Conditions: Anaplastic Thyroid Cancer Recurrent Thyroid Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This phase II trial studies how well inolitazone dihydrochloride (efatutazone dihydrochloride) and paclitaxel work in treating patients with anaplastic thyroid cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as efatutazone dihydrochloride and paclitaxel, 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 if the combination of paclitaxel and efatutazone (efatutazone dihydrochloride) improves the confirmed response rate in patients with advanced anaplastic thyroid cancer.

SECONDARY OBJECTIVES:

I. To estimate the overall survival (OS), duration of response, progression-free survival (PFS), and adverse event rates for the combination of paclitaxel and efatutazone.

TERTIARY OBJECTIVES:

I. The association of biomarkers with clinical outcome data will be assessed in an exploratory translational analysis.

OUTLINE:

Patients receive paclitaxel intravenously (IV) over 3 hours on day 1 and efatutazone dihydrochloride orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 28 days, every 8 weeks until disease progression, and then every 6 months for 5 years.

Arms:
arm 1: Patients receive paclitaxel IV over 3 hours on day 1 and efatutazone dihydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: efatutazone intervention 2: paclitaxel
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Version Date 05/31/2018 
1 
Update #03 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A091305 
 
A PHASE 2 STUDY OF EFATUTAZONE, AN ORAL PPAR AGONIST, IN COMBINATION WITH 
PACLITAXEL IN PATIENTS WITH ADVANCED ANAPLASTIC THYROID CANCER  
 
Industry-supplied agent: Efatutazone (IND #121997, NSC #776711); 
Commercial agent: Paclitaxel 
 
ClinicalTrials.gov Identifier: NCT02152137 
 
Study Co-Chair 
Study Co-Chair 
Robert C. Smallridge, M.D. 
Michael Menefee, M.D. 
 
 
 
 
 
Community Oncology Co-chair 
Correlative Study Co-chair 
 
 
 
 
 
 
 
Experimental Therapeutics 
Committee Chair 
Experimental Therapeutics 
Committee Chair 
 
 
 
 
 
 
 
Primary Statistician 
 
 
 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
Participating Organizations: 
ALLIANCE/ Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 


 Alliance A091305 
Version Date 05/31/2018 
2 
Update #03 
Study Resources: 
Expedited Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers/ 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
 
A091305 Nursing Contact 
 
 
A091305 Pharmacy Contact 
 
 
Alliance Biorepository at Ohio State (OSU) 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model consent revisions: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Ohio State 
 
 
 
 


 
 
Alliance A091305 
Version Date 05/31/2018 
3 
Update #03 
 
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. 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 ............................................................................................................................ 7 
1.1 
STUDY RATIONALE ...................................................................................................................... 7 
1.2 
NONCLINICAL STUDIES ................................................................................................................ 8 
1.3 
CLINICAL EXPERIENCE ................................................................................................................ 8 
2.0 
OBJECTIVES ................................................................................................................................ 9 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 9 
2.2 
SECONDARY OBJECTIVE............................................................................................................... 9 
2.3 
CORRELATIVE SCIENCE OBJECTIVE ............................................................................................. 9 
3.0 
PATIENT SELECTION ............................................................................................................... 9 
3.1 
ON-STUDY GUIDELINES ............................................................................................................ 10 
3.2 
ELIGIBILITY CRITERIA ............................................................................................................... 10 
4.0 
PATIENT REGISTRATION ...................................................................................................... 11 
4.1 
CTEP INVESTIGATOR REGISTRATION PROCEDURES ................................................................. 11 
4.2 
CTSU REGISTRATION PROCEDURES ......................................................................................... 12 
4.3 
PATIENT ENROLLMENT .............................................................................................................. 14 
4.4 
REGISTRATION TO CORRELATIVE STUDY A091305-ST1 .......................................................... 14 
5.0 
STUDY CALENDAR .................................................................................................................. 16 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................. 18 
6.1 
DATA COLLECTION AND SUBMISSION ........................................................................................ 18 
6.2 
SPECIMEN COLLECTION AND SUBMISSION ................................................................................. 18 
7.0 
TREATMENT PLAN/INTERVENTION.................................................................................. 20 
8.0 
DOSE AND TREATMENT MODIFICATIONS ...................................................................... 21 
8.1 
ANCILLARY THERAPY, CONCOMITANT MEDICATIONS, AND SUPPORTIVE CARE ........................ 21 
8.2 
DOSE MODIFICATIONS ............................................................................................................... 22 
9.0 
ADVERSE EVENTS ................................................................................................................... 24 
9.1 
ROUTINE ADVERSE EVENT REPORTING ...................................................................................... 24 
9.2 
CTEP ADVERSE EVENT REPORTING SYSTEM (CTEP-AERS) ................................................... 25 
10.0 
DRUG INFORMATION ............................................................................................................. 28 
10.1 
GENERAL CONSIDERATIONS: ..................................................................................................... 28 
10.2 
EFATUTAZONE DIHYDROCHLORIDE MONOHYDRATE (CS-7017) (ALLIANCE IND #121997) .... 28 
10.3 
PACLITAXEL (TAXOL) ................................................................................................................ 29 
11.0 
MEASUREMENT OF EFFECT ................................................................................................ 32 
11.1 
SCHEDULE OF EVALUATIONS: ................................................................................................... 32 
11.2 
DEFINITIONS OF MEASURABLE AND NON-MEASURABLE DISEASE ........................................... 32 
11.3 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ...................................................... 33 
11.4 
MEASUREMENT OF TREATMENT/INTERVENTION EFFECT ......................................................... 34 
11.5 
DEFINITIONS OF ANALYSIS VARIABLES ..................................................................................... 37 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................. 38 
12.1 
DURATION OF TREATMENT........................................................................................................ 38 
12.2 
MANAGING INELIGIBLE AND CANCELED PATIENTS AND MAJOR PROTOCOL VIOLATIONS ......... 38 
12.3 
EXTRAORDINARY MEDICAL CIRCUMSTANCES .......................................................................... 38 
13.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 39 


 
 
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13.1 
STUDY OVERVIEW ..................................................................................................................... 39 
13.2 
PRIMARY ENDPOINT .................................................................................................................. 39 
13.3 
SECONDARY ENDPOINTS ........................................................................................................... 39 
13.4 
TRANSLATIONAL STUDIES ......................................................................................................... 40 
13.5 
TOTAL SAMPLE SIZE .................................................................................................................. 40 
13.6 
EXPECTED ACCRUAL AND ACCRUAL DURATION ...................................................................... 40 
13.7 
ANTICIPATED TIME TO STUDY COMPLETION.............................................................................. 40 
13.8  
AE STOPPING RULE ................................................................................................................... 40 
13.9  
ACCRUAL MONITORING STOPPING RULE .................................................................................. 41 
13.10 
PRIMARY ENDPOINT COMPLETION TIME ESTIMATION (FOR CLINICALTRAILS.GOV REPORTING):
 
41 
13.11 
 DESCRIPTIVE FACTORS ............................................................................................................. 41 
13.12 
INCLUSION OF WOMEN AND MINORITIES .................................................................................. 41 
14.0 
CORRELATIVE AND COMPANION STUDIES .................................................................... 43 
14.1 
CORRELATIVE SCIENCE ............................................................................................................. 43 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING .................... 43 
16.0 
REFERENCES ............................................................................................................................. 44 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ................................. 47 
APPENDIX II 
 PATIENT DIARIES .................................................................................................. 48 
 
 
 


 
 
