Clinical trial NCT02066181
Conditions: Desmoid Fibromatosis
Sponsor: National Cancer Institute (NCI)
Start date: 2014-03-21; Completion date: 2022-12-01
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This randomized phase III trial compares the effects, good and/or bad, of sorafenib tosylate in treating patients with desmoid tumors or aggressive fibromatosis. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. \[Funding Source - FDA OOPD\]

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) rates of patients with desmoid tumors (DT)/deep fibromatosis (DF) who receive either sorafenib (sorafenib tosylate) or placebo using a double-blinded randomized phase III study.

SECONDARY OBJECTIVES:

I. To assess toxicity. II. To assess time to surgical intervention. III. To assess tumor response rates and survival.

TERTIARY OBJECTIVES:

I. To evaluate changes in magnetic resonance imaging (MRI) Tesla (T)2 to predict (or correlate) with a biological effect such as tumor growth (by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1), and pain palliation. (Correlative companion study) II. The mechanism of action of sorafenib in DT/DF remains unknown. In patients consenting to undergo the paired tumor biopsies (A091105-ST1), treatment induced changes will be quantified by histology, gene expression profiling, proteomic changes and selected interrogation of key pathways by western blot and reverse transcription-polymerase chain reaction (RT-PCR). (Correlative companion study) III. To collect archival tissue, baseline (tumor, blood) and day 8 (tumor, blood) specimens for basic science research (A091105-ST1). (Correlative companion study) IV. To assess patient-reported adverse events and quality of life (QOL) as measured by the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the single-item overall Linear Analogue Self-Assessment (LASA) (A091105-HO1). (Correlative companion study) V. To assess pain palliation measured by the "worst pain" item of the Brief Pain Inventory Short Form (A091105-HO1). (Correlative companion study)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive placebo PO QD on days 1-28. Patients may crossover to Arm I upon disease progression.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually for up to 3 years.

Arms: arm 1: Patients receive sorafenib tosylate PO QD on days 1-28. arm 2: Patients receive placebo PO QD on days 1-28. Patients may crossover to Arm I upon disease progression.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Placebo Administration intervention 3: Quality-of-Life Assessment intervention 4: Sorafenib Tosylate
Intervention descriptions: intervention 1: Optional correlative studies intervention 2: Given PO intervention 3: Optional ancillary studies intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
1
Update #06 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO A091105 
_________________________________________ 
 
A PHASE III, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF SORAFENIB IN DESMOID 
TUMORS OR AGGRESSIVE FIBROMATOSIS (DT/DF) 
NCI-supplied agent(s): sorafenib (NSC # 7247722, IND#116279) 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
X Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
X Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other :  
 
 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines. 
  
UPDATES TO THE PROTOCOL 
 
Cover Page 2 
- 
In the table entitled “Protocol-related questions may be directed as follows,” the contact name and 
email address for questions regarding CTEP-AERS reporting has been updated from Regulatory 
Affairs Manager to Alliance Pharmacovigilance Inbox and from regulatory@alliancenctn.org to 
pharmacovigilance@alliancenctn.org, respectively. The phone number previously listed for the 
Regulatory Affairs Manager has been removed as all questions should be submitted via email. 
- 
The document history table has been removed. This table now appears as a separate document on the 
protocol landing page on the member side of the Alliance web site.  
 
Section 5.2.1 (CTEP Investigator Registration Procedures) 
This section has been updated in its entirety with the revised CTSU verbiage. 
 
Section 5.2.2 (CTEP Associate Registration Procedures/CTEP-IAM Account) 
This section has been removed in its entirety to reflect the revised CTSTU verbiage. Subsequent sections 
have been renumbered. References to the sections have been updated throughout the protocol. 
 


 2
Section 5.2.2 (CTSU Site Registration Procedures) 
This section has been revised in its entirety with the revised CTSU verbiage.  
 
Section 5.3 (Patient Registration/Randomization Procedures) 
This section has been updated in its entirety with the revised CTSU verbiage.  
 
Section 7.0 (Required Data) 
- 
The header of the third column has been updated. 
- 
After one year of treatment on sorafenib, the frequency of visits has decreased (from every cycle to 
every other cycle). Footnote C has been added beneath the table to reflect this change. References to 
footnote C have been added to the table in the third column.  
- 
The frequency of scans beyond year 3 has decreased, therefore footnote A has been updated.  
 
Section 10.1.2 (Methods) 
A second paragraph has been added under “Analysis of the data.” 
 
Section 10.2.3 (Specific Hypotheses) 
A second paragraph has been added to the end of this section.  
 
Section 10.3.2 (Methods) 
A second paragraph has been added to the end of this section.  
 
Section 13.1 (Schedule of Evaluations) 
The information in this section has been updated based on the revised scan schedule.  
 
Section 13.4.4 (Overall Objective Status) 
The “**” has been removed from the “Overall Objective Status Column” of the CR/PR row.  
 
Section 14.1 (Clinical Follow-Up Phase) 
A new bullet has been added to describe the follow-up for those patients who crossed over to sorafenib.  
 
Section 15.1 (Primary Endpoint) 
A second paragraph has been added to this section.  
 
Section 15.1.1 (Sample Size & Statistical Power) 
A new paragraph has been added to the end of this section. 
 
Section 15.1.6 (Evaluability & Assessment of Patients) 
A third paragraph has been added to this section.  
 
Section 15.2 (Secondary Endpoints) 
A note has been added as the first paragraph of this section. 
 
Section 15.2.2 (Surgical Intervention) 
The following sentence has been added to the end of the first paragraph in this section, “See the note at 
the beginning of Section 15.2.” 
 
Section 15.2.3 [Overall Survival (OS)] 
The following sentence has been added to the end of the first paragraph in this section, “See the note at 
the beginning of Section 15.2.” 
 


 3
Section 15.2.4 (Tumor Response) 
The following sentence has been added to the end of the first paragraph in this section, “See the note at 
the beginning of Section 15.2.” 
 
Section 15.3.1 (Statistical Design-Imaging Study) 
The following sentence has been added to the end of the first paragraph in this section, “Data, analyses, 
and censoring will also follow the note described in Section 15.2.” 
 
Section 15.3.3 (Statistical Design for Correlative Study A091105-ST1) 
The following sentence has been added as the first sentence in this section, “See the note in Section 15.2, 
which will apply to all analyses for this section A091105-ST1.” 
 
Section 16.2 (Expedited Adverse Event Reporting) 
- 
The last three sentences in the first paragraph have been updated to reflect the use of CTCAE version 
5.0 for expedited adverse event reporting purposes. 
- 
The third note in the FDA reporting table which reads, “Deaths clearly due to progressive disease 
should NOT be reported via CTEP-AERS but rather should be reported via routine reporting methods 
(e.g., CDUS and/or CTMS).” has been removed.  
- 
The following changes have been made under “Additional Instructions or Exclusion to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND”:  
- 
Five new bullets have been added to describe reporting of death, pregnancy loss, and neonatal 
death. 
- 
The now ninth bullet describing reporting of new malignancies has been updated in its entirety. 
 
Appendix VI (A091105 Optional Medication Diary) 
- 
Placebo is no longer used. This has been removed from the diary.  
- 
Beginning with cycle 14 patients are seen every other cycle. This has been reflected in instruction #1. 
Additional rows have been added to the diary to account for this change. 
 
 
UPDATES TO THE MODEL CONSENT: 
No changes have been made to the model consent form.  
 
 
 
A replacement protocol document and model consent form have been issued. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 


 
Version Date: 12/18/2018 
1 
Update #06  
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A091105 
 
A PHASE III, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF SORAFENIB IN 
DESMOID TUMORS OR AGGRESSIVE FIBROMATOSIS (DT/DF) 
NCI-supplied agent(s): sorafenib (NSC # 7247722, IND#116279), IND Holder: CTEP 
ClinicalTrials.gov Identifier: NCT02066181 
 
Study Chair 
Mrinal M. Gounder, M.D. 
300 E 66th St. 
Memorial Sloan-Kettering Cancer Center 
New York, NY 10065 
Tel: 646-888-4167 Fax: 646-888-4252 
gounderm@mskcc.org 
 
Community Oncologist Co-Chair 
Kirsten Leu, M.D. 
Tel: 402-354-8124 Fax: 402-354-8127 
Email: kleu@nebraskacancer.com 
 
Imaging Co-Chair 
Study Pathologist 
Robert Lefkowitz, M.D. 
Narasimhan Agaram, M.D.  
Tel: 212-639-2747   
Tel: 212-639-5905  
Email: lefkowir@mskcc.org 
Email: agaramn@mskcc.org 
 
Experimental Therapeutics 
Experimental Therapeutics 
Committee Co-Chair 
Committee Co-Chair 
Pamela Munster, M.D. 
Gary K. Schwartz, M.D. 
Tel: 415 502-3598 Fax: (415) 353-7779 
Tel: 212-305-2055 Fax: 212- 305-3035 
Pmunster@medicine.ucsf.edu 
gks2123@cumc.columbia.edu 
 
Primary Statistician 
Michelle R. Mahoney, MS 
Tel: 507-266-4456 Fax: 507-266-2477 
mahoney.michelle@mayo.edu 
 
Health Outcomes Statistician 
Protocol Coordinator 
Amylou Dueck, Ph.D. 
Krista L. Garbacz 
Tel: 480-301-6159 
Tel: 773-702-9269 Fax: 312-345-0117 
dueck.amylou@mayo.edu 
kgarbacz@uchicago.edu 
 
Participating NCTN Groups:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, 
NRG / NRG Oncology, SWOG / SWOG, NCIC-CTG/NCIC Clinical Trials Group 


ALLIANCE A091105 
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Update #06 
Alliance Statistics and Data Center  
Mayo Clinic 
200 First St. SW 
Rochester MN 55905 
 
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 
 
Protocol Resources: 
A091105 Data Manager 
Barb Mulhern 
Tel: 507-538-0269, mulhern.barbara@mayo.edu 
  
A091105 Nursing Contact 
Lisa Kottschade, RN, MSN, CNP 
507-538-7888  
kottschade.lisa@mayo.edu 
A091105 Pharmacy Contact 
Heidi Finnes, PharmD,BCOP 
507-538-7066 
finnes.heidi@mayo.edu 
Alliance Biorepository at Ohio State 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
Alliance Imaging Core Lab 
The Ohio State University 
Wright Center of Innovation 
395 W. 12th Ave., RM #414 
Columbus, OH 43240 
Tel: 614-293-9151  Fax: 614-293-9275 
Alliance091105@imagingcorelab.com 
 
 
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, or (where available) Data Manager  
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent 
Protocol Coordinator 
Questions related to IRB review   
Regulatory Affairs Manager:  
regulatory@alliancenctn.org 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
pharmacovigilance@alliancenctn.org 
Questions regarding specimens/specimen 
submissions: 
appropriate Alliance Biorepository 
 
 
 


ALLIANCE A091105 
Version Date: 12/18/2018 
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Update #06 
 
 
CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
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 ctsucontact@westat.com. 
 
 
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 – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 


ALLIANCE A091105 
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A PHASE III, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF SORAFENIB IN 
DESMOID TUMORS OR AGGRESSIVE FIBROMATOSIS (DT/DF) 
 
ELIGIBILITY CRITERIA (see Section 4.0) 
Required Initial Laboratory Values 
Patients must have confirmation of DT/DF 
absolute neutrophil   
Patients may have been treated with locoregional therapies  
count (ANC) 
≥ 1500/mm3 
   completed 4 weeks prior to registration and recovered to   
hemoglobin 
≥8g/dl   
   < CTCAE grade 2 (see § 4.2.1) 
platelets 
≥ 75,000/mm3 
Patients may have been treated with cytotoxic, biologic 
total bilirubin 
≤ 1.5 x ULN 
   (antibody), immune or experimental therapy, tyrosine  
SGOT(AST)  or 
 
   kinase inhibitors, hormone inhibitors or NSAIDs 
SGPT(ALT) 
≤ 1.5 x ULN 
   completed 4 weeks prior to registration and recovered 
creatinine 
Calculated creatinine 
   to < CTCAE grade 2 (see § 4.2.2) 
 
Clearance ≥50 mL/min 
No prior sorafenib 
 
 
No concomitant treatment with strong CYP3A4 inhibitors or inducers (see § 4.2.4)  
Patients must have measurable disease as defined in Section 13.0. 
The patient must meet one of the following criteria: 
   1) Disease determined unresectable or entailing unacceptable morbid surgery based on 1 or more of the following: 
• Multifocal disease  
• Disease in which there is involvement or inadequate plane from neurovascular bundle, bone, skin, or viscera 
• Large size in relationship to location OR multicompartment involvement 
   2) Progression by radiographic imaging (10% increase in size by RECIST 1.1 within 6 months) 
   3) Patients with symptomatic disease with a BPI score ≥ 3 AND 1 of the following: 
• Inability to control pain with NSAIDs and considering the addition of narcotics  
• >30% increase in current use of narcotics OR 
• Addition of new opioid narcotic 
Age ≥ 18 years 
ECOG performance status ≤2 
No pregnancy or nursing 
No history of cardiac disease as in §4.7.1 
No inadequately controlled hypertension (see § 4.7.2) 
No clinically significant GI bleeding or bleeding diathesis within 30 days of registration 
 
SCHEMA 
1 Cycle =28 Days 
 
 
 
 
   
 
 
 
R 
A 
 
Sorafenib 400 mg/day 
PD*  
 
Survival and 
Disease Status 
Follow-up 
 
 
 
N 
 
 
 
 
 
 
D 
 
 
 
 
 
 
O 
 
 
 
 
 
 
M 
 
 
 
 
 
 
I 
Z 
E 
 
 
Placebo 2 pills/day 
PD* 
 
Sorafenib 400 mg/day  
PD  
 
 
Survival and 
Disease Status 
Follow-up 
 
 
 
 
 
 
 
PD= Progression of Disease 
* Patients are unblinded after first incidence of progressive disease 
 
NOTE: Patients discontinuing for reasons other than PD and earlier than 1 year post-randomization 
must continue in Clinical Follow-up until 1 year post-randomization to capture study endpoints. 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION ................................................................................................................................. 7 
1.1 
Pathology ...................................................................................................................................... 7 
1.2 
Epidemiology and Clinical Presentation ....................................................................................... 7 
1.3 
Treatment(s) .................................................................................................................................. 7 
1.4 
Sorafenib in Desmoid Tumors/ Deep Fibromatosis (DT/DF) ....................................................... 8 
1.5 
Methods......................................................................................................................................... 9 
1.6 
Patient and Tumor Characteristics ................................................................................................ 9 
1.7 
Treatment Characteristics ............................................................................................................. 9 
1.8 
Sorafenib administration ............................................................................................................... 9 
1.9 
Clinical Outcome on Sorafenib ................................................................................................... 10 
1.10 
Radiological response assessment .............................................................................................. 10 
1.11 
Registration Fatigue/Uniscale Assessment ................................................................................. 11 
1.12 
Inclusion of Women and Minorities ........................................................................................... 11 
2.0 
OBJECTIVES .................................................................................................................................... 11 
2.1 
Primary Objective ....................................................................................................................... 11 
2.2 
Secondary Objective(s) ............................................................................................................... 11 
2.3 
Correlative Companion Study Objectives ................................................................................... 12 
3.0 
ON-STUDY GUIDELINES ................................................................................................................. 12 
4.0 
ELIGIBILITY CRITERIA .................................................................................................................. 12 
4.1 
Documentation of Disease .......................................................................................................... 13 
4.2 
Prior Treatment ........................................................................................................................... 13 
4.3 
Measurable Disease .................................................................................................................... 14 
4.4 
Disease Status ............................................................................................................................. 14 
4.5 
Age and performance status ........................................................................................................ 14 
4.6 
Pregnancy/nursing status............................................................................................................. 14 
4.7 
Patient History ............................................................................................................................ 14 
4.8 
Required Initial Laboratory Values: ........................................................................................... 15 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION ........................................................... 15 
5.1 
Patient Registration Requirements .............................................................................................. 15 
5.2 
Registration Procedures .............................................................................................................. 15 
5.3 
Patient Registration/Randomization Procedures ......................................................................... 18 
5.4 
Registration to Companion Studies ............................................................................................. 19 
5.5 
Re-Registration at the time of crossover to open label sorafenib arm ........................................ 19 
5.6 
 Stratification ............................................................................................................................... 19 
6.0 
DATA AND SPECIMEN SUBMISSION ............................................................................................... 20 
6.1 
Medidata Rave® ......................................................................................................................... 20 
6.2 
A091105-HO1 (QOL) data submission ...................................................................................... 20 
6.3 
Specimen Submission ................................................................................................................. 21 
6.4 
MR Imaging Data Submission .................................................................................................... 23 
7.0 
REQUIRED DATA ............................................................................................................................ 25 
8.0 
TREATMENT PLAN ......................................................................................................................... 27 
8.1 
Sorafenib/Placebo ....................................................................................................................... 27 
8.2 
Crossover .................................................................................................................................... 27 
8.3 
Duration of Treatment ................................................................................................................. 27 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ......................................................... 27 


