Clinical trial NCT02249949
Conditions: Liposarcoma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2015-02-11; Completion date: 2023-05-01
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well efatutazone dihydrochloride works in treating patients with previously treated myxoid liposarcoma that cannot be removed by surgery. Drugs used in chemotherapy, such as efatutazone dihydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the confirmed response rate for efatutazone dihydrochloride (efatutazone) in patients with advanced myxoid liposarcoma whose disease has progressed on at least one prior therapy.

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS), overall survival (OS), and adverse event rates for efatutazone treated patients with advanced myxoid liposarcoma whose disease has progressed on at least one prior therapy.

TERTIARY OBJECTIVES:

I. To assess the predictive value of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptors (RXR) tumor expression from archived patient tumor samples.

II. To assess the predictive value of the expression of PPARgamma-regulated markers of adipocytes differentiation.

III. To assess the predictive value of the expression of PPARgamma-regulated cell cycle proteins.

IV. To assess the effects of efatutazone treatment on serum adiponectin levels.

OUTLINE:

Patients receive efatutazone dihydrochloride orally (PO) twice daily (BID) continuously. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years and then every 6 months for up to 5 years.

Arms: arm 1: Patients receive efatutazone dihydrochloride PO BID continuously. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: efatutazone
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 




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CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact  the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at 
 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Include this statement if applicable: Permission to view and 
download this protocol and its supporting documents is restricted and is based on person and site roster 
assignment housed in the CTSU RSS.   
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 




 
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Table of Contents 
 
Section 
Page 
1.0 
BACKGROUND 
................................
................................
............................................................ 6 
1.1 
AN UNMET NEED IN ADVANCED MYXOID LIPOSARCOMAS 
........................................................ 6 
1.2 
PPARGAMMA AGONISTS AS ANTI-C
ANCER THERAPY 
...............................................................
 6 
1.3 
MYXOID LIPOSARCOMAS AND PPARGAMMA 
................................
............................................. 8 
1.4 
EFATUTAZONE (CS-7017,
 DAIICHI-S
ANKYO) 
................................
............................................. 9 
1.5 
REGISTRATION QUALITY OF LIFE (QOL)
 MEASUREMENTS 
...................................................... 10 
1.6 
DESIGN CHANGE 
...................................................................................................................... 10 
2.0 
OBJECTIVES 
................................
................................
.............................................................. 11 
2.1 
PRIMARY OBJECTIVE 
................................................................................................................ 11 
2.2 
SECONDARY OBJECTIVE............................................................................................................. 11 
2.3 
CORRELATIVE SCIENCE OBJECTIVES.......................................................................................... 11 
3.0 
PATIENT SELECTION ............................................................................................................. 12 
3.1 
ON-S
TUDY GUIDELINES ............................................................................................................ 12 
3.2 
PRE-R
EGISTRATION ELIGIBILITY CRITERIA .............................................................................. 13 
3.3 
REGISTRATION/R
ANDOMIZATION ELIGIBILITY CRITERIA 
......................................................... 13 
4.0 
PATIENT REGISTRATION 
.................................................................................................... 15 
4.1 
CTEP I
NVESTIGATOR REGISTRATION PROCEDURES 
................................................................ 15 
4.2 
CTSU REGISTRATION PROCEDURES ......................................................................................... 15 
4.3 
PATIENT ENROLLMENT 
............................................................................................................ 17 
4.4 
A091202 PRE-R
EGISTRATION AND REGISTRATION REQUIREMENTS 
........................................ 18 
4.5 
REGISTRATION TO CORRELATIVE STUDY 
................................................................................. 18 
5.0 
STUDY CALENDAR 
................................
................................
.................................................. 20 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................. 22 
6.1 
SPECIMEN COLLECTION AND SUBMISSION 
................................................................................ 22 
7.0 
TREATMENT PLAN/INTERVENTION.................................................................................. 25 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING 
.......................................... 26 
8.1 
ANCILLARY THERAPY,
 CONCOMITANT MEDICATIONS,
 AND SUPPORTIVE CARE 
........................ 26 
8.2 
DOSE MODIFICATIONS 
............................................................................................................. 28 
8.3 
UNBLINDING PROCEDURES (
PRIOR TO UPDATE #02) 
................................................................ 29 
9.0 
ADVERSE EVENTS ................................................................................................................... 29 
9.1 
ROUTINE ADVERSE EVENT REPORTING 
..................................................................................... 29 
9.2 
CTCAE ROUTINE STUDY REPORTING REQUIREMENTS 
............................................................ 29 
9.3 
EXPEDITED ADVERSE EVENT REPORTING (CTEP-AERS) ......................................................... 30 
10.0 DRUG INFORMATION 
................................
................................
............................................. 33 
10.1 EFATUTAZONE DIHYDROCHLORIDE MONOHYDRATE (CS-7017)
 (A
LLIANCE IND
 #121997) 
.... 33 
11.0 MEASUREMENT OF EFFECT 
................................
................................
................................ 34 
11.1 SCHEDULE OF EVALUATIONS: 
................................
................................
................................... 34 
11.2 DEFINITIONS OF MEASURABLE AND NON-M
EASURABLE DISEASE 
........................................... 34 
11.3 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
...................................................... 35 
11.4 MEASUREMENT OF TREATMENT/I
NTERVENTION EFFECT 
......................................................... 36 
11.5 DEFINITIONS OF ANALYSIS VARIABLES 
................................
..................................................... 39 
12.0 END OF TREATMENT/INTERVENTION ............................................................................. 40 


 
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12.1 DURATION OF TREATMENT........................................................................................................ 40 
12.2    
MANAGING INELIGIBLE PATIENTS AND REGISTERED PATIENTS WHO NEVER RECEIVE PROTOCOL 
INTERVENTION 
................................
................................
........................................................... 40 
12.3 EXTRAORDINARY MEDICAL CIRCUMSTANCES 
......................................................................... 40 
13.0 STATISTICAL CONSIDERATIONS 
................................
....................................................... 41 
13.1 STUDY OVERVIEW 
................................
................................
..................................................... 41 
13.2 PRIMARY ENDPOINT AND STUDY DESIGN 
................................
................................................. 41 
13.3 SECONDARY ENDPOINTS ........................................................................................................... 41 
13.4 STATISTICAL ANALYSIS FOR TRANSLATIONAL STUDIES 
.......................................................... 41 
13.5 TOTAL SAMPLE SIZE,
 ACCRUAL DURATION,
 AND ANTICIPATED TIME TO STUDY COMPLETION
  
42 
13.6 AE STOPPING RULE 
................................
................................
................................................... 42 
13.7 ACCRUAL MONITORING STOPPING RULE 
................................................................................. 42 
13.8 PRIMARY ENDPOINT COMPLETION TIME ESTIMATION (F
OR CLINICALTRAILS.
GOV REPORTING)
  
42 
13.9 DESCRIPTIVE FACTORS 
............................................................................................................ 43 
13.10 I
NCLUSION OF WOMEN AND MINORITIES 
................................................................................. 43 
14.0 CORRELATIVE STUDIES 
...................................................................................................... 44 
14.1 BACKGROUND 
.......................................................................................................................... 44 
14.2 OBJECTIVES 
................................
................................
...............................................................
 45 
14.3 METHODS 
................................................................................................................................ 45 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
.................... 47 
16.0 REFERENCES 
........................................................................................................................... 48 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
................................. 52 
APPENDIX II  PATIENT DIARIES 
................................................................................................ 53 
 


 
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1.0  BACKGROUND 
1.1 
An Unmet Need in Advanced Myxoid Liposarcomas 
Liposarcoma (LPS) is the most common subtype of soft tissue sarcoma, constituting about 20% 
of the 13,000 soft tissue sarcomas diagnosed in the United States each year (about 2500 cases) 
[1, 2].  Liposarcomas are classified into three main subtypes, as per the 2002 WHO classification 
[1, 3, 4].  This includes well-diﬀerentiated and de-diﬀerentiated liposarcomas, accounting for 
about 45-50% of all LPS; myxoid and round cell liposarcomas (MLS), accounting for 30-35% 
of all LPS; and pleomorphic liposarcomas, accounting for only 5-10% of all LPS. 
 Like most solid cancers, liposarcomas are only curable if surgically resectable.  However, as a 
group, 50% of liposarcomas are advanced – either locally advanced unresectable or metastatic.  
For these patients, treatment is palliative, aimed at extending survival while maintaining as high 
a quality of life as possible.  Treatment for such advanced patients is generally chemotherapy, 
and while for many patients with liposarcomas, chemotherapy can be effective, the toxicities are 
significant, and the efficacy can be short lived [1, 2].  Adriamycin-based regimens have resulted 
in a wide range of response rates, generally around 30% [1]. Combination therapy can induce a 
higher  response  rate,  but  has  not  been  shown  to  improve  survival.  
  Other  commonly  used 
regimens  in  STS,  including  gemcitabine  plus  docetaxel  [5] and  pazopanib  [6] have  shown 
modest benefits in LPS. The marine-derived anti-cancer agent trabectedin has also been tested 
in LPS and initially demonstrated a promising response rate as high as 51% and a progression 
free  survival  (PFS)  up  to  17  months,  specifically  for  patients  with  MLS  [7].  However, 
subsequent  results  in  LPS  in  general  showed  tempered  enthusiasm.  For example,  a  large 
expanded access program of trabectedin revealed a response rate of only 6.9% and a median 
progression-free survival of only 3.3 months [8]. Moreover, trabectedin does have significant 
toxicity and is still not FDA approved in the United States.  Thus, for MLS, newer therapies are 
needed that could offer increased anti-tumor activity, ideally with fewer toxicities. 
1.2 
PPARgamma Agonists as Anti-Cancer Therapy 
1.2.1 Overview 
Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone 
receptor  family  of  ligand  activated  transcription  factors  [9-12].  The  PPARs  were  first 
identified as the targets of compounds found to induce peroxisomal proliferation in the liver, 
but soon after were found to be effective agents in the treatment of diabetes, acting as insulin 
sensitizing  agents.  
  Further  study  has  
revealed  a  significant role  
in  adipocyte regulation, 
inflammation, and atherosclerosis. 
Specifically,  agonists  of  the  nuclear  hormone  receptor  PPARγ,  such  as  the 
thiazolidinediones (TZDs) have shown promising potential in the treatment of a variety of 
cancer types, and particularly in liposarcoma, in vitro and in mouse models [9-12].  PPARγ 
ligands have been shown to reduce cell growth and induce differentiation in a number of 
cancer cell lines including breast, colon, gastric, pancreatic, bladder, prostate, and lung [9, 
13-16].    Mechanistically,  PPARγ agonists  act  to  inhibit  tumorigenesis  through several 
pathways [17-27].  PPARγ inhibits cellular progression through the cell cycle by inducing 
upregulation  of  the  cell  cycle  inhibitors,  p18,  p21,  and  p27  while  concurrently 
downregulating  the  cell  cycle  mediator,  cyclin  D1.    PPARγ agonists  also  inhibit 
angiogenesis, partly by reducing the expression of VEGF.  PPARγ agonists also stimulate 
apoptosis.  Finally, PPARγ agonists induce cellular differentiation.  In vivo, PPARγ agonists 
slow the growth of tumors in rodents, both in carcinogen-induced tumor models, and from 
ectopically implanted cancer cell lines (breast, colon, prostate) [9, 28].  


