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Azacitidine (AZA) in Minimal Residual Disease (MRD) Chronic Myeloid Leukemia (CML)

Primary Purpose

Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Azacitidine (AZA)
Tyrosine kinase inhibitor (TKI)
Azacitidine
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring Leukemia, Chronic Myeloid Leukemia, CML, Complete cytogenetic remission, CCyR, Minimal residual disease, Philadelphia chromosome (Ph)-, BCR/ABL-positive, Tyrosine kinase inhibitor, TKI, Azacitidine, 5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816

Eligibility Criteria

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

Inclusion Criteria:

  1. Patients 16 years or older with Philadelphia chromosome (Ph)- or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR).
  2. Patients must have received FDA-approved TKI therapy for at least 18 months and not have increased their dose of FDA-approved TKI in the last 6 months. Patients participating on frontline protocols 2005-0048 (nilotinib) and 2005-0422 (dasatinib) are eligible for enrollment on this study.
  3. Phase II patients must be in complete cytogenetic remission. For the phase I portion of the study, patients may be included without a complete cytogenetic remission provided they are in chronic phase.
  4. Phase II patients must have detectable BCR-ABL transcript levels meeting at least one of the following criteria: Patient has never achieved a major molecular response, and transcript levels have shown in at least two consecutive measures separated by at least 1 month to have increased by any value, or Achieved a major molecular response that has been lost with an increase in transcript levels by at least 1-log, confirmed in two consecutive analyses separated by at least 1 month, or The patient has received therapy for at least 2 years and does not have a sustained major molecular response, or The patient has received therapy for at least 5 years and does not have a sustained complete molecular response. Patients included in the phase I portion of the study are eligible regardless of their level of BCR-ABL transcripts.
  5. Patients must not have had a known continuous interruption of imatinib therapy of greater than 14 days or for a total of 6 weeks in the 6 months prior to enrollment.
  6. Patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital.
  7. ECOG performance status </= 2.
  8. Adequate organ function defined as: bilirubin < 2x upper limit of normal (ULN) (unless associated with Gilbert's syndrome), and ALT or AST </= 2.5x ULN.
  9. ANC >/=1 x10(9)/L and platelets >/= 50 x10(9)/L.
  10. Serum creatinine < 1.8 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault Equation*. Males(mL/min):(140-age)* ABW(kg) / 72* (serum creatinine(mg/dl)); Females (mL/min):0.85*(140-age)* ABW(kg) / 72*(serum creatinine (mg/dl))
  11. Women of childbearing potential should be advised to avoid becoming pregnant and practice effective methods of contraception. Men should be advised not to father a child while receiving treatment with azacitidine. Azacitidine is classified as Pregnancy Category D. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
  12. Women of childbearing potential should have a pregnancy test within 7 days before initiation of study drug.

Exclusion Criteria:

  1. Patients receiving any other investigational agents.
  2. Patients who are pregnant or breast-feeding.
  3. Patients with clinically significant heart disease (NYHA Class III or IV).
  4. Known or suspected hypersensitivity to azacitidine or mannitol.
  5. Patients with advanced malignant hepatic tumors.

Sites / Locations

  • University of Texas MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Dose Escalation Group (AZA)

Expansion Group (AZA MTD)

Arm Description

Azacitidine (AZA) starting dose 50 mg/m2 a day for 3 days subcutaneous or intravenous of 28 day cycle. TKI at dose received during last 6 months.

Dose Escalation Group plus additional 36 participants for Azacitidine 75 mg/m2 (or Phase I MTD) either subcutaneous or intravenous every day for 3 days of 28 day cycle. TKI at dose received during last 6 months.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Azacitidine
MTD is defined as the highest dose level in which 6 patients have been treated and one or fewer patient experiences Dose-Limiting Toxicity (DLT) within the first course of treatment.
Number of Participants with Decrease of Transcript Levels by at Least One Log (or Undetectable Transcript Level) Within 12 Months
Participants with response defined as a greater than a one-log reduction of BCR-ABL transcript levels from the baseline level at the time vaccination was initiated, or a disappearance of BCR-ABL transcripts (i.e., complete molecular response) within 12 months.