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9.1 
Dose levels .................................................................................................................................. 27 
10.0 
COMPANION STUDIES .................................................................................................................... 29 
10.1 
Imaging companion study incorporated within A091105: Evaluation of MRI T2 signal as a 
novel imaging biomarker in DT/DF treated with sorafenib .................................................................... 29 
10.2 
QOL Sub-Study-A091105-HO1 (Optional) ................................................................................ 30 
10.3 
A091105-ST1 “Analysis of archival tissue, and pre-treatment and day 8 tumor biopsy and blood 
samples” (Optional) ................................................................................................................................ 32 
11.0 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION ....................................................... 36 
11.1 
General Considerations ............................................................................................................... 36 
11.2 
Sorafenib (BAY 43-9006, Nexavar; NSC 724772 / IND #116279) / Placebo ............................ 36 
11.3 
Nursing Guidelines ..................................................................................................................... 42 
12.0 
ANCILLARY THERAPY ................................................................................................................... 42 
12.1 
Supportive Care .......................................................................................................................... 42 
12.2 
Treatment with other chemotherapeutic agents .......................................................................... 43 
12.3 
Palliative radiation therapy ......................................................................................................... 43 
12.4 
Surgery ........................................................................................................................................ 43 
12.5 
Alliance Policy Concerning the Use of Growth Factors ............................................................. 43 
13.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE (SOLID TUMORS) ............................ 43 
13.1 
Schedule of Evaluations .............................................................................................................. 43 
13.2 
Definitions of Measurable and Non-Measurable Disease ........................................................... 43 
13.3 
Guidelines for Evaluation of Measurable Disease ...................................................................... 44 
13.4 
Measurement of Effect ................................................................................................................ 45 
14.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ................................................................ 48 
14.1  
Clinical Follow-Up Phase ....................................................................................................... 48 
14.2 Survival and Disease Follow-Up Phase .......................................................................................... 48 
14.3 
Managing ineligible and canceled patients and major protocol violations ................................. 48 
14.4 
Extraordinary Medical Circumstances ........................................................................................ 49 
15.0 
STATISTICAL CONSIDERATIONS .................................................................................................... 49 
15.1 
Primary Endpoint ........................................................................................................................ 49 
15.2 
Secondary Endpoints .................................................................................................................. 51 
15.3 
 Correlative Companion Study Endpoints................................................................................... 53 
15.4 
Inclusion of Women and Minorities ........................................................................................... 55 
16.0 
ADVERSE EVENT REPORTING ....................................................................................................... 57 
16.1 
Solicited Adverse Events ............................................................................................................ 57 
16.2 
Expedited Adverse Event Reporting ........................................................................................... 57 
16.3 
CAEPR for Sorafenib ................................................................................................................. 60 
17.0 
REFERENCES ................................................................................................................................... 66 
APPENDIX I- REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ......................................................... 69 
APPENDIX II- QOL QUESTIONNAIRE .................................................................................................... 71 
APPENDIX III- DRUGS WITH RISK OF TORSADES DE POINTES .............................................................. 79 
APPENDIX IV- AGENT ACCOUNTABILITY ................................................................................................ 85 
APPENDIX V- BRIEF PAIN INVENTORY QUESTION #1 FOR STRATIFICATION ......................................... 87 
APPENDIX VI – A091105 OPTIONAL MEDICATION DIARY ..................................................................... 89 


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1.0 
INTRODUCTION 
1.1 
Pathology  
Desmoid tumors, also known as deep fibromatosis (DT/DF), are rare fibroblastic sarcomas that 
arise from musculoaponeurotic stromal elements.  Histologically, they have a bland appearance, 
consisting of small bundles of spindle cells with rare mitosis in an abundant collagenous and 
fibrous stroma.  DT/DF can arise in any location, although the most common sites include 
extremities, abdominal cavity (root of the mesentery) and retroperitoneum and abdominal wall.  
The majority of DT/DF are sporadic, however 4–20% are associated with familial adenomatous 
polyposis (FAP) or Gardner syndrome in which the adenomatosis polyposis coli (APC) gene 
sustains bi-allelic mutations.  Patients with FAP have a high risk of developing colorectal cancer 
and are recommended prophylactic colectomies.  In these cases, surgery appears to be the 
inciting factor.  In FAP patients, there is a ~2% risk of developing DT/DF, a 1000-fold increased 
risk in comparison to the general population.  In addition, there appears to be a weak link 
between antecedent surgery/ trauma and/or pregnancy and subsequent development of DT/DF.  
In the majority of patients with sporadic DT/DF, mutations in beta-catenin are commonly 
observed with dysregulation of the Wnt signaling pathway. 
1.2 
Epidemiology and Clinical Presentation 
DT/DF have an annual incidence of ~1000 in the United States, exhibiting a slight female 
preponderance and a wide age distribution (15-60 years). DT/DF have a wide range of 
presentation and have a variable natural history.  DT/DF typically exhibit indolent growth, and 
if asymptomatic may be observed as primary management. In a subset of patients, DT/DF can 
have a waxing and waning pattern and on rare occasions exhibit spontaneous remission.  
However, DT/DF can cause significant deformity, loss of function, pain through mass effects 
requiring narcotics and poor quality of life. Mortality from DT/DF is low and is secondary to 
compromising vital structures in the abdominal cavity and retroperitoneum resulting in 
hydronephrosis and/or bowel/bladder obstruction or perforation. Given the low mortality, the 
prevalence of DT/DF is expected to be much higher.  
1.3 
Treatment(s)  
There is no standard of care for the treatment of DT/DF. To date, case series and small Phase II 
trials, but no randomized trials inform the role of surgery, radiation or choice of systemic 
therapies. If asymptomatic, patients may be actively observed.  In those patients with symptoms 
or progressive disease, definite primary treatment involves complete surgical resection with 
wide margins. Local recurrence rate after surgery range from 19 – 38%. To date, the importance 
of margin status to predict local recurrence remains controversial. In many patients, limb 
amputations, deforming surgeries, extensive bowel resections and frequent ureteral stent 
exchanges remain the only surgical options resulting in profound morbidity in this young 
population (median age 30 years). Radiation therapy (RT) is used in some patients with high-
risk features (e.g. R1 resection) or in recurrent disease not amenable to surgery. However, the 
long-term consequences of radiation induced secondary cancers must be considered in this 
young population.  
Systemic therapies are typically employed when surgery and radiation therapy are unable to 
achieve adequate local control. To date, there are no randomized controlled trials to inform 
initial choice of therapy. Physicians tailor therapy based on patient characteristics, preference 
and urgency to induce a response. Non-cytotoxic therapies include single agent non-steroidal 
anti-inflammatory agents (NSAIDs), anti-hormonal therapies or their combinations. In adults, 
the effectiveness of these agents largely stem from case reports and small case series. The 
Children’s Oncology Group conducted a Phase II trial (ARST0321) evaluating the combination 


ALLIANCE A091105 
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of sulindac and tamoxifen in advanced, unresectable DT/DF. Duration of therapy was 12 months 
with evaluation of response every 3 months.  60/70 patients were eligible for evaluation. 40 
patients discontinued therapy due to disease recurrence, withdrawal of consent or toxicities. 
Among the 60 eligible patients, four (4) PRs and one CR were noted for an overall response rate 
of 8%. The 1-year event free survival (EFS) was estimated to be 44% with three deaths observed.  
Adverse events included asymptomatic ovarian cysts secondary to tamoxifen in 30% of women. 
Of note, DT/DF have variable expression of estrogen receptor (ER), in particular ER-beta, 
however, response to hormonal intervention does not appear to correlate with receptor status. 
Cytotoxic chemotherapy is usually reserved for symptomatic and rapidly proliferating disease 
that is not amenable to surgical or radiation treatment. Doxorubicin or liposomal doxorubicin 
(Doxil®) has been evaluated in case series of 2 – 12 patients and noted to have prolonged 
response of 20 – 36% for 7 - 40 months. A small retrospective case series of 12 patients from 
the Royal Marsden Hospital reported a 36% response rate with liposomal doxorubicin (Doxil®) 
administered over 6 months. Anthracyclines in combination with decarbazine have slightly 
higher response rates with expected increase in cardiac, hematologic and mucosal toxicities.  A 
well studied regimen includes vinorelbine/methotrexate and single agent decarbazine or 
temozolomide or combinations employing one of these agents.  The Pediatric Oncology Group 
conducted a Phase II trial (POG/CCG Intergroup P9650) evaluating vinorelbine and 
methotrexate in advanced, unresectable DT/DF. Chemotherapy was administered weekly for 26 
weeks and then every other week for a total of 52 weeks with minimal toxicities. Imaging was 
performed every 3 months and in 25 evaluable patients the responses were two CR, five PR, ten 
SD and 8 PD. One year progression free survival was estimated to be 58%. In a similar Phase II 
study conducted in 30 adult patients the response rates were 40% PR, 60% SD and at a median 
follow up of 75 months, the 10 year PFS was 67%.  
DT/DF are known to have variable expressions of KIT and PDGFRA/B by IHC and RT-PCR, 
without any consistent evidence of activating mutations in these genes. Imatinib, an oral tyrosine 
kinase inhibitor of ABL, ARG, KIT, CSF-1R, PDGFRA and PDGFRB has shown minor activity 
in this disease. In a large Phase II study of 51 patients with aggressive fibromatosis who received 
imatinib, 36 patients (80%) reached the primary endpoint of clinical benefit; defined as either 
complete or partial response at two months, or stable disease at four months. The median time 
to treatment failure was 6.8 months. Here PDGFRA deletions were found in only 4 of 22 
available tumor biopsies. Importantly, there was no correlation to clinical response to expression 
of KIT or PDGFRA/B. Another Phase II trial evaluated imatinib in 186 patients with advanced 
cancers (solid and liquid) expressing potential imatinib sensitive tyrosine kinase evaluated a 
cohort of 20 patients with AF. Objective response in AF was limited to 2 patients with PR and 
8 patients with SD. Tumor samples were positive for PDGFRB however not positive for 
phosphorylated PDGFRA/B or KIT mutations. Again no correlation was drawn between 
response and mutational status. In a trial of 19 patients with AF evaluated with high dose 
imatinib, three patients had PR and 4 had SD lasting more than 1 year. Tumors expressed non 
phosphorylated form of PDGRFB by IHC, but no activating mutations were found in KIT or 
PDGFRA/B. 16 of 19 patients had mutations in the Wnt (APC, CTNNB1) pathway however no 
correlation to clinical response was observed. 
1.4 
Sorafenib in Desmoid Tumors/ Deep Fibromatosis (DT/DF) 
Sorafenib, an oral multi-kinase inhibitor, blocks tumor cell proliferation by targeting 
Raf/MEK/ERK signaling at the level of Raf kinase, and exerts an anti-angiogenic effect by 
targeting vascular endothelial growth factor receptor-2/-3 (VEGFR-2/-3), and platelet derived 
growth factor receptor-beta (PDGFR-beta) tyrosine kinases (1). Based on improved survival 
demonstrated in randomized studies in advanced HCC and RCC, sorafenib is approved by the 
FDA for these indications. Sorafenib is available for patients and physicians through an 


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expanded access program. Based on the data with imatinib, an index DT/DF patient evaluated 
at MSKCC received sorafenib through the expanded access program and was observed to have 
clinical and radiological benefit with this therapy.  This prompted a retrospective review of the 
collective experience of twenty six DT/DF patients treated with sorafenib. This was presented 
at ASCO 2010, CTOS 2010 and recently published.   
1.5 
Methods  
Following institutional IRB approval (waiver WA0209-04), medical records of 26 patients from 
February, 2008 to October, 2010 who received sorafenib for DT/DF was reviewed. The 
following data was collected: age at the date of diagnosis, presentation status (primary or 
recurrent), gender, presence of Gardner syndrome, primary site, primary size, radiological 
appearance (diffuse versus nodular), number and type of surgeries, use of radiation therapy, 
lines, duration and response on prior therapies (hormonal, cytotoxic and tyrosine kinase 
inhibitors), reason for treatment discontinuation, time to progression, documentation of 
progression before initiation of sorafenib, dose and toxicities of sorafenib, overall survival and 
status. Imaging modalities employed in evaluating this heterogeneous group of patients include: 
1) MRI with gadolinium for tumors of the extremities, chest wall, or neck 2) CT with intravenous 
contrast or oral contrast only for tumors involving mesentery, abdominal wall or thorax.   
1.6 
Patient and Tumor Characteristics 
There were 17 females and 9 males in this cohort. Median age at diagnosis and presentation was 
29.5 and 31 years, respectively. At diagnosis, 16 patients underwent surgical resection and 10 
patients were deemed surgically unresectable or only resectable with unacceptable deformity 
(amputation) or morbidity.  At the start of sorafenib therapy, all 26 patients had unresectable 
disease.  The histological diagnosis was confirmed at MSKCC. Primary locations included: 
abdomen/pelvis (12), extremity (6), trunk/chest wall (6) and head and neck (2).  Radiological 
appearance of the tumor was nodular (6) or diffuse/infiltrative (20). The primary tumor size was 
<5 cm (4), 5–10 cm (11) and >10 cm (11). 
1.7 
Treatment Characteristics  
At initial diagnosis, sixteen patients underwent surgery for resectable disease. Four of 26 
patients received adjuvant radiation following primary resection. The use of NSAIDs was not 
evaluated. Prior systemic therapy included hormonal manipulation, chemotherapy and tyrosine 
kinase inhibitors. Fifteen patients received a median of 2 prior systemic treatments while 11 
patients had sorafenib as first-line treatment.  8/15 patients received hormonal therapy for a 
median of 8 months before progression.  Best response to hormonal treatment included stable 
disease and one minor response. There was a median of two lines of prior cytotoxic 
chemotherapy administered for a median of 7 months which consisted of single agents or 
combinations involving doxorubicin, liposomal doxorubicin, decarbazine, methotrexate and/or 
cyclophosphamide.   Toxicity with anthracyclines included congestive heart failure, alveolar 
bone loss in the jaw, mucositis, alopecia, nausea and fatigue. Tyrosine kinase inhibitors other 
than sorafenib had been employed in 6 patients with one minor response as best outcome.   
1.8 
Sorafenib administration 
Sorafenib was initiated when progression was noted on imaging in 23/26 patients while 3/26 
patients had RECIST stable disease on chemotherapy, but experienced worsening pain. 
Sorafenib was started in 15/26 patients after a median of 2 lines of prior systemic and as a first 
line therapy in 11/26 patients at the time of progression.  At the time of this concept submission, 
1st and 2nd line patients received sorafenib for a median of 10 months (1–46+) and 15 (2–32) 
months, respectively.  Sorafenib was started at a maximum dose of 400 mg daily and decreased 


