Clinical trial NCT01838317
Conditions: Cancer of the Pancreas
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-05-01; Completion date: 2017-09-20
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to determine whether or not addition of the oral medication, pioglitazone to standard chemotherapy, results in improvement of blood tests that measure the body's ability to utilize sugar (glucose and insulin metabolism). In addition the investigators want to determine whether or not treatment with pioglitazone results in (1) improvement in the size of the tumor, (2) weight gain, (3) improved ability to function during the day and (4) quality of life.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pioglitazone
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
A Phase II Study of Pioglitazone for 
patients with cancer of the pancreas 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:   
 
Muhammad Shaalan Beg, MD (Hematology/Oncology 
 
 
 
 
 
 
CO-PRINCIPAL INVESTIGATORS:  
 
Philipp Scherer, PhD (Touchstone Diabetes Center 
Yull Arriaga, MD (Hematology/Oncology) 
 
 
CO-INVESTIGATORS:  
 
 
Udit Verma, MD (Hematology/Oncology) 
Sirisha Karri, MD (Hematology/Oncology) 
Samira Syed, MD (Hematology/Oncology) 
Letica Khosama, NP-C (Hematology/Oncology) 
Takeshi Yokoo, MD (Department of Radiology) 
 
Ivan Perdrosa, MD (Department of Radiology) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIOSTATISTICIAN:      
 
 
Yang Xie, PhD 
 
 
 
 
 
 
PROTOCOL VERSION:                           Version 4.0   March 21, 2014 
Amendment #1:  
 
 
Version 5.0, April 25, 2014 
This confidential document is the property of the UT Southwestern Medical Center. No 
unpublished information contained in this document may be disclosed without prior 
writtenapproval of UT Southwestern Medical Center. 


 
2 
 
 
 
 
Table of Contents 
 
 
I. 
Contact Information ....................................................................................4 
 
II. 
Abbreviations .............................................................................................5 
 
III. 
Introduction ..............................................................................................6 
 
 
IV. 
Schema ....................................................................................................10 
 
V. 
Hypothesis ...............................................................................................10 
 
VI. 
Objectives ................................................................................................10 
 
VII. 
Endpoints .................................................................................................10 
 
VIII. 
Study Design ............................................................................................11 
 
A. Recruitment..............................................................................................11 
 
IX. 
Eligibility Criteria.......................................................................................11 
 
X. 
Informed Consent Process.......................................................................12 
 
XI. 
Study Subject Identification Number ........................................................13 
 
XII. 
Subject Registration .................................................................................13 
 
XIII. 
Study Procedures and Treatment Plan ....................................................13 
 
A. Screening Evaluations .............................................................................13 
 
B. Baseline Evaluations ................................................................................14 
 
C. Treatment Plan.........................................................................................14 
 
D. Dose Modifications and Discontinuation ..................................................15 
 
E: Concomitant medication/Treatments………………………………………………16 
 
F. 
Treatment Evaluations .............................................................................16 
 
G. Imaging Procedures and Lab Evaluations..............................................19 
 
H.   Schedule of Events ..................................................................................21 
 
XIV. 
Treatment Duration ..................................................................................22 
 
XV. 
Withdrawal of Subjects.............................................................................22 
 
XVI. 
Efficacy Assessments ..............................................................................22 
 
XVII.   Response Criteria ....................................................................................23 
 
XVIII.  Data handling and record keeping ...........................................................24 
 
XIX. 
Safety Monitoring .....................................................................................24 


 
3 
 
 
 
A. 
Adverse Event Definition ..........................................................................24 
B. 
Serious Adverse Event Definition .............................................................25 
 
C. Expected Adverse Event Definition ..........................................................25 
 
D. Unexpected Adverse Events Definition ....................................................25 
 
E. 
Attribution .................................................................................................26 
 
F. 
Adverse Event Reporting .........................................................................26 
 
G.   Follow-up..................................................................................................27 
 
H. Data and Safety Monitoring Plan..............................................................27 
 
XX. 
Data analysis and Statistical Methods......................................................28 
 
A. 
Study Design and Sample Size ................................................................ 28 
 
B. 
Statistical Analysis Plan ...........................................................................29 
 
XXI. 
References...............................................................................................30 
 
 
 
Appendix 1 - ECOG Performance Status Scale……………………………………32 
 
Appendix 2 - Weight Log……………………….……………………………………..33 
 
Appendix 3 - Subject Pill Diary……………………………………………………….34 
 
Appendix 4 - FACT-Hep Questionnaire……………………………………………..35 
 
 
 
 
 
 
 
 
 


 
4 
 
 
 
 
 
I.   Contact Information 
 
Principal Investigator:        Muhammad Shaalan Beg, MD 
Assistant Professor of Medicine 
University of Texas Southwestern Medical Center 
Harold C. Simmons Comprehensive Cancer Center 
5323 Harry Hines Boulevard 
Dallas, TX 75390-8852 
Office: (214) 648-4178 
Fax: (214) 648-1955 
Email: muhammad.beg@utsouthwestern.edu 
 
 
Co- Principal Investigators: Philipp E. Scherer, PhD 
Professor, Department of Internal Medicine 
Gifford O. Touchstone Jr. and Randolph G. Touchstone 
Distinguished Chair in Diabetes Research 
Director, Touchstone Diabetes Center 
The University of Texas Southwestern Medical Center 
5323 Harry Hines Blvd. 
Dallas, TX 75390-8549 
Yull E. Arriaga, MD 
Assistant Professor of Medicine 
University of Texas Southwestern Medical Center 
Harold C. Simmons Comprehensive Cancer Center 
5323 Harry Hines Boulevard 
Dallas, TX 75390-8852 
Office: (214) 648-4178 
Fax: (214) 648-1955 
Email: Yull.Arriaga@UTSouthwestern.edu 
 
 
Research Manager:   
Tyson Dudley, MPH, MBA 
Clinical Research Manager - GI Program 
Harold C. Simmons Cancer Center, NB2.418 
UT Southwestern Medical Center at Dallas 
5323 Harry Hines Blvd 
Dallas, Texas 75390-9179 
Phone: 214-648-7031 
Fax: 214-648-1906 
Email: tyson.dudley@utsouthwestern.edu 


 
5 
 
 
 
 
 
II.  Abbreviations 
 
ALT – alanine amino transferase 
AST – aspartate amino transferase 
BUN – blood urea nitrogen 
Ca - calcium 
 
CBC – complete blood count 
 
Cl - chloride 
CO2 - bicarbonate 
 
CR - complete response 
 
CRF – case report form 
 
CRO – Clinical Research Office 
 
CT – computed tomography 
 
CTCAE - Common Terminology Criteria for Adverse Events 
 
DSMC - Data and Safety Monitoring Committee 
ECOG - Eastern Oncology Cooperative Group 
IRB – institutional review board 
K – potassium 
LAT - lateral 
Na - sodium 
OR - objective response 
PA – posterior to anterior 
PI - principal investigator 
PPAR - peroxisome proliferator-activated  receptor gamma 
 
PR - partial response 
 
RECIST - Response Evaluation Criteria in Solid Tumors 
 
SCCC -Simmons Comprehensive Cancer Center 
 
TDP - time to disease progression 
 
TZDs - thiazolidinedione 
 
 
 


 
                                                                                                                                                                                      6 
 
III. Introduction 
A.  Background 
Pancreatic cancer is a cause of significant morbidity and mortality and effective treatment 
strategies are lacking. The annual incidence of pancreas  cancer in the United  States is 9 cases 
per 100,000  people.  In  2008  there  will  be  approximately  37,680  new  cases  and 34,290 deaths 
from pancreas cancer in the United States [1]. Pancreas cancer is the  fourth  leading  cause  of  
cancer-related  mortality  in  North  America.  Early systemic spread is seen in most patients with 
pancreas cancer. Eighty percent of patients  with pancreas  cancer present  with clinical evidence  of 
distant metastases.  With currently  available  therapies,  the  5-year  overall  survival  of patients with 
pancreas cancer is less than 5%.Treatment of patients with unresectable or metastatic pancreas cancer 
and good performance with the pyrimidine anti- metabolite gemcitabine results in a median overall 
survival off less than 6 months and  a  clinical  benefit  response  of  24%[2].   
Cancer related cachexia is a cause of significant morbidity and no effective therapies exist. 
Cachexia, a syndrome characterized by significant loss of adipose and skeletal muscle tissue accounts 
for more than 50% of cancer related death. Patients with cancer and cachexia have a short overall 
survival and decreased response to chemotherapy [3]. Insulin resistance is a hallmark of cancer-
associated cachexia [4] and is in part mediated by c ytok ines such as TNF- [5]. Severe 
malnutrition and cachexia develops in 85% of patients with pancreas cancer during the course of 
their illness.  
Pancreatic cancer provides an excellent model to study cancer associated cachexia and insulin 
resistance. Up to 85% of pancreatic cancer patients will experience cachexia in their lifetime. In addition 
type 2 diabetes mellitus occurs in 70 to 80% of patients with pancreas cancer. The development of 
diabetes in patients with pancreas cancer is likely secondary to a marked decline in pancreatic  cell 
function and profound peripheral  insulin  resistance.  Patients  with advanced  pancreas  cancer  
display many of the metabolic abnormalities seen in type 2 diabetes mellitus including glucose 
intolerance, increased hepatic glucose production, recycling, and insulin resistance. 
Thiazolidinediones (TZD) lead to improved insulin sensitivity and weight gain, but effects on 
pancreatic cancer patients are unknown. Therapies that decrease cachexia-associated wasting, also 
result in increased peripheral tissue insulin sensitivity [6]. The thiazolidinediones (TZDs) are a class of 
medications that produce insulin sensitizing effects in animal models [6-9] and in insulin  resistant  
human  subjects [10-12].  The  TZDs  are high affinity ligands   for  the  nuclear   receptor,   peroxisome   
proliferator-activated   receptor gamma  (PPAR)  which  transactivates   PPAR-responsive   gene  
promoters[13]. Some of the insulin-sensitizing properties of PPAR agonists are thought to be mediated 
through their anti-inflammatory activity. In peripheral monocytes, peritoneal macrophages, and 
adipocytes, PPAR agonists are reported to inhibit the production of inflammatory cytokines. The anti-
inflammatory activity of PPAR agonists   appears   to   be   mediated   through   inhibition   of  the   
activation   of transcription  factors such as nuclear factor-B  (NF-B),  activator protein-1 (AP-1), and 
signal transducer and activator of transcription (STAT). Additionally, the insulin-sensitizing  effects of 
PPAR agonists may in part be related to a positive regulation  and  increase  in  serum  levels  of  
the  adipocyte-specific   secretory protein adiponectin, a mediator of systemic insulin sensitivity [14, 
15]. Serum levels of adiponectin  may serve as a marker for gain of insulin sensitivity  in patients 
treated with PPAR agonists. Intracellular lipid accumulation in myocytes and hepatocytes  has been 
associated  with decreased  insulin sensitivity.  Treatment with PPAR agonists in humans and in 