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1.0 
BACKGROUND 
While thyroid cancer is the most common endocrine malignancy, anaplastic thyroid cancer (ATC) is 
extremely rare.  In 2013, the estimated incidence rate for thyroid cancer in the United States (US) is 
about 60,220 newly diagnosed cases (1), of which ATC comprises less than 2% (2, 3).  ATC is an 
undifferentiated, highly aggressive tumor with a median survival of 5 months from diagnosis and a 
1-year survival of no more than 20%.  Patients with ATC die from distant metastases or locoregional 
disease that obliterates the airway.  Median age at diagnosis ranges between 63 and 74 years.  ATC 
affects women more frequently than men (3).  Symptoms at diagnosis include hoarseness (due to 
invasion of the trachea, larynx, or recurrent laryngeal nerve), dysphagia (due to invasion of the 
esophagus) and dyspnea (3).  A diagnosis of ATC frequently follows a prior or concurrent diagnosis 
of well‑ differentiated thyroid cancer or benign nodular thyroid disease, and synchronous pulmonary 
metastases may be present in up to 50% of patients (3).  If detected early, extensive surgery offers 
the best chance of cure.  Combination chemotherapy and hyperfractionated radiotherapy (RT) are 
used with limited success, but several clinical studies using taxanes have shown benefit (4-7). More 
effective targeted therapies based on a better understanding of the molecular and signaling pathways 
that are disrupted in ATC are needed (8-11).  
The molecular pathogenesis of thyroid cancer is beginning to be understood, with recent studies 
describing distinct gene expression patterns (12-20).  A progression model from more differentiated 
papillary and follicular carcinomas to undifferentiated ATC has been suggested (21).  Genomic 
profiling has been performed to identify genes unique to benign versus malignant lesions (22), 
including 1 study of patients with ATC (23).  For ATC, oncogenic mutations and frequencies of 
mutation have been identified for Ras (20% to 60%) and B‑ Raf (0% to 20%) (23, 24). 
1.1 
Study Rationale 
Mechanisms of peroxisome proliferator-activated receptor (PPAR) mediated antitumor activity 
by thiazolidinediones (TZDs) include induction of cellular differentiation, promotion of cell 
cycle arrest, antiangiogenic effects, and induction of apoptosis (25).  PPAR agonists induce cell 
cycle arrest via a p53 independent pathway (26-28).  In thyroid cancer, PPAR may act as a tumor 
suppressor gene (28).  PPAR agonists are known to antagonize anti‑ apoptotic pathways such 
as survivin, which may account for synergy between PPAR agonists and taxanes, since taxanes 
upregulate survivin (29-31).  Since survivin is highly expressed in poorly differentiated cancers 
including ATC (26, 32), it is hypothesized that the combination of efatutazone, a PPAR agonist 
that may antagonize survivin, and paclitaxel may enhance antitumor activity. 
Paclitaxel is a potent suppressor of microtubule dynamics.  By binding to the paclitaxel site on 
tubulin, it induces mitotic arrest through polymerization and stabilization of microtubules.  
Paclitaxel induces cell death by apoptosis (33-36).  However, its effectiveness is limited because 
many tumors develop resistance.  One mechanism of resistance is the result of apoptotic 
blockade due to expression of survivin, which counteracts paclitaxel‑ induced apoptosis (37).  
While undetectable in most normal adult tissues, survivin is highly expressed in poorly 
differentiated cancers, including ATC.  Its expression is associated with carcinogenesis, cancer 
progression, poor prognosis, drug resistance, and short duration of survival (38).  Inhibition of 
survivin expression and/or function in tumor cells by survivin antisense or dominant‑ negative 
mutants triggers apoptosis as well as a defect in cell division (39-41). 
Paclitaxel has been shown to have antineoplastic activity in ATC cells in vitro and in vivo.  
Enhancement of paclitaxel activity by manumycin is mediated through p21 (42).  In a study in 
ATC cells, Pushkarev et al. (43) examined mechanisms of paclitaxel action in KTC‑ 2 and 
KTC‑ 3 cells and found differential sensitivity with respect to induction of apoptosis.  Low 
doses of paclitaxel phosphorylated Bcl2 (antiapoptotic protein), causing its degradation; 


 
 
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increased Bax (proapoptotic protein) levels; and resulted in accumulation of survivin 
(antiapoptotic protein) and X chromosome‑ linked inhibitor of apoptosis.  c‑ jun‑ NH terminal 
kinase activation was essential for apoptosis, and Raf/MAPK kinase/ERK and P13K/Akt were 
survival mechanisms stimulated by paclitaxel.  Survivin and c‑ IAP‑ 1 were elevated in ATC 
cells; silencing of these proteins with siRNA increased ATC cell sensitivity to chemotherapy 
(26). 
1.2 
Nonclinical Studies 
Copland et al. (25) (published and unpublished data) found that functional PPARγ and retinoid 
X receptor (RXR) α were present in multiple ATC cell lines, and that efatutazone (formerly 
RS‑ 5444; CS-7017) was a high affinity agonist, stimulating the PPAR‑  response element and 
inhibiting cell proliferation and colony formation in ATC cell lines.  This 
efatutazone‑ dependent inhibition of ATC cell proliferation was prevented by concomitant use 
of GW9662 (a pharmacologic PPARγ inhibitor), PPARγ siRNA, or lentiviral shRNA. 
Efatutazone upregulates p21WAF1/CIP1 and downregulates cyclin E in vitro and in ATC 
xenografts implanted in nude mice.  Efatutazone also upregulates Ras homolog gene family, 
member B (RhoB) mRNA and protein in cell culture and in xenografts.  Silencing RhoB inhibits 
the effect of efatutazone on both p21WAFI/CIPI and cell proliferation.  These studies led to the 
current model in which binding of efatutazone to PPARγ:RXR heterodimer up‑ regulates 
transcription of RhoB mRNA and protein, then p21WAFI/CIPI mRNA and protein, and finally 
inhibits cell cycle progression. 
An important observation by Copland et al. (25) was that efatutazone has no direct effect on 
apoptosis in ATC cells, but synergistically enhances the apoptotic effect of paclitaxel.  The 
synergism is negated by p21 siRNA.  When efatutazone and paclitaxel were used as single 
agents in an ATC xenograft model, they inhibited tumor growth by 63% and 73%, respectively.  
However, in combination they reduced tumor size by 96%.  These studies, in aggregate, have 
provided preclinical data to support a clinical study using these 2 agents in subjects with ATC. 
1.3 
Clinical Experience 
A Phase 1, open-label, dose-escalation study of oral efatutazone as a single agent given twice 
daily to 31 patients (27 evaluable) with advanced malignancies determined the recommended 
phase 2 dose to be 0.5 mg PO twice daily. One patient had a sustained partial response (690 
days) and 10 had stable disease for >60 days. There were three episodes of dose limiting toxicity, 
all related to fluid retention (which was managed by diuretics—furosemide and spironolactone). 
Common adverse events included peripheral edema (51.6%), weight increase (54.8%), anemia 
(38.7%), and fatigue (45.2%). Plasma adiponectin increased 6-to 14-fold at doses of 0.10 to 1.15 
mg twice daily.  The active metabolite R-150033 had a peak plasma level at 2-3 hours, and an 
apparent half-life from 5.7 to 14 hours. Immunohistochemistry of archived tissue samples 
showed greater expression of PPAR-gamma and retinoid-x-receptor (RXR) in patients with 
stable disease for >60 days or a partial response (44). 
Several studies have shown activity of taxanes in ATC patients: Ain et al, (4) described a single 
agent transient response rate of 53% in 19 patients receiving paclitaxel alone. Bhatia et al, (5) 
had one long term survivor out of six patients receiving paclitaxel and twice daily radiation. In 
9 stage IVB patients receiving preoperative paclitaxel, Higashiyama (6) reported a 33% response 
(with one CR) and 44% one-year survival, while Troch et al, (7) treated six patients with 
docetaxel and IMRT and had 2 PRs and 4 CRs. Pertinent to the current protocol, study CS7017-
A-U103 was a phase 1 study of efatutazone, an oral PPAR agonist, in combination with 
paclitaxel in subjects with advanced anaplastic thyroid cancer (45).  Patients received 
efatutazone orally BID for one week (run-in phase), followed by a 3 h iv infusion of paclitaxel 
(175 mg/m2) every 3 weeks in combination with efatutazone BID. Efatutazone doses were 


 
 