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for toxicity.  No patient was treated at 400 mg twice daily, the FDA approved dose in renal cell 
or hepatocellular carcinoma. The median dose of sorafenib was 200 mg daily.  Some patients 
required further dose reductions for toxicities to 200 mg every other day while others tolerated 
alternating doses of 400 mg and 200 mg daily (300 mg/day).  Sorafenib related toxicities 
included hand-foot syndrome, fatigue, skin rash, trichodynia, hypertension, mild alopecia and 
diarrhea.  Side effects were well controlled with dose adjustments and inclusion of anti-diarrhea 
and anti-hypertensive drugs.   
1.9 
Clinical Outcome on Sorafenib 
Median follow up on sorafenib was 12 months (range: 1–46+).  Approximately 70% patients 
(16/22) reported subjective decrease in pain and analgesic use after initiation of sorafenib; these 
data were not quantitated using a validated pain scale. Some examples of clinical benefit include: 
(1) A 21 year old male had tumor extending from axilla to brachial artery, median and ulnar 
nerve which resulted in significant pain, swelling and loss of mobility. Forequarter amputation 
remained the only option to render the patient disease-free. Within 2 months of sorafenib the 
patient experienced a RECIST PR, complete resolution of symptoms and thus averting a 
forequarter amputation; (2) a 24 year old female had a large desmoid tumor displacing her 
mediastinum and had signs of impending cardiopulmonary collapse despite other systemic 
therapies. Within one week of sorafenib she had dramatic improvement in orthopnea, dyspnea 
and lower extremity edema; (3) a 21 year old woman with inoperable cervical spine mass 
presented with pain and compromised mobility. Therapy did not result in change in tumor size; 
however there was loss of MRI T2 signal and significant pain relief. Notably, no symptomatic 
benefit was reported by patients with intra-abdominal desmoids. Three patients stopped 
sorafenib within 2 months due to abdominal pain, uncontrolled hypertension or visual 
disturbances. Neither cardiac toxicity nor bleeding was observed.  
1.10 
Radiological response assessment 
Background 
MRI is a standard of care in extra-abdominal DT/DF.  All patients undergoing MRI as part of 
their response evaluation will be included in this exploratory study.  Response evaluation by 
RECIST will be performed by ALLIANCE designated central, independent radiology review.  
For the exploratory study, images of patients treated with sorafenib will be obtained from 
ALLIANCE Core lab for evaluation by musculoskeletal radiologist Drs. Robert Lefkowitz 
(Radiology) and Yousef Mazaheri (Medical Physics).   
Background #2: The optimal imaging modality to evaluate DT/DF remains undefined17.  In the 
study of sorafenib in DT/DF, 6 of 24 patients experienced a RECIST PR and 7/24 had minor 
response. We noted in our study that patients with changes in T2 signal had described 
symptomatic improvement without having a RECIST response. We also noted that T2 changes 
preceded a RECIST response by six months15.  Studies have shown that areas of desmoid tumor 
that are hyperintense on T2-weighted and STIR images are associated with active fibroblastic 
proliferation (Sundaram et al, 1987; Vandevenne et al, 1997). MRI T2 signal is a unit less 
number with no intrinsic meaning except for comparative purposes. We therefore developed a 
reproducible, quantifiable metric where the ratio between the T2 intensity of the tumor (C1) and 
adjacent skeletal muscle (M1) was calculated in pre-treatment and week 12 images (i.e. [C2/M2] 
/ [C1/M1])15.  A 30% decrease of T2 signal intensity was arbitrarily defined as significant.  T2 
changes were seen in 12/13 (~90%) patients with extra-abdominal disease and 100% of patients 
with a RECIST PR (Figure 5).  Changes in T2 signal occurred as early as 6 months prior to a 
RECIST response.  In the figure below, patients on the right side had a significantly decreased 
amount of time on the drug compared to the patients on the left side.  The sensitivity and 
specificity of T2 signal loss as a predictor of RECIST PR was 100% and 12%, respectively. We 


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hypothesize that T2 signal in extra-abdominal DT/DF is 1) an early predictor of RECIST 
response and 2) a predictor of clinical benefit in patient with stable disease.    
We will also be evaluating diffusion-weighted MR imaging (DW-MRI) in a subset of patients 
having extra-abdominal disease. DW-MRI is a non-invasive technique that derives its image 
contrast from differences in the motion of water molecules between tissues.  The degree of water 
diffusion in biologic tissue is inversely correlated to tissue cellularity and the integrity of cell 
membranes.  The motion of water molecules is more restricted in tissues with high cellular 
density associated with numerous intact cell membranes (e.g., tumor tissue).  Quantitative 
analysis of DW-MRI is achieved by calculation of the apparent diffusion coefficient (ADC).  
The ADC is calculated for each pixel of the image and is displayed as a parametric map.  
RECIST 1.1: Twenty four of 26 patients were evaluable for response. CT or MRI was obtained 
at a median interval of 4 months. Responses by RECIST 1.1 were: 0/24 complete responses, 
6/24 partial responses (25%), 17/24 (70%) with stable disease and 1 patient with progressive 
disease. Seven patients experienced minor response (defined as 10–29% decrease). Bi-
dimensional WHO size measurements were highly correlated (R2=0.92) with RECIST (not 
shown). RECIST PR was achieved at a median of 10 months and a minor response (i.e. reduction 
> 10% by RECIST) was noted at a median of 4 months of starting therapy. PR and SD were 
mostly seen in extra-abdominal tumors (p=0.03, t-test) and there was no difference between 
those who received sorafenib as first-line or second-line (p = 0.9, t-test).  
Survival: The 26 patients were followed for a median of 50 months (3–209 months) from initial 
diagnosis.  Median follow-up from the start of sorafenib was 12 months (1-46+). Median time 
to progression was not reached.  Five patients progressed despite sorafenib, defined as increasing 
tumor size (2), symptoms (1) or drug intolerance (2). Twenty-five of 26 patients are alive with 
disease. 
1.11 
Registration Fatigue/Uniscale Assessment  
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 North Central 
Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center oncology clinical trials, the 
second involving 43 clinical trials. Routine inclusion of these measures should be considered 
similar to that of including performance status, either as stratification or prognostic covariates.   
1.12 
Inclusion of Women and Minorities 
All studies must address the issue of inclusion of women and minorities in clinical research and 
whether gender or race/ethnicity differences in the intervention effect are to be expected. The 
statisticians will provide statistical analysis of past phase III studies as well as how the review 
of the literature will be reflected in the statistical section. 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
To compare the progression-free survival (PFS) rates of patients with DT/DF who receive either 
sorafenib or placebo using a double-blinded randomized phase III study. 
2.2 
Secondary Objective(s) 
2.2.1 
To assess toxicity. 


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Update #06 
2.2.2 
To assess time to surgical intervention. 
2.2.3 
To assess tumor response rates and survival. 
2.3 
Correlative Companion Study Objectives 
2.3.1 To evaluate changes in MRI T2 to predict (or correlate) with a biological effect such as 
tumor growth (by RECIST v1.1), and pain palliation. 
2.3.2 The mechanism of action of sorafenib in DT/DF remains unknown.  In patients consenting 
to undergo the paired tumor biopsies (A091105-ST1), treatment induced changes will be 
quantified by histology, gene expression profiling, proteomic changes and selected 
interrogation of key pathways by Western blot and RT-PCR. 
2.3.3 To collect archival tissue, baseline (tumor, blood) and day 8 (tumor, blood) specimens for 
basic science research (A091105-ST1). 
2.3.4 To assess patient-reported adverse events and quality of life (QOL) as measured by the PRO-
CTCAE and the single-item overall LASA (A091105-HO1). 
2.3.5 
To assess pain palliation measured by the “worst pain” item of the Brief Pain Inventory 
Short Form (A091105-HO1). 
3.0 
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.  
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 (Norplant), or double barrier method (diaphragm plus 
condom).  
• 
Patients must be able to swallow tablets. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Study Chair. Please note that the 
Study Chair cannot grant waivers to eligibility requirements.  
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. 


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4.1 
Documentation of Disease  
Patients must have confirmation of DT/DF by local pathologist prior to registration.  
4.2 
Prior Treatment 
4.2.1 Patients may have been treated with locoregional therapies such as major surgery, radiation, 
radiofrequency ablation, or cryosurgery provided this has been completed at least 4 weeks 
prior to registration and recovered from therapy related toxicity to less than CTCAE grade 
2.  
4.2.2 Patients may have been treated with cytotoxic, biologic (antibody), immune or experimental 
therapy, tyrosine kinase inhibitors, hormone inhibitors or NSAIDs provided this has been 
completed at least 4 weeks prior to registration (6 weeks for mitomycin and nitrosoureas) 
and recovered from any therapy related toxicity to less than CTCAE grade 2. 
4.2.3 Patients with prior or current treatment of sorafenib are excluded. 
4.2.4 No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or 
warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents 
(e.g., clopidogrel). Low dose aspirin (≤81 mg/day), low-dose warfarin (≤1 mg/day), and 
prophylactic low molecular weight heparin (LMWH) are permitted. Please note that drugs 
that strongly induce or inhibit CYP3A4 or are associated with a risk of Torsades are not 
allowed. Chronic concomitant treatment of CYP3A4 inducers is not allowed 
(e.g., dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
rifapentin, 
phenobarbital, and St. John’s Wort). Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians’ 
Desk Reference may also provide this information. As part of the enrollment/informed 
consent procedures, the patient will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product. 
The following drugs are strong inhibitors of CYP3A4 and are not allowed during the 
treatment with sorafenib: 
•       Boceprevir 
•       Indinavir 
•       Nelfinavir 
•       Lopinavir/ritonavir 
•       Saquinavir 
•       Telaprevir 
•       Ritonavir 
•       Clarithromycin 
•       Conivaptan 
•       Itraconazole 
•       Ketoconazole 
•       Mibefradil 
•       Nefazodone 


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•       Posaconazole 
•       Voriconazole 
•       Telithromycin 
Drugs with possible or conditional risk of torsades should be used with caution knowing 
that sorafenib could prolong the QT interval. Please see Appendix III for more details. 
Chronic daily NSAID use as treatment for controlling desmoid tumors is not allowed, and 
should be stopped ≥ 3 days prior to registration.  NSAIDS are allowed when used for 
desmoid tumor-related pain or for symptoms that are unrelated to desmoid disease (eg 
headache, arthritis). 
4.3 
Measurable Disease 
Patients must have measurable disease as defined in Section 13.0.   
4.4 
Disease Status  
Patients have to meet one of the following criteria to be eligible: 
1. Disease determined unresectable or entailing unacceptably morbid surgery based on 1 or 
more of the following characteristics: 
• 
Multifocal disease 
• 
Disease in which there is involvement or inadequate plane from: neurovascular 
bundle, bone, skin, or viscera 
• 
Large size in relationship to location OR multi-compartment involvement 
2. Progression by radiographic imaging (10% increase in size by RECIST v1.1 within 6 
months of registration) 
3. Patients with symptomatic disease which meets the following criteria BPI score greater 
than or equal to 3 AND one of the following: 
• 
Inability to control pain with NSAIDs and considering addition of narcotics OR 
• 
>30% increase in current use of narcotics OR 
•  
Addition of a new opioid narcotic 
4.5 
Age and performance status 
4.5.1 Age ≥ 18 years of age  
4.5.2 ECOG Performance Status ≤2 
4.6 
Pregnancy/nursing status 
Patients who are pregnant or nursing are not eligible because of the potential teratogenic/growth 
inhibitory effects of sorafenib. 
4.7 
Patient History 
4.7.1 No patients with a history of cardiac disease: congestive heart failure > class II New York 
Heart Association (NYHA); active coronary artery disease (CAD) (myocardial infarction or 
unstable angina within 6 months prior to study entry) 
4.7.2 No patients with inadequately controlled hypertension (defined as a blood pressure of ≥150 
mmHg systolic and/or ≥90 mmHg diastolic), or any prior history of hypertensive crisis or 
hypertensive encephalopathy 


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4.7.3 No patients with clinically significant gastrointestinal (GI) bleeding or bleeding diathesis 
within 30 days prior to registration 
4.8 
Required Initial Laboratory Values:  
Patients must have normal organ and marrow function as defined below: 
absolute neutrophil count ≥1,500/mm3 
hemoglobin ≥8g/dl 
platelets ≥75,000/mm3 
total bilirubin ≤ 1.5 x upper limits of normal (ULN)  
SGOT(AST)/SGPT(ALT) ≤1.5 X ULN  
creatinine  Calculated creatinine clearance ≥50 mL/min* 
* using the Cockcroft-Gault equation  
CrCl = (140 - age) x IBW / (Scr x 72)        (x 0.85 for females) 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION  
5.1 
Patient Registration Requirements 
5.1.1 Informed Consent  
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. Human protection 
committee approval of this protocol and a consent form are required. 
5.1.2 Patient Completed Booklets 
Patient questionnaire booklets are to be ordered prior to the registration of any patients. 
Patient completed booklets can be ordered by downloading and completing the CTSU 
supply request form (located under the site registration documents section of the A091105 
CTSU site) and faxing the form to the CTSU data operations center at 1-888-691-8039. 
Samples of the booklets are found in Appendix II, which are to be used for reference and 
IRB submission only. They are not to be used for patient completion. 
5.2 
Registration Procedures 
5.2.1 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 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. 
 


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Update #06 
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 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
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 < RCRHelpDesk@nih.gov >. 
5.2.2 CTSU Site 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 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 


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Update #06 
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 IRBManager 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. 
 
5.2.2.1 Downloading Site Registration Documents  
Site registration forms may be downloaded from the A091105 protocol page located on 
the CTSU members’ website. 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. 
• 
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 # A091105 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided 
5.2.2.2 Requirements for A091105 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). 
5.2.2.3 Checking Your Site’s Registration Status  
You can verify your site registration status on the members’ section of the CTSU 
website. Check the status of your site’s registration packets by querying the RSS site 
registration status page of the members’ section of the CTSU website.  (Note: Sites will 
not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.)  
• 
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 


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Update #06 
5.2.2.4 Submitting Regulatory Requirements  
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: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
5.3 
Patient Registration/Randomization Procedures 
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 {add if a Rave study: 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. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
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 1-888-823-5923 or ctsucontact@westat.com. 
NOTE: The patient should be registered to optional companion studies A091105-HO1 and 
A091105-ST1 at the same time they are registered to A091105. 


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Update #06 
5.4 
Registration to Companion Studies 
5.4.1 
Registration to Substudy described in Section 10.2 
This companion study must be offered to all English-speaking patients enrolled on 
A091105 (although patients may opt to not participate). The assessments cannot be 
translated, so patients who do not speak English, may not participate in this substudy. This 
optional substudy included within A091105 is: 
•  A091105-HO1, “QOL study” 
If a patient answers “yes” to “I choose to take part in the Quality of Life study and will fill 
out these forms:”, question #1 in the model consent, they have consented to participate in 
the substudy described in Section  10.2. 
5.4.2 
Registration to Substudy described in Section 10.3 
This correlative science study must be offered to all patients enrolled on A091105 
(although patients may opt to not participate). This optional substudy included within 
A091105 is: 
•  A091105-ST1, “Analysis of archival tissue, and pre-treatment and 8 day tumor biopsy and 
blood samples” 
If a patient answers “yes” to “My coded samples and related coded information may be 
used in the research described above to learn about, prevent, find or treat cancer. This may 
also include research on inherited traits (genes passed on in families).” question #2 in the 
model consent, they have consented to participate in the substudy described in Section 10.3.  
5.5 
Re-Registration at the time of crossover to open label sorafenib arm 
Upon confirmation of progression, patients will be unblinded to their treatment assignment. 
Patients who were initially assigned to placebo will be allowed to cross over to the open label 
sorafenib arm. 
Re-registration procedures: 
OPEN may be accessed at https://open.ctsu.org, from the OPEN tab on the CTSU website at 
https://www.ctsu.org, or from the OPEN Registration tab on the Alliance website. 
To enroll a patient within OPEN, institution staff must have: 
1. A valid and active CTEP-IAM account. This is the same user ID and password used for 
CTSU’s 
website (for more 
information 
see 
https://www.ctsu.org/public/CTEP-
IAM_Factsheet.pdf). 
2. Enrollment of patients on Alliance coordinated protocols requires a “Registrar” role in the 
Alliance roster. Assignment of the “Registrar” role is managed through the Alliance Central 
Protocol Office via submission of a roster update form signed by the Principal Investigator 
of the member network. 
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information is 
provided on the CTSU members’ website OPEN tab, or within the OPEN URL. For any 
additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923, 
or 
ctsucontact@westat.com.  
5.6 
 Stratification 
Patients will be stratified at randomization by: 
1) intra-abdominal disease:  yes vs no 


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Update #06 
2) baseline level of pain (BPI “Worst Pain” Item: 0-<3; 3 – <7 vs 7 – 10). See Appendix V. 
We will be using a 2:1 randomization scheme to improve accrual to the study given that is has 
an observation arm and to also reduce biopsies performed for patients who have been enrolled 
to the placebo group. The randomization algorithm used by the Alliance Statistics & Data Center 
uses dynamic allocation procedure27 which balances the marginal distributions of the 
stratification factors between treatment regimens. 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Medidata Rave® 
This study will use Medidata Rave® for remote data capture (RDC) of all study data. The Rave 
system can be accessed through the iMedidata portal at https://login.imedidata.com. For 
additional information regarding account setup or training, please visit the training section of 
the Alliance Web site. Copies of forms and a data submission schedule are also available for 
download at the Alliance Web site. 
Common Terminology Criteria for Adverse Events: This study will utilize the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for toxicity and adverse event 
reporting. 
6.2 
A091105-HO1 (QOL) data submission 
QOL booklet ordering instructions can be found in Appendix II. For patients who consent to 
model consent question #1, the assessments in the table below are to be completed at the 
following timepoints: 
 
