Clinical trial NCT01655719
Conditions: Thyroid Cancers That Contain the PAX8-PPARgamma Fusion Gene
Sponsor: University of Michigan
Start date: 2012-04-01; Completion date: 2017-03-31
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: Pioglitazone
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Phase 2 Study of Pioglitazone in thyroid cancers that contain the 
PAX8-PPARgamma fusion gene 
 
 
 
Principal Investigator: 
 
 
Ronald J. Koenig, MD, PhD 
 
5560 MSRB-2 
 
SPC 5678 
 
Phone 615-9497 
 
Fax 936-6684 
 
rkoenig@umich.edu 
 
Investigational Product:  
 
 
pioglitazone hydrochloride tablets for oral use 
 
 
 
manufactured by Takeda Pharmaceuticals or FDA  
 
 
 
 
approved generic equivalent. 
 
 
 
Study Centers: 
 
 
University of Michigan 
 
Current Version of Protocol:  
13May2015 
 
Previous Versions of Protocol: 
16Oct2014 
01May2014 
21Aug2013 
18Mar2013 
12Feb2013 
08Jun2012 
05Mar2012 
13 May 2011 
 
 
 
 
 
04Oct2011 
 
Oversight, Initial and Annual:  
University of Michigan Comprehensive Cancer Center 
Protocol Review Committee  
 
 
 
 
 
 
University of Michigan Comprehensive Cancer Center Data 
and Safety Monitoring Board 
 
University of Michigan Institutional Review Board: 
IRBMED  FWA# 00004969 
 
 
 


 
Co-Investigators: 
 
 
Pathology:  Thomas J. Giordano, MD, PhD 
C570 MSRB-2 
SPC 5669 
Phone 615-4470 
Fax 647-1358 
Giordano@umich.edu 
 
 
Medical Oncology:  Francis P. Worden, MD 
C343 MIB 
SPC 5848 
Phone 936-0453 
Fax 647-8792 
fworden@umich.edu 
 
Endocrinology:  Megan R. Haymart, MD 
3A17 NIB 
SPC 5419 
Phone 615-6745 
Fax 763-7672 
meganhay@umich.edu 
 
Radiology: Elaine M. Caoili, MD, MS 
UH B1 D530C,  
SPC 5030     
Phone 615.5677 
Fax 647.9339 
caoili@med.umich.edu 
 
Statistician: 
 
Stephanie Daignault-Newton, MS 
 
300 N. Ingalls, 8D09 
 
SPC 5473 
 
Phone 647-3271 
 
Fax 936-4540 
 
sfaruzzi@umich.edu 
 
 
Responsible Research Coordinator: 
 
Carole A. Ramm, MS 
 
5570 MSRB-2 
 
SPC 5678 
 
Phone 615 8914 
 
Fax 936-6684 
 
cmcr@umich.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Co-Investigators at other sites: 
Marcia Brose, MD, PhD, Assistant Professor of Cancer Genetics, Dept of Otorhinolaryngology,   
Univ of Pennsylvania Health System,  
Philadelphia PA 19104  
brosem@mail.med.upenn.edu 
 
Bryan Haugen, M.D., Professor of Medicine, and Chief of the Division of Endocrinology, 
Metabolism & Diabetes 
University of Colorado School of Medicine,  
Aurora, Colorado 80045  
Bryan.Haugen@UCDenver.edu 
 
Manisha Shah, MD, Associate Professor of Internal Medicine, Division of Endocrinology, 
Diabetes and Metabolism,  
The Ohio State University Medical Center,  
Columbus, OH 43210   
manisha.shah@osumc.edu 
 
Eric J. Sherman, MD, Medical Oncology Head and Neck Cancer Division 
Memorial Sloan Kettering Cancer Center,  
New York NY 10065 
shermane@mskcc.org 
 
Steven I. Sherman, MD, Chair, Department of Endocrine Neoplasia and Hormonal Disorders, 
Division of Internal Medicine,  
The University of Texas MD Anderson Cancer Center,  
Houston, TX  77030  
sisherma@mdanderson.org 


 
SCHEMA 
 
Patients with PAX8-PPARgamma – positive thyroid cancer that is either metastatic s/p 
thyroidectomy and radioiodine (if appropriate), or is locally advanced/recurrent not a candidate 
for further surgery, radioiodine or external beam radiotherapy 
↓ 
ECOG PS 0-2; adequate hepatic function; nondiabetic; with measurable and progressive disease 
↓ 
Pioglitazone 30 mg daily x 4 weeks 
↓ 
Pioglitazone 45 mg daily x 8 weeks 
↓ 
Response evaluation 
(radiologic imaging, serum thyroglobulin) 
 
 
 
 
CR/PR/SD 
PD or Unacceptable toxicity 
 
↓ 
↓ 
 
Pioglitazone 45 mg daily x 12 weeks 
off therapy 
 
 
 
 
 
Response evaluation (radiologic imaging, serum thyroglobulin) 
 
↓ 
 
 
 
 
 
 
CR/PR/SD 
PD or Unacceptable toxicity 
 
 
 
↓ 
 
 
 
off therapy 
 
 
 
 
Confirmatory response required by RECIST       Confirmatory response not required by RECIST 
 