 
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1.2.2 Classification and mechanisms of action 
PPARs were first cloned from a Xenopus cDNA library in 1992[9, 10] .  There are three 
main subtypes,α γ, and δ. They are typical nuclear hormone receptors that, when bound to 
a  ligand,  heterodimerize  with  members  of  the  RXR  family  and  bind  to  peroxisomal 
proliferator response elements (PPREs) in the promoter region of a number of genes.  There 
they interact with several coactivators and corepressors and act to modulate expression of a 
variety of target genes.  The expression pattern of the subtypes and their biological roles 
differ [12].  PPARα is expressed in several tissues including liver, kidney, heart, skeletal 
muscle, and adipose tissue. In general, PPARα is involved in fatty acid catabolism. PPARγ 
exists  as  two  isoforms  created  by  alternative  splicing.  
  PPARγ2  is  highly  expressed  in 
adipocytes while PPARγ1 is expressed in lower levels in a variety of tissues including heart, 
skeletal muscle, colon, SI, kidney, pancreas, and spleen [12].  PPARγ is generally involved 
in  adipocyte  differentiation,  lipid  homeostasis,  and  regulation  of  blood  glucose  levels, 
though these effects may be predominately mediated by PPARγ2 [9, 12].  The effects of 
PPARγ1 are harder to elucidate, but PPARγ1 may play a larger role in the regulation of 
cellular differentiation and proliferation. 
 Finally, PPARδ 
is expressed in a variety of tissues, 
but with particularly high levels in the brain, adipose, skin, and in the developing embryo.  
PPARδ is  involved  in  embryonic  development,  myelogenesis,  and  may  act  to  enhance 
tumorigenesis. 
1.2.3 Ligands 
The endogenous ligands of the PPARs include a number of fatty acids and eicosanoids [12].  
Their role in normal biological function, however, is not well defined, particularly because 
most of the endogenous ligands identified so far are effective at micromolar concentrations, 
too high for true biological activity.  There are, however, a number of synthetic ligands [9, 
10].  The TZDs were found to be potent PPARγ agonists, and efatutazone in particular has 
a very high affinity for PPARγ.  Aryl-tyrosine derivatives such as GW 1929 are also PPARγ 
specific.  Fibric acid derivatives are weak PPARα agonists, and there are a variety of more 
potent  experimental  PPARα  agonists.  
  There  are  also  PPARα and  PPARγ dual  
receptor 
specific derivatives. Some NSAIDs have weak PPARα and PPARγ activity.  Finally, there 
are no selective PPARδ inhibitors. 
1.2.4 Biological Effects 
The PPARs are involved in a wide variety of biologic pathways [9-12].  PPARα may be 
involved  in  fatty  acid/cholesterol  regulation.    It  is  the  target  of  the  antihyperlipidemic 
fibrates,  and  
it  may  have  some  role  
in  cancer  prevention  and/or  
inflammation.  
  PPARδ 
alternatively may play a role in tumorigenesis.  PPARδ also appears to be involved in the 
maintenance of fertility by affecting embryonic implantation, as well as in myelogenesis in 
the  CNS.  
  Finally,  PPARγ has  the  widest  variety  of  effects including  the  inhibition  of 
inflammation,  induction  of  differentiation,  enhancement  of  insulin  sensitization,  and 
anticancer effects, the last of which will be the focus below.  
  
1.2.5 PPARs and Cancer 
The  interest  in  PPARγ as  a  potential  cancer  therapy  target  first  developed  with  the 
observation that ectopic expression of PPARγ in a fibroblast cell line, in the presence of 
small  amounts  of  
ligand,  could  
induce  adipogenesis,  essentially  terminal  differentiation 
[29].  Based on these observations, PPARγ agonists were tested in human liposarcoma cells, 
which normally express much higher levels of PPARγ.  These cells underwent a dramatic 


 
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differentiation  
to  adipocytes  
in  
response to  PPARγ ligands  
[30, 31].  
  Since  
then  PPARγ 
ligands have been shown to reduce cell growth and induce differentiation in a number of 
cancer  cell  
lines  
including  breast,  colon,  gastric,  pancreatic,  bladder,  prostate,  and  
lung.  
These  effects  are  often  additive  
to  
the  effects  of  
retinoids  
[13-15, 32].  
  Mechanistically, 
PPARγ agonists act to inhibit tumorigenesis through several pathways [17].  PPARγ inhibits 
cellular  progression  through  the  cell  cycle  by  inducing  upregulation  of  the  cell  cycle 
inhibitors, p18, p21, and p27 while concurrently downregulating the cell cycle mediator, 
cyclin D1[18-24]. PPARγ agonists also inhibit angiogenesis and inflammation via the COX-
2 and PGE2 pathway, and partly by reducing the expression of VEGF [33].  PPARγ agonists 
also induce autophagy via the AMPK and mTORC1 pathwa y[34].  PPARγ agonists also 
stimulate apoptosis.  They also reduce cytokine production such as interleukin (IL)-6 and 
IL-8 via NF-κB [35].  PPARγ agonists also disrupt tumor-stromal interactions required for 
metastasis  through  PTEN  and  pAKT  [33, 35].    They  prevent  cell  migration  via  the 
suppression of Snail and upregulation of E-cadherin [35] and exert several effects with the 
ERK  cascade  [36].    Finally,  PPARγ agonists  induce  cellular  differentiation,  the  exact 
mechanisms  of  which  are  not  clear,  but  do  include  modulation  of  the  cadherin-catenin 
system.  Ohta, et al, demonstrated that use of a PPARγ agonist results in a dramatic increase 
in expression of E-cadherin, with a concomitant shift of β-catenin to the cell membrane [25, 
26].  Furthermore, PPAR activity may directly affect the β-catenin/TCF pathway.  Liu and 
Farmer  have  shown  that  a  PPARγ agonist  induces  proteosome-mediated β-catenin 
degradation [37].  
In vivo, PPARγ agonists slow the growth of tumors in rodents, both in carcinogen-induced 
tumor models, and from ectopically implanted cancer cell lines (breast, colon, prostate) [9, 
28].    More  limited  data  is  available  in  humans.  In  a  large  (87,678  patient  records) 
epidemiologic study, a statistically significant 33% reduction (relative risk = 0.67; 95% CI, 
0.51 to 0.87; P = .0033) in lung cancer risk among thiazolidinedione users versus nonusers 
was observed [38].  Mueller, et al reported that Rosiglitazone led to either a decrease in or 
prolonged stabilization of PSA levels in patients with prostate cancer.  One of 41 patients 
with androgen dependent prostate cancer had a decrease in PSA of greater than 50%.  Less 
prominent declines in PSA were noted in both patients with androgen dependent (3/12) and 
androgen  
independent  (4/29)  prostate  cancer [39].  
  The  therapy  was  well  
tolerated,  
the 
majority of toxicities being mild to moderate. The only severe toxicities reported were one 
patient with reversible diarrhea, and another with transaminase elevation.   
1.3  Myxoid Liposarcomas and PPARgamma 
The potential role of PPARγ agonists as anticancer agents in liposarcoma was first described by 
Tontonoz, et  al.  
  They  demonstrated  
the  ability  of  a  PPARγ agonist,  
troglitazone  
to  
induce 
terminal  differentiation  of  liposarcoma  cell  lines [30].      Demetri, et  al,  were  later  able  to 
demonstrate in patients with liposarcoma who underwent serial tumor biopsies, before and after 
treatment with troglitazone, the re-differentiation of liposarcoma tumors into adipocytic tissue 
[31].  
 Later,  Eposti, et  al,  reported  
that  
three  out  of  four  patients  with  
recurrent,  metastatic 
liposarcoma treated with PPARγ agonist Pioglitazone had prolonged disease stabilization [40] 
Moreover, myxoid liposarcomas (MLS), which include round cell liposarcomas (RCL) may be 
particularly sensitive to treatment with a PPARγ agonist.   
MLS/RCL are defined by a chromosomal translocation: 90% of patients with MLS/RCL carry 
a t(12;16)(q13;p11) translocation resulting in the FUS-DDIT3 fusion gene (previously referred 
to as TLS-CHOP); while 10% carry a variant t(12;22) that results in an EWSR1-DDIT3 fusion 
gene [41-43].  The t(12;16)(q13;p11) fusion gene results in an mRNA fusion transcript that links 
the FUS gene on chromosome 12  with the DDIT3 gene on chromosome 16.  FUS is an RNA 


 
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binding  protein,  while  DDIT3  is  a  DNA-binding  basic  leucine  zipper  transcription  factor.  
Therefore, the FUS-DDIT3 acts as an abnormal transcription factor only found in MLS/RCL.  
The FUS-DDIT3 transgene blocks terminal differentiation of preadipocytes in vivo and in vitro.  
FUS-DDIT3  transgenic  mice  developed  MLS/RCL-like  tumors  in  adipose  tissue,  and 
transfection of FUS-DDIT3  
into  HT-1080 fibrosarcoma cells induces the transformation  
into 
liposarcomas [44, 
45]. 
 PPARγ 
plays a critical role in regulating the maturation of pre-adipocytes 
into  mature  adipocytes,  and  the  FUS-DDIT3  gene  product  blocks  expression  of  PPARγ.  
However, the rescue of PPARγ expression or the addition of a PPARγ agonist can overcome the 
block in maturation, and induce terminal differentiation [44, 45].  Thus, PPARγ agonists may 
be  particularly  active  as  anti-cancer  agents  
for  patients  with  MLS.  
 It  should  be  noted,  
that 
Debrock, et  al conducted  a  clinical  trial  of  12  patients  with  LPS  treated  with  the  second 
generation TZD, rosiglitazone. In that trial, which included six patients with MLS, the median 
progression free survival was only 5.5 months, and there were no responses.  It is possible that 
a more potent, third generation TZD may be more effective in patients with MLS. 
1.4 
Efatutazone (CS-7017, Daiichi-Sankyo) 
1.4.1 Pre-clinical Data 
Efatutazone is a novel, third-generation thiazolidinedione that selectively activates PPARγ-
mediated transcription, with little effect on other PPAR subtypes. Efatutazone is ≥ 50-times 
more  potent  than  rosiglitazone  and  500-times  more  potent  than  troglitazone  at  PPAR 
response element-activation and inhibition of cancer cell growth [46].  Efatutazone inhibits 
proliferation  of  human  pancreatic  and  anaplastic  thyroid  tumor-cell  cultures,  as  well  as 
growth of human colorectal tumor xenografts in nude rodents [47].  The antitumor activity 
of  efatutazone in  vivo may  be  enhanced  
in  combination  with  cytotoxic  agents  
including 
gemcitabine, paclitaxel, and irinotecan [48].  
1.4.2 Phase I Experience with Efatutazone 
We completed a Phase I clinical trial of the PPARγ 
agonist, efatutazone in refractory patients 
with advanced malignancies [49].  31 patients were treated at doses ranging from 0.10–1.15 
mg  twice  a  day  (BID).  While  the  maximally  tolerated  dose  was  not  reached,  based  on 
pharmacodynamic and pharmacokinetic data, 0.5mg orally BID was selected as the RP2D.  
The  drug  was  reasonably  well  tolerated. A  majority  of  patients  experienced  peripheral 
edema (55%) often requiring diuretics, which was unrelated to the dose of therapy.  Of 27 
evaluable patients, one sustained partial response (690 days on therapy) was observed in a 
patient with myxoid liposarcoma.  In addition, 12 patients had stable disease (SD), 7 for > 
80 days (81–290 days).   
1.4.3 Efatutazone Pharmacokinetics 
Following  oral  administration  of efatutazone,  the drug  gets  converted  to  the  active 
metabolite  R-150033.  In  plasma,  the  peak  concentrations  (Cmax)  of  R-150033  were 
observed at 2 to 3 hours post-dose. The mean apparent half-life ranged from 5.7 to 14 hours 
and appeared to be similar across all dose levels. Following single and multiple doses of 
efatutazone,  
the  
increase  
in  exposure  
(AUC  and  Cmax)  of  R-150033  appears to  be  dose 
proportional over the investigated dose range of 0.10 mg to 1.15 mg BID. Based on trough 
plasma concentrations, efatutazone BID  appeared to reach steady-state levels by cycle 2, 
week  1.  Accumulation  with  multiple  dosing  
to  steady  state  was  approximately  140%  
to 
180% across all doses, which is consistent with the half-life and dosing regimen.  