 
                                                                                                                                                                                      7 
 
rodents results in significant weight gain primarily due to increased fat mass, despite improved insulin 
sensitivity. One possible mechanism of action of PPAR agonists may rely on their ability to redistribute  
triglycerides  from  muscle  and  liver  towards  adipose  tissue.  The anabolic  effects  of PPAR  
agonists  would  be highly  desirable  in patients  with metastatic  pancreas  cancer.  PPAR  agonists  
increase  systemic  insulin sensitivity, adipose mass, and significantly decrease inflammation 
at the level of adipocytes and macrophages. The anti-inflammatory, insulin sensitizing, and 
anabolic effects of PPAR agonists may offer an ideal approach to counter many of the 
symptoms associated with metastatic pancreas cancer. 
TZDs have been used in a number of cancer-related  settings. In a retrospective study in type II 
diabetic patients there was a 33% decreased incidence of lung cancer among TZD users compared 
with nonusers after adjusting for confounder interactions.  The risk for colorectal  and prostate  
cancers  was not significantly altered [16].  TZDs have been used in the context of liposarcomas. 
Several studies report a positive impact of a TZD regimen, demonstrating induction of solid tumor 
differentiation by TZDs in patients with liposarcoma .  Other studies in contrast concluded that TZDs 
are not effective anti-tumoral drugs in the treatment of liposarcomas [17]. Of particular interest are the 
studies in breast cancer patients. Activation of PPAR is associated with anti-proliferative  effects on 
human breast cancer cells in preclinical studies. However, clinical trials using PPAR ligands in 
patients  with  treatment-refractory  metastatic  breast  cancer  failed  to show  any clinical benefits [18]. 
In contrast to pancreatic cancers, PPAR tends to be highly suppressed in breast cancer cells [19]  and 
as such, these cells not offer high levels of    PPAR  target  for  the  TZDs  to  act  upon.  The  
commonly  observed  up- regulation  of  PPAR  in  pancreatic  ductal  adenocarcinoma [20]  may  
predispose these cells to a high level response to the TZDs. 
Preliminary data from UT Southwestern in patients receiving pioglitazone as second line therapy for 
metastatic pancreatic cancer demonstrated significant TZD response. Among treated patients, the 
increase in adiponectin levels varied from 50% to three times the baseline. However this study was 
terminated due to poor accrual. Adequate follow up was not possible due to poor survival of patients, 
demonstrating selection of terminally ill patients to the protocol. Also the effect on other markers of insulin 
resistance is not known. 
(MRI will be performed on UT Southwestern and PHHS patients ONLY) We propose to evaluate 
the use of MRI to quantitate changes in a) intratumoral fat deposition in pancreatic cancer and 
b) visceral/subcutaneous fat distribution in pancreatic cancer patients treated with pioglitazone 
in this phase II study. To determine intratumoral fat content, we will use a previously described 
advanced chemical shift-based gradient-echo MRI technique that measures the proton density 
fat fraction (PDFF) [21]. In addition, MRI will allow quantitative determination of body fat volume 
in the abdomen e.g. subcutaneous/visceral adipose tissue (SAT/VAT) depots, which have been 
shown to have an important role in insulin resistance [22, 23]. TZD therapy has shown to 
increase ‘good’ SAT and have a concomitant decrease in ‘bad’ VAT and liver fat in patients with 
diabetes but has not been studied in patients with pancreatic cancer related weight loss.  
MRI examination will be performed on a clinical whole body system (Philips Achieva) at 3.0 
Tesla at Rogers MRI Center equipped with a dedicated transmit/receive body coil and images 
will be interpreted by a dedicated study radiologist,(Department of Radiology). Scan protocol 
include a preliminary localizing sequence and a 3D multi-echo spoiled gradient echo sequence, 
with scan parameters optimized for fat quantification as previously described [21].   
 


 
                                                                                                                                                                                      8 
 
We propose this study to determine, what is the effect of PPAR agonist therapy with pioglitazone on 
adiponectin levels and markers of insulin sensitivity (fasting glucose, OGTT 0, 2 hour, I/G ratio) in 
pancreatic cancer patients. In addition we will evaluate the effects of pioglitazone therapy on weight, 
ECOG functional status, quality of life and disease response. 
In order to differentiate pioglitazone related effects from chemotherapy related effects we will enroll a 
cohort of pancreatic cancer patients for correlative analysis only and will serve as a control arm. These 
patients will meet all eligibility criteria as detailed above but will not receive pioglitazone. Pioglitazone 
General: Pioglitazone is one of two currently available PPAR agonists on the market. It is sold in the 
US under the name ActosTM. The other drug in this class on the market is rosiglitazone 
(AvandiaTM). 
Alternative   Names  and Clinical   Structure:   ActosTM.   Pioglitazone  has been approved by the FDA 
as an oral anti-diabetic in 1999 and has been used widely since then with a good safety profile for 
long term use in type 2 diabetics.  10 million patients have been prescribed ActosTM  in the US to 
date. 
Presentation:  Pioglitazone is dosed  once  daily orally  without  regard  to meals. The  suggested  dose  
here  is  45  mg  per  diem,  a dose  used  in  many  clinical studies, including the recent PROactive 
study. 
Mechanisms of Action: Pioglitazone is a transcriptional activator of the nuclear receptor PPAR. 
Preclinical  Activity:  Pioglitazone  has a good preclinical  safety profile. This is a drug that has been 
widely studied. We have shown that a significant portion of its insulin-sensitizing  activity is mediated 
via induction of the adipokine adiponectin. However, there are additional PPAR transcriptional 
targets involved as well. 
Clinical Studies: Pioglitazone is an oral anti-diabetic agent that acts primarily by decreasing insulin 
resistance. 
Pharmacokinetics: Serum concentrations of total pioglitazone (pioglitazone plus active metabolites)  
remain  elevated  24 hours after once daily dosing.  Steady- state  serum  concentrations   of  both  
pioglitazone   and  total  pioglitazone   are achieved within 7 days. At steady-state, two of the 
pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum 
concentrations  equal to or greater than pioglitazone.  In both healthy volunteers and in patients with 
type 2 diabetes, pioglitazone comprises approximately  30% to 50% of the peak total pioglitazone 
serum concentrations  and 20% to 25% of the total area under the serum concentration-time curve 
(AUC). 
Maximum  serum  concentration  (Cmax),  AUC,  and trough  serum  concentrations (Cmin) for both 
pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. 
There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 
60 mg per day. 
The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 
hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. 


 
                                                                                                                                                                                      9 
 
Safety Profile: Systemic and hematologic: Pioglitazone may be associated with hypoglycemia, edema, 
anemia (lower hemoglobin levels and hematocrit due to edema), weight gain (increased fat cell 
differentiation), and/or ovulation in premenopausal, anovulatory women. The most common adverse 
events (5%) reported to date include upper respiratory tract infection, headache, sinusitis, myalgia, 
tooth disorder, aggravated diabetes mellitus, and pharyngitis. 
Gastrointestinal (GI)/Liver: Reports of hepatitis and of hepatic enzyme elevations to three or more 
times the upper limit of normal (ULN) have been reported with pioglitazone.  Very  rarely,  these  
reports  have  involved  hepatic  failure  with  or without  fatal  outcome,   although   causality   has  not  
been  established.   Liver enzymes, including serum ALT, need to be evaluated in all patients at 
initiation of therapy  with  pioglitazone,  and  periodically  thereafter.  If  ALT  >2.5X  ULN  at baseline 
or if the patient exhibits clinical evidence of active liver disease, pioglitazone will be discontinued. 
Systemic: Like other thiazolidinediones (TZDs), pioglitazone can cause fluid retention when used alone 
or in combination with other anti-diabetic agents, including   insulin.  Fluid  retention   may  lead  to  or  
exacerbate   heart  failure. However,  in  the  context  of  pancreatic  cancer,  these  potential  issues  
seem relatively   minor.   Nevertheless,   we  will  exclude   patients   with  a  history   of previously 
existing cardiac disease. 
Cardiovascular:  The Endocrinologic  and Metabolic  Drugs and Drug Safety and Risk Management 
Advisory Committees to the FDA recently met jointly to review the  cardiovascular  ischemic/thrombotic   
risks  of  the  thiazolidinediones  (TZDs) class, with focus on rosiglitazone.  At this stage, there were 
no concerns raised with respect to the cardiovascular safety of pioglitazone. 
Pioglitazone  has been prescribed  in many patients  with pancreas  cancer  who have a diagnosis of 
type 2 diabetes mellitus in routine clinical practice. To our knowledge,   no  unexpected   serious  
adverse  events  have  been  reported  in patients with pancreas cancer receiving treatment with 
pioglitazone. 
             Table 1: Adverse Effects of Pioglitazone 
 
Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events 
Reported at a Frequency  5% of Patients Treated with ACTOS 
 
 
 
 
 
 
 
(% of Patients) 
Adverse Effects 
Placebo 
N=259 
ACTOS N=606 
Upper Respiratory 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 


 
                                                                                                                                                                                      10 
 
Diabetes Mellitus Aggravated 
8.1 
5.1 
Pharyngitis 
0.8 
5.1 
 
 
Rationale for the Selection of Dose and Schedule 
 
We plan to prescribe pioglitazone 45 mg per mouth daily, which is the maximum U. S. Food and Drug 
Administration (FDA) approved dose for the treatment   of  type   2  diabetes   mellitus.   Pioglitazone   
has  been   extensively prescribed in humans at the planned doses for this study. The safety and 
toxicity profile of pioglitazone is well established. We do not expect a higher than usual toxicity in 
patients with pancreas cancer receiving pioglitazone. 
 
IV. Schema 
This is an open label, double arm Phase 2 study. We plan to enroll 15 patients with adenocarcinoma of 
the pancreas to this study of oral pioglitazone 45 mg daily. Patients are allowed to continue on 
antineoplastic therapy while on this study and this will be determined by the treating physician. 
A control cohort of up to 10 patients will be enrolled for correlative (blood and radiological) testing alone. 
These patients will meet all criteria set forth for the study and follow the same study visits, but not be 
treated with pioglitazone.  
 
V.  Hypothesis 
Prior  studies  have  shown  that  a  significant   proportion   of  patients  with metastatic pancreas 
cancer have metabolic changes consistent with insulin resistance.   Treatment   of   insulin   
resistance   in   patients   with   metabolic disorders like type 2 diabetes mellitus is associated with 
improved outcomes and  less  morbidity.  We  propose  an  exploratory  clinical  trial  to study  as a 
primary aim, the effects of the oral inhibitor of the peroxisome proliferator- activated   receptor   
gamma   (PPAR)   pioglitazone   in   markers   of  insulin resistance in patients with pancreas 
cancer. 
 
Our primary hypothesis is that patients with pancreas cancer will  have  significant  improvements  in 
markers  of insulin  resistance when treated with pioglitazone.  
 
As secondary aims, we will evaluate c hanges  in cancer related symptoms, performance status, 
and weight. W e  w i l l  a l s o  e v a l u a t e  the objective response of measurable lesions  and  the  
time  to  disease  progression   in  patients  with  pancreas cancer. MRI will be used to assess for 
changes in body fat distribution and changes in intratumor fat content (UT Southwestern and PHHS 
patients ONLY). We will compare change in blood biomarkers and MRI between the pioglitazone and 
control arms. 
 
VI. Objectives 
 
Primary objective 
 
1. Describe change in markers of insulin resistance, including in adiponectin levels standard glucose tolerance test, and 
serum levels of insulin and glucose in patients with pancreas cancer receiving pioglitazone. 
 
Secondary Objectives 
 
1. To determine the tumor response by RECIST in patients   with   pancreas cancer receiving pioglitazone. 
2. To   describe   changes   in weight   in patients   with   pancreas cancer receiving pioglitazone. 
3. To describe changes  in  ECOG  performance   status    in  patients   with   pancreas cancer receiving 
pioglitazone. 


 
                                                                                                                                                                                      11 
 
4. To describe changes in symptoms and quality of life using the FACT-Hep scale, version 4 (see Appendix 4). 
5. Compare change in blood biomarkers and MRI between the pioglitazone and control arms. 
 
 
 
VII. Endpoints 
 
We will assess the primary and secondary endpoints of the study as follows: 
 
Primary End point 
The primary end point will be improvement in insulin resistance markers:  
a.   Change in serum adiponectin level. We w i l l  o b t a i n  s e r u m  l e v e l s  o f  a d i p o n e c t i n  a t    
b a s e l i n e  a n d  after 8 weeks of treatment with pioglitazone. 
b.   Changes in standard glucose tolerance test. We will perform the area  under the  oral  glucose 
tolerance test at bas eline and after 8 weeks of treatment with pioglitazone.  
c.   Fasting levels of serum glucose and insulin. We will obtain serum  levels  of  fasting  glucose  and  
insulin  every  four  weeks  in all patients receiving pioglitazone 
 
 
Secondary End points 
a. Objective response (OR) is the proportion of patients with confirmed complete response (CR) or confirmed 
partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Progression 
free survival (PFS) and overall survival (OS) of patients on treatment with pioglitazone.  
b. Changes   in weight   in patients   with   pancreas cancer receiving pioglitazone. 
c. Changes  in  ECOG  performance   status    in  patients   with   pancreas cancer receiving pioglitazone. 
d. Changes in symptoms and quality of life using the FACT-Hep questionnaire, version 4 (see Appendix 4). 
e. Characterize MRI determined changes in a) pancreatic intratumor fat; and b) body fast distribution in pancreatic 
cancer patients treated with pioglitazone (pilot study on 8-10 patients chosen by PI/investigator discretion) (UT 
Southwestern and PHHS patients ONLY).  
f. 
Compare changes in serum and MRI end points between pioglitazone and control arms. 
 
 
 
 
VIII. Study Design 
Study Arm: 
We plan  to  enroll   fifteen   patients   with  metastatic or locally advanced pancreas cancer into a 
double arm pilot exploratory study of oral pioglitazone 45 mg daily.  
Treatment will be administered for 8 weeks and then stopped. 
Control Arm: 
Up to ten patients meeting eligibility criteria will be enrolled in the control arm. Patients will be treated 
per standard of care treatment at the discretion of the treating team and will not be treated with 
pioglitazone. 
 
 
Treatment arm assignment: 
Treatment arm will be assigned by the principal investigator or treating MD at their discretion. Given the exploratory 
nature of this study, randomization will not be performed.  
 
Control arm patients can include the following examples: 
- 
patient declines pioglitazone therapy but agrees to biomarker testing (Adiponectin, a hormone made by fat cells, will 
be measured). Additional assays may be performed 
- 
Patient is enrolled in another clinical trial which does not allow experimental therapy (pioglitazone) to be given. 
The protocol of the patient’s study will be reviewed to ensure biomarker testing (Adiponectin, a hormone made by 
fat cells, will be measured) as defined in this study is not specifically prohibited. 


 
                                                                                                                                                                                      12 
 
- 
Patients enrolled after completion of the 15 study arm patients  
- 
Other patients as deemed appropriate by the PI or co-Is 
 
A.  Recruitment 
 
Eligible study patients will be screened, recruited, and enrolled at the following institutions: 
 
1. University of Texas Southwestern Medical Center at Dallas:      
a.  Harold C. Simmons Comprehensive Cancer Center      
b.  University Hospital – Zale Lipshy 
c.  University Hospital – Saint  Paul 
2. Parkland Health and Hospital System (PHHS)   
3. VA North Texas (Dallas) 
 
Study patients will be recruited from the practices of the PI and co- investigators.   Potentially eligible 
patients will be approached by their health care providers who can refer them to the study coordinator 
for screening. All patients being considered for the study and eligible must sign an informed consent for 
the study prior to any study specific procedures. 
 
 
IX. Eligibility Criteria 
Inclusion Criteria 
 
 
Inclusion Criteria 
Reason 
Signed informed consent 
Document patient participation and understanding 
of study requirements 
Histologically proven adenocarcinoma of the 
pancreas 
Disease of interest 
Radiologically measureable disease 
Target lesion to follow response to therapy 
ECOG functional status  0-2 
Those with worse functional status may not have 
reasonable survival to demonstrate meaningful 
follow up   
Exclusion Criteria 
Reason 
Prior radiation therapy for pancreatic cancer 
Radiation effect can alter metabolic effects of the 
pancreas. If patient has measurable disease which has 
not been radiated, they may be enrolled.  
If chemotherapy is planned, new chemotherapy 
regimen should have started no more than 21 days 
prior to enrollment 
Start pioglitazone as close to the start of a chemotherapy 
regimen  
Surgery or radiation planned within 8 weeks of 
starting therapy 
Allow adequate exposure to TZD (minimum 8 weeks) 


