treatment of Newly Diagnosed Philadelphia Chromosome or BCR-ABL Positive Chronic Myeloid Leukemia in Chronic Phase

Primary Purpose

Chronic Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dasatinib
Decitabine and Cedazuridine
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Phase Chronic Myelogenous Leukemia

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early chronic phase CML (i.e., time from diagnosis =< 12 months). Except for hydroxyurea and/or 1 to 2 doses of cytarabine patients must have received no or minimal prior therapy, defined as < 1 month (30 days) of prior Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI)

    • Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study
  • Eastern Cooperative Oncology Group (ECOG) performance of 0-2
  • Total bilirubin < 1.5 x upper limit of normal (ULN) (unless secondary to Gilbert's disease, in which case should be < 2.5 x ULN)
  • Serum glutamic pyruvic transaminase (SGPT) < 3 x ULN
  • Creatinine < 1.5 x ULN
  • Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital

Exclusion Criteria:

  • New York Heart Association (NYHA) cardiac class 3-4 heart disease
  • Cardiac Symptoms: Patients meeting the following criteria are not eligible unless cleared by Cardiology:

    • Uncontrolled angina within 3 months
    • Diagnosed or suspected congenital long QT syndrome
    • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
    • Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 460 msec)
    • History of significant bleeding disorder unrelated to cancer, including:

      • Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
      • Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
  • Patients with active, uncontrolled psychiatric disorders include: psychosis, major depression, and bipolar disorders
  • Subject is known to be positive for human immunodeficiency virus (HIV) (HIV testing is not required)
  • Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    • Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
    • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
  • Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug. Pregnant or breast-feeding women are excluded. All WOCBP must have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive study drug and must not be enrolled in the study
  • Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months), accelerated (except as noted in inclusion criteria) or blast phase are excluded. The definitions of CML phases are as follows:

    • Early chronic phase: time from diagnosis to therapy =< 12 months
    • Late chronic phase: time from diagnosis to therapy > 12 months
    • Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow
    • Accelerated phase CML: presence of any of the following features:

      • Peripheral or marrow blasts 15% or more
      • Peripheral or marrow basophils 20% or more
      • Thrombocytopenia < 100 x 10^9/L unrelated to therapy
      • Documented extramedullary blastic disease outside liver or spleen

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (dasatinib, decitabine and cedazuridine)

Arm Description

Patients receive dasatinib PO QD on days 1-28. Beginning cycle 4, patients also receive decitabine and cedazuridine PO QD on days 1-3. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days for up to 12 years in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Rate of molecular response 4 (MR4)
Will be estimated with 95% credible intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.

Secondary Outcome Measures

Rate of MR4.5
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Major molecular response rate
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Treatment-free remission rate
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Time to progression
Survival time will be estimated using the Kaplan-Meier method. Patients who drop out of the study will be included in the time to event data as "censored data". The two-sided log-rank test will be used to assess the differences of time to events between groups.
Overall survival
Survival time will be estimated using the Kaplan-Meier method. Patients who drop out of the study will be included in the time to event data as "censored data". The two-sided log-rank test will be used to assess the differences of time to events between groups.

Full Information

First Posted
August 9, 2021
Last Updated
October 2, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI), Astex Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05007873
Brief Title
ASTX727 and Dasatinib for the Treatment of Newly Diagnosed Philadelphia Chromosome or BCR-ABL Positive Chronic Myeloid Leukemia in Chronic Phase
Official Title
Phase II Study Assessing Safety and Clinical Activity of the Combination of ASTX727 With Dasatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 21, 2021 (Actual)
Primary Completion Date
October 30, 2024 (Anticipated)
Study Completion Date
October 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI), Astex Pharmaceuticals, Inc.