↓ 
Pioglitazone 45 mg daily x 4 wks 
 
↓ 
Response evaluation (radiologic imaging) by scan 
 


 
TABLE OF CONTENTS 
1.  OBJECTIVES ............................................................................................................................ 1 
1.1  Primary Objectives ............................................................................................................... 1 
1.2  Secondary Objectives ........................................................................................................... 1 
1.3.  Correlative Objectives (Optional) ....................................................................................... 1 
2.  BACKGROUND ....................................................................................................................... 1 
2.1  Study Disease ....................................................................................................................... 1 
2.2  Rationale .............................................................................................................................. 2 
2.3  Correlative Studies Background .......................................................................................... 3 
3.  PATIENT SELECTION ............................................................................................................ 4 
3.1  Inclusion Criteria.................................................................................................................. 4 
3.2  Exclusion Criteria ................................................................................................................ 5 
3.3  Inclusion of Women and Minorities .................................................................................... 6 
4.  TREATMENT PLAN ................................................................................................................ 6 
4.1  Pioglitazone Administration ................................................................................................ 6 
4.2  General Concomitant Medication and Supportive Care Guidelines .................................... 7 
4.3  Duration of Therapy ............................................................................................................. 7 
4.4  Duration of Follow Up ......................................................................................................... 7 
4.5  Criteria for Removal from Study ......................................................................................... 7 
4.6  Continued treatment of responding patients after completion of the study ......................... 7 
4.7  Study Calendar ..................................................................................................................... 8 
5.  DOSING DELAYS/DOSE MODIFICATIONS ........................................................................ 9 
6.  ADVERSE EVENTS: .............................................................................................................. 10 
6.1  Known Adverse Events and Mitigation Strategy ............................................................... 10 
6.2  Adverse Event Reporting ................................................................................................... 11 
6.3  Data and Safety Monitoring ............................................................................................... 11 
6.4  Pregnancy ........................................................................................................................... 12 
7.  CORRELATIVE/SPECIAL STUDIES ................................................................................... 12 
7.1  Laboratory Correlative Studies .......................................................................................... 12 
8.  MEASUREMENT OF EFFECT .............................................................................................. 13 
8.1  Antitumor Effect – Solid Tumors ...................................................................................... 13 
8.2  Response Criteria (using tumor related imaging CT) ........................................................ 13 
8.3  Other Response Parameters ............................................................................................... 15 
9.  STATISTICAL CONSIDERATIONS ..................................................................................... 15 
9.1  Study Design ...................................................................................................................... 15 
9.2  Analysis Plan...................................................................................................................... 15 
9.3  Sample Size/Accrual Rate .................................................................................................. 16 
REFERENCES ............................................................................................................................. 18 


 
APPENDIX A  PERFORMANCE STATUS CRITERIA ............................................................ 20 
APPENDIX B  RECIST VERSION 1.1 ....................................................................................... 21 
APPENDIX C  CTCAE VERSION 4.0 ........................................................................................ 22 
APPENDIX D  ACTOS (PIOGLITAZONE) PACKAGE INSERT V JAN 2011 ....................... 23 
APPENDIX E  ACTOS (PIOGLITAZONE) MEDICATION GUIDE ........................................ 24 
APPENDIX F  ACTOS (PIOGLITAZONE) FDA APPROVED GENERIC EQUIVALENTS .. 25 
 


1 
 
1.  OBJECTIVES 
 
1.1  Primary Objectives  
 
Determine the overall response (complete and partial response) rates of patients with 
PAX8-PPARgamma fusion gene-positive thyroid carcinomas treated with 
pioglitazone. 
 
1.2  Secondary Objectives 
 
 
Determine if pioglitazone decreases serum thyroglobulin in patients with thyroid 
carcinomas that contain the PAX8-PPARgamma fusion gene. 
 
Measure toxicities experienced by patients with PAX8-PPARgamma fusion gene-
positive thyroid carcinomas treated with pioglitazone. 
 
1.3.  Correlative Objectives (Optional) 
 
Determine (by MRI) if pioglitazone induces lipid accumulation in thyroid carcinomas 
that contain the PAX8-PPARgamma fusion gene. 
 
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. 
 
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.  
 
2.  BACKGROUND 
 
2.1  Study Disease 
 
Follicular carcinoma and follicular variant of papillary carcinoma (together called 
follicular-patterned thyroid carcinomas) constitute about 15% of thyroid carcinomas. 
Approximately one-third of follicular carcinomas (1, 2),  as well as a subset of 
follicular variant of papillary carcinomas that has been reported to vary from 0 – 38% 
(3, 4), contain a chromosomal translocation that fuses the genes encoding PAX8 and 
PPARgamma, resulting in the production of a PAX8-PPARgamma fusion protein 
(PPFP).  
 


2 
 
In general the therapy of thyroid cancer is surgical thyroidectomy followed by 
radioactive iodine (5). These therapies are effective in the majority of cases, resulting 
in a 10 year survival of ~85% in follicular carcinoma (6). However, distant metastases 
occur, primarily in the lung and less commonly in organs such as liver and bone. 
Metastatic disease is not always responsive to radioiodine – in some cases the tumor 
concentrates radioiodine but not at sufficient levels to cause a response, and in other 
cases the metastases do not concentrate radioiodine. There is no accepted 
chemotherapy or other therapy for these patients, and for these reasons, the median 
survival of AJCC stage IV follicular carcinoma is only ~4 years (6).  
 