 
                                                                                                                                                                                      13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X.           Informed Consent Process 
The research coordinator  or the investigators  will review the consent form with  the  subject  page  by page  
describing  the  purpose  of the  study,  the research procedures, risks and alternatives. The subject will be 
given the opportunity to ask questions or voice concerns at this time.  The informed consent counseling will 
take place in an area that provides privacy. The PI or co-investigator will describe all available options to 
potential patients, to answer questions, and to help the patients make participation decisions in a non-
directive m a n n e r .  The  original signed informed consent document will be stored in a locked cabinet with 
the  patient’s  case  report  forms  (CRFs)  in  the  Clinical  Research  Office (CRO), one copy will be given to 
the patient and one copy will be placed on the chart per institutional policy. Patients who are sedated or 
deemed emotionally or mentally unable to provide informed consent for any reason are not eligible for 
enrollment. 
Prior exposure to Thiazolinedione (TZD) therapy in 
the past 12 months 
Markers of interest will be altered by previous TZD 
exposure 
Hypersensitivity of TZD 
Contraindication to pioglitazone 
New York heart association class III/IV heart failure.  
Contraindication to pioglitazone 
Known HIV positive 
HIV/AIDS related cachexia may alter metabolic findings. 
Pregnant or lactating women 
Contraindication to pioglitazone.  
Pregnancy class C, not recommended in lactating women 
History of, or active bladder cancer 
Contraindication to pioglitazone 
Inadequate hepatic function documented within 14 
days of enrollment 
Total bilirubin level > 1.5 x ULN 
AST  and  ALT  > 2.5  x ULN,  unless  there  are  liver  
metastases  in which case AST and ALT or > 5 x ULN 
TZD Clearance is significantly lower in hepatic 
impairment  


 
                                                                                                                                                                                      14 
 
XI. 
Study Subject Identification Number 
All  subjects  will  be  assigned  a  study  number  that  is  not  linked  to  their personal identifiers to prevent 
loss of confidentiality.  The number will be the IRB Protocol Number f o l l o w e d  by a sequentially number 
starting with number 01.   For example, the first subject enrolled will be assigned study subject number 
072012-036-01; the next will be 072012-036-02, and so forth. This number will be assigned by the Clinical 
Research Manager (CRM) upon confirmation of subject eligibility during the subject registration process. 
Subject registration will be confirmed once the following documents have been received by the CRM:  
• 
Signed copy of the Informed Consent signature page 
• 
Inclusion/Exclusion worksheet signed by the coordinator and treating physician 
XII. S u b j e c t  Registration 
All study subjects must be entered into the Velos database in a timely manner after obtaining the informed 
consent of the subject. Following completion of baseline assessments and confirmation of subject eligibility, 
patients will be registered and assigned a subject identification number by the CRM, Subject registration will be 
confirmed (within 24 hours) once the following documents have been received by the CRM:  
• 
Signed copy of the Informed Consent signature page 
• 
Inclusion/Exclusion worksheet signed by the coordinator and treating physician 
Since this is a double arm, pilot study, randomization to different treatment arms is not required. 
XIII. 
Study Procedures and Treatment Plan 
A.  Screening Evaluations (for both treatment and control arms) 
The following Screening assessments must be performed within 28 days before the first treatment of study 
drug: 
1 . S i g n e d  I nf orm e d  C on s e nt 
2. Complete medical history (Med Hx), including documentation of current medications (CM), and 
Adverse Event (AE) assessment; 
3. ECOG Performance Status  
 
4. Complete Physical Examination (PE); 
5.    Vital Signs - BP, HR, RR, and Temp (○C) 
6. H e i g h t  (c m ) a nd  Weight (kg)(Record on weight log – see Appendix 2); 
 
7. Laboratory requirements: 
• 
Hematology: CBC with differential and platelets 
• 
S e r u m  Chemistry: Na, K, CL, Ca, CO2, glucose, BUN, creatinine, AST, ALT, alkaline          
phosphatase, total bilirubin, total protein, albumin 
• 
S e r u m  pregnancy test (women <60 years only) 
 
8. Pathology report confirming adenocarcinoma histology 
 
9. Staging work-up: 
a.  Posterior to anterior (PA) and lateral (LAT) chest x ray (unless CT 
chest done) 
b.  CT scan of abdomen and pelvis with IV and PO contrast 
Following completion of the pretreatment assessments and confirmation of eligibility, 
patients will be registered, assign a subject identification number, evaluated and followed up 
according to the study procedures described below. Since this is a double arm, pilot study, 


 
                                                                                                                                                                                      15 
 
randomization to different treatment arms is not required. 
 
B. Week 0 (Baseline evaluation) 
The following baseline evaluations assessment will be performed on cycle 1 day 1 prior to the first dose of 
study drug: Control arm patients will have the same evaluation but will not receive study drug) 
 
•   Complete Physical Examination (PE) 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
•   Weight (kg, record on weight log) 
•   ECOG Performance Status 
• 
AE/Toxicity Assessment 
•   Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
Pregnancy test (WOCBP ONLY) 
o 
CA19-9 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
 
o 
Glucose tolerance test (0 baseline and 2 hr ingestion) 
o 
Insulin level (0 hr baseline and 2 hr post ingestion) 
o 
Adiponectin (0 hr baseline) 
 
o 
MCP-1 level (0 hr baseline) 
     •   FACT-Hep Questionnaire  
• 
MRI abdomen noncontrast (Research)Should be done +/- 7 days of starting pioglitazone (7 days pre or 7 
days after starting pioglitazone) MRI will be done on 8-10 patients chosen at PI/investigator discretion (UT 
Southwestern and PHHS patients ONLY).  
 
C. Treatment Plan 
 
1.  Prescription Information 
How Supplied:   Pioglitazone is available in 15 mg, 30 mg, and 45 mg tablets.   The 15 mg tablets are 
white to off-white, round, convex, non- scored tablets with “ACTOS” on one side and “15” on the other side.  
The 30 mg and 45 mg tablets are white to off white, round, flat, non-scored tablets with “ACTOS” on one 
side and “30” or “45” (respectively) on the other side.  Availability:  Each (15 mg, 30 mg and 45 mg) are 
available in bottles of 30, 90 or 500. 
Storage:   Pioglitazone   should   be s t o r e d    at 2 5 °C   (77°F);   excursions permitted to 15-30°C (59-86°F).   
Keep the container closed tightly, and protect from moisture and humidity. 
 
Ordering: The investigational drug pharmacist will purchase a bulk (cost efficient) supply of pioglitazone and 
dispense to study participants. 
 
Cost Coverage:  UT Southwestern Medical Center - Touchstone Diabetes Center is covering the costs of the 
pioglitazone for subjects enrolled onto this study. Invoices for reimbursement must be interoffice mailed to 
Judy Hollingsworth a t  mail code 8549.  (Mailing  Address:  UT  Southwestern Medical  Center  at  Dallas,  
Touchstone  Diabetes  Center,  Room  L5.210,  5323   Harry   Hines   Boulevard,   Dallas,   TX,   75390-8549   
Attn:   Judy Hollingsworth) 
 
Dispensation: Each subject should be given a one month (28-day) supply of pioglitazone per cycle. 
 


 
                                                                                                                                                                                      16 
 
Accountability: The investigator and investigator site are responsible for maintaining an accurate inventory and 
accountability logs for the study drug, pioglitazone, for patients enrolled on this study.  The site is permitted to use 
their own drug accountability form to record study drug dispensation and patient returned tablets.  These forms 
should be stored in the site’s dispensing pharmacy. Use of standard pharmacy accountability logs is acceptable. 
 
2.  Administration schedule: 
Patients will be instructed to take pioglitazone (45mg daily by mouth) and will be instructed on how to take 
the pioglitazone for the entire cycle (one cycle equals 28 days).   Subjects will continue taking pioglitazone  
daily for two cycles (no more than 8 weeks) or until one of the following criteria mentioned in section XIII D. 
Subjects will record their daily drug administration on a dosing diary, supplied by the study coordinator, in 
order to verify subject dosing compliance. 
 
 
See table below for treatment schedule (cycle one and subsequent cycles) 
 
Study Drug 
Cycle 1 
Cycle 2 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Pioglitazone 
daily 
daily 
daily 
daily 
daily 
daily 
daily 
daily 
 
D. Dose Modifications and Discontinuation 
• Patients developing a treatment-related CTCAE  v4 Grade 1 or 2 adverse event will have their dose 
continued at the same level. 
• Pioglitazone must be held for any grade 3 or 4 toxicity until the event resolves to at least grade 2.  Following 
the resolution, the dose of pioglitazone must be reduced to level -1. 
• The following table describes potential dose level modifications for pioglitazone. If a subject requires a dose 
reduction is beyond level -2, pioglitazone must be discontinued.    
• Patients removed from treatment for intolerable toxicity must be followed for evaluation of their time to 
disease progression (TDP). 
 
Agent 
Initial Dose 
Level -1 
Level -2 
Pioglitazone 
45 mg /day 
30 mg/day 
15 mg/day 
 
 
For all toxicities: 
 
Standard  symptomatic  treatment  will be offered  by the treating physician. 
There is no dose modification of pioglitazone for grade 1 or grade 2 toxicity 
 
Interruption in pioglitazone for greater than 14 days is not allowed.   Subjects must discontinue treatment if this 
occurs. 
 
• 
Hematologic Toxicities 
There is no need to modify or discontinue pioglitazone due to hematologic toxicity. 
• 
Diarrhea 
For grade 3 or 4 diarrhea, hold pioglitazone until diarrhea resolves to  grade 2, then it may be resumed 
at one lower dose level. 
• 
Nausea and Vomiting 
For grade 3 or 4 nausea or vomiting, hold pioglitazone until nausea and vomiting resolve to  grade 2, 


 
                                                                                                                                                                                      17 
 
then it may be resumed at one lower dose level. 
• 
Liver Function Tests 
For  grade  3  or  4  elevation  of  the  liver  function  tests,  hold  pioglitazone  until elevation of the liver 
function tests resolve to  grade 2, then gemcitabine and pioglitazone may be resumed at one lower dose 
level. 
• 
Weight Gain 
For grade 3 or 4 weight gain, hold pioglitazone until peripheral edema resolves to grade 2, then it may be 
resumed at one lower dose level. 
 