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escalated (0.15, 0.3, or 0.5 mg). Tissue biopsies were obtained at baseline and at one and three 
weeks for immunohistochemistry of PPAR- γ responsive proteins; serum efatutazone PK studies 
were also performed. Nineteen patients were enrolled, but 4 were not dosed (3 due to 
progression, 1 ineligible). Seven participated in efatutazone dose levels 1a/1b (0.15 mg BID), 
six in dose level 2 (0.3 mg BID), and two in dose level 3 (run-in phase only—0.5 mg BID). Of 
the 15 treated patients, 10 (67%) were women. Median age was 59 years (range: 43-82). 
Of 15 patients receiving drug, one had a confirmed partial response (PR) lasting from Day 69 to 
Day 175, and eight had stable disease (SD) as their best response. Median Time to Progression 
in 7 patients at Dose Level 1 was 49 days, but 70 days in Dose Level 2 (43% prolongation); 
corresponding median survival was 99 (0.15 mg BID) vs. 140 days (0.3 mg BID, 42% increase). 
Median peak efatutazone blood level was 8.6 ng/mL (range: 5.1 to 13.7) for Level 1 and 22.0 
ng/mL (17.0 to 31.5) for Dose Level 2. Ten patients had AEs ≥ Grade 3, with two (anemia and 
localized edema) related to efatutazone.  Thirteen events of fluid retention/edema were reported 
in 8 patients, with only 2 events of CTCAE grade ≥ 3. Eight patients had ≥ one SAE, with one 
(anemia) due to efatutazone. One SAE (anaphylactic reaction) was related to paclitaxel. No 
dose-limiting toxicity was observed. Biopsies were available on 7 patients at baseline, in 5 
patients at one week of efatutazone and in 2 patients after one cycle of combination therapy. 
PPAR-γ, RXR-α, RhoB were present in all; angiopoietin-like 4 was induced by efatutazone. 
Combination therapy with efatutazone and paclitaxel was tolerated and has biologic activity in 
patients with metastatic anaplastic thyroid carcinoma, with initial exploratory data suggesting a 
dose-dependent improvement in time to progression and survival in response to escalating 
efatutazone dosage.  
Several recent studies have shown that aggressive multimodal therapy (surgery, if possible; 
IMRT; plus cytotoxic chemotherapeutics, usually including a taxane) have prolonged survival 
in ATC patients with Stages IVA and IVB, but not IVC disease (46, 47). The death rate is still 
high, even in patients with only locoregional disease at presentation, and so different agents need 
to be tested, based upon preclinical results, to identify drug combinations that will improve 
outcomes in both the adjuvant and metastatic settings. The current protocol, based on 
encouraging preclinical data and evidence of biologic activity and acceptable safety in a phase 
1 trial, would potentially alter clinical practice if results are positive for efatutazone being used 
with paclitaxel. Even if negative, the trial will identify members in ALLIANCE with an interest 
in ATC, and establish a venue for future trials of new agents in this rare, lethal tumor. 
2.0 
OBJECTIVES  
2.1 
Primary objective  
To determine if the combination of paclitaxel and efatutazone improves the confirmed response 
rate in patients with advanced anaplastic thyroid cancer. 
2.2 
Secondary objective 
To estimate the overall survival (OS), duration of response, progression-free survival (PFS), and 
adverse event rates for the combination of paclitaxel and efatutazone.  
2.3 
Correlative science objective 
The association of biomarkers with clinical outcome data will be assessed in an exploratory 
translational analysis. 
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.  


 
 
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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. There is an exception for patients 
with a history of well differentiated thyroid cancer that has progressed to anaplastic 
thyroid cancer. 
• 
Patients who cannot swallow oral formulations of the agent(s). 
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. 
3.2 
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 page(s). 
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. 
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). 
___ 
3.2.1 Documentation of Disease:  
Patients must have histologically or cytologically diagnosed advanced ATC. 
___ 
3.2.2 Patients must have Measurable disease as defined in Section 11.0.  
___ 
3.2.3 Patients must have either metastatic (stage IVC) or locally advanced unresectable disease 
(stage IVB). 
___ 
3.2.4 Prior Treatment:  


 
 
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• 
Patients should have resolution of any toxic effects of prior therapy (except alopecia) to 
NCI CTCAE, Version 4.0, grade 1. 
• 
There is no limit to the number of prior lines of treatment a patient has received. 
• 
No treatment with chemotherapy, radiation therapy, immunotherapy, biological 
therapy, hormonal therapy, or other thiazolidinediones (TZDs) ≤ 21 days before study 
registration.   
• 
No prior taxane therapy ≤ 6 months, except as a radiosensitizer. 
___ 
3.2.5 No history of the following:  
• 
Class III or IV congestive heart failure (CHF). 
• 
Grade 3 or 4 thromboembolic event < 6 months. 
• 
Pericardial effusion < 12 months (any grade). 
• 
Pericardial involvement with tumor. 
• 
Grade 2 or higher pleural effusion < 6 months. 
___ 
3.2.6 No current symptomatic, untreated, or uncontrolled brain metastases present. 
___ 
3.2.7 No major surgery < 14 days prior to registration. 
___ 
3.2.8 No grade 2 or higher neuropathy 
___ 
3.2.9 No known history of severe hypersensitivity reactions to any of the components of 
efatutazone or paclitaxel formulations. 
___ 
3.2.10 Not pregnant and not nursing, because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing 
potential only, a negative pregnancy test done ≤ 7 days prior to registration is required. 
___ 
3.2.11 Age ≥ 18 years  
___ 
3.2.12 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. 
___ 
3.2.13 ECOG Performance Status ≤2 
___ 
3.2.14 Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Creatinine 
≤ 1.5 x ULN mg/dL OR 
Calc. Creatinine Clearance 
≥ 60 mL/min 
 
Bilirubin 
≤ 1.5 x upper limit of normal (ULN) 
AST 
≤ 2.5 x upper limit of normal (ULN) 
4.0 
PATIENT REGISTRATION 
4.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 


 
 
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registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at 
 
4.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
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 


 
 
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• 
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. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the A091305 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 link to expand, then select trial protocol #A091305 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.  
Requirements for A091305 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)  
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 RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
 
 
 


 
 
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Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 
 in order to receive further instruction and 
support. 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab  
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or 
the enrolling investigator’s status with the NCI or their affiliated networks. 
4.3 
Patient Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar' role on either the LPO or participating organization roster.  Registrars must hold a 
minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org.  To assign an IVR or NPIVR as 
the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer 
in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used 
on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All 
patients 
have 
signed 
an 
appropriate 
consent 
form 
and 
HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.   Please print this confirmation for your records.  
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 
Registration to Correlative Study A091305-ST1 
There is one substudy within Alliance A091305. This correlative science study must be offered 
to all patients enrolled on Alliance A091305 (although patients may opt to not participate). This 
substudy does not require separate IRB approval. The substudy included within Alliance 
A091305 is: 
• 
Tissue Biomarkers as Predictors of Response in Paclitaxel +/- Efatutazone Anaplastic 
Thyroid Carcinoma Protocol, Alliance A091305-ST1  


 
 
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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 #1 in the model consent, they have consented to participate in the substudy 
described in Section 14.1. The patient should be registered to Alliance A091305-ST1 at the same 
time they are registered to the treatment trial (A091305). Samples should be submitted per 
Section 6.2.   


 
 
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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 ≤ 16 DAYS before registration: All laboratory studies, history and physical. 
• 
To be completed ≤ 28 DAYS before registration: Any scan of any type which is utilized for tumor 
measurement per protocol. 
• 
To be completed ≤ 28 DAYS before registration: Any baseline exams used for screening, or any 
X-ray, scan of any type or ultrasound of uninvolved organs which is not utilized for tumor 
measurement. 
 
Prior to 
Registration* 
Day 1 of each 
cycle (+/- 3 days) 
Post treatment 
follow up** 
Tests & Observations 
 
 
 
History and physical, weight, 
PS*** 
X 
X 
X 
Height 
X 
 
 
Pulse, Blood Pressure 
X 
X 
X 
ECG (physician discretion, 
not required) 
X 
 
X 
Adverse Event Assessment 
 
X 
X 
Patient Medication Diary 
 
X(1) 
 
Patient Weight Diary 
 
X(1) 
 
Registration Fatigue/Uniscale 
Assessment 
X(2) 
 
 
Laboratory Studies 
 
 
 
Complete Blood Count, 
Differential, Platelets, 
X 
X 
X 
Serum Creatinine, Na, K, Mg 
X 
X 
X 
Calcium, albumin, glucose 
X 
X 
X 
AST, ALT, Alk. Phos., Bili 
X 
X 
X 
Triglycerides, cholesterol, 
HDL, LDL (physician 
discretion, not required) 
X 
 
 
TSH 
X 
X(3) 
 
Thyroglobulin and 
thyroglobulin antibody 
X 
 
 
Serum or Urine HCG 
X(4) 
 
 
Staging 
 
 
 
PET scan  
X 
 
 
CT or MRI  
X(5) 
A 
 
Correlative study A091305-ST1: For patients who consent to participate 
Tissue samples 
Slides (or slide and block) from prior surgery/biopsy 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 14 days 
prior to treatment. For subsequent cycles, labs, scans, tests and observations may be obtained ≤ 
72 hours prior to day of treatment.  