2.2  Rationale 
 
PPFP is a fusion protein between two transcription factors, PAX8 and PPARgamma 
(1). PAX8 is required for thyroid development, and in the mature thyroid, it drives the 
expression of thyroid specific genes. PPARgamma is expressed at very low levels in 
the normal thyroid and has no known function in that organ. PPARgamma is the 
master transcriptional regulator of adipogenesis, and in the mature adipocyte it drives 
the expression of adipocyte specific genes (7). PPARgamma is a nuclear hormone 
receptor. In clinical practice, it is best known because agonist ligands 
(thiazolidinediones) are insulin sensitizers (8). Thus, thiazolidinediones are 
commonly used to treat type 2 diabetes mellitus. One such drug, pioglitazone (trade 
name Actos® or generic equivalent), will be used in this study. 
 
PPFP contains the entirety of PPARgamma, and hence thiazolidinediones also bind to 
PPFP. In cell culture transfection studies, we have shown that a PPARgamma-
responsive promoter is induced by PPFP plus thiazolidinedione, similar to the action 
of PPARgamma plus thiazolidinedione (9). Furthermore, human PPFP thyroid 
cancers have increased expression of PPARgamma responsive genes, relative to 
PPFP-negative thyroid cancers (9). 
 
We have produced an animal model of follicular thyroid carcinomas by creating mice 
that have both thyroid-specific expression of PPFP and thyroid-specific deletion of 
the tumor suppressor Pten (hererafter denoted PPFP;PtenΔ mice) (10). PPFP 
expression alone causes mild benign hyperplasia, and PtenΔ alone causes a much 
greater degree of benign hyperplasia but no tumors. In contrast, the combined 
PPFP;PtenΔ mice develop thyroid cancer with local invasion into soft tissues, 
vascular invasion, and distant metastases. The reason we combined PPFP expression 
with PtenΔ is that we previously found that human PPFP cancers have high 
expression of phosphorylated AKT, which is not replicated in mice by PPFP 
expression alone. Pten is a negative regulator of AKT phosphorylation, so Pten 
deletion is known to increase phosphorylated AKT levels. We treated PPFP;PtenΔ 
mice with pioglitazone or control diet beginning at 2 months of age for 10 weeks. Ten 
mice received pioglitazone and 12 mice served as controls. Ultrasound measurements 
showed that, over the 10 week treatment period, the control mouse thyroids grew 3-
fold in size and the pioglitazone-exposed thyroids decreased to less than half their 
starting size. At the end of the study, the control mouse thyroids were 7 fold larger 


3 
 
(by weight) than the pioglitazone mouse thyroids. Seven of the 12 control mice had 
distant metastases, whereas none of the pioglitazone mice had metastases (P<.005).   
 
Perhaps the most striking result pertained to the histology of the thyroid glands in the 
pioglitazone treated mice. The thyroid cells were laden with lipid droplets, suggesting 
that pioglitazone caused a trans-differentiation of the thyroid cells into adipocyte-like 
cells. These cells express PPFP and the thyroid specific markers TTF-1 and 
thyroglobulin, indicating they are thyroid in origin. However, we also examined the 
expression of 17 adipocyte PPARgamma target genes, and all 17 were induced in the 
pioglitazone-treated thyroids. 
 
To test whether this adipogenic response is dependent on PPFP, we also studied 
PtenΔ mice that do not have PPFP. Eleven PtenΔ mice received pioglitazone and 15 
served as controls. Pioglitazone had no effect on either thyroid size or histology.  
 
We conclude that pioiglitazone has a remarkable therapeutic effect in this 
PPFP;PtenΔ mouse model of thyroid cancer, and that the effect requires the 
expression of PPFP. The effect involves the trans-differentiation of PPFP expressing 
thyroid cells into adipocyte-like cells, which reflects the PPARgamma-like action of 
PPFP in the presence of pioglitazone, a PPARgamma ligand. If similar activity is 
seen in human PPFP thyroid cancers, pioglitazone should have a powerful salutary 
effect on this disease. Furthermore, pioglitazone is commonly used to treat type 2 
diabetes, and it has a well established safety profile in that setting in chronic use. 
Therefore, dosing in this study will adhere to the levels for the approved indication. 
 
The duration of therapy in the proposed clinical trial is 24 weeks. The rationale for 
this duration is as follows. In the mouse model of PPFP thyroid cancer, 10 weeks of 
pioglitazone decreased thyroid diameter to less than half that of untreated mice, and 
completely eliminated metastatic disease. Therefore, we believe that a response in 
patients should be measurable by 24 weeks of therapy, if a response is to occur. 
 
2.3  Correlative Studies Background 
 
Serum thyroglobulin levels will be measured. Thyroglobulin is a well established 
tumor marker in thyroid cancer. Serial serum thyroglobulin measurements are part of 
the accepted standard of care for thyroid cancer management (5).  
 