E: Concomitant medication/Treatments: 
 
Pioglitazone is metabolized through the cytochrome P450 2C8/9 and 3A4 pathways.  The metabolic pathway of 
concomitant medications will be checked prior to prescribing with pioglitazone.  According to the pioglitazone 
prescribing information, co administration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases 
pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg 
daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.   
Other strong CYP2C8 inhibitors include fluconazole, ketoconazole, nicardipine, sulfonamides, and some NSAIDS.  
Concomitant medications that are inhibitors of CYP 3A4 are likely to increase pioglitazone exposure as well and 
CYP 3A4 inducers may decrease pioglitazone concentrations.   
Concomitant administration of pioglitazone with thioridazine is contraindicated 
 
 
 
 
F.  Treatment Evaluations 
Same procedure will be followed for pioglitazone (treatment) and control arms except the control arm will 
not receive study drug (pioglitazone) and therefore will not have a pill diary 
 
2-week visit (+/- 7 days) 
• 
S ym ptom  DrivenPhysical Examination (PE) 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight (kg, record on weight log) 
• 
ECOG performance status  
• 
AE/Toxicity assessment 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
o 
Insulin level (0 hr baseline) 
o 
Adiponectin (0 hr baseline) 
 
o 
MCP-1 level (0 hr baseline) 
 
4 Week Visit (+/- 7 days) 
• 
S ym ptom  Driven Physical Examination (PE) 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight (kg, record on weight log) 
• 
ECOG Performance Status  
• 
AE/Toxicity assessment 


 
                                                                                                                                                                                      18 
 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
CA19-9 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
 
o 
Glucose tolerance test (0 baseline and 2 hr post ingestion) 
o 
Insulin level (0 hr baseline and 2 hr post ingestion) 
o 
Adiponectin (0 hr baseline) 
o 
MCP-1 level (0 hr baseline) 
• 
FACT-Hep Questionnaire 
• 
Review of Patient Pill Diary 
• 
Patient will receive 4 week refill of Pioglitazone 
6-week visit (+/- 7 days) 
• 
S ym ptom  Driven Physical Examination (PE) 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight  (kg, record on weight log) 
• 
ECOG Performance Status 
• 
 AE/Toxicity assessment 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
Albumin 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
 
• 
 Exploratory Research Lab Evaluations 
o 
Insulin level (0 hr baseline) 
o 
Adiponectin (0 hr baseline) 
o 
MCP-1 level (0 hr baseline) 
 
8 week visit (+/- 7 days) 
• 
S ym ptom  Physical Examination (PE) 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight measurement (kg, record on weight log) 
• 
ECOG performance status  
• 
AE/Toxicity Assessment 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
CA19-9 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
 
o 
Glucose tolerance test (0 hr baseline and 2 hr post ingestion) 
o 
Insulin level (0 hr baseline and 2 hr post ingestion) 
o 
Adiponectin (0 hr baseline) 


 
                                                                                                                                                                                      19 
 
o 
MCP-1 level (0 hr baseline) 
• 
FACT-Hep Questionnaire 
• 
Disease Assessment  
• 
Chest x-ray or CT scan of the chest 
• 
CT scan of the abdomen and pelvis 
• 
Review of Patient Pill Diary 
• 
MRI Abdomen non-contrast (research study) (UT Southwestern and PHHS patients ONLY) 
 
Early-Term or End of treatment visit (ET/EOT) (Early-Term, if patient discontinues treatment before 8 
weeks for any reason) (+/-7 days) 
• 
Complete physical examination 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight (kg on weight log) 
• 
ECOG Performance Status e 
• 
AE/Toxicity assessment 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
CA19-9 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
 
o 
Glucose tolerance test (0 hr baseline and 2 hr post ingestion) 
o 
Insulin level (0 hr baseline and 2 hr post ingestion) 
o 
Adiponectin (0 hr baseline) 
o 
MCP-1 level (0 hr baseline) 
• 
FACT-Hep Questionnaire 
MRI Abdomen non-contrast (research study) (UT Southwestern and PHHS patients ONLY) 
 
Follow up (2 weeks after completing treatment or last treatment date if Early-term (ET)) (+/- 7 days)  
(this corresponds to week 10 of control arm patients) 
• 
Complete physical examination 
• 
Vital Signs - BP, HR, RR, and Temp (○C) 
• 
Weight (kg, record on weight log) 
 
• 
ECOG Performance Status 
• 
Laboratory assessments: 
o 
Hematology: CBC with differential and platelet count 
o 
Serum  chemistry:  Na,  K,  Cl,  Ca,  bicarbonate,  BUN,  creatinine, 
AST,   ALT,   alkaline   phosphatase,   total   bilirubin,   total   protein, 
albumin 
o 
CA19-9 
o 
C-reactive protein level 
o 
Serum fasting glucose (fasting for at least 8 hours) 
• 
Exploratory Research Lab Evaluations 
 
o 
Glucose tolerance test (0 hr baseline and 2 hr post ingestion) 
o 
Insulin level (0 hr baseline and 2 hr post ingestion) 
o 
Adiponectin (0 hr baseline) 
o 
MCP-1 level (0 hr baseline) 
• 
FACT-Hep Questionnaire 


 
                                                                                                                                                                                      20 
 
• 
Toxicity/AE assessment 
Long term Follow-up 
Patient’s chart will be reviewed intermittently by the study team to assess:  
o 
Disease status 
o 
Vital status  
 
 
 
 
G.  Imaging Procedures 
• 
Chest, abdomen and pelvic CT scans will be performed at the treating physicians’ discretion. The 
respective institution’s imaging protocols will be followed. Contrast exams will be preferred if there is no 
contraindication to contrast.  
• 
Baseline CT Scans will be performed and then again every 8 weeks thereafter until disease progression 
or 2 years – whichever comes first.  
• 
If CT Scans are performed within four (4) weeks after discontinuing pioglitazone, then they do not have 
to be repeated if the investigator’s deems it unnecessary.  
• 
(UT Southwestern and PHHS patients ONLY) MRI Abdomen non-contrast will be performed at the 
Roger’s MRI (Department of Radiology) at baseline (7 days before starting therapy with pioglitazone or 
within 7 days of starting pioglitazone) and a second scan after the end of treatment at week 8 (to be done 
within 2 weeks of ending pioglitazone).If a patient is unable to complete 8 weeks of pioglitazone but has 
completed 6-8 weeks of therapy, a follow up MRI will be ordered (also to be done within 2 weeks of 
ending pioglitazone)  
 
 
 
H. Routine and Exploratory Lab Assessments 
 
• 
Blood for routine CBC, chemistry will be drawn per the laboratory protocol and performed in the clinical 
laboratory of the respective institutions. Results will be recorded as reported in the electronic medical 
record.  
• 
A Standard 75 gram oral glucose tolerance test will be performed and blood collection for glucose levels 
will be obtained prior to the ingestion of the solution (pre-dose (0 hr) and at 2 hours following 
ingestion). Insulin levels at 0 hr (fasting at least 8 hours) and 2 hours post ingestion will be used to calculate 
insulin resistance . Record the date of collection, time of collection, and subject ID, on the blood collection 
source document for exploratory labs. All samples should be labeled for each time point for each patient per 
study visit. Specimen labels will be provided to each site for each patient. 
• 
The following exploratory labs will be collected in a serum separator tube and sent to Dr. Scherer’s 
laboratory for evaluation: 
o 
Adiponectin Levels : performed at the UT Southwestern Metabolic core as described previously 
[1] 
o 
Insulin level at 0 and 2 hours: Analysis will be performed at the UT Southwestern Metabolic 
Phenotypic core as described previously [1] 
o 
Monocyte Chemoattractant Protein-1 (MCP-1)  performed at the MagPix multiplexing matching 
housed at the UT Southwestern Metabolic Core [2] 
o 
PAI-1 performed at the MagPix multiplexing matching housed at the UT Southwestern Metabolic 
Core [2] 
• 
Prior to shipment, complete the sample inventory logs for each patient so that specimen chain of custody 
can be established. Include in each batch shipment copies of; 1) the blood collection source documents for 
each patient; and 2) copies of each subjects specimen inventory form. Keep originals of these documents in 
the patient chart. Please see appendix XX, Specimen Processing and Shipment Instructions for further 
details. 