 
 
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** 
Physical examination and staging scans are required ≤ 28 days after the end of treatment, then 
every 8 weeks until disease progression. Thereafter, survival and disease status information is 
required every 6 months until 5 years following registration. This does not require that the 
subject be seen and/or examined. For example, follow-up may be done through a telephone call 
to the subject or his treating physician. See also Section 12.0.  
*** Drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
1 
The diaries, found in Appendix II, must begin the day the patient starts taking the medication 
and must be completed daily per protocol and returned to the treating institution OR compliance 
must be documented in the medical record by any member of the care team. 
2 
To be completed after registration and ≤ 21 days prior to treatment, see Appendix I. 
3 
TSH every other cycle starting with cycle 3. 
4 
For women of childbearing potential (see Section 3.2.10). Must be done ≤ 7 days prior to 
registration. 
5 
Baseline scans include a PET scan and diagnostic CT, spiral CT, or MRI performed with both 
IV and oral contrast, and the CT acquired with 5 mm or less slice thickness. Documentation 
(radiologic and pathology report) of the diagnosis scan must be submitted.  
A 
Every 6 weeks (beginning prior to Cycle 3) until evidence of progression or relapse. 
Documentation (radiologic) must be provided at progression of disease. Scans may be done up 
to 7 days prior to beginning a cycle. Response assessment should include assessment of all sites 
of disease and use the same imaging method as was used at baseline. For partial or complete 
response, a scan must be performed within 4 weeks to confirm response.  
 


 
 
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6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data collection and 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 
 
6.2 
Specimen collection and submission  
For patients registered to substudy A091305-ST1: All participating institutions must ask 
patients for their consent to participate in the correlative substudies planned for Alliance 
A091305-ST1, although patient participation is optional. Biomarker studies will be performed. 
Rationale and methods for the scientific components of these studies are described in Section 
14.0. For patients who consent to participate, tissue will be collected at the following time points 
for these studies: 
 
< 30 days 
after 
registration 
Submit to:  
For patients registered to A091305-ST1, submit the following: 
At least one (two if possible) 
H&E stained slides with 
representative tumor from 
primary and metastatic tumor 
(if available) 
X 
OSU 
Either a minimum of 10 
unstained slides OR 1 paraffin 
block 
X 
OSU 


 
 
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6.2.1 Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials.  Authorized individuals may access BioMS at the following URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer).  For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, 
and training videos.  To report technical problems, such as login issues or application errors, 
please contact: 
.  For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A091305), Alliance 
patient number, patient’s initials and date and type of specimen collected. 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Shipment on Monday through Friday by overnight service to assure receipt is encouraged. 
If shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For 
Saturday delivery.” Do not ship specimens on Saturdays. 
All specimens should be sent to the following address: 
  
 
 
 
 
 
6.2.2 Collection of slides and/or paraffin block of archived anaplastic thyroid cancer 
primary and metastatic tumors 
For patients who consent to participate, specimens will be used for the analyses described 
in Section 14.1. 
At least 1 (prefer 2) H&E slides from primary tumor and metastatic tumor (if available) and 
either a minimum of 10 unstained slides OR 1 paraffin block should also be retrieved from 
the surgical pathology department. Slides should be cut at 5 µm.  A de-identified surgical 
pathology report should be sent with all blocks and slides. Usually, this is generated by 
obscuring all PHI (names and dates) with white-out or a black magic marker, labeling each 
page of the report with the Alliance patient ID, and photocopying the report. Specimens 
should be sent to the Alliance Biorepository at Ohio State (OSU). Please specify the source 
of the tumor block (primary or metastatic site).  


 
 
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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 OSU is to provide investigators with quality histology sections for their 
research while maintaining the integrity of the tissue. All paraffin blocks that are to be stored 
at the OSU will be vacuum packed to prevent oxidation and will be stored at 4º C to 
minimize degradation of cellular antigens. For these reasons it is preferred that the OSU 
bank the block until the study investigator requests thin sections. All blocks will be stored 
by the appropriate Alliance biorepository but will be returned at the written request of a site. 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days following registration. 
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) window 
before and after the protocol-defined date for Day 1 of a new cycle. For example, if the treatment due 
date is a Friday, the window for treatment includes the preceding Thursday through the following 
Monday. In addition, patients are permitted to have a new cycle of chemotherapy 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. 
Protocol therapy will consist of continuous cycles administered every 21 days. Treatment will 
continue until disease progression, unacceptable adverse event, or a minimum of 2 cycles beyond a 
complete response (CR).  
NOTE: Effective with Update #02 this will no longer be a randomized study. All patients will 
be assigned to the ARM A treatment. ALL PATIENTS SHOULD BE TREATED WITH 
PACLITAXEL AND EFATUTAZONE. 
 
A091305 Arm A dose table: 
Agent 
Dose 
Route 
Day 
Retreatment 
Paclitaxel 
175mg/m2 
IV 
Day 1 
every 21 days 
Efatutazone 
0.5 mg 
PO 
BID 
every 21 days* 
* taken continuously with no break between cycles 
 
A091305 Arm B dose table: 
Agent 
Dose 
Route 
Day 
Retreatment 
Paclitaxel 
175mg/m2 
IV 
Day 1 
every 21 days 
 
Treatment cycles will be 21 days in duration.  Disease assessments will be performed every 42 days 
(6 weeks) of study participation. Treatment will continue until disease progression, unacceptable 
toxicity, or consent withdrawal.  There is no limit to the number of treatment cycles that can be 
administered.  After discontinuation from the study treatment, subjects will be followed at 6-month 
intervals to obtain information about subsequent treatment and survival status.  
Patients assigned to arm A will receive both paclitaxel and efatutazone as described in the A091305 
Arm A dose table (above). Patients assigned to arm B will receive paclitaxel alone as described in 
the A091305 Arm B dose table (above). However, please note that with update #2, arm B is closed 
and all patients should receive paclitaxel and efatutazone. 
The number of efatutazone tablets required should be calculated and dispensed into a pharmacy bottle 
with Child Resistant Cap Closure. Efatutazone tablets are to be self-administered PO BID, with or 


 
 
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Update #03 
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. 
In Arm A, Efatutazone and paclitaxel will be administered as combination treatment. On day 1 of 
each cycle, administer paclitaxel IV infusion over 3 hours immediately following administration of 
efatutazone.  To prevent severe hypersensitivity reactions, the patient should be premedicated in 
accordance with institutional standards for paclitaxel (26).  
The patient’s weight will be measured daily and recorded in the Patient Weight Diary, found in 
Appendix II. Drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
At each study visit, collect unused efatutazone tablets and determine compliance with dosing regimen 
using the Patient Medication Diary (Appendix II).  
The End of Treatment visit is to occur within 21 to 35 days after the last dose of study drugs.  Protocol 
specified withdrawal procedures are the same as the End of Treatment visit procedures. 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
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); and intermittent use of dexamethasone 
as an antiemetic. 
8.1.4 Antiemetics may be used at the discretion of the attending physician. 
8.1.5 Diarrhea: This could be managed conservatively with loperamide. The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
8.1.6 Palliative radiation therapy:  Patients who require radiation therapy during protocol 
treatment will be removed from protocol therapy due to disease progression. 
8.1.7 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) 


 
 
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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. 
8.1.8 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. 
8.1.9 Anemia: Patients have developed anemia associated with efatutazone. Full supportive care 
should be utilized at the discretion of the treating investigator. 
8.1.10 Edema: Edema/fluid retention is a common side effect of this medication. Patients should 
follow their weight, and should be weighed with all visits. 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 
8.1.11 Hypersensitivity/infusion reactions: Treat hypersensitivity and infusion reactions to 
paclitaxel as per institutional standards. 
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 and paclitaxel will not be re-escalated once reduced 
• 
If dose reductions beyond dose level -2 is required or efatutazone or paclitaxel is held for 
21 days, efatutazone or paclitaxel 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. 