Optional for enrolled patients who consent: MRI will be used to assess fat content of 
the cancer metastases. MRI is an accepted non-invasive method to assess tissue fat 
content. Our mouse tumor model data indicate that pioglitazone causes a lipogenic 
response (i.e. the mouse tumors accumulate lipid droplets), which reflects the PPARγ-
like action of PPFP. To assess feasibility, we performed thyroid MRIs on two 
PPFP;PtenΔ mice that were treated with pioglitazone and two that were not. Thyroid 
fat content was 13% in the two control diet mice, and 25 to 26% in the pioglitazone-
treated mice.  This optional MRI consent will allow us to assess whether a similar 
effect occurs in patients, and will provide another index of a response to pioglitazone. 


4 
 
 
Optional for enrolled patients who consent: Unstained tumor tissue slides from 
archival paraffin blocks, and/or fresh biopsy of tumor metastases, and/or peripheral 
blood (sera and/or DNA) will be collected and stored for potential analyses of tumor 
markers that may predict response or insensitivity to pioglitazone. 
 
Optional radioiodine scan, and potentially radioiodine therapy, at the end of 
pioglitazone therapy. In non-PPFP thyroid carcinomas, thiazolidinediones have been 
shown to induce radioiodine uptake in some patients with otherwise non-iodine avid 
metastases, although in general the level of uptake has been clinically insignificant 
(11, 12), with rare exception (13, 14). It seems unlikely that pioglitazone would 
induce clinically useful radioiodine uptake in PPFP carcinomas, since in the mouse 
model the thyroid cells differentiate toward adipocytes, not thyrocytes. However, 
radioiodine uptake in patients should be determined to formally address this question. 
Patients with clinically significant uptake would be considered for radioiodine 
therapy, if clinically appropriate. This will be addressed in a separate follow-up 
protocol available to subjects completing this study. 
 
3.  PATIENT SELECTION 
 
3.1  Inclusion Criteria 
 
3.1.1 Patients must have histologically confirmed thyroid carcinoma with the 
PAX8-PPARgamma translocation.  
 
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 unless there has been progression of the lesion since treatment (see 
criteria 3.1.7). 
 
3.1.2 Measurable disease by RECIST 1.1 criteria. 
 
3.1.3 Disease progression in the past 14 months. 
 
3.1.4 Availability of histological material (primary tumor or metastases) for review 
of the diagnosis and demonstration of PAX8-PPARgamma fusion gene. 
 


5 
 
3.1.5 Adequate TSH suppression (<0.5 mIU/L) 
 
3.1.6 Prior chemotherapy or surgery must have been completed at least 28 days 
prior to registration, and all toxicities must have resolved.  
 
3.1.7 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. 
 
3.1.8 Age ≥18 years. 
 
3.1.9 Life expectancy of greater than 6 months. 
 
3.1.10 ECOG performance status 2 or less. 
 
3.1.11 Patients must have normal organ function as defined below: 
 
AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal 
(within 1 month of study Day 1) 
 
3.1.12 Patients must be able to consume oral medications. 
 
3.1.13 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). 
 
3.1.14 All patients must sign an informed consent prior to enrollment. 
 
 
3.2  Exclusion Criteria 
 
3.2.1 Patients may not be receiving any other investigational agents. 
 
3.2.2 Patients with known untreated brain metastases. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pioglitzaone. 
 
3.2.4 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 
 
3.2.5 Therapy with rosiglitazone (Avandia) or pioglitazone (Actos) at any time 
since the diagnosis of thyroid cancer. 


6 
 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmias.  
 
3.2.7 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. 
 
3.2.8 
No concurrent radiotherapy or chemotherapy may be given to the patient 
during the administration of the study drug. 
 
3.2.9 
Patients with uncontrolled malabsorption syndromes. 
 
3.2.10 Patients with a history of congestive heart failure of any New York Heart 
Association class. 
 
3.2.11 Any medical or psychiatric illness which, in the opinion of the principal 
investigator, would compromise the patient’s ability to tolerate this treatment 
regimen. 
 
3.2.12  Use of rifampin (strong CYP2C8 inducer) within 14 days of study Day 1.  
 
3.2.13  Other current malignancy than the disease under study. 
 
3.2.14  Grade 2 or worse edema within 14 days prior to study Day 1, per CTCAE v4. 
 
3.3  Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
 
4.  TREATMENT PLAN 
 
4.1  Pioglitazone Administration 
 
This study will be conducted under an exemption of IND (# 113,492) granted by the 
FDA. Pioglitazone will be obtained from an outpatient pharmacy using a prescription 
issued by a study investigator.  
 
Drug information is available in the drug package insert (See link in Appendix D). 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 6.  Appropriate dose modifications for 


7 
 
pioglitazone are described in Section 5.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to 
treat the patient’s malignancy. 
 
Pioglitazone will be administered once daily without regard to meals. The initial 
dosage will be 30 mg daily, increased to 45 mg after 4 weeks unless side effects 
require otherwise. 
 
4.2  General Concomitant Medication and Supportive Care Guidelines 
 
Pioglitazone may decrease the efficacy of oral contraceptive pills. Women taking 
OCPs also should use barrier contraception.  
Levothyroxine should be administered to the same target TSH as would be done if the 
patient were not enrolled in this clinical trial. 
 
