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)
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.
Disease Group: Leukemia
Treatment Agent: Azacitidine
Treatment Location: Only at MD Anderson
Sponsor: Celgene Corporation
Primary Objective: Phase I: To determine the DLT and MTD of the combination of azacitidine (AZA) and a tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). Phase II: To determine the clinical activity of the combination of AZA and a TKI in patients with CML in complete cytogenetic remission (CCyR) with minimal residual disease. Secondary Objectives: Phase I To determine the clinical activity of the combination of AZA and a TKI in patients with CML Phase II To determine the safety of the combination of AZA and a TKI in patients with CML in CCyR with minimal residual disease. Both phases Determine the effect of therapy over DNA methylation. Investigate the correlation of DNA methylation and response to therapy.
IRB Review and Approval Date: 08/08/2012
Recruitment Status: Closed
Projected Accrual: N/A
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.
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.