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

NCT02730195

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

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

DrugSynonymsArms
Pioglitazone HydrochlorideActos, Pioglitazone HClPioglitazone & TKI therapy
Tyrosine Kinase Inhibitor (TKI)Protein Tyrosine Kinase Inhibitors, PTK Inhibitors, TK InhibitorsPioglitazone & 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 hydrochloride 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 hydrochloride with TKI therapy may be effective in treating patients with CML.

Detailed Description

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.

Trial Arms

NameTypeDescriptionInterventions
Pioglitazone & TKI therapyExperimentalPatients receive pioglitazone hydrochloride 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 Hydrochloride
  • 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 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

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. 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).

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:Recruiting
Lead Sponsor:Emory University

Trial Keywords

    Last Updated

    October 18, 2016