Assessment 
Within 28 days 
prior to 
randomization 
Within 
28 days 
prior to 
treatment 
Weeks 4, 8, 12, 
16, 20, 24, 28, 
and 32  of 
treatment (+/- 3 
days)  
(i.e. Cycles 1-8, 
Days 22-28) 
End of 
randomized 
treatment 
Brief 
Pain 
Inventory Short 
Form 
X 
 
X 
X 
PRO-CTCAE 
X 
 
X 
X 
Single-item 
overall LASA 
X 
 
X 
X 
Pain Medication 
Diary 
 
X* 
X 
X 
* Daily reporting for 7 consecutive days via paper diary prior to treatment. Pain medication 
diary is not found in QOL booklet. 
The Brief Pain Inventory Short Form, PRO-CTCAE and Single-item overall LASA are all 
contained with the QOL questionnaire booklets (see Appendix II). Samples of QOL 
questionnaires found in Appendix II of the protocol document are for reference and 
IRB submission only. They are not to be used for patient completion. 
The pain medication diary is not part of the QOL Booklet and must be printed. The pain 
medication diary should be completed during treatment weeks 4, 8, 12, 16, 20, 24, 28, and 


ALLIANCE A091105 
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Update #06 
32 weeks. Therefore, since a cycle is 28 days, the pain medication diary should be completed 
the last week of each cycle.  
On Day 1 of each cycle site staff should prepare the pain medication diary by listing the pain 
medication names, routes and strengths in the appropriate columns on the pain medication 
diary. Site staff must then send the partially completed diary home with the patient and ask 
that they complete it for the 7 days leading up to the next appointment. 
The QOL assessments cannot be translated, therefore, only English-speaking patients may 
enroll on this substudy. 
6.3 
Specimen Submission 
Specimen 
Baseline3 
Cycle 1, Day 8 
(+7 days) 
Location  
Archival tissue block 
(FFPE)1 
X 
 
OSU 
Peripheral 
whole 
blood2 
X 
X 
OSU 
Research 
tumor 
biopsy2 
X 
X 
OSU 
Plasma2 
X 
X 
OSU 
1  Required for all patients registered to A091105.  For patients who consent to A091105-ST1, this 
tissue block will also be used for study described in Section 10.3 
2 For patients consenting to optional study A091105-ST1 
3 Obtain prior to the start of protocol treatment and between days 8 and 11 of Cycle 1  
6.3.1 Formalin Fixed, Paraffin Embedded (FFPE) Tissue 
Archival Tissue: All patients must submit an archival tumor specimen block for required 
retrospective pathology review.  This block will be used by the study pathologist to confirm 
diagnosis of desmoid tumor (DT/DF). For patients who consent to A091105-ST1, this tissue 
block will also be used for the study described in Section 10.3. 
At least 1 adequate-sized archival paraffin block(s) representative of the primary tumor from 
a diagnostic or therapeutic procedure at time initial diagnosis or subsequently, should be 
retrieved from the surgical pathology department. Blocks which contain minimal amounts 
of tissue specimen (less than 0.5 cm2 on the block face) or that are very thin (less than 0.5 
cm in depth) should not be submitted unless the block is the only representative tissue for 
the case.  A de-identified surgical pathology report should be sent with all blocks. 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.  
Paraffin blocks retrieved from the surgical pathology department should have a label affixed 
to them that includes the protocol number, Alliance patient ID, and patient initials. The 
surgical pathology case number and block identifier should be maintained on the report so 
that it can be matched with the physical labeling on the block. Paraffin blocks should be 
shipped within 30 days of starting protocol treatment to Alliance Biorepository at Ohio State 
(OSU).  Upon receipt at OSU, representative H&E slides and/or scanned images will be 
provided to designated study pathologist for retrospective pathology review.  The 


ALLIANCE A091105 
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Update #06 
pathologist and/or study chair will request block shipping periodically (approximately every 
4 months). All blocks will be held by the appropriate Alliance biorepository but will be 
returned within 30 days of a written request.   
In instances where a tissue block cannot be released due to institutional or 
governmental policy, please contact the Alliance OSU to obtain information about 
submission of tissue sections as an alternate specimen. 
Archival blocks should be requested at time of consent. Blocks should be shipped overnight 
to Alliance OSU. 
6.3.2 Research frozen tumor core biopsy submission (optional study A091105-ST1) 
When safe and feasible, according to the treating investigator and proceduralist obtaining 
biopsy, consenting patients will undergo 2 biopsies (procuring 5 cores for each biopsy) for 
correlative study A091105-ST1. Depending on tumor location, biopsies can be obtained at 
the discretion of surgeon or interventional radiology under image guided CT or Ultrasound.  
Core biopsies should be performed with either 14 (prefer) or 18 gauge needles. When 
possible, different areas of the tumor should be biopsied. Each core sample will be 
transferred to individual cryovials. The cryovials containing the 5 research core biopsy 
specimens should be immediately immersed in liquid nitrogen for 5 minutes. If liquid 
nitrogen is not available, the specimen may be immersed in a refrigerated cryobath, available 
in most surgical pathology frozen section rooms. If using a cryobath, one should be certain 
that the temperature of the bath is at or below -40°C. As a last option, specimens may be 
frozen by complete immersion in an ethanol / dry-ice bath. Specimens should be left in the 
cryobath or dry ice bath for at least 15 minutes to ensure complete freezing. Specimens 
should not be frozen by placing fresh tissue in a -70°C freezer or inside a cryostat. Once 
frozen, tissue may be stored in at least -70°C mechanical freezer or in dry ice until shipping. 
Once frozen, take extreme care not to let the tissue specimen thaw.  Specimens should be 
shipped on dry ice within 30 days of collection to Alliance OSU. For sites that do not have 
-70 C freezer, tissue should be frozen as described above and shipped within 24 hours of 
collection according to Section 6.3.6.   
6.3.3 Peripheral Whole Blood Submission (optional study A091105-ST1) 
Collect 2 vials of 6 mL of peripheral venous whole blood in 9 mL lavender top (EDTA 
anticoagulant) vacutainer tube(s). Invert tubes approximately 10 times to mix the EDTA. 
Specimens should be refrigerated within 30 minutes of the blood draw until 
shipped/transported. The sample should be shipped the same day that the blood is drawn. 
The specimen should be placed in a biohazard bag and shipped according to IATA 
guidelines with a cold refrigerant pack by overnight carrier to the Alliance OSU. Shipment 
on Monday through Thursday by overnight service to assure receipt is encouraged. Do not 
send specimens on a Friday or Saturday or the day before a federal holiday.   
6.3.4  Plasma Specimen Submission (optional study A091105-ST1) 
1. For EDTA plasma, draw 6 mL of peripheral blood into 9 mL lavender or purple top 
vacutainer(s) (K2EDTA anticoagulant). Invert approximately 8 times and centrifuge for 15 
minutes at 2500 x g using a refrigerated centrifuge at 2-8o C.  Within 15 minutes, transfer 
the plasma sample into (4) labeled 2 mL cryovials.  
2. Label and freeze cryovials at –70°C or colder. Samples should be shipped within 30 days 
on dry ice by overnight express courier to the Alliance OSU. For sites that do not have -70 
C freezer, plasma samples may be temporarily stored at -20o C and shipped within 24 hours 
of collection.   


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Update #06 
6.3.5 Specimen Labeling 
Research peripheral whole blood, plasma, and frozen tumor specimen tubes must be labeled 
with the following information (using a Sharpie or Cryopen): 
1. Alliance study number (i.e., A091105) 
2. Alliance patient ID number 
3. Patient’s initials 
4. Date of specimen procurement 
5. Sample type (i.e. whole blood, plasma-EDTA, plasma citrate, urine, marrow aspirate, 
metastatic site, etc.) 
6.3.6 Specimen Shipping 
All shipments should follow the International Air Transport Association (IATA) guidelines 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/Pages/infectious_substanc
es.aspx) including shipment in a biohazard bag and should be sent by overnight 
shipping service. A shipping service should be selected that is secure and traceable.. 
Extreme heat precautions should be taken when necessary. The specimens should be 
sent Monday through Thursday to OSU. Do not send specimens on a Friday or 
Saturday or the day before a federal holiday. 
All samples should be sent to the following address: 
Alliance Biorepository at Ohio State  
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
6.3.7 Alliance Biospecimen Management System Instructions 
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.wustl.edu/bioms 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: 1-855-
55-BIOMS.  For assistance in using the application or questions or problems related to 
specific specimen logging, please contact: 1-855-55-BIOMS. 
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. 
6.4 
MR Imaging Data Submission 
Once the image acquisition has been completed (at baseline and every 8 weeks), the entire 
study (complete data sets in digital DICOM format), along with Alliance Adjunctive Data 
Form (if applicable) and Alliance Image Measurement Form (if applicable), must be 


ALLIANCE A091105 
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Update #06 
submitted to the ALLIANCE Imaging Core Laboratory within no more than 3 business days.  
BMP files, JPG files, or hard copies (films) are not acceptable.  The raw data of the entire 
study should be saved until the scan is accepted by the Imaging Core Lab. De-identify the 
patient data using institutional procedures to remove patient name and medical record 
number while preserving the Alliance patient ID number and protocol number. The de-
identified digital images may be temporarily burned to a CD or transferred to a PC based 
system.  
Data should be transferred electronically (recommend) to the Alliance ICL as follows:  
Electronically 
1) Web Transfer (http://upload.imagingcorelab.com) 
Any PCs with internet access and web browser (e.g., Internet Explorer, Mozila Firefox) can 
be used to web transfer DICOM images and other required files to the Imaging Core Lab. 
The standard Web Transfer information will be provided separately through the specific trial 
e-mail, per the request by participating sites before their first data submission. 
2) FTP Transfer 
Any FTP software can be used to initiate access to the secure FTP Server of the Imaging 
Core Laboratory. The standard FTP access information will be provided separately through 
the specific trial e-mail, per the request by participating sites before their first data 
submission. 
Mail/CD Shipment 
Only if electronic data transfer approaches cannot be achieved, the de-identified images in 
digital DICOM format can be burned to a CD and mailed to the Imaging Core Lab. Submit 
only one patient’s images per CD, with the patient’s Alliance ID number, study type, date 
of scans, and name of submitting institution. 
Submit these data to: 
ALLIANCE Imaging Core Lab 
Attn: Alliance Trial A091105 
The Ohio State University 
395 W. 12th Avenue, Suite 414 
Columbus, Ohio, 43210 
Tel: 614-293-9151 
Fax: 614/293-9275 
Once the imaging data submission is done, send an e-mail to the Imaging Core Lab at the 
specific trial email Alliance091105@ImagingCoreLab.com to inform that the study has 
been submitted from the institution. Please include the basic information of submitted data 
sets as follows: 
1) 
Alliance patient ID number  
2) 
Scan time point (i.e., baseline) 
3) 
Date of scans 
4) 
Institution name  
The ALLIANCE Imaging Core Lab will acknowledge receipt of the imaging data via email 
confirmation to the institution within 1 business day of receipt, and will notify the 
institution and Alliance imaging committee of the quality check report within 3 business 
days. 


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Update #06 
7.0 
REQUIRED DATA 
Pre-Study Testing Intervals  
To be completed within 28 DAYS before registration: 
• 
All bloodwork 
• 
History and physical 
• 
CT or MRI of lesion 
 
Prior to 
Registration* 
Day 1 and 15 (+/- 3 
days) of Cycle 1 
(Clinical Follow up)** 
Day 1 (+/- 3 days) starting 
with Cycle 2  
(Clinical Follow up)** 
Survival and 
Disease Status 
Follow up*** 
Tests & Observations 
 
 
 
 
Physical Examination  
X 
X 
X, C 
 
Pulse, Blood Pressure 
X 
X 
X, C 
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Performance Status 
X 
X 
X, C 
 
Tumor Measurements 
X (1) 
 
X (1) 
B 
EKG 
PRN 
 
PRN 
 
Registration Fatigue/Uniscale 
Assessment 
X (2) 
 
 
 
Adverse Event Assessment 
X 
X 
X, C 
 
Brief Pain Inventory Question #1 
(see Appendix II and V) 
X(6) 
 
 
 
 
 
 
 
 
Laboratory Studies 
 
 
 
 
CBC with Differential, Platelets 
X 
X 
X, C 
 
Pregnancy Test (serum) B 
X (4) 
 
 
 
Na, K, chloride, bicarb, BUN, 
creatinine, glucose, Ca, SGOT 
(AST), SGPT (ALT), bili, total 
protein, albumin 
X 
X 
X, C 
 
 
 
 
 
 
Staging 
 
 
 
 
Spiral CT Scan or MRI of lesion 
X(7) 
 
A(7) 
B 
 
 
 
 
 
Companion Studies 
 
 
 
 
QOL Assessments 
X (3) 
X (3) 
X (3) 
 
Archival Block 
X (5) 
 
 
 
Tumor Biopsy and blood† 
 
See Section 6.3 
* 
Pre-registration labs may be used for day 1 of cycle 1 tests if obtained within 28 days prior to day 1 of Cycle 1. 
** 
For patients discontinuing treatment for reasons other than progressive disease (PD) and prior to 1 year post-
randomization, Clinical Follow-up continues at least every 8 weeks after discontinuing treatment until the earliest PD 
or until 1 year after randomization. Patients on the placebo arm may cross over to the sorafenib arm upon PD, and 
continue in Clinical Follow-Up. Treatment with sorafenib after crossover must begin within 28 days following 
documentation of progression. 
*** After progression on sorafenib, patient will be followed per. Section 14.1 
† 
For patients who consent to A091105-ST1. Not required for patients who have crossed over to sorafenib. 
1 
To be performed only for patients with palpable disease.  Submit measurements in cm with two dimensions.  
2 
To be completed within 21 days prior to registration, see Appendix I. 
3 
Within 28 days prior to randomization, every 4 weeks up to Week 32 while on randomized treatment, and at the end 
of randomized treatment; see Section 6.2. These items are not required after patients have crossed over to sorafenib. 
4 
For women of child bearing potential. To be obtained within 3 days prior to day 1 of Cycle 1, and after crossover, < 
7 days prior to starting treatment with sorafenib. 
5 
Required for all patients registered to A091105 and will be used for confirmation of diagnosis as described in Section 
6.3.1. For patients who consent to A091105-ST1, this tissue block will also be used for study described in Section 
10.3.  


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Update #06 
6 
Must be completed within 28 days of registration. Patients who consent to A091105-HO1 will meet this requirement 
by answering question #1 on baseline QOL assessment (see Appendix II). For patients who do not consent to A091105-
HO1, see Appendix V. 
7 
All MRI images are to be submitted to the Alliance ICL per Section 6.4 and will be analyzed as described in Section 
10.1 
A 
Every 2 cycles (i.e. 8 weeks) +/- 7 days after Day 1 of Cycle 1 (i.e. Day 1 of Cycle 3, 5, 7, etc) for the first 3 years. 
For patients receiving initial treatment beyond 3 years from randomization date; scans may be performed every 4 
months through 5 years from randomization, then scans may be performed every 6 months. Patients who crossover 
must have a scan within 28 days of starting sorafenib. The scan schedule after crossover to sorafenib will be every 2 
cycles for three years. For patients receiving crossover treatment beyond 3 years from re-registration; scans may be 
performed every 4 months through 5 years from re-registration, then scans may be performed every 6 months. 
B 
As clinically indicated per institutional standard of care 
C 
Effective with Update #06, For crossover patients only: Beginning with Cycle 14 (i.e. after 1 year of sorafenib 
treatment) complete every other cycle. 