 
 
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Dose Level 
Drug Name 
Dose 
 0* 
 
Paclitaxel 
175 mg/m2 every 21 days 
 
-1 
 
Paclitaxel 
135 mg/m2 every 21 days 
-2 
 
Paclitaxel 
100 mg/m2 every 21 days 
 
8.2.2 Hematologic Toxicities  
• 
For grade 3 neutrophil count decreased on Day 1, delay paclitaxel until grade ≤ 
2, then resume paclitaxel at same dose  
• 
For grade 4 neutrophil count decreased or febrile neutropenia, delay paclitaxel 
until grade ≤ 2, then resume paclitaxel with one dose level decreased  
• 
For grade 2 platelet count decreased, delay paclitaxel until grade ≤ 1, then resume 
paclitaxel at same dose 
• 
For grade 3 or 4 platelet count decreased, delay paclitaxel until grade  ≤ 1, then 
resume paclitaxel at one dose level decreased 
8.2.3 Neurotoxicity 
• 
For grade 2 neuropathy, delay paclitaxel until grade ≤ 1, then resume paclitaxel at 
same dose level 
• 
For grade 3 neuropathy, delay paclitaxel until grade ≤ 1, then resume paclitaxel at 
one dose level decreased. If grade 3 neuropathy recurs, discontinue paclitaxel 
• 
For grade 4 neuropathy, discontinue paclitaxel  
8.2.4 Gastrointestinal Toxicity 
• 
For grade 3 nausea or vomiting, delay paclitaxel until grade ≤ 2, then restart 
paclitaxel at same dose 
• 
For grade 4 nausea or vomiting, delay paclitaxel until grade ≤ 2, then restart 
paclitaxel at one dose decreased 
• 
For grade 3 diarrhea, delay paclitaxel until grade ≤ 2, then restart paclitaxel at 
same dose 
• 
For grade 4 diarrhea, delay paclitaxel until grade ≤ 2, then restart paclitaxel at one 
dose decreased 
8.2.5 Hepatobiliary Toxicity 
• 
For grade 2 or 3 AST or ALT elevated, delay paclitaxel until grade ≤ 1, then restart 
paclitaxel at one dose level decreased 
• 
For grade 4 AST or ALT elevated, discontinue paclitaxel 
• 
For grade 2 or 3 bilirubin elevated, delay paclitaxel until grade ≤ 1, then restart 
paclitaxel at one dose level decreased 
• 
For grade 4 bilirubin elevated, discontinue paclitaxel 
8.2.6 Cardiac Toxicity 


 
 
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For grade 3 or 4 pericardial effusion, discontinue efatutazone 
8.2.7 General disorders 
• 
For grade 2 edema, omit efatutazone until grade < 2, then resume efatutazone at 
same dose 
• 
For grade 3 edema, omit efatutazone until grade < 2, then resume efatutazone at 
one dose level decreased 
8.2.8 Pulmonary Toxicity 
• 
For grade 2 pleural effusion, omit efatutazone until grade ≤ 1, then resume 
efatutazone at one dose decreased 
• 
For grade 3 or 4 pleural effusion, discontinue efatutazone. 
8.2.9 Non-hematologic Toxicities 
For all other grade 3 or 4 non-hematologic toxicities likely related to paclitaxel and/or 
efatutazone, omit paclitaxel and/or efatutazone until resolved to < grade 1, then resume 
paclitaxel and/or efatutazone at one dose decreased   
8.2.10 Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is performed according to actual body weight. Therefore, all dosing is to be determined 
solely by actual weight without any modification unless explicitly described in the protocol. 
This will eliminate the risk of calculation error and the possible introduction of variability 
in dose administration. Failure to use actual body weight in the calculation of drug dosages 
will be considered a major protocol deviation. Physicians who are uncomfortable with 
calculating doses based on actual body weight should recognize that doing otherwise would 
be a protocol violation. Physicians may consult the published guidelines of the American 
Society of Clinical Oncology Appropriate Chemotherapy Dosing for Obese Adult Patients 
with Cancer: American Society of Clinical Oncology Clinical Practice Guideline.  J Clin 
Oncol 30(13): 1553-1561, 2012. 
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.-  


 
 
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CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Neutrophil count decreased 
Investigations 
Platelet count decreased 
Investigations 
Anemia 
Blood and lymphatic system disorders 
Peripheral sensory neuropathy 
Nervous system disorders 
Edema limbs 
General Disorders 
Weight gain 
Investigations 
Pleural Effusion 
Respiratory disorders 
Pericardial Effusion 
Cardiac disorders 
Cholesterol high 
Investigations 
Hypertriglyceridemia 
Metabolism and nutrition disorders 
9.2 
CTEP Adverse Event Reporting System (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 CTEP Adverse Event 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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9.2.1 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND ≤ 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 


 
 
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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 A091305 uses a drug under an Alliance IND. These reporting requirements apply for 
all agents (any arm) in this trial. 
• 
Grade 3/4 hematosuppression 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.  
• 
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. 
• 
Treatment expected adverse events include those listed in Section 10.0, in the IB for efatutazone, 
and in the package insert for paclitaxel. 
• 
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), hematologic 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 during therapy or within 28 days 
after completion of treatment on A091305 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).  
• 
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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10.0 DRUG INFORMATION 
10.1 
General Considerations: 
• 
The total administered dose of paclitaxel may be rounded up or down within a range of 5% 
of the actual calculated dose.  
• 
It is not necessary to change the doses of paclitaxel due to changes in weight unless the 
calculated dose changes by ≥10%. 
10.2 
Efatutazone dihydrochloride monohydrate (CS-7017) (Alliance IND #121997) 
Procurement 
 
Efatutazone dihydrochloride monohydrate (Efatutazone) will be provided and distributed by 
Daiichi Sankyo. Use the order form found on the Alliance A091305 web page (under the 
supplemental materials tab) or on the A091305 study page on CTSU web page (under the 
Pharmacy Tab) to order efatutazone. The form must be completed with each order. Sites must 
have IRB approval before ordering efatutazone. Note: No starter supplies are available.  
Institutions should complete the top portion of the form, including and up to “Date Drug Supply 
is 
Needed 
at 
Site.” 
Submit 
the 
completed 
form 
via 
email 
to 
. Questions regarding orders should be directed to 
 
Note: Please allow for a 4-5 business day turn-around time to receive drug.  
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 100ct amber glass bottles. The number of tablets required 
should be calculated and dispensed into a pharmacy bottle with Child Resistant Cap Closure. 
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).   
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 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.   


 
 
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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. 
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. 
Nursing Guidelines 
1. 
Edema and fluid retention have been noted. Instruct patient to report any swelling or weight 
gain to the study team. 
3. 
Lipid abnormalities have been reported. Monitor lipid panel as per protocol. Instruct patient 
on appropriate diet. 
4. 
Monitor CBC w/diff. Instruct patients to report any signs/symptoms of infection or 
bleeding to the study team. 
6. 
Agent may be taken with or without food. 
10.3 
Paclitaxel (Taxol) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 6 mg/mL (5 mL, 16.7 mL, 25 mL, and 50 mL) [contains 
alcohol and purified Cremophor EL (polyoxyethylated castor oil)]. 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions.  Store intact vials 
at room temperature and protect from light.  Dilute in 250-1000 mL D5W or 0.9% NaCl to a 
concentration of 0.3 – 1.2 mg/mL.  Solutions in D5W and 0.9% NaCl are stable for up to 3 days 
at room temperature.  Chemotherapy dispensing devices (e.g., Chemo Dispensing Pin) should 
not be used to withdraw paclitaxel from the vial. 