 
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1.4.4 Efatutazone Biomarker Analysis 
Plasma adiponectin levels were increased 6- to 14-fold by efatutazone administration at all 
dose  levels  of  0.10  mg  to  1.15  mg  twice-daily.  Although  the  increase  in  adiponectin 
appeared to be dose dependent, because of the small sample size (3 to 6 patients) and high 
inter-patient  variability,  a  definitive  conclusion  was  not  possible,  and  statistical  analysis 
revealed  no  significant  dose-dependent  effect  on  the efatutazone -mediated  increase  in 
plasma adiponectin levels.  
Archived tumor tissue was available for 21 of the 31 study patients. Freshly cut slides were 
used to perform immunohistochemical analysis of several key proteins. Recognizing that 
the formation of a bimolecular complex of PPARγ and RXR requires both analytes to be 
present in the same cell, we compared the product of the expression frequencies (determined 
as  the  percentage  positive  cells)  of  PPARγ  and  RXR  in  tumor  specimens  (an  indirect 
approximation to the percentage of cells actually expressing both receptors), in those who 
received  clinical  benefit  (SD  for  ≥60  days  or  PR)  versus  those  who  did  not.    When 
comparing samples that demonstrated increased expression frequencies of both PPARγ and 
RXR, the difference in outcome was highly statistically significant (nonparametric version 
of O’Brien’s test, 1-sided P = 0.0079).  Finally, to provide a preliminary indication of the 
performance characteristics that such a comparison might have, we performed a receiver-
operating  curve  
(ROC)  analysis  of  sensitivity  versus  specificity  of  
the  comparison,  as  a 
function of the cutoff value between predicted clinical benefit and lack of clinical benefit. 
Based on limited data, the optimal cutoff (closest distance to the point of 100% sensitivity 
and 100% specificity) is 10, corresponding to a sensitivity of 0.83 and a specificity of 0.91. 
The area under the ROC curve was 0.89 indicating a statistically significant difference from 
the null line (P = 0.0003). Thus, immunohistochemistry of archived specimens for PPARγ 
and  
retinoid-X  
receptor  expression levels is  a  
likely  predictive  biomarker  of  
response to 
efatutazone. 
Given the strong pre-clinical rational above, and based on the success of the Phase I trial of 
efatutazone,  we  now  propose  a  Phase  
II  
trial  of efatutazone for  patients  with  advanced, 
unresectable or metastatic myxoid liposarcoma, whose disease has progressed on at least 
one prior systemic therapy.  
1.5 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two  separate  meta-analyses  
recently  presented  at  ASCO,  
the  
first  
involving  23  NCCTG  and 
Mayo  Clinic  Cancer  Center  oncology  clinical  
trials,  
the  second  
involving  43  clinical  
trials. 
Routine  inclusion  of  these  measures  should  be  considered  similar  to  that  of  including 
performance status, either as stratification or prognostic covariates [50, 51].  
1.6 
Design Change 
Due to slow accrual to the trial, the decision was made to change the study design from a double 
blind, placebo controlled trial of efatutazone in myxoid liposarcoma, to single arm efatutazone 
in myxoid liposarcoma. The impact of the trial is critical as additional effective therapies are 
needed in this rare and aggressive malignancy, and the prior data is compelling that the agent 
may have activity. 
 
 


 
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2.0  OBJECTIVES  
2.1  Primary objective  
To determine  
the  confirmed  
response  
rate  
for  efatutazone in patients  with  advanced  myxoid 
liposarcoma whose disease has progressed on at least one prior therapy. 
2.2 
Secondary objective 
2.2.1 To assess the progression free survival (PFS), overall survival (OS), and adverse event rates 
for  efatutazone  treated patients  with  advanced  myxoid  liposarcoma  whose  disease  has 
progressed on at least one prior therapy. 
2.3 
Correlative science objectives 
2.3.1 To  assess  the  following  in  patients  with  advanced  unresectable  or  metastatic  myxoid 
liposarcoma treated with efatutazone: 
1) 
The  predictive  value  of  PPARg  and  RXR  
tumor  expression  
from  archived  patient 
tumor samples 
2) 
The  predictive  value  of  the  expression  of  PPARγ-regulated  markers  of  adipocyte 
differentiation. 
3)  The predictive value of the expression of PPARγ-regulated cell cycle proteins 
4)  The effects of efatutazone treatment on serum adiponectin levels 


 
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3.0  PATIENT SELECTION 
For  questions regarding  eligibility  criteria,  see the  Contact  
Information  page.  Please  note  
that  
the 
Study Chair cannot grant waivers to eligibility requirements 
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All  relevant  medical  and  other  considerations  should  be  taken  into  account  when  deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and  benefits  of  any  therapy,  and  therefore  only  enroll  patients  for  whom  this  treatment  is 
appropriate.  
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol: 
• Psychiatric illness which would prevent the patient from giving informed consent. 
• Medical  condition  such  as  uncontrolled  
infection  
(including  HIV),  uncontrolled  diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• Patients  with  a  “currently  active”  second  malignancy  other  than  non-melanoma  skin 
cancers. Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are free of disease for ≥ 3 years. 
• Patients who cannot swallow oral formulations of the agent(s). 
• Patients with a life expectancy < 12 weeks 
• Diabetic patients using insulin therapy are excluded from enrollment unless they are able to 
discontinue  insulin  use  (in  exchange,  for  example,  for  non-insulin  antihyperglycemic 
medications) due to the risk of dangerous and rapid fluid retention with the concurrent use 
of insulin and efatutazone (see Section 3.3.7) 
In addition: 
• Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study due to the teratogenic potential of 
the therapy utilized in this trial. Appropriate methods of birth control include abstinence, 
oral  contraceptives,  implantable  hormonal  contraceptives  or  double  barrier  method 
(diaphragm plus condom).  
• Efatutazone is metabolized by CYP3A4/5, and inhibits CYP2C8, 2C9, 2C19, and 3A4, and 
is  a  substrate  of  PgP  and  BCRP.  The  clinical  significance  of any  drug  interactions is 
unknown to date.  
 
 
 


 
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3.2 
Pre-Registration Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following pages. 
When  calculating  days  of  
tests  and  measurements,  
the  day  a  
test  or  measurement  
is  done  
is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later 
would be considered Day 28. 
 
  
3.2.1 Central pathology review submission:  
  
 
Patients  must  have a  FFPE  tumor  block OR 1  representative  H&E  and 20 
unstained myxoid  
liposarcoma tissue  slides  available  for  submission  
to  central 
pathology review.  This  review is  mandatory  prior  to  registration  to  confirm 
eligibility. See Section 4.4 for details on slide/block submission.   
3.3  Registration/Randomization Eligibility Criteria  
___ 
3.3.1 Measurable disease as defined in Section 11.0. 
  ___  
3.3.2 Prior Treatment:  
 
Progression  on  at  least  one  prior  systemic  chemotherapy  for  advanced, 
unresectable or metastatic disease. Prior adjuvant or neoadjuvant therapy is not 
included as prior systemic chemotherapy unless treatment occurred within the 6 
months prior to study enrollment.  
• There is no limit to the number of prior lines of treatment a patient has 
received. 
• No  treatment with  biologic  therapy,  immunotherapy,  chemotherapy, 
investigational agent for malignancy, or radiation ≤ 28 days before study 
registration.  No  treatment  with  nitrosourea  or  mitomycin  ≤  42  days 
before study registration. 
• Patients should have resolution of any toxic effects of prior therapy 
(except alopecia) to NCI CTCAE, Version 4.0, grade 1 or less. 
___ 
3.3.3  No history of the following: 
• Class III or IV congestive heart failure (CHF). 
• Pericardial effusion < 12 months (Grade 3 or 4). 
• Pericardial involvement with tumor. 
• Grade 2 or higher pleural effusion < 6 months. 
___ 
3.3.4  
No symptomatic, untreated, or uncontrolled brain metastases present.  
___ 
3.3.5 
Not pregnant and not nursing, because this study involves an investigational 
agent whose genotoxic, mutagenic and teratogenic effects on the developing 
fetus  and  newborn  are  unknown. Therefore,  for women  of  childbearing 
potential  only,  a  negative pregnancy  
test done  ≤  7  days  prior to registration  
is 
required. A female of childbearing potential is a sexually mature female who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been 
naturally postmenopausal for at least 12 consecutive months (i.e., has had menses 
at any time in the preceding 12 consecutive months). 


 
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___ 
3.3.6 
Concomitant medications:  
• Patients with diabetes mellitus requiring concurrent treatment with insulin or 
thiazolidinedione (TZD) oral agents are not eligible. 
• Patients with known hypersensitivity to any TZD oral agents are not eligible. 
___ 
 
3.3.7  Age ≥ 18 years  
___ 
3.3.8 
ECOG Performance Status 0-2 
___  
3.3.9 
Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) ≥ 1,000/mm
3 
Platelet Count ≥ 75,000/mm3  
Creatinine ≤ 1.5 mg/dL x upper limits of normal (ULN)  
 OR 
Calc. Creatinine Clearance ≥ 30 mL/min**  
 
Bilirubin ≤ 1.5 x upper limits of normal (ULN) 
SGOT (AST) and SGPT (ALT) ≤ 2.5 x upper limits of normal (ULN) * 
*For subjects with liver metastases, SGOT (AST) and SGPT (ALT) < 5 X the upper normal 
limit of institution
's normal range and bilirubin ≤ 3 x ULN are allowed 
** To be calculated by the Cockcroft-Gault formula as follows:  
CrCl (ml/min) =  (140 – age in years) x actual wt (in kg) 
    
  
  72 x serum creatinine (mg/dl) 
 
  
3.3.10  Documentation of Disease:  
Histologic  Documentation: Eligible  patients  must  have  histopathologically 
confirmed myxoid liposarcoma with confirmation of DDIT3 rearrangement. 
 