Secondary Outcome Measures

Full Information

First Posted
October 24, 2011
Last Updated
March 3, 2020
Sponsor
M.D. Anderson Cancer Center
Collaborators
Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT01460498
Brief Title
Azacitidine (AZA) in Minimal Residual Disease (MRD) Chronic Myeloid Leukemia (CML)
Official Title
Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic Myeloid Leukemia Who Have Minimal Residual Disease While Receiving Therapy With Tyrosine Kinase Inhibitors (VZ-CML-PI-0236)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
August 8, 2012 (Actual)
Primary Completion Date
August 7, 2019 (Actual)
Study Completion Date
August 7, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
Celgene Corporation

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
This is a 2 part study. The goal of the first part of this clinical research study is to find the highest tolerable dose of azacitidine that can be given with a TKI that you are already taking (such as Gleevec, Sprycel, or Tasigna). The safety of this drug will also be studied. The goal of the second part is to see if this combination may improve your response to the TKI you are already taking. Azacitidine is designed to change genes that are thought to cause leukemia. By changing these genes, the drug may help to stop them from causing the disease to grow.
Detailed Description
Study Drug Administration: If you are found to be eligible to take part in this study, you will continue receiving the same TKI at the dose you had been receiving for the last 6 months. You will receive azacitidine either as an injection under your skin or through a vein every day for 3 to 7 days of each 28-day cycle. The dose and how often you take the drug will depend on when you enter the study. The study staff will tell you how often you will receive the drug. In the first part of the study, you will be assigned to a dose level of azacitidine based on when you join this study. Up to 2 dose levels of azacitidine will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. The next group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of azacitidine is found. This is called the Dose Escalation Group. Once the highest tolerated dose has been found, an extra 36 participants will receive azacitidine at this dose level. This is called the Expansion Group. If you have severe side effects from the study drug, the study doctor may decide to reduce and/or stop drug dosing until your side effects improve. If the doctor thinks it is in you best interest, your dose may be increased. Study Visits: At every visit, you will be asked about any side effects you have had and to list any drugs you may be taking. Every 1-2 weeks for 8 weeks, then at the start of every cycle, blood (about 1 teaspoon) will be drawn for routine tests. Every 2-4 weeks for 8 weeks, then before each cycle, blood (about 1 teaspoon) will also be drawn to test your kidney and liver function. Before each cycle for 3 cycles, then every 3-6 cycles until 1 year, then every 6-12 cycles, blood (about 1 tablespoon) drawn for molecular testing. Every 3-6 months in Year 1, then as often the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease. If you are in the Expansion Group, every 3 months (+/- 1 month) for the first 6 months, then every 6-12 months, you will have a complete physical exam. If you are in the Dose Escalation Group, every 2 weeks for the first month, Months 1, 2, 3, and 6 (+/- 1 month), and then every 6-12 months, you will have a complete physical exam. Length of Study: You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over once you have completed the end-of-treatment and follow-up visits. This is an investigational study. TKIs are approved for the treatment of CML. Azacitidine is FDA approved and commercially available for the treatment of patients with MDS. The combination of these drugs to treat CML is investigational. Up to 48 patients will take part in this study. All will be enrolled at MD Anderson.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
Leukemia, Chronic Myeloid Leukemia, CML, Complete cytogenetic remission, CCyR, Minimal residual disease, Philadelphia chromosome (Ph)-, BCR/ABL-positive, Tyrosine kinase inhibitor, TKI, Azacitidine, 5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation Group (AZA)
Arm Type
Experimental
Arm Description
Azacitidine (AZA) starting dose 50 mg/m2 a day for 3 days subcutaneous or intravenous of 28 day cycle. TKI at dose received during last 6 months.
Arm Title
Expansion Group (AZA MTD)
Arm Type
Experimental
Arm Description