 
 
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Paclitaxel should be dispensed in either glass or non-PVC containers (e.g., Excel/PAB). Use 
nonpolyvinyl (non-PVC) tubing (e.g., polyethylene) to minimize leaching.  
Administration 
Infuse IV over 3 hours, or per institutional standards. Infuse through a 0.22 micron in-line filter 
and nonsorbing administration set. 
Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP2C8, CYP3A4; Induces CYP3A4 (weak).  
Increased Effect/Toxicity: CYP2C8 inhibitors may increase the levels/effects of paclitaxel. 
Refer to the package insert or LexiComp1 for example inhibitors. 
Decreased Effect: CYP2C8 inducers may decrease the levels/effects of paclitaxel. Refer to the 
package insert or LexiComp1 for example inducers. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in estrogen-dependent 
tumors. Avoid valerian, St John’s wort (may decrease paclitaxel levels), kava kava, gotu kola 
(may increase CNS depression). 
Pharmacokinetics 
Distribution: Vd: Widely distributed into body fluids and tissues; affected by dose and duration 
of infusion 
Vdss: 1- to 6-hour infusion: 67.1 L/m2 
Vdss: 24-hour infusion: 227-688 L/m2 
Metabolism: Hepatic via CYP2C8 and 3A4; forms metabolites (primarily 6α-
hydroxypaclitaxel). 
Half-life elimination: 1- to 6-hour infusion: Mean (beta): 6.4 hours, 
3-hour infusion: Mean (terminal): 13.1-20.2 hours 
24-hour infusion: Mean (terminal): 15.7-52.7 hours 
Excretion: Feces (~70%, 5% as unchanged drug); Urine (14%) 
Clearance: Mean: Total body: After 1- and 6-hour infusions: 5.8-16.3 L/hour/m2; after 24-hour 
infusions: 14.2-17.2 L/hour/m2 
Adverse Events 
Consult the package insert for the most current and complete information. Percentages reported 
with single-agent therapy. U.S. Boxed Warning: Bone marrow suppression is the dose-limiting 
toxicity; do not administer if baseline absolute neutrophil count (ANC) is <1500 cells/mm3 
(1000 cells/mm3 for patients with AIDS-related KS); reduce future doses by 20% for severe 
neutropenia. U.S. Boxed Warning: Severe hypersensitivity reactions have been reported. 
Common known potential toxicities, > 10%:   
Cardiovascular: Flushing, ECG abnormal, edema, hypotension. 
Dermatologic: Alopecia, rash. 
Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis, abdominal pain (with 
intraperitoneal paclitaxel)  
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, bleeding. 
Hepatic: Alkaline phosphatase increased, AST increased. 
Local: Injection site reaction (Erythema, tenderness, skin discoloration, swelling). 
Neuromuscular & skeletal: Peripheral neuropathy, arthralgia, myalgia, weakness. 


 
 
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Renal: Creatinine increased. 
Miscellaneous: Hypersensitivity reaction, infection. 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Bradycardia, tachycardia, hypertension, rhythm abnormalities, syncope, venous 
thrombosis. 
Dermatologic: Nail changes. 
Hematologic: Febrile neutropenia. 
Hepatic: Bilirubin increased. 
Respiratory: Dyspnea. 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Anaphylaxis, ataxia, atrial fibrillation, AV block, back pain, cardiac conduction abnormalities, 
cellulitis, CHF, chills, conjunctivitis, dehydration, enterocolitis, extravasation recall, hepatic 
encephalopathy, hepatic necrosis, induration, intestinal obstruction, intestinal perforation, 
interstitial pneumonia, ischemic colitis, lacrimation increased, maculopapular rash, malaise, MI, 
necrotic changes and ulceration following extravasation, neuroencephalopathy, neutropenic 
enterocolitis, ototoxicity, pancreatitis, paralytic ileus, phlebitis, pruritus, pulmonary embolism, 
pulmonary fibrosis, radiation recall, radiation pneumonitis, pruritus, renal insufficiency, seizure, 
skin exfoliation, skin fibrosis, skin necrosis, Stevens-Johnson syndrome, supraventricular 
tachycardia, toxic epidermal necrolysis, ventricular tachycardia  (asymptomatic), visual 
disturbances. Investigators ordering and/or dispensing supplied agents at any time for study 
treatment must be currently registered with PMB, DCTD, NCI. A registered investigator must 
co-sign for other non-registered personnel prescribing the supplied agents. 
Nursing Guidelines 
• 
Premedicate with steroids, antihistamines, and H2 blockers as per institutional 
guidelines. 
• 
Mix the infusion bag well.  Thorough admixture of this drug often prevents a 
hypersensitivity reaction.  An inline filter of <0.22 micron should be used distal to the 
infusion pump.  Filter may need to be changed if infusion is to be prolonged >12 hours.  
Inspect solution for excessive particulate matter, if present do not use. 
• 
Assess the patient frequently for the first 30 minutes.  Paclitaxel hypersensitivity 
reactions, which may include chest pain, back pain, flushing, diaphoresis, dyspnea, 
pruritus, hypotension, hypertension, bronchospasm and/or urticaria, usually occur early 
in the infusion.  Have the anaphylaxis tray available. 
• 
If a reaction occurs, stop the infusion immediately.  Follow institutional protocol or 
treating provider orders for management. 
• 
Approximately 60% of patients experience peripheral sensory neuropathy (numbness, 
tingling, burning pain, fine motor skills impairment, paresthesias, distal sensory loss).  
Patients receiving higher doses at shorter infusion times are at greater risk.  Most cases 
have been reported at doses >170 mg/m2/day and with cumulative doses over multiple 
courses of therapy.  The nerve damage may take months to resolve.  Nonsteroidal anti-
inflammatory agents and opiates have not been effective in treating neuropathic pain.  
Consult MD about trying tricyclic antidepressants or possibly gabapentin.   
• 
Mucositis can usually be managed with a salt and soda mouthwash (1 tsp. Salt, 1 tsp. 
Soda and 1 quart boiled water). 


 
 
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• 
Narcotics and nonsteroidal anti-inflammatory drugs may be used to manage the 
myalgias. 
• 
Monitor CBC closely.  Neutropenia is most severe in patients who have had previous 
chemotherapy.  Instruct patient to report signs or symptoms of infection, unusual 
bruising or bleeding to the health care team. 
• 
Monitor IV site closely and establish patency before administration.  Paclitaxel is an 
irritant, however rarely rash, radiation recall, and ulceration have occurred with 
infiltration of drug. 
• 
Monitor liver function tests 
• 
Inform patient about total alopecia. 
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) (50). 
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.   
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. 
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).   
Note: Tumor lesions in a previously irradiated area are considered measurable disease under 
the following conditions: Disease progression prior to study entry at the same location that 
was treated with radiation. 
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. 


 
 
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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, 
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 uptake 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 


 
 
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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. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance has been described 
in the protocol and supported by disease-specific medical literature for the 
indication. However, it must be acknowledged that both approaches may lead to 
false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
11.3.3 Measurement at Follow-up Evaluation:   
• 
A subsequent scan must be obtained at least 4 weeks following initial documentation of 
an objective status of either complete response (CR) or partial response (PR).  
• 
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 (e.g., residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain.) 
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 lesions, 
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.   
• 
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 


 
 
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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). 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.  
b. At least a 20% increase 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 MSD (Section 11.4.1).  In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from 
the MSD.  
c. See Section 11.3.2 for details in regards to the requirements for PD via 
FDG-PET imaging. 