 
 
 
x .85 (for female patients) 




 
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Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol  and  submit  IRB  approval  and  supporting  documentation  to  the  CTSU  Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
•  An active roster affiliation with the Lead Network or a participating organization 
•  A valid IRB approval 
• Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
•  The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 Downloading Site Registration Documents:   
Site  
registration  
forms  may  be  downloaded  
from  
the A091202 protocol  page  
located  on  
the 
CTSU members’ website.   
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Protocols tab in the upper left of your screen 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand 
• Click on the Alliance folder to expand, then select trial protocol A091202 
• Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided 
4.2.2 Requirements for A091202 Site Registration:   
• IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB  Certification/Declaration  of  Exemption  Form,  or  combination  is 
accepted)  
4.2.3 Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, where they will be entered and tracked in the CTSU 




 
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Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the  CTSU  website  at https://www.ctsu.org or  at https://open.ctsu.org.  For  any  additional 
questions contact the CTSU Help Desk at 
 
4.4  A091202 Pre-Registration and Registration Requirements 
4.4.1 Pre-registration requirements 
• Informed consent: the patient must be aware of the neoplastic nature of his/her disease 
and  willingly  consent  after  being  informed  of  the  procedure  to  be  followed,  the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, 
and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and registration. 
• Pre-Registration eligibility criteria: Patients who meet the pre-registration eligibility 
criteria  will  be  pre-registered using  
the  OPEN  
registration  system  as  above.  Once  a 
patient  is  pre-registered,  the FFPE  tumor  block OR 1  representative  H&E  and  20 
unstained myxoid liposarcoma tissue slides from diagnostic biopsy should be sent to the 
Alliance  Biorepository  at  Ohio  State  (OSU) along  with  the  completed  “Central 
Pathology  Review  Form,” per Section  6.1. Failure  to  submit  this  form with  the 
specimens will delay turnaround time for central pathology review. The specimen will 
be centrally reviewed to confirm the patient meets the pathology criteria for myxoid 
liposarcoma  with  confirmation  of  DDIT3  
rearrangement.  Once  
the  site has  
received 
confirmation from the Alliance, and the Registration and Randomization Eligibility 
Criteria have been met, the patient can be registered to the study. 
4.4.2 Registration requirements 
• Registration Procedures: Sites will be notified via e-mail within 21 business days of 
receipt, whether or not the patient is eligible based on the central pathology review. The 
results  section  of  “Central  Pathology  Review  Form”  will  be  completed  by  the 
pathologist, scanned and sent via e-mail to the Responsible CRA listed on the form. 
After receiving the results form via e-mail, the institution must forward the form to the 
Alliance  Patient  Registration  office  at 
in  order  
to  register  
the 
patient. Once the form is forwarded to the Alliance Patient Registration Office and the 
Registration and Randomization Eligibility Criteria have been met, the patient can then 
be registered using the OPEN system (registration will occur within 14 days of specimen 
submission). The CRA should enter the ID number obtained at pre-registration into the 
OPEN system to register the patients. The OPEN system will provide the institution 
with  a  printable  confirmation  of  
registration.  Please  print  
this  confirmation  
for  your 
records. Retain the “Central Pathology Review Form” confirming eligibility for your 
records and to upload via Rave. 
Follow the OPEN enrollment procedures as detailed in Section 4.3. 
4.5 
Registration to Correlative Study 
4.5.1 Registration to Substudy described in Section 14.0 
There is one substudy  within  Alliance  A091202. This correlative science  study must  be 
offered to  all  patients enrolled  on  Alliance  A091202 (although  patients  may  opt  
to  not 
participate). This substudy does not require separate IRB approval. The substudy included 
within Alliance A091202 is: 
• Analysis  of  Cell  Cycle  Regulated  Proteins  and  Markers  of  Differentiation,  Alliance 
A091202-ST1 (Section 14.2) 


 
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If a patient answers “yes” to “I agree to have my specimen collected and I agree that my 
specimen sample(s) and related information may be used for the laboratory study described 
above.” Question #2 in the model consent, 
they have consented to participate in the substudy 
described in Section 14.0. The patient should be registered to Alliance A091202-ST1 at the 
same time they are registered to the treatment trial (A091202). Samples should be submitted 
per Section 6.0.   
 
 


 
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5.0  STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
on this trial. 
Pre-Study Testing Intervals  
•  To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical. 
• To be completed ≤ 28 DAYS before registration: Any imaging modality which is utilized for 
tumor measurement per protocol.  
• To be completed ≤ 42 DAYS before registration: Any baseline exams used for screening, or any 
imaging of any type which is not utilized for tumor measurement. 
 
 
Prior to 
Registration
* 
Days 1 (+/- 4 days) of 
each cycle through 
Cycle 4; then Day 1 (+/- 
7 days) of every odd 
numbered cycle for 
Cycle 5 and beyond  
Weeks 2 
and 3 (+/- 2 
days) of 
Cycle 1 
Post 
treatment 
follow 
up*** 
At PD, 
withdrawal, 
or 
removal****  
Tests & Observations 
History and physical, 
weight, PS 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Pulse, Blood Pressure 
X 
X 
X 
 
 
Adverse Event Assessment 
 
X 
X 
 
X 
Registration 
Fatigue/Uniscale 
Assessment 
X(1) 
 
 
 
 
Laboratory Studies 
Complete Blood Count, 
Differential, Platelets 
X 
X 
 
 
 
Creatinine,  
X 
X 
 
 
 
Albumin, glucose 
X 
X 
 
 
 
AST, ALT, Alk. Phos., 
Bili 
X 
X 
 
 
 
Fasting Triglycerides, total 
cholesterol 
 
X(5) 
 
 
 
Serum or Urine HCG 
X(2) 
 
 
 
 
Staging 
 
 
 
 
 
Central pathology review 
for eligibility 
X(3) 
 
 
 
 
Tumor Measurement 
X 
A 
 
X 
 
CT/MRI 
chest/abdomen/pelvis 
X(4) 
A 
 
A 
 
A091202-ST1 Correlative studies: For patients who consent to participate 
Archival block OR slides 
X 
 
 
 
 


 
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* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 14 days 
prior to treatment. 
*** For patients who are removed from protocol therapy for reasons other than progression: 
Physical 
examination and  staging  scans are  required every 12 weeks (+/- 7  days) (after  the  end  of 
treatment) until disease progression.  On completion of study treatment, all patients are followed 
for survival only every 6 months (+/- 30 days) until death or a maximum follow-up of 5 years. 
See also Section 12.0. 
**** Visit and AE assessment should be completed 4 weeks (+/- 7 days) after completion of protocol 
therapy 
1  
To be completed after pre-registration and prior to registration, see Appendix I. 
2 
For  women  of  childbearing  potential  (see Section 3.3).  Must  be  done ≤ 7  days  prior  to 
registration and ≤ 7 days prior to re-registration at crossover.  
3 
See Sections 4.5 and 6.1. 
4 
Baseline scans  can include  either:  1) a  CT,  spiral  CT,  or  MRI, or  2)  an  FDG-PET  scan  and 
diagnostic CT performed with both IV and oral contrast, and the CT acquired with 5 mm or less 
slice thickness. If a bone scan is used for baseline scan, please note in ECRF, but bone scans are 
not mandatory. 
Documentation (radiologic and pathology report and 
clinic note) of the diagnosis 
scan must be submitted. 
5 
Fasting triglycerides and total cholesterol will be done on Day 1 of Cycles 3 and 6 (+/- 7 days). 
A 
Every 6 weeks  
(approximately  every  2  cycles) through  24  weeks,  and  
then  every  12  weeks 
(approximately every 4 cycles) after week 24 until evidence of progression or relapse. Scans 
may be done up to 7 days prior to beginning a cycle. Confirmatory scans should also be obtained 
at least 4 weeks following documentation of objective response (see Section 11.0).  
 
If the baseline scans were a CT or MRI and bone scan, follow-up bone scans are required only 
for patients with bone metastases as the only site of evaluable disease, and are optional for other 
patients. Response assessment should include assessment of all sites of disease and use the 
same imaging method as was used at baseline. Documentation (radiologic and clinic note) 
must be provided at progression of disease. 
 
 
 


 
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6.0  DATA AND SPECIMEN SUBMISSION  
Data  collection  for  
this  study  will  be  done  exclusively  
through  
the  Medidata  Rave  clinical  data 
management system.  Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS).  To access Rave 
via  iMedidata,  the  site  user  must  have  an  active  CTEP-IAM  account  (check  at  < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >)  and the  appropriate  Rave  role  (Rave  CRA,  Read-Only,  Site 
Investigator) on either the LPO or participating organization roster at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-
IAM  user  name  and  password,  and  click  on  the  “accept”  link  in  the  upper  right-corner  of  the 
iMedidata page.  Please note, site users will not be able to access the study in Rave until all required 
Medidata  and  study  specific  
trainings  are  completed.  Trainings  will  be  
in  
the  
form  of  electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Users  
that  have  not  previously  activated  
their  
iMedidata/Rave  account  at  
the  
time of  
initial  site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account.  Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance).  
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 
 or by e-
mail at 
   
6.1 
Specimen collection and submission  
For all patients pre-registered to Alliance A091202: Real-time histopathology review will be 
conducted using the myxoid liposarcoma tissue from the diagnostic biopsies. 
 
≤ 3 days from pre-
registration 
Submit to: 
Mandatory for all patients registered to A091202: 
Archival FFPE tumor block 
OR 1 representative H&E and 
20 unstained myxoid 
liposarcoma tissue slides (if 
site does not have 20 slides, 
please send as many as 
possible, up to 20) 
X 
OSU 
 
For  patients  registered  to  substudy  A091202-ST1: All  participating  
institutions  must  ask 
patients  for  their  consent  to  participate  in  the  correlative  substudy planned  for  Alliance 
A091202-ST1,  although  patient  participation  is  optional.  Rationale  and  methods  for  the 
scientific components of these studies are described in Section 14.0. For patients who consent 
to  participate, a  portion  of the  archival  FFPE  
tumor  block OR tissue  slides  will  be used to 
complete the correlative study. 
 
 




 
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magic  marker,  labeling  each  page  of  the  report  with  the  Alliance  patient  ID,  and 
photocopying the report. 
In  addition  to  the  pathology  report,  the  institution  must  complete  and  submit  the 
“Central  Pathology  Review  Form”  with  the  tumor  block  or  slides  to  the  Alliance 
Biorepository  at  OSU.  Failure  to  submit  this  form  with  the  specimens  will  delay 
turnaround  time  for  central  pathology  review. The  top  portion  of  
the  form  must  be 
completed by typing and cannot be handwritten. For Alliance members, the form may be 
found  on  the  A091202  study  page  on  the  Alliance  website  under  the  “Supplemental 
Materials”  tab.  For  non-Alliance  institutions,  the  form  can  be  found  under  the  “LPO 
Documents” tab on the CTSU A091202 study page (www.ctsu.org). 
When  shipping  blocks  and  /or  FFPE  slides,  it  is  important  to  avoid  extreme  heat.  If 
environmental conditions indicate, specimens may be shipped in containers containing cold 
packs. The diagnostic slides must be appropriately packed to prevent damage (e.g. slides 
should be placed in appropriate slide container) and placed in an individual plastic bag. It is 
also  
important  
that  blocks  are  shipped  
in  appropriately  padded  and  secure  containers  
to 
avoid physical damage.  Do not wrap blocks or slides in tissue or paper toweling that is in 
direct contact with the paraffin. 
The  Alliance  has  
instituted  special  considerations  for  the  small  percentage  of  hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block.  
The goal of the Alliance is to provide investigators with quality histology sections for their 
research while maintaining the integrity of the tissue. All slides/blocks may be returned with 
written request by the site. 
 
 
 


 
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7.0  TREATMENT PLAN/I
NTERVENTION 
Protocol treatment is to begin ≤ 7 days from registration.  
Patients are permitted to have a new cycle of treatment delayed up to 7 days for major life events 
(e.g., serious illness in a family member, major holiday, vacation that cannot be rescheduled) without 
this being considered a protocol violation. Documentation to justify this delay should be provided. 
Patients will receive efatutazone, 0.5mg orally twice daily.  Each cycle is 21 days (3 weeks). 
If at reimaging there is no evidence of disease progression, and the patient is tolerating therapy, then 
the patient will continue to remain on treatment until progression. 
A091202 dose table: 
Agent 
Dose 
Route 
Day 
ReRx 
Efatutazone 
0.5 mg 
PO 
BID 
Every 21 days* 
*Taken continuously with no break between cycles 
 
Efatutazone tablets are to be self-administered PO BID, with or without food. The intended dosing 
schedule for efatutazone dosing is every 12 hours.  However, dosing may occur within ± 2 hours of 
the scheduled administration time. 
Treatment  is  to  continue  until  disease  progression  or  unacceptable  adverse  event. After disease 
progression or unacceptable adverse event, patients will be followed for a maximum of 5 years, as in 
Section 5.0. 
 