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Update #06 
8.0 
TREATMENT PLAN 
Protocol treatment is to begin within 14 days of randomization. One cycle is equal to 28 days. 
Questions regarding treatment should be directed to the Alliance Study Chair.  
8.1 
Sorafenib/Placebo  
Patients will be randomized to receive either sorafenib 400 mg PO once daily or placebo (two 
pills) once daily.  
Sorafenib/placebo should be taken by mouth once daily on an empty stomach (at least 1 hour 
before or 2 hours after a meal) and with at least 250 ml of water. Patients should take their daily 
dose at approximately the same time each day.  Patients should use the study pill diary to record 
their daily dose of sorefenib/placebo. Patients should bring the pill diary with them each time 
they return for a study follow-up visit. 
8.2 
Crossover 
Upon disease progression, patients treated with placebo will be allowed to crossover to the open 
label sorafenib arm. Patients who undergo surgical excision of their tumors must start sorafenib 
within 28 days of surgery.  After excision, the patient must have measureable disease (per 
RECIST v1.1). 
8.3 
Duration of Treatment 
Study treatment is not based on a pre-defined number of cycles. Refer to Section 14.0 for criteria 
for removal of patients from study treatment.  
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY  
Should unanticipated circumstances arise that might require minor variances from the prescribed 
dosing and schedule of the protocol therapy or recommended supportive care, the Study Chair should 
be contacted in advance for discussion and approval in order to ensure safety and allow patients to 
continue to receive treatment on study. 
 9.1 
Dose levels 
Dose reduction of sorafenib/placebo will be performed according to the table below. 
Sorafenib/placebo will be permanently discontinued for patients who require dose interruptions 
of > 28 days or who experience dose limiting toxicities at dose level -1. Missed doses of 
sorafenib/placebo will not be made up.  
Dose level 
Sorafenib/placebo 
0 
400 mg once daily 
-1 
200 mg once daily 
 
• 
If dose reductions beyond the lowest dose level are required discontinue all protocol 
therapy. 
• 
Doses that have been reduced will not be re-escalated, except in the case of skin toxicity.  
9.1.1 Dose Modifications for Hematologic Toxicities 
Grade ≥3 neutropenia, thrombocytopenia, or neutropenic fever: Interrupt 
sorafenib/placebo until ≤ grade 2, then resume with one dose level reduction of 
sorafenib/placebo for all subsequent doses. 


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Update #06 
9.1.2  Dose Modifications for Gastrointestinal Toxicities 
• Grade ≥ 3 diarrhea: Interrupt sorafenib/placebo until diarrhea improves to ≤ grade 2, then 
resume sorafenib/placebo with one dose level reduction. 
• GI Perforation: Discontinue sorafenib/placebo. 
9.1.3 Dose Modifications for Hepatic Dysfunction 
• Grade 2 blood bilirubin increased: Interrupt sorafenib/placebo until improved to grade 
1, then resume sorafenib/placebo at same dose. 
 • Grade 3 blood bilirubin increased: Interrupt sorafenib/placebo until improved to grade 
1, then resume sorafenib/placebo at 1 dose level reduced. 
• Grade 4 blood bilirubin increased: Discontinue sorafenib/placebo. 
• Grade 3 transaminase increased: Interrupt sorafenib/placebo until improved to grade 1, 
then resume sorafenib/placebo at 1 dose level reduced. 
• Grade 4 transaminase increased: Discontinue sorafenib/placebo. 
9.1.4 Dose Modifications for Hypertension 
• For hypertension >140/90 and ≤160/100: Continue sorafenib/placebo. Consider adding or 
adjusting anti-hypertensive medications (e.g., calcium channel blockers). 
• For persistent (>160/100) or symptomatic hypertension: Interrupt sorafenib/placebo. Resume 
when blood pressure improves to ≤160/100. If sorafenib/placebo is interrupted for > 4 weeks, 
discontinue all protocol therapy. 
• Grade 4 hypertension: Discontinue all protocol therapy. 
9.1.5 Dose Modifications for Cardiotoxicity  
• Myocardial ischemia: Discontinue sorafenib/placebo. 
9.1.6 Dose Modifications for Skin Toxicity (palmar-plantar erythrodysesthesia (PPE) 
syndrome) 
Skin Toxicity  
Occurrence 
Suggested Dose Modification 
Numbness, dysesthesia, paresthesia, 
tingling, painless swelling, erythema 
or discomfort of the hands or feet 
relief which does not disrupt the 
patient’s normal activities 
Any occurrence 
Continue treatment with 
sorafenib/placebo and consider topical 
therapy for symptomatic relief 
 
Painful erythema and swelling of the 
hands or feet and/or discomfort 
affecting the patient’s normal 
activities 
1st occurrence 
Continue treatment with 
sorafenib/placebo and consider topical 
therapy for symptomatic relief. If no 
improvement within 7 days, see below 
No improvement 
within 7 days or 
2nd or 3rd 
occurrence 
Interrupt sorafenib/placebo until toxicity 
resolves to Grade 0-1. When resuming 
treatment, decrease sorafenib/placebo 
dose by one dose level 
 
4th occurrence 
Discontinue sorafenib/placebo 
Moist desquamation, ulceration, 
blistering or severe pain the hands or 
feet, or severe discomfort that causes 
the patient to be unable to work or 
perform activities of daily living 
1st or 2nd 
occurrence 
Interrupt sorafenib/placebo until toxicity 
of resolves to Grade 0-1. When resuming 
treatment, decrease sorafenib/placebo 
dose by one dose level 
3rd occurrence 
Discontinue sorafenib/placebo  


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9.1.7 Dose Modifications for Other Non-hematologic Toxicities 
For other clinically significant grade 3/4 non-hematologic toxicities likely related to 
sorafenib/placebo, interrupt sorafenib/placebo. Resume sorafenib/placebo at 1 dose level 
reduced when the toxicity resolves to a clinically acceptable level (grade 1/2). 
10.0 COMPANION STUDIES  
There will be 1 mandatory imaging companion for patients whose disease is being monitored 
by MRI. There will also be 2 optional sub-studies: A091105-HO1 (Health Outcomes) and 
A091105-ST1 (Correlative Science). A091105-HO1 and A091105-ST-1 must be offered to all 
patients for their consent, although patient participation is optional.  
10.1 
Imaging companion study incorporated within A091105: Evaluation of MRI T2 signal as 
a novel imaging biomarker in DT/DF treated with sorafenib 
10.1.1 Objectives 
In a retrospective study, DT/DF patients treated with sorafenib demonstrated decrease in 
MRI T2 signal intensity suggesting a decrease in cellularity.  In this prospective trial, we 
will undertake exploratory studies to test whether MRI T2 changes can predict (or correlate) 
with a biological response such as RECIST response, and pain palliation (for patients whose 
disease is being monitored by MRI). 
10.1.2 Methods 
Methods Study:   
The goal of the MRI portion of this study is to assess the T2-weighted sequences to 
determine the percentage of the entire tumor volume that is hyperintense relative to normal 
muscle at baseline compared with follow-up examinations.  The patient will undergo an MR 
examination on a 1.5 T (or greater) whole body scanner located at one of the participating 
institutions.  T2-weighted MR images with fat-saturation will be obtained with standard fast 
spin-echo pulse sequences with the following sequence parameters: TR = 4000-6600ms, TE 
= 60-70 ms, echo-train length = 24, number of slices = 30, 4-5 mm thickness, FOV = 320 
mm, matrix size = 256x192.  If adequate fat saturation cannot be achieved due to the location 
of the tumor, metal artifacts or patient positioning, the patient will be excluded from T2-
signal analysis portion of this study. STIR may be performed but cannot replace T2 with fat 
saturation in the data analysis for the purpose of this research.  
Analysis of the data will be performed in two phases: semi-quantitative and quantitative 
analysis. All images (DICOM compatible with sensitive patient information de-identified) 
will be analyzed by two reference radiologists and a physicist from Memorial Sloan-
Kettering Cancer Center. In phase one, a reference radiologists will review the images in 
regions suspicious of desmoid to measure changes in signal intensity for clinical assessment. 
A region-of-interest (ROI) is drawn to include the entire tumor at its greatest cross-sectional 
diameter. The ratio of mean ROI tumor signal intensity to the signal intensity of an ROI on 
the adjacent skeletal muscle is calculated. In the second phase, images will be analyzed to 
quantify the loss of MRI T2 signal intensity using a histogram analysis.  
The Alliance Statistics and Data Center A091105 Statistician will prepare analysis datasets 
in conjunction with clinical/outcome data.  Analyses will be coordinated by the A091105 
Statistician and conducted using the analysis datasets used for the analysis of the clinical 
endpoints to ensure consistent data is reported for the primary and secondary endpoints (e.g. 
data associated with censoring, proper inclusion of crossover data, and data to be excluded 
in cases of consent withdrawals for follow-up and correlative studies). 


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DW-MR images will be obtained by using a spin-echo echo-planar imaging (SE-EPI) 
sequence with a pair of rectangular-shaped gradient pulses along three orthogonal axes.  
Imaging parameters are TR = 4000-5475ms, TE = 77.6–110.3 ms, FOV = 320 mm, 4-5 mm 
thickness, no inter-slice gap; b-values were 0, 400, and 700 s/mm2.  The advantage of two 
non-zero b-values as opposed to one b value is that estimated parameters are less influenced 
by the choice of b-value and may be more appropriate than ADC for use in multi-
institutional studies. The orientation and location prescribed are identical to those prescribed 
for the transverse T2W images.  Four to eight signal averages are obtained for this portion 
of the exam with an approximate imaging time of 5 - 7 minutes to acquire the two sets of b-
values.  
Absolute T2-values are obtained with a multi echo (dual echo) fast spin echo imaging 
sequence at 4 different echo times (TEs). TE values will be: 50, 80,110,150 ms (there is 
flexibility in the values acquired to within 10 ms). The acquisition parameters are: TR = 
6600 ms; FOV = 320 mm; 4-5 mm thickness; number of signal acquired, one; echo train 
length, 24; matrix, 256 ×192. The images are acquired at the same location, FOV, and 
coverage and the DW-MR images. Using a dual echo fast spin echo sequence, two echoes 
are acquired per sequence with a total of two sequences acquired. 
Summary of Histogram analysis:  Using custom-made software developed in MATLAB 
environment (version 7.1, Mathworks, Natick, MA) the 25th and 50th (median) percentile 
values, kurtosis, and skewness of the ROI histograms are computed. Kurtosis provides a 
quantitative measure of how sharply peaked a histogram is compared with the histogram of 
a normal distribution. Accordingly, whereas a normal distribution has a kurtosis of 0, a more 
peaked histogram has a positive kurtosis value. Skewness provides a quantitative measure 
of the degree of asymmetry of a histogram: a perfectly symmetric histogram has a skewness 
of 0; a histogram with a long right tail has a positive skewness, whereas a negative skewness 
is due to the presence of a long left tail.  
10.2 
QOL Sub-Study-A091105-HO1 (Optional) 
There is clinical evidence to suggest that sorafenib improves the quality of life by improving 
pain and/or decreasing in narcotic drug use.  Based on a retrospective review by Gounder et al. 
(2011)15, approximately 70% DT/DF patients (16/22) reported subjective decrease in pain and analgesic 
use after initiation of sorafenib.  However, these data were not quantitated using a validated pain scale.  
Thus, patient-reported outcomes (PRO) will be a key secondary endpoint in this trial, both to 
assess for improvement in disease-related symptoms/QOL and for impact of sorafenib treatment.   
Also, evidence has arisen indicating that baseline single-item assessments of fatigue and overall 
QOL are strong prognostic indicators for survival in cancer patients, independent of 
performance status. This evidence was derived from two separate meta-analyses recently 
presented at ASCO, the first involving 23 NCCTG and Mayo Clinic Cancer Center oncology 
clinical trials, the second involving 43 clinical trials. Routine inclusion of these measures should 
be considered similar to that of including performance status, either as stratification or 
prognostic covariates. 
10.2.1 Objectives 
• To compare pain palliation (primary) and time to pain progression (secondary) between 
arms using three items from the Brief Pain Inventory Short Form and Pain Medication Diary. 
• To compare patient-reported adverse events and QOL between arms as measured by the 
PRO-CTCAE and the single-item overall LASA.   


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10.2.2 Methods 
The following patient assessments will be included in this study: 
Brief Pain Inventory – Short Form:  The Brief Pain Inventory (BPI) is a pain assessment 
tool used with cancer patients to measure both pain intensity (sensory dimension) and pain 
interference (reactive dimension) in the patient’s life29.   The BPI has been validated in >30 
different languages across a range of cancer types.  To minimize patient burden, only three 
items will be used from the BPI, the item assessing “worst pain” severity and two items 
assessing inference with general activity and sleep.  
PRO-CTCAE:  Completed on paper at the following time points:  prior to randomization; 
and every 4 weeks up to Week 32 while on randomized treatment; and at end of randomized 
treatment.  
The PRO-CTCAE is a group of items currently being developed by the NCI for direct 
patient-reporting of adverse symptoms in cancer trials.  To date, 78 symptomatic adverse 
events in the CTCAE have been developed for patient self-reporting via the PRO-CTCAE, 
and have undergone refinement in a cognitive testing study. A large validation of the PRO-
CTCAE has been completed across various cancer types and is expected to provide 
comprehensive results in support of validation at ASCO 2012 for items selected for this 
study.  In this study, we will administer PRO-CTCAE items for 11 symptoms pertinent to 
patients in this trial and in this population: insomnia, constipation, pain, fatigue, nausea, 
vomiting, diarrhea, rash, hand-foot syndrome, decreased appetite, and mouth or throat sores.  
Single-item overall LASA: Completed on paper at the following time points:  prior to 
randomization and every 4 weeks up to Week 32 while on randomized treatment; and at end 
of randomized treatment. 
The Linear Analogue Self-Assessment (LASA6) consists of six single-item numeric 
analogue scales.  For this study, we will employ only the one item that measures overall 
QOL36,37 on a scale of 0-10.  LASA items such as these have been validated as general 
measures of global QOL dimensional constructs in numerous settings31,32,34,38.   The LASA 
has been validated at the Mayo Clinic for use in cancer patients and have been successfully 
used in numerous clinical trials28.  The single-item overall LASA has been shown to be 
prognostic for survival in a range of cancer types39.  
• Pain Medication Diary:  Daily reporting for 7 consecutive days via paper diary prior to 
randomization, every 4 weeks through Week 32 while on randomized treatment, and at end 
of randomized treatment. This pain medication diary will be used to quantify opioid narcotic 
use for computing pain palliation and pain progression. 
10.2.3 Specific hypotheses 
Our primary hypothesis is that pain palliation will be improved on the sorafenib arm as 
compared to the placebo arm as suggested by the retrospective review by Gounder et al.  
Our secondary hypothesis is that time to pain progression will be extended on the sorafenib 
arm as compared to the placebo arm, based on our hypothesis that sorafenib will prolong 
progression-free survival.  To understand the impact of the hypothesized pain improvement 
associated with sorafenib on patients, pain interference on general activity and sleep will 
also be compared between arms, where we expect interference in both domains to be 
improved on the sorafenib arm as compared to the placebo arm.  In terms of patient-reported 
adverse events, we hypothesize that pain and insomnia will be improved on the sorfenib arm 
as compared to the placebo arm; and that fatigue, gastrointestinal toxicity (constipation, 
nausea, vomiting, diarrhea, decreased appetite, and mouth or throat sores) and skin toxicity 
(rash, hand-foot syndrome) will be negatively impacted on the sorafenib arm as compared 


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to the placebo arm given the adverse event profile of sorafenib in other patient populations 
and based on the adverse events reported in the retrospective review by Gounder et al. 
Lastly, given the possibility of improved pain and insomnia at the cost of increased treatment 
toxicity, we will compare overall quality of life between arms and hypothesize that quality 
of life will be improved on the sorafenib arm as compared to the placebo arm (i.e., that larger 
improvement in pain will offset the added toxicity of sorafenib treatment). 
The Alliance Statistics and Data Center A091105-HO1 Statistician collaborate with the 
A091105 Statistician to prepare analysis datasets in conjunction with clinical/outcome data.  
Analyses will be conducted by the A091105-HO1 Statistician, using the analysis datasets 
used for the analysis of the clinical endpoints to ensure consistent data is reported for the 
primary and secondary endpoints (e.g. data associated with censoring, proper inclusion of 
crossover data, and data to be excluded in cases of consent withdrawals for follow-up and 
correlative studies). 
10.3 
A091105-ST1 “Analysis of archival tissue, and pre-treatment and day 8 tumor biopsy 
and blood samples” (Optional) 
10.3.1 Objectives 
•  The mechanism of action of sorafenib in DT/DF remains unknown.  All patients will 
undergo treatment tumor biopsies. Treatment induced changes will be quantified by 
histology, gene expression profiling, proteomic changes and selected interrogation of key 
pathways by Western blot and RT-PCR.   
•  To collect archival tissue, pre-treatment biopsies and blood and day 8 biopsies and blood 
specimens for basic science research. 
Three recurrent mutations in beta-catenin gene have been documented and prognosticate 
risk of local recurrence after surgery. However, there is no study that has attempted to 
evaluate whether these mutations are predictive biomarkers of response to sorafenib.  We 
will attempt to answer this question in this prospective study. 
10.3.2 Methods 
All correlative studies will be performed in the laboratory of Mrinal Gounder (correlative 
chair). From archival FFPE specimen in patients who consent to A091105-ST1, sections 
(preferably 40 micron x1 or 20 micron rolls x2, cut from blocks with at least 50% tumor 
content after review by designated study pathologist) will be prepared by OSU and sent to 
the Schwartz laboratory. DNA sequencing will be performed as previously described by 
Lazar et al.  DNA will be extracted from FFPE material using the QIAamp DNA mini kit 
DNA isolation kit (Qiagen Valencia, CA). Polymerase chain reaction (PCR) will use 
primers (BCAT-DES-F: 5_-AGTCACTGGCAGCAACAGTC-3_ and BCAT-DES-R: 5_-
TCTTCCTCAGGATTGCCTT- 3) and under thermocycling conditions previously reported 
to amplify exon 3 of CTNNB1 (phosphorylation domain, codons 30 to 48) with appropriate 
controls.  PCR products will be detected by gel electrophoresis in 2% agarose, and amplicon 
bands further purified using the QIAquick gel extraction kit (Qiagen). Direct sequencing 
used the above primers (forward and reverse), ABI Prism dye terminator cycle sequencing 
ready reaction kit, and ABI Prism 3100-Avant genetic analyzer (Applied Biosystems, Foster 
City, CA). Both strands will be analyzed by the NCBI Blast Alignment Tool 
(http://www.ncbi.nlm.nih.gov/blast/Blast.cgi) to identify mutations. 
The Alliance Statistics and Data Center A091105 Statistician will prepare analysis datasets 
in conjunction with clinical/outcome data.  Analyses will be coordinated by the A091105 
Statistician and conducted using the analysis datasets used for the analysis of the clinical 
endpoints to ensure consistent data is reported for the primary and secondary endpoints (e.g. 