4.3  Duration of Therapy 
 
Subjects will continue treatment for 28 weeks unless one of the following applies; 
• 
Progressive Disease per RECIST criteria at any time 
• 
Stable Disease per RECIST at 24 weeks 
• 
Best Response per RECIST at 12 weeks and confirmed at 24 weeks 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse events 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient’s condition render the patient  
  
 
unacceptable for further treatment in the judgment of the investigator. 
 
4.4  Duration of Follow Up 
 
Patients will be followed for 6 months after removal from study or until death, 
whichever occurs first.  In addition, patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
4.5  Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 4.3 
applies.  The reason for study removal and the date the patient was removed will be 
documented in the Case Report Form. 
 
4.6  Continued treatment of responding patients after completion of the study 
 
Patients who complete the study and are responding without significant adverse 
effects will be allowed to continue on pioglitazone provided that they are under the 
care of a study investigator or another appropriately qualified licensed clinician who 
is willing to use this product “off-label” and can provide them with a prescription. 


8 
 
Patients would be able to use this prescription to obtain the product at any pharmacy. 
Continued treatment in the “off-label” setting will not be conducted under the 
auspices of this trial, and continued follow up will not be conducted for study.  
There are no plans to continue to provide pioglitazone for long-term follow up studies 
at this time.  
 
4.7  Study Calendar 
 
   
Pre-
Study 
Day  
1 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
 8 
Wk 
10 
Wk 
12 
Wk 
14 
Wk  
16 
Wk 
18 
Wk 
20 
Wk 
24/ 
EOT 
Wk 
 28 
Post 
treatm
ent 
 
Pioglitazonea 
 
 
X 
Daily from study day 1 through week 24-28 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
 
 
 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightb 
Pre-study and once/week through week 28 
 
 
Performance status 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistrycd 
 
X 
 
Xg 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
CBCd 
 
X 
 
Xg 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Thyroid blood testsde 
 
X 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
β-hCGdf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluationh 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Tumor related imagingi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Other correlative studiesj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


9 
 
a: Dose per protocol; orally administered once daily for 24-28 weeks.. 
b: Weight obtained at each study site visit and once/week on each subject’s same home scale. 
c: Pre-Study and Day 1 chemistries: bicarbonate, BUN, chloride, creatinine, glucose, potassium, SGOT[AST], sodium. At weeks 8, 
16, 24: glucose, AST. 
d: Blood tests can be performed locally. 
e: TSH, Free T4, thyroglobulin, thyroglobulin antibodies. All thyroglobulin measurements are to be performed in the same 
laboratory. Serum thyroglobulin will not be used as a response parameter if endogenous antibodies invalidate the measurement. 
f: Pregnancy test in women of childbearing potential only. 
g: Within 1 month prior to administration of protocol therapy. Pre-Study assessments if within 1 month will suffice. 
h: Adverse events evaluations at weeks 2, 4, 18 and post treatment (within 4 weeks and at 6 months) will be by telephone. 
i: Baseline CT or MRI scans must be done within 4 weeks prior to the start of therapy.  Baseline CT includes neck, chest and 
abdomen. Follow-up imaging for disease response is at sites of disease detected at baseline and must include abdomen in cases of 
elevated AST to evaluate for liver metastases. Week 28 confirmatory CT for patients who need such for RECIST criteria 
confirmation. Baseline MRI includes: areas with lesions on CT for which there is reasonable diagnostic uncertainty that may be 
clarified by MRI; and/or brain if clinically indicated.  
j: Optional correlative studies at Pre-Study and within 1 day of final dose of pioglitazone. Baseline optional tumor lipid MRI includes 
areas of measurable disease. Follow-up tumor lipid MRI to be at sites of quantifiable tumor lipid at baseline, and is done at week 24 
or end of treatment, whichever comes first. 
k: All visits beyond day 1 shall occur at their designated timepoint ± 5 days. 
 
 
5.  DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose Level 
Pioglitazone Dose 
-1 
15  mg, daily 
(1 tablet, 15 mg) 
0 
30  mg, daily 
(1 tablet, 30 mg) 
+1 
45  mg, daily 
(1 tablet, 45 mg) 
 
Initial therapy is 30 mg po once daily. After 4 weeks, the dose is increased to 45 mg PO 
once daily and is maintained at that dose unless a dosage reduction is indicated, as 
described below. Excursions to this plan may be permitted based on medical need after 
consultation with the PI. 
 
Weight gain of more than 5 pounds in the first week, or more than 15 pounds during 
therapy, prompts evaluation for fluid retention. If there is significant edema, the dose is 
reduced one level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to discontinue drug). 
 
Serum ALT is measured every two months. Dosage reduction by one level is indicated if 
ALT exceeds 2.5x ULN. 
 
Congestive heart failure of New York Heart Association Class II (slight limitation of 
physical activity; comfortable at rest, but ordinary physical activity results in fatigue, 
palpitation, or dyspnea), dosage reduction by one level. NYHA Class III (marked 
limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea), dosage reduction by two levels. NYHA Class IV (unable 
to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency 


10 
 
at rest. If any physical activity is undertaken, discomfort is increased) discontinue 
pioglitazone. 
 
The principal investigator may consider rechallenging with the prior dose should the 
toxicity resolve. 
 