 
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8.0  DOSE AND TREATMENT MODIFICATIONS,
 UNBLINDING  
8.1 
Ancillary therapy, concomitant medications, and supportive care 
8.1.1 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint. 
8.1.2 Patients  should  receive  
full  supportive  care while  on  
this  study.  
  This  
includes  blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
8.1.3 Treatment  with  hormones or  other  chemotherapeutic  agents  may  not  be  administered 
except for steroids given for adrenal failure; hormones administered for non-disease-related 
conditions (e.g., non-TZD oral agents for diabetes). 
8.1.4 Antiemetics may be used at the discretion of the attending physician. 
8.1.5 Palliative  radiation  therapy:   Patients  who  require  radiation  therapy  during  protocol 
treatment will be removed from protocol therapy due to disease progression. 
8.1.6 Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional  policies  and  recommendations.    The  use  of  growth  factors  should  follow 
published  guidelines  of  the  American  Society  of  Clinical  Oncology  2006  Update  of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based, 
Clinical Practice Guideline.  J Clin Oncol 24(19): 3187-3205, 2006. 
Darbepoietin  or Epoetin  (EPO):  Use  of  darbepoietin  or epoetin  in  this  protocol  is 
permitted at the discretion of the treating physician. 
Filgrastim (G-CSF) and sargramostim (GM-CSF) 
 Filgrastim/pegfilgrastim and sargramostim may not be used: 
a.  To avoid dose reductions or delays. 
b. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs 
may  be  
indicated  
in  patients  who  have  prognostic factors  
that  are  predictive  of 
clinical  deterioration  such  as  pneumonia,  hypotension,  multi-organ  dysfunction 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines.  Investigators 
should therefore use their own discretion in using the CSFs in this setting.  The use 
of  CSF  (filgrastim/pegfilgrastim  or  sargramostim)  must  be  documented  and 
reported.  
c. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
8.1.7 Hyperlipidemia: Elevations of lipids is a known side effect of this medication. The use of 
medications for hyperlipidemia is permitted at the discretion of the treating physician. 
8.1.8 Anemia: Patients have developed anemia associated with efatutazone. Full supportive care 
should be utilized at the discretion of the treating investigator. 
8.1.9 Edema: Edema/fluid retention is a common side effect of this medication. Patients should 
maintain the weight diary, and should be weighed with all visits. Patients should contact 


 
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their physician with a weight gain of over 5lb. for further management. The following is a 
suggested regimen for fluid retention but is NOT required: 
• With  weight  gain  of  5 lbs.  or  more,  start furosemide 20mg  daily  and  spironolactone 
25mg daily 
• For additional weight gain unresponsive to initial diuretics, increase dose of furosemide 
to 40mg daily and spironolactone to 50mg daily 
• For patients allergic to sulfa-containing drugs where there may be concern over the use 
of furosemide, bumetanide may be used in place of furosemide at doses of 1mg daily, 
and increased to 2 mg daily, as needed for weight gain unresponsive to initial diuretics. 
 
 


 
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8.2 
Dose Modifications 
General rules for dose modification: 
• If multiple adverse events are seen, administer dose based on greatest reduction required 
for any single adverse event observed.  Reductions or increases apply to treatment given 
in the preceding cycle and are based on adverse events observed since the prior dose. 
• Efatutazone will not be re-escalated once reduced 
• If dose reductions beyond dose level -2 is required or efatutazone is held for 21 days, 
efatutazone will be discontinued.  
CTEP-AERS reporting may be required for some adverse events (See Section 9.0) 
8.2.1 Dose Levels 
Dose Level 
Drug Name 
Dose 
 0* 
 
Efatutazone 
0.5 mg BID 
 
-1 
 
Efatutazone 
0.5 mg every morning, 0.25mg every 
evening 
-2 
 
Efatutazone 
0.25 BID 
*Dose level 0 refers to the starting dose. 
8.2.2  Cardiac Toxicity 
For grade 3 or 4 pericardial effusion, discontinue efatutazone 
8.2.3 General disorders 
• For grade 2 edema, omit efatutazone until grade < 2, then resume efatutazone at 
same dose with diuretic support 
• For grade 3 edema, omit efatutazone until grade < 2, then resume efatutazone at 
one dose level decreased with diuretic support 
8.2.4  Pulmonary Toxicity 
• For grade  2  pleural  effusion,  omit  efatutazone  until  grade  ≤  1,  then  resume 
efatutazone at one dose decreased with diuretic support 
• For grade 3 or 4 pleural effusion, discontinue efatutazone with diuretic support 
8.2.5  Metabolism and nutrition disorders 
For grade  3  or  4  hypertriglyceridemia that  has  physiologic  or  life-threatening 
consequences,  omit  efatutazone  until  physiologic  or  life-threatening  consequences  have 
resolved, then resume at same dose. If grade 3 or 4 hypertriglyceridemia is based on the 
numeric  value  and  there  are  no  physiologic  or  life-threatening  consequences,  do  not 
interrupt drug. 
8.2.6 Non-hematologic Toxicities 
For all other grade 3 or 4 non-hematologic toxicities likely related to efatutazone, omit 
efatutazone until resolved to < grade 1, then resume efatutazone at one dose decreased   


 
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8.3 
Unblinding Procedures (prior to update #02) 
As of 10/01/16, the study was redesigned from a double-blind placebo controlled study to 
an open label single arm study of efatutazone, due to slow accrual to the trial. Therefore, on 
10/01/16 the study was unblinded and all participants were placed on open label efatutazone.   
9.0  ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. 
However, CTCAE v5.0 must be used for serious AE reporting through 
CTEP-AERS  as  of  April  1,  2018. The  CTCAE  is  available  at  http://ctep.cancer.gov/ 
reporting/ctc.html. Attribution to protocol treatment for each adverse event must be determined by 
the investigator and reported on the required forms, using the codes provided. 
9.1 
Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, Rave is used for routine AE 
reporting. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence  should  be  solicited,  and  severity  graded,  at  baseline  and  
for  each  cycle  of 
treatment.  
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Neutrophil count decreased 
Investigations 
Anemia 
Investigations 
Edema limbs 
General Disorders 
Weight gain 
Investigations 
Pleural Effusion 
Respiratory disorders 
Pericardial Effusion 
Cardiac disorders 
Cholesterol high 
Investigations 
Hypertriglyceridemia (See Section  5.0, 
Footnote “5”).  
Investigations 
Fatigue 
General Disorders 
9.2 
CTCAE Routine Study Reporting Requirements 
*Combinations  of  CTCAE  Grade  & Attribution  Required  for  Routine  AE  Data 
Submission on Case Report Forms (CRFs) 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 


 
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Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse  Events:  Other  CRF - Applies  to  AEs  occurring  between  registration  and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
 9.3 Expedited adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below. Alliance investigators are required to notify the Alliance Central Protocol Operations 
Program Office, the Study Chair, and their Institutional Review Board if a patient has an adverse 
event requiring expedited reporting. All such events must be reported in an expedited manner 
using the NCI Adverse Event Expedited Reporting System (CTEP-AERS). The descriptions and 
grading  scales  
found  
in  
the  
revised  NCI  Common  Terminology  Criteria  
for  Adverse  Events 
(CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version  
5.0  
can  
be  
downloaded  
from  the  
CTEP  
web  
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The Alliance requires investigators to route all expedited adverse events through the Alliance 
Central Protocol Operations Program Office for Alliance-coordinated studies.  Be sure to read 
this entire protocol section, as requirements are described in both the table and bullet points 
following the table. 
 The bullet points (additional instructions or exclusions) are protocol specific 
and in the case of a conflict, the additional instructions or exclusions supersede the table. 




 
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Additional Instructions or Exclusions: 
• All  adverse  events  reported  via CTEP-AERS (i.e.,  serious  adverse  events)  should  also  be 
forwarded to your local IRB, according to local IRB policies. 
• Alliance A091202 uses a drug under an Alliance IND. These reporting requirements apply for 
all agents (any arm) in this trial. 
• Grade 3/4 myelosuppression or febrile neutropenia and hospitalization resulting from such do not 
require CTEP-AERS, but should be submitted as part of study results via routine reporting.  
• Treatment expected adverse events include those listed in Section 10.0, in the IB for efatutazone. 
• All new malignancies must be reported through CTEP-AERS whether or not they are thought to 
be related to either previous or current treatment. All new malignancies should be reported, i.e. 
solid  tumors  (including  non-melanoma  skin  malignancies),  hematologoc  malignancies, 
myelodysplasic  syndrome/acute  myelogenous  
leukemia,  and  
in  situ  
tumors.  
In  CTCAE  v5.0, 
secondary  malignancies  may  be  
reported  as  one  of  
the  
following  
three  options:  1)  Leukemia 
secondary  
to  oncology  chemotherapy,  2)  Myelodysplastic  syndrome,  or  3)  Treatment-related 
secondary  malignancy. Whenever  possible,  the CTEP-AERS reports  for  new  malignancies 
should  include  tumor  pathology,  history  or  prior  tumors,  prior  treatment/current  treatment 
including  duration,  any  associated  risk  factors  or  evidence  regarding  how  long  the  new 
malignancy may have been present, when and how the new malignancy was detected, molecular 
characterization or cytogenetics of the original tumor (if available) and of any new tumor, and 
new malignancy treatment and outcome, if available. 
• All pregnancies and suspected pregnancies occurring in female patients during therapy or within 
28 days after completion of treatment on A091302 must be reported via CTEP-AERS. In CTCAE 
version 5.0, pregnancy loss is defined as “Death in utero,” and any pregnancy loss should be 
reported  as  “Pregnancy  
loss”  under  
the  Pregnancy,  puerperium  and  perinatal  conditions  SOC 
(grade 4).  
o 
CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). Fetal deaths should be reported as “Death neonatal” 
under the General disorders and administration SOC (grade 4).  
o 
The CTEP-AERS 
report should be amended for any neonatal deaths occurring within 
28 days of birth considered at least possibly related to treatment. Use the event term 
“Death neonatal” under the General disorders and administration SOC (grade 4).  
• Death  due  
to  progressive  disease  should  be  
reported as  Grade  5 “Disease  progression”  
in  
the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth  or  progression:  clinical  deterioration  associated  with  a  disease  process)  should  be 
submitted. 
• The  reporting  of  adverse  events  described  
in  
the  table  above  is  in  addition  to  and  does  not 
supplant the reporting of adverse events as part of the report of the results of the clinical trial, e.g. 
cooperative group data reporting. 