 
 
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• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.4.3.3   Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
• 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short axis to <1.0 cm. 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-target 
lymph nodes. 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.   
b. Unequivocal progression of existing non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal progression should not normally trump 
target lesion and target lymph node status.  It must be representative of 
overall disease status change.)  
c. See Section 11.3.2 for details in regards to the requirements for PD via 
FDG-PET imaging. 
11.4.4 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s status 
on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, and new 
disease as defined in the following table:  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 


 
 
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* 
See Section 11.4.3.1 
11.4.5 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic 
deterioration. 
11.5 
Definitions of analysis variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 


 
 
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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
12.1.1 CR, PR, or SD: Patients who are in CR, PR or SD will continue on therapy indefinitely.   
12.1.2 Disease Progression: Remove from protocol therapy any patient with disease progression. 
Document details, including tumor measurements, on data forms. 
After disease progression, patients should be followed for survival per the study calendar 
(Section 5.0). 
12.1.3 Discontinuation of study agent: If the patient discontinues paclitaxel and efatutazone, 
patients should be followed for survival per the study calendar (Section 5.0). 
12.2 
Managing ineligible and canceled patients and major protocol violations 
Data must be submitted per Section 5.0 for patients deemed ineligible or canceled. See also the 
Forms Packet for full details of data submission requirements. 
12.2.1 Definitions 
Cancelled Patient: A study participant who is registered to the trial but never receives study 
treatment. 
Ineligible Patient: A study participant who is registered to the trial but does not meet all of 
the eligibility criteria at time of registration. 
Clinical Follow-up: The follow-up period where the study participant is no longer receiving 
treatment, but is still following the study calendar for tests, exams, and correlative endpoints 
(e.g., specimen collection, quality of life, disease assessments as required by the study). 
Survival Only Follow-up: The follow-up period where the study participant is monitored 
for long-term endpoints, is no longer receiving study treatment, and is not required to follow 
the study calendar for tests, exams, and correlative endpoints (e.g., specimen collection, 
quality of life, disease assessments as required by the study). In this follow-up period, there 
is a schedule in which case report forms should be submitted, but the physician visits are 
based on the standard of care. 
12.2.2 Follow-up Requirements 
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, data submission will continue as if the 
patient were eligible. Notification of the local IRB may be necessary per local IRB policies. 
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 
NOTE: THE FIRST 6 PATIENTS WERE ENROLLED AS PART OF THE ORIGINAL RANDOMIZED DESIGN (3 
TO EACH ARM).  PATIENTS RANDOMIZED TO ARM B WILL NOT BE INCLUDED IN THE NEW SINGLE ARM 
TRIAL.  THE 3 ARM A PATIENTS WILL BE INCLUDED IN THE NEW SINGLE ARM TRIAL.   
13.1 
Study Overview  
This single arm Phase II trial will assess the confirmed response rate of efatutazone in 
combination with paclitaxel in patients with advanced Anaplastic Thyroid Cancer.  In addition 
to the confirmed response rate, this trial will also estimate the overall survival (OS), duration of 
response, progression-free survival (PFS), and adverse event rates for the combination of 
efatutazone and paclitaxel.  Finally, the association of biomarkers with clinical outcome data 
will be assessed in an exploratory translational analysis. 
13.2 
Primary Endpoint   
The primary endpoint for this study will assess the confirmed response rate (by RECIST 1.1) of 
efatutazone in combination with paclitaxel in patients with advanced Anaplastic Thyroid 
Cancer.  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 
MinMax design will be utilized (see below). This design has 90% power to detect an 
improvement in the confirmed response rate from 15% to 50%, with a significance level of 0.10.  
See 2-stage design details below: 
First Stage:  Enroll 5 eligible patients (need 2 additional patients after design change to 
single arm trial) and temporarily close the study.  If at least 1 confirmed response is 
observed in the first 5 eligible patients, we will open the trial to the second stage and 
continue the study to a full accrual of 12 eligible patients.  Otherwise, the study will be 
permanently closed due to lack of efficacy.  
Second Stage:  If the trial is a success during the first stage analysis, we will enroll another 
7 eligible patients to the second stage (12 eligible total).  If at least 4 confirmed responses 
are observed in the first 12 eligible patients (33%), the combination 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 as well: overall survival, duration of confirmed 
response, progression-free survival, and adverse events.   
Overall Survival: Overall Survival (OS) is defined as the time from study entry to death from 
any cause. OS will be estimating using the Kaplan-Meier method.  
Duration of Confirmed Response: The duration of confirmed responses will be assessed using 
the Kaplan-Meier method, where the duration of confirmed response will be defined as the time 
from the first documented date of confirmed response (CR or PR) to the date at which 
progression is first documented.   
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. 


 
 
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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 
Translational Studies   
We plan to correlate the tumor markers (PPAR, RXR, RhoB, p21WAF1/CIP1, and 
angiopoietin‑ like 4) with clinical endpoints like confirmed response, survival, PFS, and adverse 
events.  Statistical and graphical techniques will be used to evaluate the relationships between 
tumor markers and clinical data. For time-to-event endpoints, we will use Cox proportional 
hazards models, and for confirmed response we will use Logistic regression models. In addition, 
we will use the Chi-square or Fisher’s exact tests to test the association between categorical 
marker data and confirmed response/adverse events. Continuous marker data will be assessed 
using 2-sample t-tests (or the nonparametric equivalent for non-normal data).  Descriptive 
statistics and graphical techniques will be used to summarize this data by treatment arm.  Given 
the small sample size, all these analyses will be considered hypothesis generating and 
exploratory.   
13.5 
Total Sample Size   
A maximum of 15 evaluable patients (12 for single arm trial + 3 Arm B patients enrolled during 
randomized phase II study) will be accrued onto this phase II study unless the study is closed 
early for excessive toxicity or lack of efficacy.  We anticipate accruing an additional 25% of 
patients to account for ineligibility, cancellation, major treatment violation, or other reasons.  
Therefore, maximum accrual is 20 patients. 
13.6 
Expected Accrual and Accrual Duration   
The expected accrual rate is about 0.50 patients per month for the Alliance group.  With this 
accrual rate, we expect to finish accrual within about 4 years, assuming we accrue 20 total 
patients.  
13.7 
Anticipated time to study completion 
We anticipate that the study will take approximately 5 years to complete.  This allows a 12-
month follow-up for the final patient enrolled, along with data entry, data clean-up, and analysis.  
13.8  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, 2 of the initial 5 treated patients or 40% or more of all patients (i.e. when 
accrual is greater than 5 patients) have experienced a grade 4 non-hematologic, non-
edema adverse  
• 
If at any time, 1 patient has experienced a grade 5 adverse event (non -progressive 
disease). 


 
 
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13.9  Accrual Monitoring Stopping Rule 
Given the expected accrual rate is around 0.50 patients per month, it is expected that the study 
will take around 4 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. 
13.10 Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting): 
The primary endpoint is to assess the confirmed response rate, as discussed in detail in section 
13.2.  The final analysis is expected to take place around 5 years after the study begins, so we 
expect that the primary endpoint completion time to be around 5 years after study activation. 
13.11  Descriptive Factors 
• 
Prior RT:  Yes vs. No 
• 
Prior Surgery:  Yes vs. No 
• 
If Yes, Extent of Surgery:  R0/R1 vs. R2 resection 
• 
Prior systemic therapy: Yes vs. No 
• 
Stage 4B vs 4C 
13.12 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.  Based on prior studies involving similar disease sites, we expect about 20% of patients 
will be classified as minorities by race and about 70% of patients to be women.  Expected sizes 
of racial by gender subsets are shown in the following table: 
 
 


 
 
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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 1 
 1 
 2 
Not Hispanic or Latino 
 13 
 5 
 18 
Ethnic Category: Total of all subjects 
 14 
 6 
 20 
Racial Category 
American Indian or Alaskan Native 
 1 
 0 
 1 
Asian 
 1 
 1 
 2 
Black or African American 
 1 
 0 
 1 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 11 
 5 
 16 
Racial Category: Total of all subjects 
 14 
 6 
 20 
 