 
                                                                                                                                                                                      21 
 
 
Patients accrued at VA North Texas will have sample collected at the respective sites, frozen at  -20 to -80 
C and shipped on dry ice in batches to the UTSW Metabolic Core via overnight courier FedEx (FedEx 
number:370843180) to the following address  
Scherer Laboratory 
Touchstone Diabetes Center 
Department of Internal Medicine 
The University of Texas Southwestern Medical Center 
L5.210 
5323 Harry Hines Boulevard 
Dallas, TX 75390-8549 
Phone: (214) 648-8715 
Fax: (214) 648-8720 
 
H. Schedule of Events 
Procedures 
Screening1 Baseline 
2-Weeks 4-weeks 6-Weeks 8-Weeks 
End of 
Treatment or 
Early-Term 
(EOT/ET) 
14 –Day 
Follow-up3  
Informed Consent 
X
I/E  & Medical History
X
Concomitant Medications 
Review / AE Assessment
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
Height (cm)2 and Weight 
Measurement (Kg) 
X
X
X
X
X
X
X
Performance status 
(ECOG)
X
X
X
X
X
X
X
X
Hematology4
X
X
X
X
X
X
X
Serum Chemistry5 
X
X
X
X
X
X
X
Serum pregnancy test
X
X
CA 19-9
X
X
X
X
X
C-reactive protein 
X
X
X
X
X
X
X
Serum fasting glucose
X
X
X
X
X
Glucose tolerance 
X
X
X
X
X
Adiponectin
X
X
X
X
X
X
X
Insulin level
X6
X
X6
X
X6
X
X
2 hour insulin level 
X
X
X
X
X
MCP-1
X
X
X
X
X
X
X
Chest x-ray or Chest CT 
scan
X
X
X8
X
CT scan of abdomen and 
pelvis
X
X
X8
X
Toxicity Assessment 
X
X
X
X
X
X
FACT-Hep Questionnaire
X
X
X
X
X
MRI abdomen 
noncontrast
X9
X10
1.   Within 28 days before starting pioglitazone/Day 1 for control arm 
2. Height performed at screening only 
3.   Within 14 days after discontinuing pioglitazone/week 8 for control arm 


 
                                                                                                                                                                                      22 
 
 
4.   Hematology: CBC with differential and platelet count 
5.   Serum chemistry: Na, K, Cl, Ca, bicarbonate, BUN, creatinine, AST, ALT, alkaline phosphatase, total bilirubin, total protein, albumin 
6.   To be performed in conjunction with glucose tolerance test at 0 hr baseline and 2 hr post ingestion. 
7.   Chest x-ray must be posterior to anterior (PA) and lateral (LAT) plain chest x-ray. 
9. 8.  If performed within four (4) weeks of discontinuing pioglitazone, then not required to be completed (at the discretion of the 
investigator).. MRI will be done at Roger’s MRI. Baseline MRI to be done before start of pioglitazone or within the first 7 days of 
starting pioglitazone (UT Southwesten and PHHS patients ONLY) 
10.  Follow up MRI can be done within 14 days of end of treatment. If patient does not complete 8 weeks but has completed 6-8 weeks of 
therapy, a follow up MRI should be done as if completed 8 weeks. MRI will be done on 8-10 patients chosen at PI/investigator 
discretion. (UT Southwestern and PHHS patients ONLY).  


 
23 
 
XIV. 
Treatment Duration (N/A for control arm) 
 
Treatment will be continued for no more than 8 weeks of therapy or unless the following events 
take place: 
 
1.  Patient withdraws consent. 
2. Intercurrent illness that prevents further administration of pioglitazone 
3.  Unmanageable adverse events related to pioglitazone 
4.  General  or  specific  changes  in  the  patient’s  condition  that  in  the judgment of the 
physician renders the patient unacceptable for further treatment with pioglitazone 
5.  Patient is lost to follow-up.  Patient refuses to complete study procedures and scheduled 
appointments. 
6.  Patient requires more than two dose reductions  
7.  Interruption in study drug administration for greater than 14 days  
8.  Closure of the trial as deemed necessary by the principal investigator (PI),  the  UT  
Southwestern   Institutional   Review   Board  (IRB),  the Simmons Comprehensive Cancer 
Center Data and Safety Monitoring Committee (DSMC) or the U. S. Food and Drug 
Administration (FDA). 
 
 
XV. 
Withdrawal of Subjects 
Patients can withdraw voluntarily if they are unable to continue with the 
treatment or for any other reasons.  Patients will be encouraged to discuss 
withdrawal with their physician and the study team.  
Patient who withdraw voluntarily will not be followed. 
 
XVI. 
Efficacy Assessments 
 
The following outcome measures are required to evaluate the safety and 
efficacy of pioglitazone: 
 
1.  Measurement of insulin resistance biomarkers:   serum adiponectin level, 
oral glucose tolerance test, and fasting serum levels of glucose and 
insulin every four weeks. 
 
2.  The oral glucose tolerance test will be performed on the initial visit and 
every four weeks, in fasting state (at least 8 hrs). Patients will be asked 
to drink a standard glucose solution containing 75 g of carbohydrate. 
Blood glucose will be obtained prior to the ingestion (0 hr baseline) of 
the solution, and at 120 min (2 hr) following the ingestion. 
Blood samples  are 
collected for glucose levels. 
 
3.  Documentation of weight. We will measure weight every week in all 
patients receiving pioglitazone.  (See Appendix 2) 
 


 
24 
 
4. Documentation   Eastern  Oncology  Cooperative   Group  (ECOG) 
performance status. We will determine the ECOG performance status 
every week in all patients receiving pioglitazone. (See Appendix 
1) 
 
5.  Measurement  of changes  in symptoms  and  quality  of life using  the 
FACT-Hep Scale, version 4. (See Appendix 4). 
 
6.  RECIST  Criteria  will be used to determine  response.  At the time of 
every tumor assessment and at the time of study discontinuation, 
assignment  of  response  to  one  of  three  categories  will  be  made; 
complete response (CR), partial response (PR) or progressive disease 
(PD). Evaluation of measurable and non-measurable 
lesions in 
relationship   to  the   baseline   tumor   assessment   will   be   used   to 
determine response as follows. 
7. MRI will quantitate changes in a) intratumoral fat deposition in 
pancreatic cancer and b) visceral/subcutaneous fat distribution in 
pancreatic cancer patients treated with pioglitazone in this phase II 
study. To determine intratumoral fat content, we will use a 
previously described advanced chemical shift-based gradient-echo 
MRI technique that measures the proton density fat fraction 
(PDFF) [21]. In addition, MRI will allow quantitative determination 
of body fat volume in the abdomen e.g. subcutaneous/visceral 
adipose tissue (SAT/VAT) depots, which have been shown to have 
an important role in insulin resistance [22, 23].  
 
 
XVII.   Response Criteria 
 
Evaluation of Target Measurable 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 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. 
 
Evaluation of Non-Measurable Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 


 
25 
 
normalization of tumor marker level 
 
Incomplete Response/Stable  Disease (SD): Persistence of one or more 
non-target lesion(s) or/and maintenance  of tumor marker level above the 
normal limits 
 
Progressive  Disease  (PD):  Appearance  of  one  or  more  new  lesions 
and/or unequivocal progression of existing non-target lesions. 
 
All CR or PR cases must be confirmed with follow-up tumor assessments 
done more than 4 weeks from the assessments that formed the basis for a 
response. The follow-up assessment must also meet the criteria for CR or 
PR in relation to baseline assessments. 
 
Time to disease progression (TDP) is a secondary endpoint of this study. 
All patients  should be followed  for disease progression  every month for 
the first six (6) months, then every three (3) months thereafter, following 
discontinuation of study treatment until at least two (2) years after 
discontinuation of pioglitazone. 
 
XVIII.  Data handling and record keeping 
The  principal  investigator  will  maintain  adequate  records  so  that  the 
conduct of the study can be fully documented and monitored. Copies of 
protocols, case report forms (CRFs), test result originals, all product 
accountability  records,  correspondence,  subject  informed  consent,  and 
any other documents relevant to the conduct of the study will be kept on 
file in the Simmons Clinical Research Office for at least two (2) years after 
all investigational  use of product is discontinued.   Study documents must 
not be destroyed. A record will be kept of all subjects considered and 
screened  for the study and subsequently  deemed ineligible.  The reason 
for ineligibility must be recorded. 
 
Case Report Forms (CRFs) will be utilized for each subject entered into 
the study. Study participants will not be identified by name on any study 
documents.  Subjects will be identified  by a subject identification  number 
(see Section  XI). The clinical research  coordinator  will keep the subject 
code list in a secured locked file cabinet in the Simmons Clinical Research 
Office.  Additionally, all paper documents will be stored in a locked filing 
cabinet in the Clinical Research Office and all electronic records must be 
stored on a HIPAA Security Rule-compliant institutional server. 
 
XIX. Safety Monitoring 
 
A.  Adverse Event Definition 
Adverse Events: Definitions and Reporting 
 
Adverse Events will be reported as indicated by the appropriate following table (see below).    


 
26 
 
1.1.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a human research 
study participant, including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, clinical event, or disease, that occurs during the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur most 
commonly in the context of biomedical research, although on occasion, they can occur in the context 
of social and behavioral research. Adverse events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) and version number specified in the protocol. 
Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. Serious 
adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events completely 
unrelated to the condition under study and events that are expected in the context of the condition 
under study may be serious adverse events, independent of relatedness to the study itself. As 
examples, a car accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any hospitalization or 
death would be a serious adverse event, even if the event observed is a primary clinical endpoint of 
the study. 


 
27 
 
 
1.1.2 
Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the Protection of 
Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or outcome that meets 
each of the following criteria: 
• 
unexpected; and 
• 
related or possibly related to participation in the research; and 
• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
 
1.1.3 
Reporting 
Local events requiring expedited reporting, are submitted to the UTSW IRB through the UTSW eIRB 
and to the SCC DSMC Coordinator.  Hardcopies or electronic versions of the eIRB report; the NCI 
ADEERS, FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be forwarded to the DSMC Coordinator.  The DSMC Coordinator 
forwards the information onto the DSMC Chairman who determines if immediate action is required.  
Follow-up eIRB reports, and all subsequent SAE documentation that is available are also submitted to 
the DSMC Chair who determines if further action is required.    
  
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer Center, the DOT 
Manager or lead coordinator ensures that all participating sites are notified of the event and resulting 
action, according to FDA guidance for expedited reporting. DSMC Chairperson reviews all serious 
adverse events within upon receipt from the DSMC Coordinator.  The DSMC Chairperson determines 
whether action is required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
(Investigator: Insert names and phone numbers for required notifications) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not available) within 1 
working day to 214-648-7097. 
 