 
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Update #04 
10.0  DRUG INFORMATION 
10.1 Efatutazone dihydrochloride monohydrate (CS-7017) (Alliance IND #121997) 
Procurement  
 
Efatutazone dihydrochloride monohydrate (efatutazone) will be provided by Daiichi Sanyko and 
distributed  by  Biologics,  Inc. Use  
the  order  
form  on  
the  A091202 CTSU  webpage  
to  order 
efatutazone. 
Formulation 
Efatutazone  
is  supplied  as  0.25  mg  
tablets.  
  The  strength  of  efatutazone  
is  expressed  as  
the 
anhydrous free base. 
 Efatutazone is supplied as white uncoated tablets.  The inactive ingredients 
are mannitol, low-substituted hydroxypropyl cellulose, silicon dioxide, and magnesium stearate. 
The uncoated tablets are provided in 100 ct amber glass bottles.  
Preparation, Storage and Stability 
All drug supplies should be stored in a secure location, at room temperature, up to 25ºC (77ºF), 
with  excursions  permitted  from  up  to  30ºC  (86ºF).  At  the  end  of  the  trial,  any  expired  or 
remaining supplies should be destroyed according to institutional procedure. 
Administration 
Efatutazone should be taken twice daily at the same time each day, approximately 12 hours apart 
with or without food.   
Drug Interactions 
CYP3A4/5 is involved in the metabolism of efatutazone.  Efatutazone may inhibit CYP2C8, 
CYP2C9,  CYP2C19, and  CYP3A4.  A  drug-drug  interaction  study  with  CYP3A4  inhibitor 
ketoconazole  has  been  evaluated  in  healthy  subjects.    With  concurrent  administration  of 
ketoconazole,  total  exposure  of  efatutazone  increased  by  approximately  71%  without 
significantly affecting the peak exposure.   
Food and gastric pH effect have been evaluated in healthy subjects receiving efatutazone.  No 
clinically significant effect was observed on the oral bioavailability of efatutazone by either food 
or gastric pH.  Therefore, efatutazone can be taken together with food or gastric pH modifiers.   
In  vitro studies  indicate  that  efatutazone  has  an  inhibitory  potential  on  uptake  transporters 
(OATP1B1, OATP1B3, OAT3, and OCT2) and efflux transporters (P-glycoprotein and BCRP) 
with IC50 values of 0.508 to 16µM.  However, these levels of efatutazone are much higher than 
the exposure observed in humans; therefore drug-drug interaction on these transporters would 
be unlikely.   
Pharmacokinetics 
Absorption:   Well  absorbed  and  has  high  oral  bioavailability  (59-101.8%).   The  rate  of 
absorption is slightly slower in the fed state compared to the fasted state with respective median 
tmax values of 3 and 2 hours.  The 90% CI for the ratio of Cmax for fed to fasted states was 
from 79.3% to 89.2% associated with a 15.9% decrease in mean Cmax.  Efatutazone may be 
taken without regard to meals. 
Distribution: Vd: 16.9 L at 0.5 mg dose 
Protein binding in humans is 99.52% and low partitioning into red blood cells. 
Metabolism: In  rats  and  monkeys  efatutazone  was  mainly  metabolized  by  O-dearylation 
followed by sulfation and glucuronidation.  In vitro correlation analyses conducted using human 
liver microsomes and specific antibodies for each P50 isoform suggest that efatutazone is mainly 
metabolized by CYP3A4/5. 


 
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Update #04 
Half-life elimination: 8.37 hours 
Excretion: Feces (69.9%); urine (20.2%) 
Clearance:  1.45 L/hour 
Adverse Events 
Final safety data are available from 10 completed studies as of December 8, 2011.  Adverse drug 
reactions  which  have  a  
reasonable  causal  
relationship  
to  
treatment  with  efatutazone  
include:  
edema, facial edema, localized edema, peripheral edema, pitting edema, fluid retention, weight 
gain,  joint  swelling,  facial  swelling,  pleural  effusions,  hypercholesterolemia, 
hypertriglyceridemia, fatigue, asthenia, dyspnea, nausea, pain in the extremities, and anemia. 
Neutropenia  and  febrile  neutropenia  has  been  observed  when  efatutazone  was  given  with 
FOLFIRI. 
10.1.1 Nursing Guidelines 
1. Edema  and  
fluid  
retention  have  been  noted.  
Instruct  patient  
to  
report  any  swelling  or 
weight gain to the study team. 
2.  Lipid abnormalities  have  been  
reported.  Monitor  
lipid  panel  as  per  protocol.  Instruct 
patient on appropriate diet. 
3. Monitor  CBC  w/diff.  Instruct  patients  to  report  any  signs/symptoms  of  infection  or 
bleeding to the study team. 
4. Eye toxicity was seen in animal models but thus far has not been noted in human subjects. 
Instruct  patients  to  report  any  ocular  symptoms  immediately  (i.e., sore  or  red  eyes, 
difficulty with or changes in vision), as ulcerative keratitis has been seen in animal models 
and to a lesser extent, general eye irritation. 
5. Agent may be taken with or without food. 
11.0  MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria proposed 
by  
the  
revised  Response  Evaluation  Criteria  
in  Solid  Tumors  
(RECIST)  guidelines  
(version  1.1).  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST guideline. 
11.1 Schedule of Evaluations: 
For the purposes of this study, patients should be reevaluated every 6 weeks (approximately 
every 2 cycles) during treatment. Of note, scans should be performed according to the Study 
Calendar  
in Section  5.0.  
 In  addition  
to  a  baseline scan,  confirmatory  scans  should  also  be 
obtained ≥ 4 weeks following initial documentation of objective response 
11.2  Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measurable Disease 
A  non-nodal  lesion  is  considered  measurable  if  its  longest diameter  can  be  accurately 
measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as  assessed  using  calipers  (e.g. skin  nodules)  or  imaging.  
  In  the  case  of  skin  lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 


 
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A malignant lymph node is considered measurable if its short axis is >1.5 cm when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).   
Tumor lesions in a previously irradiated area are not considered measurable disease.   
11.2.2 Non-Measurable Disease 
All  other  lesions  (or  sites  of  disease)  are  considered  non-measurable  disease,  including 
pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm).  Bone lesions, leptomeningeal 
disease,  ascites,  pleural/pericardial  effusions,  
lymphangitis  cutis/pulmonis,  
inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
Note:    ‘Cystic  lesions’  thought  to  represent  cystic  metastases  can  be  considered  as 
measurable lesions, if they meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.  
  In  addition,  
lymph  nodes  
that  have  a  short  axis  <  1.0  cm  are  considered  non-
pathological (i.e., normal) and should not be recorded or followed. 
11.3 Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:   
• All  measurements  should  be  recorded  in  metric  notation  (i.e.,  decimal  fractions  of 
centimeters) using a ruler or calipers. 
• The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients having 
only lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both 
pre- and post-treatment tumor assessments.   
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods  have  been  used  at  the  same  evaluation  
to  assess  the  antitumor  effect  of  a 
treatment.  
11.3.2 Acceptable Modalities for Measurable Disease: 
• Conventional CT and MRI:  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. 
As  with  CT,  if  an  MRI  is  performed,  the  technical  specifications  of  the  scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  
The lesions should be measured on the same pulse sequence.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• PET-CT:  If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion  of  the  PET-CT  can  be  used  for  RECIST  measurements  and  can  be  used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.   
• Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT scans are preferable. 
• Physical  Examination:  
 For  superficial  non-nodal  lesions,  physical  examination  is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 


 
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documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
• FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in assessment 
of progressive disease (PD) and particularly possible 
'new
' disease.  A ‘positive’ FDG-
PET scanned lesion is defined as one which is FDG avid with an update greater than 
twice that of the surrounding tissue on the attenuation corrected image; otherwise, an 
FDG-PET scanned lesion is considered ‘negative.’  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:   
1)  If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.   
2)  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT at the same evaluation, additional follow-up CT scans (i.e., additional 
follow-up scans at least 4 weeks later) are needed to determine if there is truly 
progression occurring at that site. In this situation, the date of PD will be the 
date of the initial abnormal PDG-PET scan.   
3)  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, it is 
not classified as PD. 
11.3.3 Measurement at Follow-up Evaluation:   
• A subsequent scan must be obtained ≥4 weeks following initial documentation of an 
objective status of either complete response (CR) or partial response (PR).  
• In  
the  case  of  stable  disease  (SD),  follow-up  measurements  must  have  met  
the  SD 
criteria  at  least  once  after  study  entry  at  a  minimum  interval 6 weeks  (see Section 
11.4.4). 
• The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable  disease  is  mandatory  to  differentiate  between  response  or  stable  disease  (an 
effusion may be a side effect of the treatment) and progressive disease. 
•  Cytologic and histologic techniques can be used to differentiate between PR and CR in 
rare cases  
11.4 Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
• Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5, representative 
of  all  involved  organs,  should  be  identified  as  “Target  Lesions”  and  recorded  and 
measured at baseline.  These lesions can be non-nodal or nodal (as defined in 11.2.1), 
where no more than 2 lesions are from the same organ and no more than 2 malignant 
nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.   


 
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• Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. 
 It may be the case that, on occasion, 
the  largest  lesion  (or  malignant  lymph  node)  does  not  lend  itself  to  reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.   
• Baseline  Sum  of  Dimensions  
(BSD):  
  A  sum  of  
the  
longest  diameter  
for  all  
target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and  reported  as  
the  baseline  sum  of  dimensions  (BSD).  
  The  BSD  will  be  used  as 
reference  to  further  characterize  any  objective  tumor  response  in  the  measurable 
dimension of the disease.   
• Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for all 
target  lesions  plus  the  sum  of  the  short  axis  of  all  the  target  lymph  nodes  will  be 
calculated  and  reported  as  the  post-baseline  sum  of  dimensions  (PBSD).    If  the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm.  If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned.  If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non- target lesions or non-
target lymph nodes and should also be recorded at baseline.  These lesions and lymph nodes 
should be followed in accord with 11.4.3.3. 
11.4.3 Response Criteria 
11.4.3.1 All  
target  
lesions  and  
target  
lymph  nodes  
followed  by  CT/MRI/PET-CT/Chest  X-
ray/physical  examination  must  be  measured  on re-evaluation  at  evaluation  times 
specified in Section 11.1.  Specifically, a change in objective status to either a PR or 
CR cannot be done without re-measuring target lesions and target lymph nodes.  
Note:  Non-target  
lesions  and  non-target  
lymph  nodes  should  be  evaluated  at  each 
assessment, especially in the case of first response or confirmation of response.  In 
selected circumstances, certain non-target organs may be evaluated less frequently.  
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
11.4.3.2  Evaluation of Target Lesions 
• Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b.  Each target lymph node must have reduction in short axis to < 1.0 cm. 
• Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the BSD (see Section 
11.4.1). 






 
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12.0  END OF TREATMENT/I
NTERVENTION 
12.1  Duration of Treatment  
12.1.1 CR, PR, or SD: Patients who are in CR, PR or SD will continue on therapy until disease 
progression/recurrence (or withdrawal of consent).  After treatment is discontinued, patients 
will be followed per the study calendar in section 5.0. 
12.1.2  Disease  Progression: Patients  will  be  evaluated per Section  11.0. Document  details, 
including tumor measurements, on data forms. 
After  disease  progression,  patients  should  be  followed  for  survival only per  the  study 
calendar (Section 5.0). 
12.1.3 Discontinuation of study agent:  If the patient discontinues efatutazone, patients should be 
followed for survival per the study calendar (Section 5.0). 
12.2   Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may  continue protocol  
treatment,  provided the treating  physician,  study  chair,  and  executive 
officer agree there are no safety concerns if the patient continues protocol treatment. All scans, 
tests, and data submission are to continue as if the patient were eligible. Notification of the local 
IRB may be necessary per local IRB policies. 
Study  participants  who  are  
registered  
to  
the  
trial  but  never  
receive  study  
intervention  
(for  a 
reason  other  than  because  they  were  deemed  ineligible)  must  still  complete  follow-up 
requirements as specified below.  
Baseline, on-study and off-treatment notice data submission required. 
12.3 Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient
's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
•  Document the reason(s) for discontinuation of therapy on data forms. 
•  Follow the patient for protocol endpoints as required by the Study Calendar. 