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data associated with censoring, proper inclusion of crossover data, and data to be excluded 
in cases of consent withdrawals for follow-up and correlative studies). 
10.3.3 Specific hypotheses  
DT/DF is sporadic (~85%) or arise in the setting of familial adenomatosis polyposis (4 – 
20%) with germline mutations in APC1. Sporadic desmoids have mutations in the β-catenin 
gene (CTBNN1) with certain mutations associated with high local recurrance20,21.  β-
catenins function both as a cell adhesion molecule and as a transcriptional activator in the 
presence of Wnt ligand. Mutations in APC or CTBNN1 result in accumulation of nuclear β-
catenin and transcriptional activation of growth signals including Tcf, c-MYC, c-JUN, and 
cyclin D (Figure 6). Carcinomas that over-express CTNNB are associated with an indolent 
disease with lack of metastatic ability.  Sorafenib is a multi-kinase inhibitor that targets B-
Raf, PDGFR-β and VEGFR-2/-3. Both c-KIT and PDGFR-B has been shown to be over-
expressed in DT/DF without any underlying mutations. In clinical trials of imatinib in 
DT/DF, extensive search for tumor or serum biomarkers of response were unsuccessful.  
Response in DT/DF are thought to involve a shift from fibroblast to collagen deposition and 
fibrosis18,19.  We hypothesize that differences in histology, protein and gene expression 
patterns in paired tumor biopsies identify critical pathways that are transcriptionally 
upregulated in DT/DF and modulated with sorafenib. 
10.3.4 A091105-ST1 Biopsies   
Pre- and day 8 (+ 7 days) post-randomization biopsy guidelines  
A091105-ST1 must be offered to all patients enrolled on A091105 (although patients may 
opt to not participate).  Patients who consent to A091105-ST1 will undergo 2 biopsies (pre-
treatment and day 8 post-randomization).  
The following exploratory studies will be performed and analyzed in the laboratory of 
Mrinal Gounder, correlative chair. Bio-informatics analysis will be provided by MSKCC 
Bio-informatics core lab. Blood, pre-treatment and day 8 matched tumor biopsies are 
required elements of this study for patients. Patients will undergo 2 biopsies (procuring 5 
cores for each biopsy) by interventional radiology under image guided CT or U/S. Core 
biopsies will be evaluated for the following studies: 1) one core will be formalin fixed for 
pathological studies and TMA construction, 2) 1 - 2 cores will be used for gene array 
expression profiling to determine a sorafenib signature of response, whole exome 
sequencing, microRNA array and epigenetics 3) one core will be used for a constrained 
evaluation of phospho-proteomic changes utilizing a Zaptosens reverse protein array of 
selected pathways identified from genetic studies.  
Core sample #1 and #2– Nucleic acid changes   
RNA isolation, probe preparation, and expression microarray: Hybridization –Affymetrix 
platform 
Total RNA will be isolated from tissue using the DNA/RNA all prep kit(Qiagen). Quality 
of RNA will be ensured before labeling by analyzing 2 to 5 ng of each sample using the 
RNA 6000 NanoAssay and a Bioanalyzer 2100 (Agilent). Samples with a 28S/18S 
ribosomal peak ratio of 1.8–2.0 and a RIN number >7.0 will be considered suitable for 
labeling. For samples meeting this standard, 1 to 2 µg of total RNA will be used for cDNA 
synthesis using an oligo-dT-T7 primer and the SuperScript Double-Stranded cDNA 
Synthesis Kit (Invitrogen). Synthesis, linear amplification, and labeling of cRNA will be 
accomplished by in-vitro transcription using the MessageAmp aRNA Kit (Ambion) and 
biotinylated nucleotides (Enzo Diagnostics). Ten micrograms of labeled and fragmented 
cRNA will be hybridized to the Human HG-U133A2.0 GeneChip (Affymetrix) at 45 degres 


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C for 16 h. Post hybridization staining, washing were processed according to manufacturer 
(Affymetrix). Finally, chips will be scanned with a high-numerical Aperture and flying 
objective (FOL) lens in the GS3000 scanner (Affymetrix). The image will be quantified 
using GCOS 1.4 (GeneChip Operating Software, Affymetrix) with the default parameters 
for the statistical algorithm and all probe set scaling with a target intensity of 500.  
Whole exome capture using the Agilent SureSelect platform and Hiseq 2000 sequencing. 
DNA capture will be performed on 3 µg of high quality genomic DNA using the 51MB 
SureSelect  Human Exome Target Enrichment kit (Agilent) according to the protocol 
provided by Agilent.  Enriched DNA libraries will then be sequenced on a Hiseq2000 
(Illumina), using 75x75 paired end V3 sequencing chemistry. The goal will be to generate 
80 to 100 million reads per samples, to reach an average coverage of 100x on 85% of the 
targeted region. 
miRNA profiling on Agilent Human miRNA  array 
The same QC standards will be applied as for the Affymetrix Gene expression platform. 
Briefly, samples with a 28S/18S ribosomal peak ratio of 1.8–2.0 and a RIN number >7.0 
will be considered suitable for labeling.  200 ng of total RNA will be labeled using the 
miRNA Complete Labeling and Hybridization Kit (Agilent). Labeled RNA will be 
hybridized for 20hrs at 20 rpm, 55 oC.  Slides will be washed and scanned according to 
manufacturer’s instructions. Images will be quantified using Feature Extraction 10.4 
(Agilent) 
Core #3 and #4: Protein expression changes 
Evaluate changes in protein phosphorylation in pre -treatment and day 8 tumor tissue 
biopsies.  We will utilize Zeptosens technology to facilitate high-throughput profiling of 
(phospho-) protein levels in tumor tissue. The system is significantly more sensitive, faster 
and less expensive than Western blots, requiring much smaller protein amounts. The 
ZeptoMARK reverse protein array system additionally allows measurement of protein 
expression and post-translational modifications (phosphorylation, methylation etc.) in 
signaling pathways. Over 300 validated antibodies in various signaling pathways, including 
Akt, MAPK, lipid, cAMP, insulin and many others, are available for use on ZeptoMARK 
reverse arrays. Briefly, treated and control tissue material in an equivalent amount are lysed 
using ZeptoMARK reverse array lysis buffer as per manufacturer’s protocol.  The 
denaturing and enzyme inhibiting properties of the lysis buffer allows the biological 
processes within the cells to be preserved. Frozen lysates can be stored for long periods of 
time, if necessary. Further processing is carried out using robotic liquid handling equipment 
existing at MSKCC Core Facility. Lysates are normalized for further processing based on 
total protein concentrations.  Each normalized sample is diluted in a reverse array spotting 
buffer in a series of four concentrations and then reformatted from 96 to 384 well plates as 
the source for spotting.  Lysates are spotted in duplicates at 4 concentrations on the 
ZeptoMARK chip using the array spotter. The chips are coated with a proprietary high 
absorbance surface. Only per lysate are required per spot, an almost unlimited number of 
replica arrays can be prepared from about 100μl of lysate solution.  The chip is then blocked 
using ZeptoMARK reverse array blocking buffer in the blocking station. Each chip 
contains 6 arrays that are probed independently with an antibody specifically binding to 
a signaling protein or its activated form. The fluorescence markers are introduced 
by application of a labeled anti-species antibody. Only 20 μL of detection antibody (1:250 
- 1:10000 dilution of stock solution) is required per array. Surface confined fluorophores are 
measured at green or red excitation wavelengths in a wet state in the ZeptoREADER. Signal 
processing of microarray images taken by the ZeptoREADER is performed with 
the ZeptoVIEW software, and data is then exported in a standard format for further analysis, 


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for example bioinformatic pathway analysis.  We will specifically evaluate changes in Wnt 
pathway along with the Notch and Hedgehog pathways.   Other pathways to interrogate will 
include the major and minor targets of sorafenib which include VEGFR2/3, PDGFR-β, 
RAF, KIT, CDK5, Ephrin24 (EPHA1-2, EPHB4) and FGFR.  Lastly, we will also consider 
evaluating total and phosphorylated levels of Akt, p-Akt (S473), p-p70-S6K, PTEN, p-Mek 
and p-Erk.   
Core #5  
Biopsies will be descriptive and comment on 1) proliferation (Ki-67 expressed as 
percentage) to assess treatment response (pre-treatment base line and post therapy for drug 
effect) and expressed as percentage of tumor cells as <10%, 10-25%, 25-50% and >50%, 2) 
degree of fibrosis, 3) changes in vascularity, 4) necrosis and 5) ratio of nuclear to 
cytoplasmic beta catenin.    
For TMA construction, the techniques are previously well described by Lazar and 
colleagues.  Hematoxylin and eosin (H&E) stained sections will be reviewed to define areas 
of desmoid tumor; dermal scars, reactive tissue and solitary fibrous tumor will serve as 
controls. Using an automated TMA apparatus (ATA-27; Beecher Instruments, Sun Prairie, 
WI), 0.6-mm punch samples (two per case) will be obtained along with controls and 
formatted into three recipient blocks. H&E-staining of 4-micron TMA sections will be used 
to verify all samples.   
Immunohistochemistry: The polymeric biotin-free horseradish peroxide method on a 
Microsystems Bond Max stainer (Beecher Instruments, Bannockburn, IL) will be used for 
immunohistochemistry. Four-micron-thick sections will be prepared from formalin-fixed 
paraffin-embedded tissue blocks and dried in a 60-degree oven for 20 minutes. Sections will 
be placed in the automated Bond Max stainer, pretreated with enzyme-induced epitope 
retrieval for 2 minutes followed by incubation with antibodies against beta-catenin (BD 
Biosciences, San Jose, CA), midkine (Antigenix America, NY), MMP2 (Chemicon, MA) 
and ADAM12 (Abcam, MA).  Additional antibodies may be utilized to interrogate specific 
pathways identified in micro-array work. Anti-mouse secondary antibody and the Refine 
polymer detection kit (Leica) will be used for immunostaining, with 3,3-diaminobenzidine 
serving as chromagen.  Positive and negative controls will run in parallel. Labeling intensity 
grading will be performed by soft tissue pathologist (M.H) as none (_0), weak (_1), 
moderate (_2), or strong (_3).  For the ratio of cellular to nuclear beta catenins, the 
percentage of positive tumor cells will be estimated from the two paired TMA samples for 
each case.  For nuclear staining, weak (_1) will be defined functionally as having to view 
nuclei at X400 to confirm nuclear accumulation. Moderate (_2) staining could be viewed at 
X200 and the blue hematoxylin nuclear counterstain.  In strong (_3) staining, the nuclear 
counterstain will no longer be visible in the majority of nuclei.  The staining on the entire 
array will be performed in the MSKCC clinical immunohistochemistry facility on two 
occasions and each scored independently.   
Plasma and Whole Blood Analysis 
DNA will be extracted from whole blood to serve as normal tissue control for tumor studies 
outlined under: “core sample #1 and #2– Nucleic acid changes”.  In addition, DNA samples 
will be analyzed for genetic factors contributing to the subject’s response to sorafenib in 
terms of pharmacodynamics, efficacy and tolerability.  Such genetic factors may include 
genes for drug-metabolizing enzymes, drug transport proteins, genes within the target 
pathway or other genes believed to be related to drug response. Some genes currently 
insufficiently characterized or unknown may be understood to be important at the time of 
analysis. Plasma specimens will be also be utilized to evaluate known and novel markers 
(peptides/proteins and drug metabolites) of response and/or resistance to disease.   


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11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
General Considerations 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 
of chemotherapeutic agents in a self-contained, protective environment. 
11.2 
Sorafenib (BAY 43-9006, Nexavar; NSC 724772 / IND #116279) / Placebo 
• 
Chemical Name 
(4-{3-[4-chloro-3-(trifluoromethyl)-phenyl] 
ureido}-phenoxy)-
N2-methylpyridine-2-carboxamide-4-methyl-benzensulfonate. 
• 
Other Names BAY 43-9006; Nexavar®; sorafenib; BAY 54-9085 (tosylate salt)  
• 
Classification Multi-kinase inhibitor  
• 
Molecular Formula 
C12H16CIF3N4O3 X C7H8O3S    M.W.: 637 [g/mole]  
• 
Description 
Round, red 10 mm tablets 
• 
How Supplied Sorafenib tosylate is supplied by Bayer Healthcare AG and distributed by 
the DCTD, and available as 200mg coated tablets.  The inactive ingredients are 
microcrystalline cellulose, croscarmellose sodium, hydroxypropylmethyl cellulose, 
magnesium 
stearate, 
sodium 
lauryl 
sulfate, 
and 
a 
film 
coat 
with 
hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and red iron oxide.  
The 200 mg tablets are packaged in HDPE bottles containing 140 tablets. 
11.2.1 Availability 
Sorafenib and matching Placebo will be provided free of charge by Bayer Pharmaceuticals 
and distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), 
National Cancer Institute (NCI). 
Sorafenib and matching Placebo are supplied as an immediate-release, film-coated, round, 
red-colored tablet for oral administration.  Each Sorafenib tablet contains 200 mg of the 
free base (i.e., BAY 43-9006).  The Sorafenib and Placebo tablets contain croscarmellose 
sodium, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium lauryl sulfate, 
and magnesium stearate.  For Sorafenib and Placebo, the film coat consists of 
hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and red iron oxide. 
The film coating has no effect on the rate of release of the active sorafenib. 
Each tamper-evident, child-resistant, opaque, high-density polyethylene (HDPE) bottle 
contains 140 tablets of Sorafenib 200 mg or matching Placebo. 
No open-label starter supplies will be available for this study. Initial open-label, patient-
specific clinical supplies of sorafenib will be shipped from the Pharmaceutical Management 
Branch (PMB) to the registering investigator at the time of patient randomization and should 
arrive within 7 to 10 days of randomization (see Section 11.2.9) 
For BLINDED (sorafenib or placebo) THERAPY, each bottle will be labeled with…  
• 
the protocol number (i.e., “A091105”) 
• 
the bottle number (i.e., “Bottle 1 of 1) 
• 
the number of tablets (i.e., “140 tablets”) 
• 
the patient ID number (e.g., “999999", where “999999” represents a unique patient 
identifier assigned by ALLIANCE at registration).                                                                                     
• 
the patient initials (i.e., last initial, first initial, middle initial [e.g., "L, FM"]) 