Dose Escalation Group plus additional 36 participants for Azacitidine 75 mg/m2 (or Phase I MTD) either subcutaneous or intravenous every day for 3 days of 28 day cycle. TKI at dose received during last 6 months.
Intervention Type
Drug
Intervention Name(s)
Azacitidine (AZA)
Other Intervention Name(s)
5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816
Intervention Description
Starting Dose 50 mg/m2 by subcutaneous or by vein for 3 days of a 28 day cycle.
Intervention Type
Drug
Intervention Name(s)
Tyrosine kinase inhibitor (TKI)
Intervention Description
Continuation of dose already receiving during previous 6 months.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816
Intervention Description
75 mg/m2 daily for 3 days, unless MTD defined at lower dose level in Phase I then that would become dose used for Phase II.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of Azacitidine
Description
MTD is defined as the highest dose level in which 6 patients have been treated and one or fewer patient experiences Dose-Limiting Toxicity (DLT) within the first course of treatment.
Time Frame
First 28 day cycle
Title
Number of Participants with Decrease of Transcript Levels by at Least One Log (or Undetectable Transcript Level) Within 12 Months
Description
Participants with response defined as a greater than a one-log reduction of BCR-ABL transcript levels from the baseline level at the time vaccination was initiated, or a disappearance of BCR-ABL transcripts (i.e., complete molecular response) within 12 months.
Time Frame
Baseline to 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients 16 years or older with Philadelphia chromosome (Ph)- or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR). Patients must have received FDA-approved TKI therapy for at least 18 months and not have increased their dose of FDA-approved TKI in the last 6 months. Patients participating on frontline protocols 2005-0048 (nilotinib) and 2005-0422 (dasatinib) are eligible for enrollment on this study. Phase II patients must be in complete cytogenetic remission. For the phase I portion of the study, patients may be included without a complete cytogenetic remission provided they are in chronic phase. Phase II patients must have detectable BCR-ABL transcript levels meeting at least one of the following criteria: Patient has never achieved a major molecular response, and transcript levels have shown in at least two consecutive measures separated by at least 1 month to have increased by any value, or Achieved a major molecular response that has been lost with an increase in transcript levels by at least 1-log, confirmed in two consecutive analyses separated by at least 1 month, or The patient has received therapy for at least 2 years and does not have a sustained major molecular response, or The patient has received therapy for at least 5 years and does not have a sustained complete molecular response. Patients included in the phase I portion of the study are eligible regardless of their level of BCR-ABL transcripts. Patients must not have had a known continuous interruption of imatinib therapy of greater than 14 days or for a total of 6 weeks in the 6 months prior to enrollment. Patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital. ECOG performance status </= 2. Adequate organ function defined as: bilirubin < 2x upper limit of normal (ULN) (unless associated with Gilbert's syndrome), and ALT or AST </= 2.5x ULN. ANC >/=1 x10(9)/L and platelets >/= 50 x10(9)/L. Serum creatinine < 1.8 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault Equation*. Males(mL/min):(140-age)* ABW(kg) / 72* (serum creatinine(mg/dl)); Females (mL/min):0.85*(140-age)* ABW(kg) / 72*(serum creatinine (mg/dl)) Women of childbearing potential should be advised to avoid becoming pregnant and practice effective methods of contraception. Men should be advised not to father a child while receiving treatment with azacitidine. Azacitidine is classified as Pregnancy Category D. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study. Women of childbearing potential should have a pregnancy test within 7 days before initiation of study drug. Exclusion Criteria: Patients receiving any other investigational agents. Patients who are pregnant or breast-feeding. Patients with clinically significant heart disease (NYHA Class III or IV). Known or suspected hypersensitivity to azacitidine or mannitol. Patients with advanced malignant hepatic tumors.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jorge Cortes, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

Azacitidine (AZA) in Minimal Residual Disease (MRD) Chronic Myeloid Leukemia (CML)

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