PRIMARY OBJECTIVES:
I. To assess safety of the combination of pioglitazone hydrochloride (PIO) and TKI in CML subjects who experience a loss of major molecular response (MMR) following a first TKI discontinuation.
II. To assess survival without loss of MMR following a second TKI discontinuation in subjects who achieve or maintain < molecular response (MR)^4.5 with the combination PIO and TKI administered for at least 6 months.
OUTLINE:
Patients receive pioglitazone hydrochloride orally (PO) once daily (QD) on days 1-28. Patients also start or continue the same TKI therapy at the pre-discontinuation doses. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every month for 3 months, every 3 months for 1 year, and then every 6 months for 4 years.
Inclusion Criteria:
- Chronic myeloid leukemia (CML) in any phase
- Philadelphia chromosome positive acute lymphoblastic leukemia
- Loss of major molecular response (MMR) following a first TKI discontinuation trial
- Serum bilirubin < 1.5 x upper limit of normal values
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal values
- Females of child bearing potential must agree to abstain from sexual activity or to use a medically approved contraceptive measure/regimen during and for 3 months after the treatment period; women of child bearing potential must have a negative urine pregnancy test at the time of enrollment; acceptable methods of birth control include oral contraceptive, intrauterine device, transdermal/implanted or injected contraceptives and abstinence
- Males must agree to abstain from sexual activity or agree to utilize a medically-approved contraception method during and for 3 months after the treatment period
- Patient requiring anti-diabetic medications to manage hyperglycemia are eligible. Adjustments of other anti-diabetic agents will be made with close monitoring of blood glucose
- Informed consent
- Be able and willing to comply with study visits and procedures
Exclusion Criteria:
- Known loss of complete cytogenetic response (CCyR) by marrow cytogenetic or blood fluorescence in situ hybridization (FISH) for breakpoint cluster region (BCR)- v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1)
- Loss of complete hematologic response (CHR)
- Participation in another clinical trial with any investigative drug within 30 days prior to study enrollment
- Chronic graft-versus-host disease requiring systemic immunosuppression post-allogeneic hematopoietic stem cell transplantation
- Cardiovascular disease: history of congestive heart failure, myocardial infarction within the 6 months of study entry, symptomatic cardiac arrhythmia requiring treatment
- History of bladder cancer
- Gross (visible) hematuria
- Known history of osteoporosis
- Known history of macular edema
- Known history of ABL1-domain mutation that predicts resistance to the discontinued TKI
- Significant medical or psychiatric disorder that would interfere with consent, study participation, or follow-up
- Known allergy to pioglitazone
- Pregnant or breastfeeding
- Use of thiazolidinedione (TZD) within 28 days prior to enrollment
- Significant gastrointestinal condition that could potentially impair the absorption or disposition of the drug
- Uncontrolled peripheral edema (2+ or more) of any etiology
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 16 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