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• 
the agent identification (i.e., “Sorafenib 200 mg or Placebo”) 
• 
a blank line for the pharmacist to enter the patient’s name 
• 
administration instructions (i.e., “Take        tablets once daily.”) 
• 
storage instructions (i.e., “Store at controlled room temperature, not to exceed 25ºC 
(77ºF).”) 
• 
emergency contact instructions 
• 
a Julian date 
For CROSSOVER (open label sorafenib) THERAPY, each bottle will be labeled with … 
• 
the protocol number (i.e., “A091105”) 
• 
the bottle number (i.e., “Bottle 1 of 1) 
• 
the number of tablets (i.e., “140 tablets”) 
• 
the patient ID number (e.g., “999999", where “999999” represents a unique patient 
identifier assigned by ALLIANCE at registration) 
• 
the patient initials (i.e., last initial, first initial, middle initial [e.g., "L, FM"]) 
• 
the agent identification (i.e., “Sorafenib 200 mg) 
• 
a blank line for the pharmacist to enter the patient’s name 
• 
administration instructions (i.e., “Take      tablets once daily.”) 
• 
storage instructions (i.e., “Store at controlled room temperature, not to exceed 25ºC, 
77ºF).”) 
• 
emergency contact instructions 
• 
a Julian date 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the 
last two digits of the calendar year (e.g., 2013 = 13, 2014 = 14) and a day count (e.g., January 
1 = 001, December 3 = 365). For example, a bottle labeled and shipped on January 1, 2013 
would have a Julian date of ‘13001’ and a bottle labeled and shipped on December 31, 2014 
would have a Julian date of ‘14365’. The Julian date will be used by PMB for recalls. When 
a lot expires, PMB will determine the last date the expired lot was shipped and will recall 
all bottles (i.e., both Sorafenib and Placebo) shipped on or before that date thus eliminating 
any chance of breaking the blind. 
Questions about drug orders, transfers, returns, or accountability should be addressed 
to the PMB by calling 240-276-6575 Monday through Friday between 8:30AM and 
4:30PM Eastern Time. 
11.2.2 Drug Ordering, transfers, returns, and accountability 
NOTE:  No open-label starter supplies will be available for this study. Initial open- 
label, patient-specific clinical supplies of sorafenib will be shipped from the 
Pharmaceutical Management Branch to the registering investigator at the time of re-
registration and should arrive within seven to ten days (see Section 5.5). 
BLINDED (Sorafenib or Placebo) THERAPY (Active and Placebo Arms) 
No blinded starter supplies will be available for this study.  Blinded, patient specific 
supplies will be sent to the registering investigator at the time of randomization and should 
arrive within 7 to 10 days. Randomization will be performed by the ALLIANCE Statistics 
and Data Center. The assigned ALLIANCE patient ID number must be recorded by the 
registering institution for proper bottle dispersion.  Once a patient has been registered with 


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the ALLIANCE Statistics and Data Center, the ALLIANCE Statistics and Data Center will 
electronically transmit a clinical drug request for that patient to the PMB.  This request will 
be entered and transmitted by the ALLIANCE Statistics and Data Center the day the patient 
is registered and will be processed by the PMB the next business day and shipped the 
following business day.   Shipments within the United States will be sent by FedEx Ground 
(delivery within 5 days).  Thus, if a patient is registered on Monday, ALLIANCE would 
enter a clinical drug request for that patient on Monday and PMB would process that request 
on Tuesday and ship the drug on Wednesday. United States sites could expect to receive 
their order approximately Tuesday or Wednesday. Shipments to United States sites can be 
expedited (i.e., receipt on Thursday in example above) by the provision of an express courier 
account name and number to the ALLIANCE Statistics and Data Center at the time the 
patient is randomized. 
The initial request will be for 1  – 140 tablet bottle (a 2 cycle / 8 week supply at a dose of 
400 mg [2 * 200 mg tablets] orally once daily) of sorafenib or matching placebo. Six (6) 
weeks after the initial electronic request (i.e., 2 weeks before the next bottle is needed), sites 
may reorder an additional 1  – 140 tablet bottle (a 2 cycle / 8 week supply) by submitting 
an agent request through the PMB Online Agent Order Processing (OAOP) application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” 
password.  Once a CTEP IAM account has been established, go to 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx to access the OAOP application. 
The assigned patient ID number (e.g., “44444”) and the patient initials (e.g., "L, FM") 
should be entered in the "Patient or Special Code" field. 
All drug orders will be shipped directly to the registering physician at the shipping address 
provided on their current Supplemental Investigator Data Form (IDF) on file with CTEP. 
The registering investigator must maintain an active investigator registration status with 
CTEP, DCTD through the annual submission of an FDA Form 1572 (Statement of 
Investigator), a Curriculum Vitae, a Supplemental Investigator Data Form (IDF), and a 
Financial Disclosure Form (FDF). 
For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 
Monday 
through 
Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
email 
PMBAfterHours@mail.nih.gov anytime. 
NOTE: At the time of disease progression, ALL remaining clinical supplies of blinded 
sorafenib / placebo should be returned to PMB (see “Drug   Returns” below). 
CROSSOVER (open label sorafenib) THERAPY (Placebo Arm Only) 
At the time of disease progression all patients randomized to placebo will cross over to open 
label sorafenib.  This crossover will require a second registration (see Section 5.5 for re-
registration instructions). 
No open label starter supplies will be available for this study. Open-label, patient-
specific clinical supplies will be sent to the registering investigator at the time the patient is 
unblinded. This unblinding will be performed by the ALLIANCE Statistics and Data Center.  
The patient ID number will NOT change. Once the patient has been unblinded, the 
ALLIANCE Statistics and Data Center will electronically transmit a clinical drug request 
for that patient to the PMB. This request will be entered and transmitted by the ALLIANCE 
Statistics and Data Center the day the patient is unblinded and will be processed by the PMB 
the next business day and shipped the following business day. Shipments within the United 
States will be sent by FedEx Ground (generally a five day delivery). Thus, if a patient is 


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unblinded on Monday, ALLIANCE would enter a clinical drug request for that patient on 
Monday and PMB would process that request on Tuesday and ship the drug on Wednesday. 
United States sites could expect to receive their order approximately Tuesday or 
Wednesday. Shipments to United States sites can be expedited (i.e., receipt on Thursday in 
example above) by the provision of an express courier account name and number to the 
ALLIANCE Statistics and Data Center at the time the patient is unblinded. 
The initial request will be for 1 – 140 tablet bottle (an 8 week supply at a dose of two tablets 
daily) of open label Sorafenib. Six (6) weeks after the initial electronic request (i.e., 2 weeks 
before the next bottle is needed), sites may reorder an additional 1 – 140 tablet bottle (an 8 
week supply at a dose of two tablets daily) through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the 
maintenance of an "active" account status and a "current" password. Once a CTEP IAM 
account has been established, go to 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx to access the OAOP application. 
The assigned patient ID number (e.g., “44444”) and the patient initials (e.g., "L, FM") 
should be entered in the "Patient or Special Code" field. 
All drug orders will be shipped directly to the registering physician at the shipping address 
provided on their current Supplemental Investigator Data Form (IDF) on file with CTEP.  
The registering investigator must maintain an  active  investigator registration status with 
CTEP, DCTD through the annual submission of an FDA Form 1572 (Statement  of  
Investigator), a Curriculum Vitae, a Supplemental Investigator Data Form (IDF), and a 
Financial Disclosure Form (FDF). 
For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 
Monday 
through 
Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
email 
PMBAfterHours@mail.nih.gov anytime. 
NOTE: At the time of disease progression, ALL remaining clinical supplies of open-
label sorafenib should be returned to PMB (see “Drug Returns” below). 
Drug Transfers 
Bottles MAY NOT be transferred from one patient to another patient or from one 
protocol to another protocol. All other transfers (e.g., a patient moves from one 
participating clinical site to another participating clinical site, the principal investigator at 
a given clinical site changes) must be approved in advance by the PMB. To obtain an 
approval for transfer, investigators should complete and submit to the PMB (fax number 
240-276-7893) a Transfer Investigational Agent Form available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. The patient ID number 
(e.g., "999999"') and the patient initials (e.g., "L,FM") must be entered in the "Received 
on NCI Protocol No." and  the "Transferred to NCI Protocol No." fields in addition to 
the protocol number (i.e., "A091105"). 
Drug Returns 
Only undispensed clinical supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when a patient permanently 
discontinues protocol treatment, expired bottles recalled  by the PMB), investigators 
should return the study drug to the PMB using the NCI Return Drug List available on 
the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at  240-276-6575. 
The patient ID number (e.g., "999999") and the patient initials (e.g., "L,FM") should be 
entered in the "Lot Number" field. A separate line item is required for each   patient ID 
number (e.g., "999999") AND for each phase (i.e. blinded/open label) being returned. 


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Dispensed bottles with remaining tablets should be documented in the patient-specific 
NCI Investigational Agent Accountability Record (i.e., logged is as “returned by patient” 
and logged out as “destroyed on site”) and destroyed on site in accordance with 
institutional policy. 
Agent Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, disposition, and return of all drugs received from the PMB 
using the NCI Investigational Agent Accountability Record available on the CTEP home 
page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. A separate NCI 
Investigational Agent Accountability Record must be maintained for each patient ID number 
(e.g., "999999") AND for each phase (i.e., blinded/open label) on this protocol. 
11.2.3 Storage and Stability 
Store intact bottles at controlled room temperature, not to exceed 25ºC.  Stability studies are 
ongoing.  
11.2.4 Administration 
Sorafenib will be administered orally once daily on an empty stomach (at least 1 hour before 
or 2 hours after a meal) and with at least 250 ml of water according to the treatment plan 
(sorafenib absorption was reduced by 29% compared with fasting when administered with 
high fat meals).  Patients should take their daily dose at approximately the same time each 
day.  
Sorafenib undergoes metabolism by hepatic CYP3A4. Inducers of CYP3A4 activity can 
decrease the systemic exposure of sorafenib. Concomitant administration of sorafenib and 
CYP3A4 inducers, such as phenytoin, carbamazepine, phenobarbital, rifampin, or St. Johns 
Wort are not allowed. 
11.2.5 Toxicity 
The most common adverse events for sorafenib are diarrhea (49.7%), fatigue (39.2%), rash 
(31.6%), hand-foot syndrome (30.5%), nausea (26.9.1%), anorexia (26.9%), alopecia 
(26.1%) weight decrease (22.3%), and constipation (20.7%). The vast majority of the 
reported toxicities were of Grade 1 & 2 in severity. 
Gastrointestinal perforation has been reported as an uncommon event in patients taking 
sorafenib (reported in less than 1% of patients taking sorafenib). In some cases this was not 
associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued 
in the event of such an event. 
Hypertension usually mild-to-moderate early in the course of treatment, may occur and is 
amenable to management with standard antihypertensive therapy. Blood pressure should be 
checked within the first two to three weeks of starting sorafenib therapy and then monitored 
and treated, if required, in accordance with standard medical practice.  
Reversible posterior leukoencephalopathy (RPLS) has been reported as an uncommon event 
in single patients taking sorafenib. 
Increases in lipase and amylase have been observed in patients treated with sorafenib. The 
findings in the single agent pool indicate that 11.8% of all patients had CTC Grade 3 and 
additional 3.2% had CTC Grade 4 lipase elevations. Amylase was increased to CTC Grade 
3 and CTC Grade 4 in 3.3% respectively 0.6% of the patients. In most cases, these elevations 
were asymptomatic.  Hypophosphatemia appears to be associated with sorafenib therapy. 
There were no instances of severe hypophosphatemia, defined as a serum phosphate value 


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Update #06 
below 1.0 mg/dL, and there were no clinical manifestations associated with 
hypophosphatemia.  
Sorafenib was infrequently associated with peripheral neuropathy. The timing of these 
events suggests an inflammatory process rather than a cumulative neurotoxic effect. 
11.2.6 Unblinding Procedures  
Unblinding can be done only at the time of first disease progression or in the case of 
an emergency. 
Emergency unblinding will be available 24 hours a day, every day, according to the criteria 
below. Please note that, if treatment is unblinded due to an emergency, the patient must 
permanently discontinue all protocol therapy. 
Unblinding procedures upon progression 
CROSSOVER (open label sorafenib) THERAPY (Placebo Arm Only) 
 
1. Site physician deems that the patient has had radiographic or clinical progression.  
2. Site staff contacts the Alliance Registration Office at (507) 284-0661 during regular 
business hours for treatment assignment. 
3. If patient was on placebo, site may offer crossover to the patient.  
4. Site must enter data within 14 days of unblinding for quality assurance purposes.  
5. Site re-registers patient in OPEN (See Section 5.5 for re-registration instructions) 
6 
Alliance SDC orders drug and site receives open label drug from the Protocol 
Management Branch (See Section 11.2.2). 
 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
 
Contact the Alliance Executive Officer on call by calling 773-702-6800, pressing 1 to speak 
with an operator, and then asking for pager ID 8625 to return the call.  
The institution must provide the following information to the Alliance Executive Officer: 
•  
Alliance study ID (i.e., “A091105”) 
 
•  
Alliance patient ID number (e.g., “999999”) 
•  
Patient initials (e.g., “L,FM”) 
•  
Institution name 
•  
Name and telephone number of treating physician 
•  
Name and contact information of person requesting the unblinding procedure 
•  
Name and contact information of person to inform of treatment assignment 
•  
Reason for emergency unblinding 
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. 


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After the Executive Officer deems unblinding is warranted, the treatment assignment will 
be provided to the contact person at the treating site. 
11.3 
Nursing Guidelines 
11.3.1 Drug should be taken with at least 250 cc of water. Should be taken without food (at least 1 
hour before or 2 hours after meals).   
11.3.2 Patient may experience flu-like symptoms such as fatigue, fever, Tylenol may be beneficial 
for these patients. 
11.3.3 Monitor CBC.  Instruct patients to report signs and symptoms of infection and excessive 
bruising or bleeding to the MD. 
11.3.4 Monitor LFT’s. 
11.3.5 Patients may experience diarrhea. Please ensure patients have been informed of the 
possibility of diarrhea from sorafenib. They should be prepared by having medication on 
hand, such as loperamide. It should be stressed with all patients that, with the development 
of diarrhea, they need to contact their treating physician immediately for management. See 
Section 9.0. 
11.3.6 Instruct patient to report severe abdominal pain, as pancreatitis is a possibility. 
11.3.7 May cause anorexia. Encourage patient to consume small frequent meals. 
11.3.8 Monitor for sign/symptoms of hand/foot syndrome. See Section 9.0 for appropriate 
management. 
11.3.9 May cause alopecia, instruct patient of this possibility 
11.3.10 Monitor for rash. Toxic epidermal necrolysis is a rare but serious condition. Instruct patient 
to report any rash to MD. 
11.3.11 As there are many potential drug interactions, instruct patient not to start any new 
medication (including OTC’s or herbal products) without checking with their MD first.  
11.3.12 Monitor blood pressure. Instruct patients who are self-monitoring to report any increase in 
their blood pressure to the study team. 
11.3.13 Nausea and vomiting may occur. Administer antiemetics as necessary and monitor for their 
effectiveness. 
11.3.14 Bleeding has been seen (GI, respiratory, CNS). Instruct patient to report  any bleeding to 
the study team immediately. If bleeding is severe, seek out emergency medical attention. 
11.3.15 Numerous 
electrolyte 
imbalances 
may 
occur 
(hypernatremia, 
hypocalcemia, 
hypokalemia). Monitor chemistry panel and report any abnormalities to the treating 
physician. 
12.0 ANCILLARY THERAPY 
12.1 
Supportive Care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, allopurinol, rasburicase etc., when appropriate.  


ALLIANCE A091105 
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Update #06 
• For patients who experience grade 3 or 4 diarrhea, institute prophylactic anti-diarrheal 
therapy with agents such as loperamide and/or diphenoxylate/atropine, given around the 
clock. 
• Preventive skin care should be taken to help prevent/decrease the severity of PPE. Patients 
should use moisturizers, treat calluses, and should report in any rash or symptoms 
immediately. 
12.2 
Treatment with other chemotherapeutic agents  
Treatment with other chemotherapeutic agents and/or radiation therapy is prohibited while on 
protocol therapy. 
12.3 
Palliative radiation therapy  
Palliative radiation therapy may not be administered. Irradiate a symptomatic lesion, or one that 
may produce disability (e.g., unstable femur) prior to study initiation, provided other measurable 
disease is present. 
12.4 
Surgery 
Patients who require surgery during protocol treatment may proceed as such, unless the surgery 
involves resection of DT or DF. Sorafenib/placebo should be held prior to and after surgery, for 
a maximum of 28 days. If the patient requires an interruption of > 28 days, then they will be 
removed from protocol therapy. 
12.5 
Alliance Policy Concerning the Use of Growth Factors 
The use of colony stimulating factors such as erythropoietin, filgrastim (G-CSF), pegfilgrastim 
and sargramostim (GM-CSF) is discouraged.  
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE (SOLID TUMORS) 
Treatment Evaluation Using RECIST v1.1 Guideline 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST guideline. 
13.1 
Schedule of Evaluations   
Refer to the Study Calendar (section 7.0) for timing of disease assessments for this study. 
13.2 
Definitions of Measurable and Non-Measurable Disease 
13.2.1 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 not considered measurable disease.   