 
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13.0  STATISTICAL CONSIDERATIONS 
13.1 Study Overview 
This single arm Phase II trial will assess the confirmed response rate of efatutazone in patients 
with advanced, unresectable, or metastatic myxoid liposarcoma who have received at least one 
prior systemic therapy.  Prior studies have shown that the confirmed response rate is generally 
around 5%.  It is hoped that efatutazone can increase the confirmed response rate to at least 20%.  
In  addition  
to  
the  confirmed  response  rate,  
this  
trial  will  also  estimate  
the  progression-free 
survival (PFS), overall survival (OS), and adverse event rates for efatutazone. 
13.2 Primary Endpoint and Study Design 
The primary endpoint for this study will assess the confirmed response rate (by RECIST 1.1) of 
efatutazone in patients with advanced, unresectable, or metastatic myxoid liposarcoma who have 
received at least one prior systemic therapy.  Any confirmed response that occurs during the first 
8 cycles of treatment will count as a success (24 weeks).  Per RECIST 1.1, responses need to be 
confirmed (2 consecutive responses at least 4 weeks apart) to count as a response (see Section 
11).  All eligible patients who are registered and start treatment will be evaluable for response.  
A Simon’s optimal two-stage design will be utilized (see below). This design has 80% power to 
detect an improvement in the confirmed response rate from 5% to 20%, with a significance level 
of 0.10.  See design details below: 
Interim Analysis: 
 Enroll 9 eligible patients (need 6 additional patients after design change 
to  single  arm  
trial).  
  
If  at  
least  1  confirmed  
response  
is  observed  
in  
the  
first  9  eligible 
patients, we will continue the study to a full accrual of 24 eligible patients.  Otherwise, the 
study  will  be  permanently  closed  due  
to  
lack  of  efficacy.  
  The  study  will  
remain  open 
during the interim analysis phase due to slow projected accrual rate and minimal expected 
toxicity.   
Final Analysis:  If the trial is a success during the interim analysis, we will enroll another 
15 eligible patients (24 eligible total).  If at least 3 confirmed responses are observed in the 
first  24  eligible  patients  (13%),  the  treatment  will  be  considered  worthy  of  further 
investigation.  Otherwise, the study will be permanently closed due to lack of efficacy. 
13.3 Secondary Endpoints 
The  following  endpoints  will  be  assessed:  progression-free  survival,  overall  survival,  and 
adverse events. All patients who meet the eligibility criteria, and sign the consent form will be 
considered evaluable for these endpoints. 
Progression-Free Survival:  Progression-free survival (PFS) is defined as the time from study 
entry to the first of either disease progression or death from any cause, where disease progression 
will be determined based on RECIST 1.1 criteria.  PFS will be estimated using the Kaplan-Meier 
method. 
Overall Survival:  Overall survival (OS) is defined as the time from study entry to death from 
any cause. OS will be estimated using the Kaplan-Meier method.  
Adverse events:  The maximum grade for each type of adverse event will be summarized using 
CTCAE  version  4.0.    The  frequency  and  percentage  of  grade  3+  adverse  events  will be 
estimated.  
13.4 Statistical Analysis for Translational Studies   
Due to the limited sample size in this study, the proposed translational studies are considered 
exploratory and hypothesis generating.  We plan to estimate the effects of efatutazone treatment 
on the following translational endpoints: 


 
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1)  
PPARg and RXR tumor expression from archived patient tumor samples 
2) 
PPARg-regulated markers of adipocyte differentiation. 
3) 
PPARg-regulated cell cycle proteins 
We will also correlate the tumor marker data with clinical endpoints (i.e. response, PFS, OS, 
and  adverse  events).    Statistical  and  graphical  techniques  will  be  used  to  explore  these 
relationships.  For time-to-event endpoints, we will use Cox proportional hazards models, and 
for  response/toxicity we  will  use  Logistic  regression  models.  
  In  addition,  we  will  use  the 
Fisher’s exact tests to test the association between categorical marker data and response/toxicity. 
13.5 Total Sample Size, Accrual Duration, and Anticipated Time to Study Completion 
A maximum  of  24  evaluable  patients  (21  new  efatutazone  treated  patients  +  3  already 
randomized previously) will be accrued onto this randomized phase II study unless the study is 
closed early for excessive toxicity or lack of efficacy.  We anticipate accruing an additional 20% 
of patients to account for ineligibility, cancellation, major treatment violation, or other reasons.  
Therefore, maximum accrual is about 30 patients (up to 28 treated with efatutazone (25 new, 3 
already enrolled) + 2 placebo treated patients (already enrolled from prior randomized study)). 
With an expected accrual rate of 1 patient per month, we anticipate that it will take about 3 years 
to reach full accrual. We anticipate that the study will take approximately 4 years to complete.  
This allows a 6-month follow-up for the final patient enrolled, along with data entry and analysis. 
13.6 AE Stopping Rule   
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual after any temporary suspension or (2) at any time during the conduct 
of  
the  
trial  and  
in  consideration  of  newly  acquired  
information  regarding  
the  adverse  event 
profile  of  
the  
treatment(s)  under  
investigation.  The  study  
team  may  also  choose  
to  suspend 
accrual because of unexpected adverse event profiles that have not crossed the specified rule 
below. 
Accrual will be temporarily suspended to this study if at any time we observe events considered 
at  
least  possibly  
related  
to  study  
treatment  
(i.e.,  an  adverse  event  with  attribute  specified  as 
"possible", "probable", or "definite") that satisfy any of the following criteria: 
• If at any time, 3 of the initial 9 treated patients or 33% or more of all patients (i.e. 
when accrual is greater than 9 patients) have experienced a grade 4 adverse event. 
• If  at  any  
time,  2  patients  have  experienced  a  grade  5  adverse  event  
(not  due  
to 
progressive disease). 
13.7 Accrual Monitoring Stopping Rule   
Given the expected accrual rate is around 1 patient per month, it is expected that the study will 
take around 3 years to fully accrue.  We plan to monitor the accrual continually and if we only 
end  up  accruing 3 patients  or  
less  
in  
the  
first  year  
(after  study  activation),  we  will  consider 
stopping the trial for slow accrual.   
13.8  Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting) 
The  primary  endpoint  
is  
to  determine  
the  confirmed  
response  
rate, as  discussed  
in  detail  
in 
section 13.2. The final analysis is expected to take place around 4 years after the study begins, 
so  we  expect  that  the  primary  endpoint  completion  time  to  be  around  4  years  after  study 
activation. 


 
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13.9 Descriptive Factors 
• Progression prior to starting treatment: Within 1 month vs. within 2-6 months 
• Tumor characteristics: 
-  RXR expression: high vs. low 
• Number of prior lines of therapy: 1 vs. 2 or more 
• Prior anthracycline: yes of no 
• Prior trabectedin: yes or no 
13.10 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin.  
There  
is  no  
information  currently  available  regarding  differential  effects  of  
this  regimen  
in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist.  Expected sizes of racial by gender subsets are shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 1 
 1 
 2 
Not Hispanic or Latino 
 14 
 14 
 28 
Ethnic Category: Total of all subjects 
 15 
 15 
 30 
Racial Category 
American Indian or Alaskan Native 
 1 
 1 
 2 
Asian 
 1 
 1 
 2 
Black or African American 
 1 
 1 
 2 
Native Hawaiian or other Pacific Islander  1 
 1 
 2 
White 
 11 
 11 
 22 
Racial Category: Total of all subjects 
 15 
 15 
 30 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


 
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14.0  CORRELATIVE STUDIES  
There is one substudy within Alliance A091202. This correlative science study must be offered to 
all  patients enrolled  on  Alliance  A091202  (although  patients  may  opt  to  not  participate).  This 
substudy does not require separate IRB approval. The substudy included within Alliance A091202 
is: 
Analysis of Cell Cycle Regulated Proteins and Markers of Differentiation, Alliance A091202-
ST1 
14.1  Background  
PPARγ  binds  to  Retinoic  acid  receptor  RXR-beta  as  a  heterodimer,  and  a  ligand  of  either 
receptor  can  stimulate  target  gene transcription  including Pyruvate  dehydrogenase  kinase 
isozyme 4 (Pdhk4), 
Adipose differentiation related protein (Adfp), and Fatty acid binding protein 
4  (Fabp4)  [10, 53].    PPARγ agonists  have  been  shown  to  reduce  cell  growth  and  induce 
differentiation  in  a  number  of  cancer  cell  lines  including  breast,  colon,  gastric,  pancreatic, 
bladder,  prostate,  and  lung  [9, 13-16].    Mechanistically,  PPARγ agonists  act  to  inhibit 
tumorigenesis  through  several  pathways  [17-26, 37].    PPARγ inhibits  cellular  progression 
through the cell cycle by inducing upregulation of the cell cycle inhibitors, p18, p21, and p27 
while  concurrently  downregulating the  cell  cycle  mediator,  cyclin  D1.   PPARγ agonists  also 
inhibit angiogenesis, partly by reducing the expression of VEGF [33].  PPARγ agonists also 
stimulate apoptosis [34].  Finally, PPARγ agonists induce cellular differentiation, and adipocyte 
differentiation,  as  evidenced  by  FABP4,  adipsin,  and  adiponectin  expression,  as  well  as 
demonstrated by Oil-red O staining [29, 30]. 
Efatutazone specifically restrains growth of human anaplastic thyroid and colon cancer cells in 
xenograft mouse models [46, 48, 54], and inhibits formation and progression of azoxymethane 
induced  colonic  adenomas  
in  mice  [55].  
  In  
the  anaplastic  
thyroid  cancer  cells, efatutazone 
reduces cell proliferation through a PPARγ-dependent mechanism impacting activation of Rho-
related GTP-binding protein RhoB and Cyclin-dependent kinase inhibitor 1 signaling pathways 
[46, 54].  
We  demonstrated  in  a  mouse  model  of Brca1 mutation  induced  mammary  cancer  that 
efatutazone-induced  reductions  in  AKT  phosphorylation,  and  increased  expression  in  the 
PPARγ-regulated genes Adfp, Fabp4 and Pdhk4 [56]. In this model, which is deficient in two 
cell cycle regulatory proteins BRCA1 and p53, there were no consistent changes in cell cycle 
pRB,  RB,  Cyclin  D1,  Cyclin  E,  CDK4,  CDK6,  p21,  and  E2F1  either  in  malignant  or 
preneoplastic mammary tissue.  
To  determine  if  pre-treatment  expression  levels  of  PPARγ and  RXR are  correlated  with 
response, expression levels will be assessed by immunohistochemistry (IHC) and graded by a 
combined intensity and proportion of cells staining score as we have done previously [56].  We 
hypothesize that evaluation of PPARγ and RXR expression levels by IHC could be a significant 
predictor  of  response  because in  the  Phase  I  trial  of efatutazone,  we  performed 
immunohistochemistry  on  pre-treatment  
tumor  specimens  
in  21/31  patients.  
  We  found  
that 
PPARγ and RXR protein tumor expression levels in patients with clinical benefit (defined as SD 
≥60 days or PR) were significantly greater than in patients with no clinical benefit (defined as 
SD  <60  or  disease  progression),  p=0.0079,  suggesting  a  possible  predictive  biomarker  of 
response to efatutazone. 
In  an  effort  to  identify  predictive  markers  of  response  to  efatutazone,  we  will  assess  the 
expression of PPARγ-regulated genes in archived tumor samples, as well as the predictive value 
of the expression of PPARγ and RXR itself.  These studies are aimed to demonstrate: 


