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

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02730195
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive	Drug: Pioglitazone; Drug: Tyrosine Kinase Inhibitor (TKI)	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combination of Pioglitazone and Tyrosine Kinase Inhibitor (TKI) in Relapsed Chronic Myeloid Leukemia Following a First TKI Discontinuation
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone & TKI therapy 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.	Drug: Pioglitazone; Given PO; Other Names: Actos Pioglitazone Hydrochloride ; Drug: Tyrosine Kinase Inhibitor (TKI); Given TKI therapy; Other Names: Protein Tyrosine Kinase Inhibitors PTK Inhibitors TK Inhibitors

Outcome Measures

Primary Outcome Measures

1. Incidence of Adverse Events (AEs), Graded According to Common Terminology Criteria for Adverse Events Version 4.03 [Up to 30 days after the end of treatment]

   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.

2. Proportion of Subjects Who Achieve and Maintain Major Molecular Response (MMR) Following a Second Discontinuation of TKI Using Blood Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) for Breakpoint Cluster Region-Abelson1 (BCR-ABL1) [Up to 6 months]

   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. 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

1. Proportion of Subjects Who Lose MMR Following Discontinuation of Pioglitazone and TKI Using Blood qRT-PCR for BCR-ABL1 [Up to 3 years]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: William Blum, MD, Emory University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 5, 2017

More Information

Publications

None provided.

• Responsible Party: William Blum, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT02730195
• Other Study ID Numbers: IRB00086670; NCI-2016-00248; Winship3121-15
• First Posted: Apr 6, 2016
• Last Update Posted: Jan 9, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	Patients receive pioglitazone PO once a day (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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
Period Title: Overall Study
STARTED	9
COMPLETED	8
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
Overall Participants	9
Age, Customized (Count of Participants)
30-39 years old	1 11.1%
40-49 years old	2 22.2%
50-59 years old	1 11.1%
60-69 years old	4 44.4%
70-79 years old	1 11.1%
Sex: Female, Male (Count of Participants)
Female	5 55.6%
Male	4 44.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	9 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 22.2%
White	6 66.7%
More than one race	0 0%
Unknown or Not Reported	1 11.1%
Region of Enrollment (Count of Participants)
United States	9 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Adverse Events (AEs), Graded According to Common Terminology Criteria for Adverse Events Version 4.03
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.
Time Frame	Up to 30 days after the end of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
Measure Participants	9
Number of Grade 1 Events	41
Number of Grade 2 Events	0
Number of Grade 3 Events	0
Number of Grade 4 Events	0
Number of Grade 5 Events	0

2. Primary Outcome

Title	Proportion of Subjects Who Achieve and Maintain Major Molecular Response (MMR) Following a Second Discontinuation of TKI Using Blood Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) for Breakpoint Cluster Region-Abelson1 (BCR-ABL1)
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. 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).
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
Measure Participants	9
Count of Participants [Participants]	8 88.9%

3. Secondary Outcome

Title	Proportion of Subjects Who Lose MMR Following Discontinuation of Pioglitazone and TKI Using Blood qRT-PCR for BCR-ABL1
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).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
Measure Participants	9
Count of Participants [Participants]	7 77.8%

Adverse Events

Time Frame	Up to 30 days after the end of treatment
Arm/Group Title	Pioglitazone & TKI Therapy
Arm/Group Description	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: Given PO Tyrosine Kinase Inhibitor (TKI): Given TKI therapy
All Cause Mortality
	Pioglitazone & TKI Therapy
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Pioglitazone & TKI Therapy
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone & TKI Therapy
	Affected / at Risk (%)	# Events
Total	7/9 (77.8%)
Blood and lymphatic system disorders
Anemia	1/9 (11.1%)
Cardiac disorders
Palpitations	1/9 (11.1%)
Ear and labyrinth disorders
Vertigo	1/9 (11.1%)
Gastrointestinal disorders
Diarrhea	2/9 (22.2%)
Nausea	2/9 (22.2%)
Constipation	1/9 (11.1%)
General disorders
Edema limbs	5/9 (55.6%)
Fatigue	2/9 (22.2%)
Edema face	1/9 (11.1%)
Night sweats	1/9 (11.1%)
Investigations
Creatinine increased	1/9 (11.1%)
Platelet count decreased	1/9 (11.1%)
White blood cell decreased	1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Flank pain	1/9 (11.1%)
Muscle cramps	1/9 (11.1%)
Myalgia	1/9 (11.1%)
Nervous system disorders
Headache	1/9 (11.1%)
Paresthesia	1/9 (11.1%)
Peripheral sensory neuropathy	1/9 (11.1%)
Renal and urinary disorders
Urinary frequency	3/9 (33.3%)
Urine discoloration	1/9 (11.1%)
Reproductive system and breast disorders
Irregular menstruation	1/9 (11.1%)
Nipple tenderness	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	1/9 (11.1%)
Upper respiratory infection	1/9 (11.1%)
Skin and subcutaneous tissue disorders
Alopecia	1/9 (11.1%)
Bruising	1/9 (11.1%)

Limitations/Caveats

Study was terminated early due to previous principal investigator leaving institution.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.