6.  ADVERSE EVENTS: 
 
6.1  Known Adverse Events and Mitigation Strategy 
 
Adapted from Micromedex 
    * Cardiovascular: Congestive heart failure, Edema 
    * Dermatologic: Angioedema 
    * Endocrine metabolic: Diabetes mellitus exacerbation, weight gain 
    * GI: Abdominal discomfort, tooth disorder 
    * Hematologic: Anemia, decreased hemoglobin 
    * Hepatic: Hepatotoxicity, liver failure 
    * Musculoskeletal: Fracture of bone, myalgia, osteopenia 
    * Neurologic: Headache, paresthesia 
    * Ophthalmic: Diabetic macular edema, retinopathy 
    * Renal: Malignant tumor of urinary bladder 
    * Reproductive: Ovulation in premenopausal anovulatory women 
    * Respiratory: Dyspnea, pharyngitis, sinusitis, upper respiratory infection 
 
The ACTOS (pioglitazone hydrochloride) prescribing information contains the following 
information. The same side effect profile is expected in all generic equivalents.  
 
In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) 
of patients treated with pioglitazone versus 1.2% of placebo-treated patients.     
 
Placebo-Controlled Clinical Studies of pioglitazone Monotherapy: Adverse Events 
Reported at a Frequency >5% of Patients Treated with pioglitazone(% of Patients) the 
following: 
 
 
Placebo N=259 
pioglitazone N=606 
Upper Resp. Tract Infection 
8.5 
13.2 
Headache  
6.9  
9.1 
Sinusitis  
4.6 
6.3 
Myalgia  
2.7 
 5.4 
Tooth Disorder  
2.3 
5.3 
Diabetes Mellitus Aggravated 
 8.1 
 5.1 
Pharyngitis  
0.8  
5.1 
 
These known risks are the basis for several inclusion exclusion criteria.  
 
Per the current Black Box Warning, patients will be strictly monitored for signs and 


11 
 
symptoms of heart failure. They will report weight gain, new edema, and new 
dyspnea immediately to the study site.  
 
All subjects will be given the ACTOS(pioglitazone) Medication Guide as recommended 
in the 9/2009 REMS. Please see Appendix E. 
 
6.2  Adverse Event Reporting  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting, available for download 
from the CTEP web site (http://ctep.cancer.gov). 
 
• 
“Expectedness”:  All AEs will be designated as ‘Unexpected’ or ‘Expected’  
 
• 
Attribution of the AE will be designated in this manner: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
6.3  Data and Safety Monitoring 
  
6.3.1 Scheduled meetings by the study specific Data and Safety Monitoring 
Committee (DSMC) will occur quarterly or more frequently depending on the 
activity of the protocol. This committee will include the protocol investigators, 
data manager or designee, and other members of the study team involved with 
the conduct of the trial.  
6.3.2 During these regular meetings, the DSMC will discuss matters related to:  
1. safety of study participants (SAE/UaP reporting)  
2. validity and integrity of the data  
3. enrollment rate relative to expectations, characteristics of participants, retention 
of participants, adherence to protocol (potential or real protocol deviations)  
5. data completeness  
6.3.3 DSMC meetings will be documented by the Protocol Specific Data and Safety 
Monitoring Report (DSMR). The data manager or designee assigned to the 
trial will be responsible for completing the report. DSMRs will be signed by 
the Principal Investigator or by one of the co-investigators and will be kept on 
file in the study record. 
6.3.4 The University of Michigan Comprehensive Cancer Center Data and Safety 
Monitoring Board (UMCCC DSMB) will provide independent oversight of 
the safety and data integrity for this trial. DSMRs and any other pertinent 
documents will be submitted to the UMCCC DSMB for review on a quarterly 
basis unless specified more frequently by a DSMB ruling.  


12 
 
6.3.5 The Principal Investigator or designee will forward all correspondence and 
recommendations generated by the UMCCC DSMB to the Institutional 
Review Board. 
 
6.4  Pregnancy 
 
 
Any pregnancy must be reported to the Principal Investigator at the Coordinating Center 
in the same manner as a Serious Adverse Event. A subject who becomes pregnant shall 
be removed from study treatment. All pregnancies will be followed until outcome can be 
reported. 
 
7.  CORRELATIVE/SPECIAL STUDIES 
 
7.1  Laboratory Correlative Studies 
 
Detection of the PAX8-PPARgamma fusion gene. 
Eligibility requires that the tumor contain the PAX8-PPARgamma fusion gene. This will 
be assessed in specimens of the resected primary tumor or metastases obtained from all 
participating patients. Pease see supplemental Lab Manual for procedures. 
 
Optional MRI evaluation of tumor lipid. 
Since pioglitazone induces lipid accumulation in the thyroids of the mouse model, we 
predict that pioglitazone will induce lipid accumulation in the metastases of patients. For 
patients who consent, tumor lipid content will be evaluated by MRI at baseline (any time 
after informed consent and before the first dose of pioglitazone), and at 24±1 weeks or 
the end of treatment, whichever comes first. 
 
