Description:
This phase II trial studies how well pioglitazone hydrochloride and tyrosine kinase inhibitor
(TKI) therapy works in treating patients with chronic myeloid leukemia (CML) that has come
back after a period of improvement (relapsed) after a first TKI discontinuation. TKI may stop
the growth of cancer cells by blocking certain enzymes need for cell growth. Although TKI
therapies are effective against CML, there are residual cancer cells called leukemia stem
cells that are able to hide from TKIs. Pioglitazone is a drug approved by the Food and Drug
Administration to treat diabetes and has been shown in laboratory studies to increase CML
stem cell death when given together with TKI therapy. Giving pioglitazone with TKI therapy
may be effective in treating patients with CML.
Title
- Brief Title: Pioglitazone and Tyrosine Kinase Inhibitor in Treating Patients With Relapsed Chronic Myeloid Leukemia
- Official Title: Combination of Pioglitazone and Tyrosine Kinase Inhibitor (TKI) in Relapsed Chronic Myeloid Leukemia Following a First TKI Discontinuation
Clinical Trial IDs
- ORG STUDY ID:
IRB00086670
- SECONDARY ID:
NCI-2016-00248
- SECONDARY ID:
Winship3121-15
- NCT ID:
NCT02730195
Conditions
- Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Interventions
| Drug | Synonyms | Arms |
|---|
| Pioglitazone | Actos, Pioglitazone Hydrochloride | Pioglitazone & TKI therapy |
| Tyrosine Kinase Inhibitor (TKI) | Protein Tyrosine Kinase Inhibitors, PTK Inhibitors, TK Inhibitors | Pioglitazone & TKI therapy |
Purpose
This phase II trial studies how well pioglitazone hydrochloride and tyrosine kinase inhibitor
(TKI) therapy works in treating patients with chronic myeloid leukemia (CML) that has come
back after a period of improvement (relapsed) after a first TKI discontinuation. TKI may stop
the growth of cancer cells by blocking certain enzymes need for cell growth. Although TKI
therapies are effective against CML, there are residual cancer cells called leukemia stem
cells that are able to hide from TKIs. Pioglitazone is a drug approved by the Food and Drug
Administration to treat diabetes and has been shown in laboratory studies to increase CML
stem cell death when given together with TKI therapy. Giving pioglitazone with TKI therapy
may be effective in treating patients with CML.
Detailed Description
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Pioglitazone & TKI therapy | Experimental | Patients receive pioglitazone PO QD on days 1-28. Patients also start or continue the same tyrosine kinase inhibitor (TKI) therapy at the pre-discontinuation doses. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity. | - Pioglitazone
- Tyrosine Kinase Inhibitor (TKI)
|
Eligibility Criteria
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 16 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Incidence of Adverse Events (AEs), Graded According to Common Terminology Criteria for Adverse Events Version 4.03 |
| Time Frame: | Up to 30 days after the end of treatment |
| Safety Issue: | |
| Description: | The AE incidence will be described. An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product which does not necessarily have to have a causal relationship with this treatment. AEs will be assessed through scheduled assessments and subject reported diaries. |
Secondary Outcome Measures
| Measure: | Proportion of Subjects Who Lose MMR Following Discontinuation of Pioglitazone and TKI Using Blood qRT-PCR for BCR-ABL1 |
| Time Frame: | Up to 3 years |
| Safety Issue: | |
| Description: | The proportion of subjects that has reappearance of BCR-ABL1 will be described. Descriptive statistics that will summarize the changes in BCR-ABL1 testing over time will be presented. Loss of MMR is defined as a BCR-ABL1 > 0.1% by qRT-PCR confirmed within a week and associated with a rise in the titer on a confirmatory test obtained 4 weeks later (European Leukemia Net definition). Subgroup analyses will be performed by baseline potential prognostic factors. Subgroups will include: age, gender, race, underlying diagnosis, and other disease-related prognostic factors (disease status). |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Emory University |
Last Updated
January 9, 2019