Written reports to: 
(Investigator: Insert names, fax numbers, an addresses for required notifications) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 


 
28 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting documentation 
 
1. Unexpected Adverse Events 
Non-serious adverse events which are classified as both unexpected (in terms of nature, severity 
and frequency) and possibly related require reporting to the UTSW IRB within 10 working days of 
PI awareness.  
2. SAEs 
Local serious adverse events (SAEs) require reporting within 2 working days of PI awareness, or 
as described in the protocol.   
3. Unanticipated Problems  
Unanticipated problems, including those that occur as non-local events, require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs and BA/BE 
studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227
351.pdf 
 
 
G. Follow-up 
All adverse events will be followed up according to Good 
Clinical Practices. 
 
H. Data and Safety Monitoring Plan 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) is 
responsible for monitoring data quality and patient safety for all UTSW SCC clinical trials.  As 
part of that responsibility, the DSMC reviews all local serious adverse events in real time as 
they are reported and reviews adverse events on a quarterly basis.  The quality assurance 
activity for the Clinical Research Office provides for periodic auditing of clinical research 
documents to ensure data integrity and regulatory compliance.  
  
A detailed description of the Data and Safety Monitoring Plan is available in section X of the 
Clinical Research Office Operations Manual.  
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing clinical 
trials, for which it serves as the DSMC of record. The QAC works as part of the DSMC to conduct 
regular audits based on the level of risk. Audit findings are reviewed at the next available DSMC 
meeting.  In this way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the patient population to be 
studied; adequacy of the data management system; and procedures to ensure the safety of study 
subjects based on the associated risks of the study.  Protocol-specific DSMC plans must be consistent 
with these principles. The following examples can be used to begin developing DSMC plans for 
individual protocols.  


 
29 
 
 
• 
High risk examples include Phase 1 studies; Phase II or III studies where the SCC is the 
DSMC; gene therapy or recombinant DNA studies; and studies in which the investigator holds 
the IND.  
 
• 
Moderate risk examples include pilot studies and other Phase II or III studies where the SCC 
DSMC is not the DSMC of record and which involve a non-FDA approved drug. 
 
• 
Low risk examples include Phase II or III studies involving FDA-approved drugs where the 
SCC DSMC is not the DSMC of record, or trials, which involve non-therapeutic interventions. 
 
• 
Exempt examples include non-interventional studies, which are exempt from audit 
requirements outlined above. 
 
Multisite Monitoring 
 
Monitoring for multi-institutional studies conducted with SCC as the primary site and coordinating 
center are the responsibility of the DOT Clinical Research Manager (CRM). The CRM or designee 
monitors all sub-sites for safety and data quality.  The purpose of ongoing data monitoring at sub-sites 
is to ensure regulatory compliance, adherence to protocol requirements, and patient safety.   
 
Sub-sites will be monitored no less than annually.  Monitoring on site is preferred; however, remote 
monitoring is acceptable where there is not adequate funding for travel.  The research documentation 
for at least 5 subjects is reviewed each time a study is monitored.  
  
Monitoring will include verification of source documentation regarding consent, patient eligibility, 
investigational treatment, drug accountability, serious adverse events, toxicities, and treatment 
response.  Results of data monitoring of sub-sites will be documented and the results will be made 
available to the QAC, during trial audit.   
  
SAE’s and reportable AE’s must be reported to the IRB of the institution in which they occurred, the 
SCC lead investigators, and the SCC DSMC. The DOT Manager or lead coordinator ensures that the 
PIs at all of the participating sites and the respective IRBs are notified of the events and resulting 
action for events which modify the risk of the protocol or which otherwise meet FDA requirements for 
expedited reporting.  
 
 XX. 
Data analysis and Statistical Methods 
 
A.  Study Design and Sample Size 
This is a double arm, open label, Phase II study of pioglitazone in patients with pancreatic cancer. 
The primary endpoint for the sample size calculation is the adiponectin serum levels change after 
the pioglitazone treatment, which is the main indicator for insulin response improvement. We are 
interested in testing the hypothesis that pioglitazone can increase adiponectin by 40% from 
baseline. The change of adiponectin from baseline was defined as c=(x1-x0)/x0, where x1 is the 
adiponectin level after treatment, and x0 is the baseline adiponectin level. So the adiponectin 


 
30 
 
change is a continuous variable. The null hypothesis is that there is no change of adiponectin 
level. (H0: c=0). The alternative hypothesis is that the treatment will lead to 40% change of 
adiponectin from baseline ( H1: c=0.4). Assuming that the standard deviation of the change is 0.5, 
(i.e the standard deviation of c values across population is  0.5), that a sample of 15 patients will 
provide a power of 82% at a significance level of 0.05 to detect 40% changes from baseline.  This 
sample size calculation was implemented using SAS, and was reproduced using Power and 
Sample Size (PS) software. 
 
 
B.  Statistical Analysis Plan 
 
Biomarkers analyses 
Statistical graphical tools will be used to illustrate the biomarker changes over 
time.  Mean and median changes of results for glucose tolerance test, serum 
adiponectin level test, weight changes, and ECOG performance status will be 
summarized. Pre-defined cut-offs will be used to dichotomize the patients into with 
or without insulin  response  improvement which consists changes in serum 
adiponectin levels and standard glucose tolerance test. The insulin response 
improvement rate and 95% exact confidence interval will be calculated. 
 
Tumor response analyses 
Complete response rate, partial response rate, objective response rate and 
progression rate after week 8 with the exact 95% confidence intervals will be 
provided. 
 
Time to progression 
For a given patient, time to progression will be defined as the number of days from 
the day of registration to the day the patient experiences an event of disease 
progression (or death). If a patient has not experienced  an event of disease 
progression (or death) at the time of analysis, then the patient’s data will be 
censored at the date of the last available evaluation. Progression-free survival will 
be summarized using the point estimate of the median time to progression, and the 
associated 90% confidence interval. Moreover, the proportion of patients who are 
progression  free at 24 months (after entering the  study)  will  be  calculated   
and  the  90%  confidence   interval  for  this proportion will be constructed. The 
data will be presented graphically using Kaplan-Meier   plots.  Additionally,   
exploratory   analysis  may  be  performed 
including 
multivariate 
Cox 
regression 
analysis 
with 
appropriate 
baseline 
characteristics as covariates. 
 
Overall survival 
For a given patient, overall survival will be defined  as the number  of days from 
the day of registration  to the day of the patient’s  death. Patients who have not 


 
31 
 
died at the time of analysis will be censored at the time they were last known to 
be alive. Overall survival will be summarized using the point estimate o f  the median 
overall  survival  time,  and  the  associated   90% confidence interval. Moreover, 
the proportion of patients who are still alive at 
24 m o n t h s    (after e n t e r i n g    the s t u d y ) will be  calculated   and  the  90% 
confidence interval for this proportion will be constructed. The data will be presented   
graphically  using Kaplan-Meier   plots.  Additionally,   exploratory analysis may be 
performed  including  multivariate  Cox  regression  analysis with appropriate 
baseline characteristics as covariates. 
 
Correlative Analyses 
Logistic  regression  on  response  and  Cox  regression  on  progression-free 
survival  will  be  explored  with  multiple  exploratory  variables  including  the 
glucose tolerance level, serum adiponectin level, fasting serum glucose and insulin 
level, weight changes and ECOG performance. The association of response with 
other demographic baseline characteristics will be explored. 
 
MRI assessment is exploratory. 
Comparison of treatment (pioglitazone) and control arm will be exploratory. 
 
Toxicity 
Toxicities   will be  categorized   using  the  NCI-CTCAE   (version 4 .0).  The 
number and severity of toxicity and side effects incidents will be analyzed 
descriptively and summarized in tabular format. 
 
 
 
XXI. 
References 
 
1. 
Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96. 
2. 
Burris, H.A., 3rd, et al., Improvements in survival and clinical benefit with gemcitabine as first-
line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol, 
1997. 15(6): p. 2403-13. 
3. 
Tisdale, M.J., Cachexia in cancer patients. Nat Rev Cancer, 2002. 2(11): p. 862-71. 
4. 
Tayek, J.A., A review of cancer cachexia and abnormal glucose metabolism in humans with 
cancer. J Am Coll Nutr, 1992. 11(4): p. 445-56. 
5. 
McCall, J.L., J.A. Tuckey, and B.R. Parry, Serum tumour necrosis factor alpha and insulin 
resistance in gastrointestinal cancer. Br J Surg, 1992. 79(12): p. 1361-3. 
6. 
Wang, W., et al., Provision of rhIGF-I/IGFBP-3 complex attenuated development of cancer 
cachexia in an experimental tumor model. Clin Nutr, 2000. 19(2): p. 127-32. 
7. 
Bowen, L., et al., The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity 
in lean and obese Zucker rats. Metabolism, 1991. 40(10): p. 1025-30. 
8. 
Fujiwara, T., et al., Characterization of new oral antidiabetic agent CS-045. Studies in KK and 
ob/ob mice and Zucker fatty rats. Diabetes, 1988. 37(11): p. 1549-58. 
9. 
Young, P.W., et al., Repeat treatment of obese mice with BRL 49653, a new potent insulin 


