Pioglitazone in Thyroid Cancers

Phase 2 Study of Pioglitazone in Thyroid Cancers That Contain the PAX8-PPARgamma Fusion Gene

Through this trial the investigators hope to learn if a drug, Actos (pioglitazone), is useful in treating a certain kind of metastatic thyroid cancer. Actos is approved by the FDA to treat diabetes. It has not been approved by the FDA to treat cancer, so its use in this study is considered experimental.

Study Overview

• Status: Completed
• Conditions: Thyroid Cancers That Contain the PAX8-PPARgamma Fusion Gene
• Intervention / Treatment: Drug: Pioglitazone

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients must have histologically confirmed thyroid carcinoma with the PAX8-PPARgamma translocation (translocation testing will be performed on archived tissue during the screening period).

   Refractory to radioactive iodine (RAI) as defined by: the tumor does not concentrate RAI; or the patient has had RAI within the last 16 months and has had progression despite that RAI; or the last RAI treatment was >16 months ago and the patient progressed after at least two RAI treatments; or the patient has received RAI treatments with a cumulative RAI dose of ≥22.2 GBq (600 mCi)

   Not a candidate for surgery or RAI therapy with curative intent.

   Lesions that would be treated by external beam radiation therapy (EBRT) based on standard of care can be so treated, but then cannot be used as target lesions.

2. Measurable disease by RECIST 1.1 criteria.
3. Documented disease progression by RECIST 1.1 in the past 14 months.
4. Availability of histological material (primary tumor or metastases) for review of the diagnosis and demonstration of PAX8-PPARgamma fusion gene.
5. Adequate TSH suppression (<0.5 mIU/L)
6. Prior chemotherapy or surgery must have been completed at least 28 days prior to registration, and all toxicities must have resolved.
7. Prior radioactive iodine must have been completed at least 6 months prior to registration, or there must be documented disease progression since such therapy if it was within 6 months. Sites that have received EBRT must have disease progression post-EBRT to be used as sites of measurable disease.
8. Life expectancy of greater than 6 months.
9. ECOG performance status 2 or less.

10. Patients must have normal organ function as defined below:

    AST(SGOT)/ALT(SGPT) less than 2.5 X institutional upper limit of normal (within 1 month of study Day 1)

11. Patients must be able to consume oral medications.
12. Women of childbearing potential must have a negative pregnancy test at baseline prior to receiving any study drug and must practice effective contraception while on study. (Pregnant or lactating patients are excluded).
13. All patients must sign an informed consent prior to enrollment.

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents.
2. Patients with known untreated brain metastases.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pioglitazone.
4. Diagnosis of diabetes mellitus or current therapy with any drugs used to treat diabetes mellitus, including but not limited to insulin, sulfonylureas, metformin, rosiglitazone (Avandia), and pioglitazone (Actos) within 14 days of study Day 1
5. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos) at any time since the diagnosis of thyroid cancer.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure, unstable angina pectoris, or cardiac arrhythmias.
7. Pregnant women are excluded from this study because pioglitazone is a U.S. Food and Drug Administration Pregnancy Category C drug. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pioglitazone, breastfeeding should be discontinued if the mother is treated with pioglitazone.
8. No concurrent radiotherapy or chemotherapy may be given to the patient during the administration of the study drug.
9. Patients with uncontrolled malabsorption syndromes.
10. Patients with a history of congestive heart failure of any New York Heart Association class.
11. Any medical or psychiatric illness which, in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment regimen.
12. Use of rifampin (strong CYP2C8 inducer) within 14 days of study Day 1.
13. Other current malignancy than the disease under study.
14. Grade 2 or worse edema within 14 days of study Day 1, per CTCAE v4.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pioglitazone Treatment; If eligible, subjects can participate in 1 or both parts of this study as follows: Part 1: In the initial main portion of the study subjects will receive 24 -28 weeks of therapy with pioglitazone at the dosage approved for the control of diabetes. Response will be evaluated per RECIST. Safety measure are outlined in the protocol including weekly weigh ins, calls, labs, exams, etc. Part 2: A secondary protocol is then available to subjects who complete the main initial study with less than complete response per RECIST. They can undergo a radioiodine scan to see if the treatment with pioglitazone has sensitized their disease to radioiodine. If it has - they can pursue the radioiodine treatment.

Drug: Pioglitazone; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response (Change)	Response is measured by change in Tumor size (cm)	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Thyroglobulin	Determine if pioglitazone decreases serum thyroglobulin in patients with follicular-patterned thyroid carcinomas that contain the PAX8-PPARgamma fusion gene.	Baseline and 24 weeks
Toxicity	Toxicities experienced by patients with PAX8-PPARgamma fusion gene-positive follicular-patterned thyroid carcinomas treated with pioglitazone are indicated by presence of Serious Adverse Events (that show relatedness).	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	Define predictive markers of response or insensitivity to pioglitazone. Unstained tumor tissue slides from archival paraffin blocks, fresh biopsy specimens from measurable metastases, and blood samples (serum and peripheral blood cells) will be collected on enrolled patients who consented for the optional correlative studies. These will be used to identify factors that predict efficacy of pioglitazone. Analyses may include measures of expression of specific RNAs and proteins, and DNA sequence analysis.	24 weeks
Sensitization to Radioiodine Therapy	Determine if pioglitazone induces a clinically significant level of radioiodine uptake in the residual thyroid carcinoma, and if so, whether there is a therapeutic response to radioiodine. This will be addressed in a separate follow-up protocol available to subjects completing this study.	24 weeks
Lipid Accumulation in Tumor	Determine (by MRI) if pioglitazone induces lipid accumulation in follicular-patterned thyroid carcinomas that contain the PAX8-PPARgamma fusion gene.	24 weeks

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ronald J Koenig, MD, PhD, University of Michigan

Publications and helpful links

General Publications

• Giordano TJ, Haugen BR, Sherman SI, Shah MH, Caoili EM, Koenig RJ. Pioglitazone Therapy of PAX8-PPARgamma Fusion Protein Thyroid Carcinoma. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1277-1281. doi: 10.1210/jc.2017-02533.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: July 25, 2012
• First Submitted That Met QC Criteria: July 30, 2012
• First Posted (Estimate): August 2, 2012

Study Record Updates

• Last Update Posted (Actual): October 26, 2017
• Last Update Submitted That Met QC Criteria: September 27, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 2011.097; R01CA166033 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No