4. Oversight

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

5. Study Description

Brief Summary
This phase II trial studies the effect of ASTX727 and dasatinib in treating patients with newly diagnosed Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia in chronic phase. Philadelphia chromosome positive and BCR-ABL positive are types of genetic mutations (changes). Chemotherapy drugs, such as ASTX727, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. ASTX727 and dasatinib may help to control Philadelphia chromosome-positive chronic myeloid leukemia or BCR-ABL positive chronic myeloid leukemia in chronic phase.
Detailed Description
PRIMARY OBJECTIVE: I. To estimate the proportion of patients with previously-untreated chronic phase chronic myeloid leukemia (CML) who achieve molecular response 4 (MR4) after 6-months of the combination of decitabine and cedazuridine (ASTX727) and dasatinib 50 mg daily. SECONDARY OBJECTIVES: I. To estimate the proportion of patients with previously-untreated chronic phase CML who achieve MR4 after both the 3-months of the combination of ASTX727 and dasatinib 50 mg daily. II. To estimate cumulative overall rate of molecular response 4.5 (MR4.5). III. To estimate the 12-months major molecular response (MMR) rate. IV. To estimate the proportion of patients with MR4.5 at 6-, 12-, 18-, 24-, and 36-months of therapy. V. To estimate the proportion of patients with sustained MR4.5 of 3 years and more. VI. To estimate the treatment-free remission rate (TFR), time to progression, and overall survival. VII. To assess the safety of this combination. OUTLINE: Patients receive dasatinib orally (PO) once daily (QD) on days 1-28. Beginning cycle 4, patients also receive decitabine and cedazuridine PO QD on days 1-3. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days for up to 12 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia, BCR-ABL1 Positive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (dasatinib, decitabine and cedazuridine)
Arm Type
Experimental
Arm Description
Patients receive dasatinib PO QD on days 1-28. Beginning cycle 4, patients also receive decitabine and cedazuridine PO QD on days 1-3. Cycles repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days for up to 12 years in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Other Intervention Name(s)
BMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, Sprycel
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Decitabine and Cedazuridine
Other Intervention Name(s)
ASTX727, C-DEC, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, DEC-C, Inqovi
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Rate of molecular response 4 (MR4)
Description
Will be estimated with 95% credible intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Time Frame
At 6 months
Secondary Outcome Measure Information:
Title
Rate of MR4.5
Description
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Time Frame
At 12 months
Title
Major molecular response rate
Description
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Time Frame
At 12 months
Title
Treatment-free remission rate
Description
Will be presented with 95% confidence intervals. The association between molecular responses and demographic/ clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.
Time Frame
Up to 15 years
Title
Time to progression
Description
Survival time will be estimated using the Kaplan-Meier method. Patients who drop out of the study will be included in the time to event data as "censored data". The two-sided log-rank test will be used to assess the differences of time to events between groups.
Time Frame
Up to 15 years
Title
Overall survival
Description
Survival time will be estimated using the Kaplan-Meier method. Patients who drop out of the study will be included in the time to event data as "censored data". The two-sided log-rank test will be used to assess the differences of time to events between groups.
Time Frame
Up to 15 years

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early chronic phase CML (i.e., time from diagnosis =< 12 months). Except for hydroxyurea and/or 1 to 2 doses of cytarabine patients must have received no or minimal prior therapy, defined as < 1 month (30 days) of prior Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI) Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study Eastern Cooperative Oncology Group (ECOG) performance of 0-2 Total bilirubin < 1.5 x upper limit of normal (ULN) (unless secondary to Gilbert's disease, in which case should be < 2.5 x ULN) Serum glutamic pyruvic transaminase (SGPT) < 3 x ULN Creatinine < 1.5 x ULN Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital Exclusion Criteria: New York Heart Association (NYHA) cardiac class 3-4 heart disease Cardiac Symptoms: Patients meeting the following criteria are not eligible unless cleared by Cardiology: Uncontrolled angina within 3 months Diagnosed or suspected congenital long QT syndrome Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 460 msec) History of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) Patients with active, uncontrolled psychiatric disorders include: psychosis, major depression, and bipolar disorders Subject is known to be positive for human immunodeficiency virus (HIV) (HIV testing is not required) Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal) Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug. Pregnant or breast-feeding women are excluded. All WOCBP must have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive study drug and must not be enrolled in the study Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months), accelerated (except as noted in inclusion criteria) or blast phase are excluded. The definitions of CML phases are as follows: Early chronic phase: time from diagnosis to therapy =< 12 months Late chronic phase: time from diagnosis to therapy > 12 months Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow Accelerated phase CML: presence of any of the following features: Peripheral or marrow blasts 15% or more Peripheral or marrow basophils 20% or more Thrombocytopenia < 100 x 10^9/L unrelated to therapy Documented extramedullary blastic disease outside liver or spleen
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elias Jabbour
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elias Jabbour
Phone
713-792-4764
Email
ejabbour@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Elias Jabbour

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
M D Anderson Cancer Center

Learn more about this trial

ASTX727 and Dasatinib for the Treatment of Newly Diagnosed Philadelphia Chromosome or BCR-ABL Positive Chronic Myeloid Leukemia in Chronic Phase

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