Optional fresh biopsy of metastasis.  
For patients with biopsy-accessible metastases that meet RECIST criteria for measurable 
disease, optional fresh biopsies of the metastases may be obtained. Institutional 
procedures for procurement of fresh tumor biopsies will be followed. Biopsies should be 
obtained pretreatment (anytime after informed consent and before the first dose of 
pioglitazone) and also may be obtained within 1 day of the last treatment. The biopsy 
specimens will be analyzed for the PAX8-PPARgamma fusion gene per above, and will 
be stored for potential future analyses of biomarkers that may correlate with response to 
or lack of response to pioglitazone. For example, the expression of PPARgamma target 
genes may be analyzed. 
 
Optional collection of sera.  
For patients who consent, serum (up to 21 mL) may be collected pretreatment (anytime 
after informed consent and before the first dose of pioglitazone) and also may be 
collected within one day of the last treatment. Sera will be stored at -80C for potential 
future analysis of biomarkers that may correlate with response to or lack of response to 
pioglitazone.  
 
Optional collection of peripheral blood DNA 


13 
 
For patients who consent, peripheral venous blood (up to 7 mL) will be collected for the 
isolation of DNA and the determination of DNA sequence. This may be compared to 
DNA extracted from the primary tumor or metastases to identify gene mutations or 
polymorphisms that may correlate with the development of the cancer and its response or 
lack thereof to pioglitazone.  
 
Optional radioiodine scan and potential radioiodine therapy at the end of pioglitazone 
therapy. 
This will be addressed in a separate follow-up protocol available to subjects completing 
this study. 
 
8.  MEASUREMENT OF EFFECT 
 
8.1  Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 12 
±1 weeks, with a confirmatory CT 4 or more weeks after the 24 week imaging if 
required by RECIST criteria.   
 
Response and progression will be evaluated in this study using Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1.   
 
8.1.1  Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with pioglitazone. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline (an eligibility criterion), have received at least 11 
weeks of therapy and have had their disease re-evaluated; or who come off 
therapy due to progressive disease or unacceptable adverse events at any time, will 
be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below. 
 
 
8.2  Response Criteria (using tumor related imaging CT) 
 
8.2.1  Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the 


14 
 
smallest sum LD recorded since the 
treatment started or the appearance of one or 
more new lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD 
since the treatment started 
 
8.2.2  Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
serum tumor marker (thyroglobulin) level 
≤0.5 ng/mL 
 
 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target 
lesion(s) and/or serum tumor marker 
(thyroglobulin) level >0.5 ng/mL 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
8.2.3  Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 


15 
 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
8.3  Other Response Parameters 
 
Serum thyroglobulin will be reviewed for the 12 months prior to enrollment, and will 
be obtained at enrollment and at 12±1 and 24±1 weeks of therapy.  The changes in 
thyroglobulin before pioglitazone treatment and after treatment will be summarized 
overall and by response. Serum thyroglobulin will not be used as a response 
parameter if endogenous antibodies invalidate the measurement. 
 
Optional correlative study. MRI will be used to assess lipid content of target lesions 
pre-study, and at 24±1 weeks or the end of treatment, whichever comes first. The 
changes in lipid content after treatment will be summarized overall and by response. 
 
9.  STATISTICAL CONSIDERATIONS 
 
9.1  Study Design 
 
This is a phase II study with a primary endpoint of response (CR or PR per RECIST 
criteria) to pioglitazone therapy.  Best response during the 24 weeks on Pioglitazone 
therapy will be assessed in thyroid cancer patients with metastatic disease who have 
CT evidence of disease progression in the prior 14 months.  It is expected that without 
treatment there would be no improvement in the disease in these patients.  This drug 
will be of interest to pursue alone or in combination with other therapies with a 40% 
best response rate.  Accrual of 14 evaluable patients at a 95% two-sided significance 
level will provide 87% power to detect a 40% response rate compared to the expected 
5% or less.  A patient will be evaluable if they remain on treatment for 11 weeks or 
they are removed from study due to progression or toxicity. 
 
Secondary endpoints include toxicity, serial measurements of serum thyroglobulin, 
lipid content of metastases determined by MRI, and radioiodine uptake.   Since this 
drug is well known and used in humans we do not expect toxicity to be a problem.  
However, toxicity will be observed and reported throughout the trial as this is the first 
trial with Pioglitazone in this patient population. 
 
9.2  Analysis Plan 
 


16 
 
All CT and MRI scans will be reviewed centrally through the University of Michigan 
Department of Radiology. The primary endpoint analysis will report the best response 
percent and corresponding 95% binomial confidence interval.  Only those patients 
who have measurable disease present at baseline (an eligibility criterion), have 
received at least 11 weeks of therapy and have had their disease re-evaluated; or who 
come off therapy due to progressive disease or unacceptable adverse events at any 
time, will be considered evaluable for response. Each evaluable patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 8) unknown (not 
assessable, insufficient data). All of the patients who met the evaluability criteria will 
be included in the analysis of the primary endpoint. Patients in response categories 1-
2 while on treatment will be considered responders to treatment.  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate. 
 
All patients enrolled and who receive any drug will be assessable for toxicity from the 
time of their first treatment with study drug.  Toxicity will be described by grade and 
type using frequencies and percentages. 
 
Serum thyroglobulin will be reviewed for the 12 months prior to enrollment, and will 
be obtained at enrollment and at 12±1 and 24±1 weeks of therapy.  The changes in 
thyroglobulin before pioglitazone treatment and after treatment will be summarized 
overall and by response.  Patient profile plots will be created to descriptively show the 
serum thyroglobulin values over time.  Means and standard deviations or medians and 
minimum and maximums will be used to summarize all patients at each time and 
changes from baseline at the later times.  Similarly, statistical descriptions of the 
response group and the non-response groups will be reported.   
 