 
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1) The basal state of PPARγ-regulated genes in the patient tumors.  This will provide a 
surrogate understanding of how active (or inactive) PPARγ is as a transcription factor 
in each patient’s tumor, 
 presumably as a result of the degree of FUS-DDIT3 
expression 
and presumably the timing of the development of the FUS-DDIT3 translocation during 
adipocyte differentiation 
2) The degree to which the tumor sample would be “receptive” to a PPARγ agonist, based 
on  expression  of  the  target  of  efatutazone,  PPARγ itself,  as  well  as  its  obligate 
heterodimeric partner, RXR 
Therefore, we will assess archived tumor 
samples for the 
expression of known PPARγ−regulated 
target genes and markers of differentiation including the expression products (i.e. the protein 
product) of Adfp, Fabp4, Pdhk4, as well as the expression of PPARγ−regulated cellular proteins 
regulating cell proliferation, survival and adhesion (including but not limited to p18, p21, p27,  
Cyclin D1, E-cadherin, β-catenin, and Snail). The assessment of the expression of these proteins 
will be performed by IHC [20, 34-36]. 
The correlative  aims  are designed  to  build  upon  the  phase  I  trial  described  above  that 
demonstrated  presence  of  a  biomarker,  and  further  demonstrate  the  mechanisms  by  which 
efatutazone exerts an anti-cancer effect on patient tumors.   
Specific hypotheses include: 
• We  hypothesize  
that  
the  PFS  will  be  greatest  
in  patients  with  high  
tumor  
levels  of 
PPARγ and RXR expression 
• We  hypothesize  that  an  evaluation  of  cell  cycle  regulatory  proteins,  markers  of 
differentiation, and PPARγ-regulated genes will reveal additional predictive markers  of 
response to, and potentially resistance to efatutazone. 
14.2 Objectives 
We  will  examine  
the  expression  of  a  number  of  correlative  markers  
that  
reflect the  state  of 
PPARγ-trasncriptional activity in archived tumor samples, and may serve as predictive markers 
of response to therapy. 
14.3 Methods 
Upon receipt at OSU, archived tumor FFPE block or slides will be stored at room temperature.   
Batched samples will be requested from the Alliance Biorepository to be shipped in preparation 
for the correlative assays to: 
 
 
 
 
Upon receipt at  
 lab, FFPE blocks will be submitted to the Histopathology and Tissue 
Shared Resource (HTSR) in the LCCC for serial sectioning.  
14.3.1 IHC Analysis of Integrated Biomarkers (PPARγ and RXRα) 
Analytes 
• PPARγ - The target of efatutazone and a nuclear hormone receptor that functions as 
a transcription factor 


 
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• RXRα  – An  obligate  heterodimeric  partner  of  PPARγ,  RXRα is  also  a  nuclear 
hormone receptor that functions as a transcription factor 
Antibody  staining  will be  performed  on  a  DAKO  Autostainer  Plus  Universal  Staining 
System (Model LV-1) on 5 micron sections of formalin fixed paraffin embedded tissue. 
PPARγ – will be detected using PPARγ (H-100) (sc7196,  Santa Cruz Biotechnology, Inc., 
Dallas, TX), a rabbit polyclonal antibody raised against amino acids 8-106 of PPARγ of 
human origin at a concentration of 1:20. Slides will be incubated at room temperature for 1 
hour  with  the  primary  antibody.  Primary  antibody  detection  will  be  performed  using  a 
biotinylated  secondary  antibody  using the  Peroxidase  Vectastain  Avidin  Biotin Complex 
(ABC) “Rabbit IgG” system coupled with the DAKO Liquid DAB+ Substrate Chromagen 
system (DAKO Carpinteria CA). 
RXRα  –  will  be  detected  using  RXRα  (D-20)  (sc-553,  Santa  Cruz  Biotechnology, Inc., 
Dallas, TX), an affinity purified rabbit polyclonal antibody raised against a peptide mapping 
at  
the  N-terminus  of  RXRα  of  human  origin  at  a  concentration  of  1:300.  Slides  will  be 
incubated  at  room  
temperature  for  1  hour  with  
the  primary  antibody.  Primary  antibody 
detection will be performed using a biotinylated secondary antibody using the Peroxidase 
Vectastain Avidin Biotin Complex (ABC) “Rabbit IgG” system coupled with the DAKO 
Liquid DAB+ Substrate Chromagen system (DAKO Carpinteria CA). . 
Positive controls that are expected to demonstrate different levels of PPARγ and RXRα will 
include formalin-fixed  paraffin  embedded  human  
liposarcoma,  breast  and colon  cancers, 
normal breast, liver and fat tissue obtained from the tissue bank at Georgetown University 
Medical  Center.  
  All  samples  will  be  processed  
in  parallel  with  a  no-primary-antibody 
control to evaluate possible artifactual staining from the secondary antibody.  
Sources of Assay Components 
PPARγ - Santa Cruz Biotechnology Inc.; sc-7196; dilution1:20 
RXRα – Santa Cruz Biotechnology, Inc.; sc-553; dilution 1:300 
Scoring System 
Scoring will include three components: 
• Evaluation  and  comparison  of  staining  on  sections  exposed  to  the  primary  and 
secondary  antibodies  as  compared  to  negative  control  sections  that  were  not 
exposed to the primary antibody (omitting primary antibody. Tissues will be scored 
as positively stained only if they exhibit a staining pattern with the primary antibody 
that is significantly different than that found with omitting the primary antibody. 
Those  that  do  not  demonstrate  a  significant  difference  between  primary  and 
omitting primary staining will be graded as 0+no stain and 0% cells stained (see 
below).  Tissues  that  demonstrate a  significant  difference  between  the  two 
conditions will be graded as described below.  
• IHC staining will be evaluated and scored for intensity (1 = weak, 2 = moderate, 3 
= strong) and distribution (1 = focal, 2 = moderate, 3 = diffuse).  The 2 independent 
scores are multiplied by each other to reach a final score that ranges from 1 (weak 
and focal) to 9 (strong and diffuse). 
• Two  separate  and  independent  scores  will  be  provided  for  PPARγ and  RXRα 
expression 
An important application of the raw data will be the determination of the product of the 
percent positive cells for PPARγ and RXRα for each sample (as performed in our Phase I 
trial [49].   


 
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Scoring will be performed on batched samples in a blinded fashion by two board certified 
human pathologists, independently.   
Molecular Analyses and Corresponding Biostatistics of Additional Biomarkers 
Immunohistochemical  Analysis  of PPARγ-regulated Cell  Cycle  Regulated  Proteins 
and Markers of Differentiation 
20 slides, 4µm each will be cut from the FFPE block. These slides will be used for IHC 
following either manufacturers’ instructions or as previously published [20, 56-61]. 
Detection  of  protein  expression  by  
IHC  will  be  performed  with  
the  Vectastain  ABC  kit 
(Vector Laboratories, Burlingame,CA) for:  
- p18 
- p21 
- P27 
- Cyclin D1(1:50, SP4, RM-9104-S, Neomarkers, ThermoScientific, Fremont, CA) 
- aP2 (Fatty Acid Binding Protein 4, FABP4) (HPA002188, Sigma) 
- Adipsin) (1:100, sc-47683, Santa Cruz) 
- Pyruvate dehydrogenase kinase isozyme 4 (Pdhk4) 
-  Adipose differentiation related protein (Adfp) 
- E-cadherin 
- β-Catenin 
- Snail 
Qualitative scoring of the IHC will be as follows: 0 (no stain), 1 (weak), 2 (intermediate) 
and 3 (strong). The proportion of cells with staining was scored 1 (≤1/3 positive cells), 2 
(1/3 to  2/3  positive  cells) and  3  
(≥2/3  positive  cells).  The  average  of the  proportion  and 
intensity score will be used to determine a final IHC score: 0 (none), 1 (low), 2 (medium) 
and 3 (high). A board certified academic pathologist blinded to the identity and treatment 
group of the samples will read the pathology. 
15.0  GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
There are no credentialing requirements for A091202. 
 
 
 
 
 
 


 
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16.0  REFERENCES 
 
1.  
Hoffman, A., et al., New frontiers in the treatment of liposarcoma, a therapeutically resistant 
malignant cohort. Drug Resist Updat, 2011. 14(1): p. 52-66.I 
2.  
Skubitz, K.M. and D.R. D
'Adamo, Sarcoma. Mayo Clin Proc, 2007. 82(11): p. 1409-32. 
3.  
Fletcher, C.D.M., Pathology and Genetics of Soft Tissue and Bone: World Health Organzation of 
Tumors2002, Lyon, France.: Iarc Press. 
4.  
Conyers, R., S. Young, and D.M. Thomas, Liposarcoma: molecular genetics and therapeutics. 
Sarcoma, 2011. 2011: p. 483154. 
5.  
Maki, R.G., et al., Randomized phase II study of gemcitabine and docetaxel compared with 
gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance 
for research through collaboration study 002 [corrected]. J Clin Oncol, 2007. 25(19): p. 2755-
63. 
6.  
van der Graaf, W.T., et al., Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a 
randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2012. 379(9829): p. 1879-86. 
7.  
Grosso F, D.G., Blay JY, Judson I, Le Cesne A, Spreafico C, Jimeno J, Pilotti S, D
'Incalci M, 
Casali PG, Patterns of tumor response to trabectedin (ET743) in myxoid liposarcomas. Journal of 
Clinical Oncology, ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 
Supplement), 2006: 9511, 2006. 
8.  
Samuels, B.L., et al., Clinical outcomes and safety with trabectedin therapy in patients with 
advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide 
expanded access program study. Ann Oncol, 2013. 24(6): p. 1703-9. 
9.  
Kopelovich, L., et al., Peroxisome proliferator-activated receptor modulators as potential 
chemopreventive agents. Mol Cancer Ther, 2002. 1(5): p. 357-63. 
10.  
Rosen, E.D. and B.M. Spiegelman, PPARgamma : a nuclear regulator of metabolism, 
differentiation, and cell growth. J Biol Chem, 2001. 276(41): p. 37731-4. 
11.  
Kersten, S., B. Desvergne, and W. Wahli, Roles of PPARs in health and disease. Nature, 2000. 
405(6785): p. 421-4. 
12. 
Berger, J. and D.E. Moller, The mechanisms of action of PPARs. Annu Rev Med, 2002. 53: p. 
409-35. 
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Sato, H., et al., Expression of peroxisome proliferator-activated receptor (PPAR)gamma in 
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Goke, R., et al., Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced 
apoptosis by induction of p21waf1/cip1. Digestion, 2001. 64(2): p. 75-80. 


 
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Shao, J., H. Sheng, and R.N. DuBois, Peroxisome proliferator-activated receptors modulate K-
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23.  
Diep, Q.N., et al., Structure, endothelial function, cell growth, and inflammation in blood vessels 
of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-gamma. 
Circulation, 2002. 105(19): p. 2296-302. 
24.  
Kitamura, S., et al., PPARgamma agonists inhibit cell growth and suppress the expression of 
cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells. Int J 
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modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3. 
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Yoshizumi, T., et al., Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma 
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APPENDIX I  REGISTRATION FATIGUE/U
NISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 
 
 




 
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(To be completed by research staff)  
 
Number of Pills Given:____________  
 
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________  
  
  
 
Number of Pills returned:_____________ 
Research Staff signature:_________________________________________       
Date:___________________