 
32 
 
sensitizer, enhances insulin action in white adipocytes. Association with increased insulin 
binding and cell-surface GLUT4 as measured by photoaffinity labeling. Diabetes, 1995. 44(9): 
p. 1087-92. 
10. 
Chaiken, R.L., et al., Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM 
subjects. Diabetologia, 1995. 38(11): p. 1307-12. 
11. 
Nolan, J.J., et al., Improvement in glucose tolerance and insulin resistance in obese subjects 
treated with troglitazone. N Engl J Med, 1994. 331(18): p. 1188-93. 
12. 
Yamasaki, Y., et al., Pioglitazone (AD-4833) ameliorates insulin resistance in patients with 
NIDDM. AD-4833 Glucose Clamp Study Group, Japan. Tohoku J Exp Med, 1997. 183(3): p. 
173-83. 
13. 
Lehmann, J.M., et al., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome 
proliferator-activated receptor gamma (PPAR gamma). J Biol Chem, 1995. 270(22): p. 12953-
6. 
14. 
Berg, A.H., T.P. Combs, and P.E. Scherer, ACRP30/adiponectin: an adipokine regulating 
glucose and lipid metabolism. Trends Endocrinol Metab, 2002. 13(2): p. 84-9. 
15. 
Berg, A.H., et al., The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat 
Med, 2001. 7(8): p. 947-53. 
16. 
Govindarajan, R., et al., Thiazolidinediones and the risk of lung, prostate, and colon cancer in 
patients with diabetes. J Clin Oncol, 2007. 25(12): p. 1476-81. 
17. 
Demetri, G.D., et al., Induction of solid tumor differentiation by the peroxisome proliferator-
activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad 
Sci U S A, 1999. 96(7): p. 3951-6. 
18. 
Burstein, H.J., et al., Use of the peroxisome proliferator-activated receptor (PPAR) gamma 
ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer 
Res Treat, 2003. 79(3): p. 391-7. 
19. 
Wang, C., et al., Cyclin D1 repression of peroxisome proliferator-activated receptor gamma 
expression and transactivation. Mol Cell Biol, 2003. 23(17): p. 6159-73. 
20. 
Kristiansen, G., et al., Peroxisome proliferator-activated receptor gamma is highly expressed 
in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res, 
2006. 12(21): p. 6444-51. 
21. 
Patel, N.S., et al., Association between novel MRI-estimated pancreatic fat and liver histology-
determined steatosis and fibrosis in non-alcoholic fatty liver disease. Aliment Pharmacol Ther, 
2013. 37(6): p. 630-9. 
22. 
Nguyen-Duy, T.B., et al., Visceral fat and liver fat are independent predictors of metabolic risk 
factors in men. Am J Physiol Endocrinol Metab, 2003. 284(6): p. E1065-71. 
23. 
Carey, D.G., et al., Abdominal fat and insulin resistance in normal and overweight women: 
Direct measurements reveal a strong relationship in subjects at both low and high risk of 
NIDDM. Diabetes, 1996. 45(5): p. 633-8. 
 


 
33 
 
 
 
Appendix 1 
 
ECOG Performance Status Scale 
 
Grade 
 
Definition 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, office 
work 
2 
 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
 
Capable of only limited selfcare, confined to bed or chair more than 50% 
of waking hours 
4 
 
Completely disabled. Cannot carry on any selfcare. Totally confined to 
bed or chair 
5 
 
Dead 


 
34 
 
 
 
Appendix 2 
 
Weight Log 
 
 
Subject ID: 072012-036          
 
 
Weight (kg) 
 
Screening 
Cycle 1, Day 1 
(Baseline) 
x 1.1 
 
 
If the weight of the subject becomes more than   
kg, then the 
dose should be modified according to section XIV-D of the protocol. 
 
 
 
 
Study Visit 
Weight (KG)
Week 2 
Week 4 
Week 6 
Week 8 
ET or EOS 
FU 2 WK Post ET 
or EOS 


 
35 
 
 
 
Appendix 3 
Pill Diary 
 
Subject ID: _______        
Cycle:   
 
 
Take one (1) tablet of pioglitazone by mouth one time every day.  If you forget to take a dose, but 
remember that same day, take the missed dose as soon as your remember to take it.  However, if 
you do not remember until the next day, skip the missed dose and continue your regular dosing 
schedule.  Do not take more than one dose in one day and do not take a double dose to make up 
for a missed one. 
 
Day 
Date
Did you take your tablet? 
Yes or No? 
1 
/ 
2 
/ 
3 
/ 
4 
/ 
5 
/ 
6 
/ 
7 
/ 
8 
/ 
9 
/ 
10 
/ 
11 
/ 
12 
/ 
13 
/ 
14 
/ 
15 
/ 
16 
/ 
17 
/ 
18 
/ 
19 
/ 
20 
/ 
21 
/ 
22 
/ 
23 
/ 
24 
/ 
25 
/ 
26 
/ 
27 
/ 
28 
/ 


Page 40 of 40
CONFIDENTIAL
Version Date: July, 2012 
 
 
 
 
Appendix 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-Hep Questionnaire 
 
 
Version 4 


FACT-Hep (Version 4)
US English 
Copyright 1987, 1997 
3/10/03
Page 1 of 3
 
 
 
 
 
Pt. ID#: 072012-036- ____ 
Week #:_______________ 
Date:_________________ 
Below is a list of statements that other people with your illness have said are important. By 
circling one (1) number per line, please indicate how true each statement has been for you 
during  the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
 Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
GP1 
I have a lack of energy ........................................................ 
0 
1 
2 
3 
4 
 
GP2 
I have nausea ....................................................................... 
0 
1 
2 
3 
4 
 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .......................................... 
0 
1 
2 
3 
4 
 
GP4 
I have pain ........................................................................... 
0 
1 
2 
3 
4 
 
GP5 
I am bothered by side effects of treatment .......................... 
0 
1 
2 
3 
4 
 
GP6 
I feel ill ................................................................................ 
0 
1 
2 
3 
4 
 
GP7 
I am forced to spend time in bed ......................................... 
0 
1 
2 
3 
4 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
GS1 
I feel close to my friends ..................................................... 
0 
1 
2 
3 
4 
 
GS2 
I get emotional support from my family ............................. 
0 
1 
2 
3 
4 
 
GS3 
I get support from my friends.............................................. 
0 
1 
2 
3 
4 
 
GS4 
My family has accepted my illness ..................................... 
0 
1 
2 
3 
4 
 
GS5 
I am satisfied with family communication about my 
illness................................................................................... 
0 
1 
2 
3 
4 
 
GS6 
I feel close to my partner (or the person who is my main 
support) ............................................................................... 
0 
1 
2 
3 
4 
 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please check this box 
and go to the next section. 
 
GS7 
I am satisfied with my sex life ........................................... 
0 
1 
2 
3 
4 


FACT-Hep (Version 4)
US English 
Copyright 1987, 1997 
3/10/03
Page 2 of 3
 
 
 
 
 
Pt. ID#: 072012-036- ____ 
Week #:_______________ 
Date:_________________ 
 
By circling one (1) number per line, please indicate how true each statement has been for you 
during  the past 7 days. 
 
 
 
 
 
EMOTIONAL WELL-BEING 
 Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
GE1 
I feel sad .............................................................................. 
0 
1 
2 
3 
4 
 
GE2 
I am satisfied with how I am coping with my illness.......... 
0 
1 
2 
3 
4 
 
GE3 
I am losing hope in the fight against my illness .................. 
0 
1 
2 
3 
4 
 
GE4 
I feel nervous ....................................................................... 
0 
1 
2 
3 
4 
 
GE5 
I worry about dying ............................................................. 
0 
1 
2 
3 
4 
 
GE6 
I worry that my condition will get worse ............................ 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 


FACT-Hep (Version 4)
US English 
Copyright 1987, 1997 
3/10/03
Page 3 of 3
 
 
 
 
Pt. ID#: 072012-036- ____ 
Week #:_______________ 
Date:_________________ 
 
By circling one (1) number per line, please indicate how true each statement has been for you 
during  the past 7 days. 
 
 
 
 
ADDITIONAL CONCERNS  
 Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
C1 
I have swelling or cramps in my stomach area ..................... 
0 
1 
2 
3 
4 
 
C2 
I am losing weight ................................................................ 
0 
1 
2 
3 
4 
 
C3 
I have control of my bowels ................................................. 
0 
1 
2 
3 
4 
 
C4 
I can digest my food well...................................................... 
0 
1 
2 
3 
4 
 
C5 
I have diarrhea ...................................................................... 
0 
1 
2 
3 
4 
 
C6 
I have a good appetite ........................................................... 
0 
1 
2 
3 
4 
 
 
Hep 
1 
 
CNS 
7 
I am unhappy about a change in my appearance .................. 
0 
1 
2 
3 
4 
 
I have pain in my back .......................................................... 
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation............................................... 
0 
1 
2 
3 
4 
 
H17 
I feel fatigued ........................................................................ 
0 
1 
2 
3 
4 
 
An7 
I am able to do my usual activities ....................................... 
0 
1 
2 
3 
4 
 
 
Hep 
2 
 
Hep 
3 
 
Hep 
4 
 
Hep 
5 
 
Hep 
6 
 
HN 
2 
 
Hep 
8 
I am bothered by jaundice or yellow color to my skin ......... 
0 
1 
2 
3 
4 
 
I have had fevers ................................................................... 
0 
1 
2 
3 
4 
 
I have had itching.................................................................. 
0 
1 
2 
3 
4 
 
I have had a change in the way food tastes........................... 
0 
1 
2 
3 
4 
 
I have had chills .................................................................... 
0 
1 
2 
3 
4 
 
My mouth is dry.................................................................... 
0 
1 
2 
3 
4 
 
I have discomfort or pain in my stomach area...................... 
0 
1 
2 
3 
4