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 AND COMPANION STUDIES  
There will be one substudy and all patients are encouraged to participate.  
14.1 
Correlative Science  
14.1.1 Background 
Preclinical data demonstrate that PPARɣ and RXR are necessary for Efatutazone 
antiproliferative activity (25). It was further discovered that RhoB and p21 mediated the 
antiproliferative activity of PPARɣ (51).  Also shown in this publication was the fact that 
Efatutazone (a.k.a. CS-7017) in combination with paclitaxel demonstrated antitumor 
synergy. Thus, genes transcriptionally regulated by PPARɣ:RXR and their protein products 
may serve as biomarkers for response to Efatutazone therapy. In the Phase 1 clinical trial 
testing of Efatutazone with paclitaxel in ATC patients, biomarkers were tested using IHC in 
patients prior to therapy and during therapy. Angiopoietin-like 4 (ANGPTL4), a gene highly 
upregulated by PPARɣ:RXR was found to be elevated in patient tissues at the protein level 
(45). 
14.1.2 Objectives 
The association of biomarkers with clinical outcome data will be compared between the 2 
treatment arms as a translational analysis. 
14.1.3 Methods 
Biopsy or surgical tissue samples obtained prior to treatment will be collected. Tissues 
analyzed using immunohistochemistry will be mounted on slides from paraffin-embedded 
blocks and then blocked with Diluent that contained Background Reducing Components 
(Dakocytomation, Denmark) for 30 minutes and probed for specified antibodies that 
included:  RXR-α, RhoB (Santa Cruz, Santa Cruz, CA), p21 (Dako, Carpintera, CA), 
ANGPTL4 (Sigma-Aldrich, St Louis, MO), and PPARγ (kind gift from E.A. Thompson, 
Mayo Clinic Jacksonville). Negative sections will be prepared by incubating the slides in 
the absence of the primary antibody as controls and cases will be excluded from analyses if 
there is insufficient tumor tissue.  
Stain scoring will be done using algorithms generated with Imagescope software (Aperio) 
created by a histologist. H-scores will be calculated based upon signal intensity (0–3+) using 
the formula: [(1+%x1) + (2+%x2) + (3+%x3)], intensity (I)-scores will be calculated by 
dividing signal intensity by area, and nuclear (N)-scores will be calculated by dividing% 
positive nuclei by total nuclei examined per area. Cases where insufficient tumor tissue 
presented are excluded. 20× images will be obtained using Scanscope XT and Imagescope 
software. Further details can be found in Smallridge et al. (45). 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
There are no credentialing requirements for A091305. 
 


 
 
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16.0 REFERENCES 
1. 
Siegel R, Naishadham D, Jemal A 2012 Cancer statistics, 2013. CA Cancer J Clin. 63:11-30. 
2. 
Abate E, Smallridge R 2011 Managing anaplastic thyroid cancer. Expert Rev Endocrinol Metab. 
6:793-809. 
3. 
Smallridge RC, Abate E 2014 In Press Anaplastic Thyroid Carcinoma:  Clinical Aspects. In: 
Wartofsky L, Van Nostrand D, (eds) Thyroid Cancer: A Comprehensive Guide to Clinical Management. 
Third Edition ed. Springer. 
4. 
Ain KB, Egorin MJ, DeSimone PA 2000 Treatment of anaplastic thyroid carcinoma with 
paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative anaplastic thyroid cancer health 
intervention trials (CATCHIT) group. Thyroid. 10:587-594. 
5. 
Bhatia A, Rao A, Ang KK, et al, Anaplastic thyroid cancer: clinical outcomes with conformal 
radiotherapy. Head Neck 2010;32:829-836.. 
6. 
Higashiyama T, Ito Y, Hirokawa M, et al. 2010 Induction chemotherapy with weekly paclitaxel 
administration for anaplastic thyroid carcinoma. Thyroid. 20:7-14. 
7. 
Troch M, Koperek O, Scheuba C, et al. 2010 High efficacy of concomitant treatment of 
undifferentiated (anaplastic) thyroid cancer with radiation and docetaxel. J Clin Endocrinol Metab. 
95:E54-57. 
8. 
Smallridge RC, Copland JA 2010 Anaplastic thyroid carcinoma: pathogenesis and emerging 
therapies. Clin Oncol. 22:486-497. 
9. 
Smallridge RC, Marlow LA, Copland JA 2009 Anaplastic thyroid cancer: molecular pathogenesis 
and emerging therapies. Endocr Relat Cancer. 16:17-44. 
10. 
Smallridge RC, Ain KB, Asa SL, et al. 2012 American Thyroid Association guidelines for 
management of patients with anaplastic thyroid cancer. Thyroid. 22:1104-1139. 
11. 
Smallridge RC 2012 Approach to the patient with anaplastic thyroid carcinoma. J Clin Endocrinol 
Metab. 97:2566-2572. 
12. 
Segev DL, Umbricht C, Zeiger MA 2003 Molecular pathogenesis of thyroid cancer. Surg Oncol. 
12:69-90. 
13. 
Fagin JA 2004 Challenging dogma in thyroid cancer molecular genetics--role of RET/PTC and 
BRAF in tumor initiation. J Clin Endocrinol Metab. 89:4264-4266. 
14. 
Hunt JL, Fowler M, Lomago D, et al. 2004 Tumor suppressor gene allelic loss profiles of the 
variants of papillary thyroid carcinoma. Diagn Mol Pathol. 13:41-46. 
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molecular signature: results of gene profiling. Clin Cancer Res. 9:1792-1800. 
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Cancer Inst. 95:625-627. 
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De Vita G, Bauer L, da Costa VM, et al. 2005 Dose-dependent inhibition of thyroid 
differentiation by RAS oncogenes. Mol Endocrinol. 19:76-89. 
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Ciampi R, Knauf JA, Kerler R, et al. 2005 Oncogenic AKAP9-BRAF fusion is a novel 
mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 115:94-101. 
19. 
Kroll TG, Sarraf P, Pecciarini L, et al. 2000 PAX8-PPARgamma1 fusion oncogene in human 
thyroid carcinoma [corrected]. Science. 289:1357-1360. 
20. 
Gregory Powell J, Wang X, Allard BL, et al. 2004 The PAX8/PPARgamma fusion oncoprotein 
transforms immortalized human thyrocytes through a mechanism probably involving wild-type 
PPARgamma inhibition. Oncogene. 23:3634-3641. 
21. 
Hunt JL, Tometsko M, LiVolsi VA, Swalsky P, Finkelstein SD, Barnes EL 2003 Molecular 
evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the 
thyroid. Am J Surg Pathol. 27:1559-1564. 
22. 
Mazzanti C, Zeiger MA, Costourous N, et al. 2004 Using gene expression profiling to 
differentiate benign versus malignant thyroid tumors. Cancer Res. 64:2898-2903. 


 
 
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Onda M, Emi M, Yoshida A, et al. 2004 Comprehensive gene expression profiling of anaplastic 
thyroid cancers with cDNA microarray of 25 344 genes. Endocr Relat Cancer. 11:843-854. 
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combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via 
p21WAF1/CIP1. Oncogene. 25:2304-2317. 
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activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer 
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dedifferentiation of thyroid carcinoma. Oncol Rep. 10:1337-1340. 
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Pushkarev VM, Starenki DV, Saenko VA, et al. 2004 Molecular mechanisms of the effects of low 
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Smallridge R, Copland J, Brose M, et al. 2013 Efatutazone, an oral PPAR-γ agonist, in 
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46.  
Derbel O, Limem S, Segura-Ferlay C, et al, Resuolts of combined treatment of anaplastic thyroid 
carcinoma (ATC). BMC Cancer 2011;11:469-77. 
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Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
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suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth. Cancer Res. 2009 
Feb 15;69(4):1536-44. doi: 10.1158/0008-5472.CAN-08-3718. Epub 2009 Feb 10. 


 
 
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APPENDIX I 
REGISTRATION FATIGUE/UNISCALE 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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APPENDIX II 
 PATIENT DIARIES 
Patient Medication Diary 
 
A091305 “A PHASE 2 STUDY OF EFATUTAZONE, AN ORAL PPAR AGONIST, IN 
COMBINATION WITH PACLITAXEL IN PATIENTS WITH ADVANCED ANAPLASTIC 
THYROID CANCER” 
Medication: Efatutazone 
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
Efatutazone should be taken by mouth, twice daily at the same time each day, 
approximately 12 hours apart with or without food for 21 days with no break 
between cycles.  
 
Cycle number __________________________ 
 
Date 
AM  
Time 
Number of 
tablets 
PM 
Time 
Number of 
Tablets 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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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:___________________ 
 
 
 


 
 
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Patient Weight Diary 
 
A091305 “A PHASE 2 STUDY OF EFATUTAZONE, AN ORAL PPAR AGONIST, IN 
COMBINATION WITH PACLITAXEL IN PATIENTS WITH ADVANCED ANAPLASTIC 
THYROID CANCER” 
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS: Weigh yourself daily and record weight in this diary. If you 
gain more than 5 lbs, call your treating doctor for instructions. 
 
Cycle number __________________________ 
 
Date 
Weight (in 
pounds) 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(To be completed by research staff)  
 
Research Staff signature:_________________________________________       
Date:___________________