The changes in target lesion lipid content at 24±1 weeks (or the end of treatment, 
whichever comes first), compared to pre-study, will be summarized overall and by 
response. Means and standard deviations or medians and minimum and maximums 
will be used to summarize the overall patient population at each time.  Similarly, 
statistical descriptions of the response group and the non-response groups will be 
reported.  A paired t-test (or paired Wilcoxon rank test if the data distribution requires 
it) will be used to compare the changes in target lesion lipid content after treatment to 
the baseline lipid content in the overall study population with both measurements.   In 
an exploratory analysis, a logistic model will be used with the outcome being 
response and the independent predictor will be the lipid content change from baseline.  
The changes in target lesion radioiodine uptake will be summarized overall and by 
response in a follow-up protocol available to subjects completing this study.   
 
9.3  Sample Size/Accrual Rate 
 
We will accrue 15 evaluable patients, which allows for one drop out while still 
achieving the target enrollment of 14 patients.  We expect to accrue ~4-5 patients per 


17 
 
year, for a total study accrual period of ~4 years. 


18 
 
 
REFERENCES 
 
1. 
Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA 
2000 PAX8-PPARγ1 fusion in oncogene human thyroid carcinoma. Science 289:1357-60 
2. 
Nikiforov YE 2008 Thyroid carcinoma: molecular pathways and therapeutic targets. 
Modern Pathology 21:S37-S43 
3. 
Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, Vieira de 
Castro I, Cardoso-de-Oliveira M, Fonseca E, Soares P, Sobrinho-Simoes M 2006 PAX8-
PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid 
carcinoma. J Clin Endocrinol Metab 91:213-20 
4. 
Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE 2003 Molecular profile 
and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An 
unusually high prevalence of ras mutations. Am J Clin Pathol 120:71-7 
5. 
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri 
EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM 2009 
Revised American Thyroid Association management guidelines for patients with thyroid nodules 
and differentiated thyroid cancer. Thyroid 19:1167-214 
6. 
Hundahl SA, Fleming ID, Fremgen AM, Menck HR 1998 A National Cancer Data 
Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 
83:2638-48 
7. 
Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, 
Mortensen RM 1999 PPAR gamma is required for the differentiation of adipose tissue in vivo 
and in vitro. Mol Cell 4:611-7 
8. 
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA 
1995 An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-
activated receptor γ (PPARγ). J Biol Chem 270:12953-6 
9. 
Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG, Jr., Vinco 
M, Misek DE, Sanders D, Zhu Z, Ciampi R, Hanash S, Chinnaiyan A, Clifton-Bligh RJ, 
Robinson BG, Nikiforov YE, Koenig RJ 2006 Delineation, Functional Validation, and 
Bioinformatic Evaluation of Gene Expression in Thyroid Follicular Carcinomas with the PAX8-
PPARG Translocation. Clin Cancer Res 12:1983-93 
10. 
Dobson ME, Diallo-Krou E, Grachtchouk V, Yu J, Colby LA, Wilkinson JE, 
Giordano TJ, Koenig RJ 2011 Pioglitazone Induces a Proadipogenic Antitumor Response in 
Mice with PAX8-PPAR{gamma} Fusion Protein Thyroid Carcinoma. Endocrinology 152:4455-
65 
11. 
Kebebew E, Lindsay S, Clark OH, Woeber KA, Hawkins R, Greenspan FS 2009 


19 
 
Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative 
advanced differentiated thyroid cancer. Thyroid 19:953-6 
12. 
Philips JC, Petite C, Willi JP, Buchegger F, Meier CA 2004 Effect of peroxisome 
proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers. 
Nucl Med Commun 25:1183-6 
13. 
Elias AN, Lizotte P 2006 Enhanced radioiodine uptake in a patient with poorly 
differentiated papillary thyroid cancer after treatment with rosiglitazone. Clin Nucl Med 31:517-9 
14. 
Tepmongkol S, Keelawat S, Honsawek S, Ruangvejvorachai P 2008 Rosiglitazone 
effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative 
total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-
gamma. Thyroid 18:697-704 
 
 


20 
 
APPENDIX A  Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


21 
 
 APPENDIX B  RECIST Version 1.1 
 
Available for download from 
http://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf 


22 
 
APPENDIX C  CTCAE Version 4.0 
 
Available for downloaded from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 


23 
 
APPENDIX D  ACTOS (pioglitazone) Package Insert v Jan 2011 
 
Available for downloaded from  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf 


24 
 
APPENDIX E  ACTOS (pioglitazone) Medication Guide 
 
Available for downloaded from 
http://www.actos.com/actospro/patientprofile.aspx 


25 
 
APPENDIX F  ACTOS (pioglitazone) FDA approved generic equivalents 
 
Available for download from 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current
_Drug&ApplNo=021073&DrugName=ACTOS&ActiveIngred=PIOGLITAZONE%20HYDROC
HLORIDE&SponsorApplicant=TAKEDA%20PHARMS%20USA&ProductMktStatus=1&goto=
Search.Generics