Pioglitazone and Tyrosine Kinase Inhibitor in Treating Patients With Relapsed Chronic Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To assess safety of the combination of pioglitazone (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 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 in
the 6 months preceding 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

- Active cancer that requires therapy in the form of chemotherapy or radiation