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Update #06 
13.2.2 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. 
13.3 
Guidelines for Evaluation of Measurable Disease 
13.3.1 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.  
13.3.2 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 update greater than twice that 
of the surrounding tissue on the attenuation corrected image; otherwise, an FDG-PET 


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Update #06 
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:   
i. 
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.   
ii. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT at the same evaluation, additional follow-up CT scans (i.e., additional follow-up 
scans at least 4 weeks later) are needed to determine if there is truly progression 
occurring at that site. In this situation, the date of PD will be the date of the initial 
abnormal PDG-PET scan.   
iii 
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. 
13.3.3 Measurement at Follow-up Evaluation   
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.) 
13.4 
Measurement of Effect 
13.4.1 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 13.2.1) up to a maximum of 3 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 Section 13.2.1), 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 3 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.   


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Update #06 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm.  If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned.  If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the PBSD. 
13.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 13.2.2) 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 
Section 13.4.3. 
13.4.3 Response Criteria 
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 13.1.  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. 
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 13.4.1). 
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 13.4.1).  In addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the MSD.  
c. 
See Section 13.3.2 for details in regards to the requirements for PD via FDG-PET 
imaging. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 


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Update #06 
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 13.3.2 for details in regards to the requirements for PD via FDG-PET 
imaging. 
13.4.4 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 tables:  
 
For Patients with Measurable Disease  
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 
* See Section 13.4.3 


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13.4.5 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.  A patient is classified 
as having PD due to “symptomatic deterioration” if any of the following occur that are not 
either related to study treatment or other medical conditions: 
• 
Weight loss >10% of body weight. 
• 
Worsening of tumor-related symptoms in the opinion of the treating physician. 
• 
Decline in performance status of >1 level on ECOG scale. 
14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1  Clinical Follow-Up Phase   
• 
Patients who are in complete response (CR), partial response (PR), or stable disease (SD) 
will receive treatment indefinitely and until progression (PD) or unacceptable adverse 
events.  Subsequent off-study treatment is at the discretion of their attending physician.  
See Section 13.4 for the criteria for assessing response. 
• 
Patients who discontinue for non-PD reasons and prior to 1 year post-randomization will 
remain in Clinical Follow-Up until they have reached 1 year post-randomization.  
Thereafter, they will begin the Survival and Disease Status Follow-Up Phase. 
• 
Patients on the placebo arm may cross over to the sorafenib arm, upon PD, and continue in 
Clinical Follow-Up. Patients who undergo surgical excision of their tumors must start 
sorafenib within 28 days of surgery.  After excision, the patient must have measureable 
disease (per RECIST v1.1). Patients will begin Survival and Disease Status Follow-Up 
upon subsequent PD. 
• 
Patients on the sorafenib arm will begin Survival and Disease Status Follow-Up upon PD. 
• 
As of Update #06: Patients unblinded following the Alliance Data Safety Monitoring Board 
release of study data (November 17, 2017) while receiving placebo and prior to PD, may 
cross over to the sorafenib arm and continue in Clinical Follow-Up. Patients who undergo 
surgical excision of their tumors must start sorafenib within 28 days of surgery.  After 
excision, the patient must have measurable disease (per RECIST v1.1). Patients will begin 
Survival and Disease Status Follow-Up upon subsequent PD. 
14.2 Survival and Disease Follow-Up Phase 
During the Survival and Disease Follow-Up Phase, patients are monitored for off-treatment PD, 
long-term adverse events, new primaries, and survival. Here, patients should be followed per 
standard of care.  Submit the appropriate form(s), every 6 months until PD.  Thereafter, annually 
until a maximum of 3 years following randomization. 
14.3 
Managing ineligible and canceled patients and major protocol violations 
Data must be submitted per Section 6.0 for patients deemed ineligible or canceled. See also the 
Forms Packet for full details of data submission requirements. 


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14.4 
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: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy on study forms 
• 
Follow the patient for survival or secondary malignancy for a minimum of 3 years 
following randomization. 
15.0 STATISTICAL CONSIDERATIONS 
15.1 
Primary Endpoint 
We are comparing the progression-free survival (PFS) rate of patients will receive either 
sorafenib or placebo in and using randomized double-blinded placebo controlled phase 3 study 
design. PFS is defined as the time from randomization to the first occurrence of progression or 
death due to any cause.  If no event exists, the PFS will be censored at the last scheduled disease 
assessment on study. Patients who have reached their maximum follow-up and have remained 
progression-free will be censored for progression at the date of their last disease assessment. 
Data following cross over will be analyzed and summarized separately from the data from the 
main course of treatment for these patients. Intention to treat principles will be used for 
analyzing the primary endpoint, excluding patients deemed ineligible due to improper histology 
having been determined on the basis of information available prior to randomization. 
Update #06: Patients enrolled onto this trial were unblinded (November 17, 2017) and those 
receiving placebo were allowed to crossover to sorafenib, if PD had not yet occurred. This 
section has been updated to address this for the analysis. 
15.1.1 Sample Size & Statistical Power 
The placebo (control) arm is expected to have a median PFS of 6 months. We consider 
improving PFS to a median of 15 months (HR of 0.40, control versus experimental arm) 
after treatment with sorafenib (experimental arm) to be a significant clinical improvement 
of PFS in this patient population. We will be using a 1-sided Log-Rank test to determine the 
whether sorafenib significantly improves the PFS rate. We have designed this study with 
one planned interim analysis which is designed to stop the trial for “futility” and there is no 
interim analysis for efficacy. We are also using a 2:1 randomization scheme to increase 
accrual for the as well as to reduce the number of patients having biopsies while receiving 
treatment on a placebo arm. There are two stratification factors for randomization and in 
addition to randomizing membership, namely, Intra- versus Extra-abdominal disease, and 
Baseline Level of Pain (BPI Item #3: 0 to <3, 3 to <7, versus 7 to 10).  
Using 75 patients, we have 90% power at a 1-sided significance level of 0.025 to detect a 
median PFS 15 months (Ho: median PFS of 15 months for sorafenib) improvement over the 
placebo arm (Ho: median PFS of 6 months, resulting in a HR=0.40), using a 2:1 
randomization favoring the sorafenib arm, assuming we will enroll 4 patients per month, 
and requiring 12 months of follow-up for all patients. There is 50% chance of terminating 
the study for futility at the time of the interim analysis if the true median PFS in the sorafenib 
arm is 6 months. The other type of decision error we could make based on our sample is if 
we were declare sorafenib as ineffective (ie, “accept” Ho), when in fact the truth is that is 
effective in our sampling population. In this situation, we have a 1.39% chance of stopping 
for futility (ie, declaring sorafenib ineffective) at the interim analysis if the median PFS for 
the sampling population is 15 months. 


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Decision Rule: We will randomize a total of 75 patients (25-placebo, 50-sorafenib) and 
observe patients until we have reached 52 PFS events for the efficacy analysis. In the event 
the median PFS in the control group is larger than expected and long-term follow-up 
becomes a concern, we will perform the final efficacy analysis after 52 events are observed 
or after all evaluable patients have been followed for at least 3 years, whichever occurs 
earlier. If the 1-sided p-value associated with the Log-Rank test is < 0.0255 (corresponding 
to an observed HR of 0.5776), we will consider sorafenib as having shown promising 
activity in this population and may recommend it for further testing.  
Inefficacy/Futility Analysis: We will evaluate the observed PFS of the arms when 45% of 
the PFS events required for the final efficacy analysis (i.e., 24) have been observed. 
We will terminate the study for futility if the p-value associated with the test statistic from 
a Log-Rank is at least 0.5025 (corresponding to an observed HR of 1.0027). Otherwise, we 
will continue to complete full enrollment. 
Although the primary endpoint will be evaluated using the first 75 evaluable patients, final 
efficacy results will further report results (e.g., publication, presentation) using all patients 
evaluable for determining PFS and so that patient enrolled beyond these 75 may contribute 
to these estimates. 
15.1.2 Maximum Accrual  
Maximum accrual is 83 patients, which includes 10% over accrual to replace those patients 
deemed ineligible due to improper histology having been determined on the basis of 
information available prior to randomization.  
15.1.3 Study Duration 
Assuming a rate of 4 patients per month, the anticipated duration of accrual 21 months, (1.7 
years). Assuming 12 months of follow-up (with tests required for disease assessment, per 
the Study Calendar) for every patient to assess the primary endpoint will bring maximum 
duration to 33 months (2.7 years) after the study opens to accrual, at which time all patients 
will be evaluable to assess the primary endpoint.  This estimate may be adjusted if the study 
requires suspension for endpoint or toxicity concerns. All patients will be followed for a 
maximum of 3 years to capture data regarding survival, progression, and late occurring 
events.  
15.1.4 Results Reporting on ClinicalTrials.gov  
At study activation, this study will have been registered within the “ClincialTrails.gov” web 
site. The Primary and Secondary Endpoints (ie, “Outcome Measures”) along with other 
required information for this study will be reported on ClinicalTrials.gov. For purposes of 
timing of the Results Reporting and as of Update #05, the initial estimated completion date 
for the Primary Endpoint of this study is 3 years after the study closes to accrual. The 
definition of “Primary Endpoint Completion Date” (PECD) for this study is the time the last 
patient registered has been followed for at least 12 months, but may be as high as 3 years, 
depending on the rate at which the events for the primary endpoint occur and given that the 
analysis is “event” (vs “time”) driven (per 15.1.1).  
We note that the PECD may be further adjusted if the study requires suspension for toxicity 
concerns or re-design due to the planned interim look at the median PFS rate observed in 
the control arm. 


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15.1.5 Accrual Monitoring  
We will be actively seeking participation from at least one of the other entities in the newly 
formed National Cancer Trials Network (formerly Cooperative Groups).  We will follow 
the 
CTEP 
guidelines 
for 
monitoring 
accrual 
(http://ctep.cancer.gov/protocolDevelopment/docs/slow_accrual.pdf) for phase III studies.  
These rules are associated with accrual rates observed at the 5th, 6th, and 8th quarters 
following activation. 
15.1.6 Evaluability & Assessment of Patients  
We will perform an intent-to-treat analysis to assess the primary endpoint and all eligible 
patients will be included in the futility and efficacy analysis for progression-free survival, 
excluding patients deemed ineligible due to improper histology having been determined on 
the basis of information available prior to randomization. Given that the central review of 
scans and pathology reports will be completed at a later date, we will consider the local 
review as the factor determining eligibility and evaluability for the progression-free survival 
endpoint. We will consider performing a secondary analysis, without such cases identified 
as discordant from the local review and to assess the impact of such cases on the results of 
the primary endpoint. 
Patients on treated on the control/placebo arm are allowed to crossover to the sorafenib upon 
experiencing progressive disease. We will consider censoring disease assessments at the 
date of surgical or radiotherapy intervention in patients receiving such care, given that the 
patients are receiving non-protocol specified therapy (i.e.  intervention) which may impact 
endpoint(s) beyond the treatment effect we are seeking to evaluate. 
Patients who were receiving placebo and unblinded prior to progression, effective 
November 17, 2017, and crossing over to sorafenib, will be censored for the primary 
endpoint and at their most recent disease assessment prior to initiating crossover treatment. 
15.2 
Secondary Endpoints 
NOTE: All secondary analyses and endpoints (except survival data/analyses) will 
exclude/censor data for patients (as applicable) receiving crossover treatment, due to the 
unblinding of study treatment effective November 17, 2017. The summary of data collected 
during crossover will further separate such patients from those who crossed over upon PD 
occurring during initial blinded treatment. 
15.2.1 Adverse Events 
We will use NCI CTCAE v4.0 to assess toxicity. Frequency tables, summary statistics, and 
categorical analysis will be used to compare the distributions of toxicity for patients treated 
with sorafenib vs placebo.  Data for patients who have crossed over or having received 
surgical or radiotherapy intervention will be summarized independently from their primary 
course of study treatment. 
Data & Safety Monitoring 
The principle investigator(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be developing. 
The Alliance Safety Monitoring Board (DSMB) is responsible for reviewing accrual and 
safety data for this trial at least twice a year, based on reports provided by the Alliance 
Statistics and Data Center. 


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Adverse Event Stopping Rules 
The stopping rules specified below are 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 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 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 either of the following: 
• 
an excessive death rate, defined as 1% or higher mortality attributed to study drug, or 
• 
if 3 or more patients in the first 15 treated patients experience a grade 3 or higher adverse 
event. 
• 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
15.2.2 Surgical Intervention 
Surgical excision/amputation is a therapeutic and palliative options for managing this 
disease.  Time to surgical intervention during treatment is defined as time between 
randomization to the patient undergoing therapeutic surgical resection for this disease.  If 
no event exists, patients will be censored at their date of last treatment for this event.  A log 
rank test will be used to compare the distributions of time to surgical intervention between 
the two arms using a 2-sided test and alpha=0.05 level of significance.  Kaplan-Meier (1958) 
methodology will be used to estimate various time points (e.g. 1 year rate, 2 year rate, etc.) 
and 95% Confidence Intervals will be calculated for these estimates. Surgery will be 
classified by outcome (e.g. complete-macroscopic, complete-microscopic, or partial), type, 
location (e.g. limb), thereafter analyzed by categorical analysis and descriptive statistics. 
Non-parametric methods will be used, as appropriate. See the note at the beginning of 
Section 15.2. 
15.2.3 Overall Survival (OS) 
Survival will be calculated as the time between the date of randomization to until death. 
Patients who are alive at the time of the analysis will be censored for survival at the most 
recent date of the last contact (or lost to follow-up). Kaplan-Meier (1958) methodology and 
log rank tests will be used to compare OS between the groups at various time points (eg, 1 
year rate, 2 year rate, etc) and 95% Confidence Intervals will be calculated for these 
estimates. Data following crossover will be analyzed and summarized separately from the 
main course of treatment for these patients. See the note at the beginning of Section 15.2. 
15.2.4 Tumor Response 
Patients will be classified for disease status according to RECIST v1.1 (see Section 13.0). 
We will compare best objective status for the two treatment arms and using the Cochran-
Mantel-Haenszel test. Duration of response will be calculated as the time between first 
tumor response and progression. Patients will be censored for duration of response at the 
date of last assessment if they have reached maximum follow-up without PD (or are lost to 
follow-up without PD). Kaplan Meier methodology will be used to estimate the distribution 
of duration of response and the Log-Rank test will be used to test for a difference in duration 
of response between the two arms. See the note at the beginning of Section 15.2. 


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15.3 
 Correlative Companion Study Endpoints 
15.3.1 Statistical design- Imaging study 
About 50% (38 patients) are expected to have extra-abdominal disease and be evaluated by 
MRI.  Percent change in tumor size by RECIST and percent changes in MRI T2 signal will 
be calculated at baseline and at response evaluation every 8 weeks.   Best RECIST response 
(ordinal variable) and percent T2 signal change (continuous) will be correlated by 
Spearman’s rho. Careful attention will be paid to patients having received sorafenib after 
PD on the placebo arm, which may involve censoring or adjusting the patient baseline at the 
initiation of sorafenib.  The percent changes in MRI T2 signal from Week 8 to subsequent 
imaging will be compared between groups with >30% pain palliation using t-test or a 
nonparametric alternative (e.g., Wilcoxon rank-sum test). Data, analyses, and censoring will 
also follow the note described in Section 15.2. 
15.3.2 Statistical design- A091105-H01, QOL study 
Pain palliation will be defined at each time point as ≥30% decrease from baseline in the 
worst pain intensity score (BPI-SF “worst pain” item), with neither a concomitant ≥30% 
increase in average daily use of any opioid narcotic, nor addition of any new opioid narcotic, 
relative to baseline. 
A patient must meet the criteria for pain palliation at both Week 8 and Week 12 to be 
considered a responder for the primary endpoint.  The primary statistical analysis will 
include all eligible and consented patients who provide baseline pain and pain medication 
data, have a baseline pain level greater than or equal to 3, and who initiate treatment.  Any 
patient who does not provide pain and pain medication data at Week 8 and Week 12 will be 
considered a non-responder (i.e., a “failure” for the endpoint but will be included in the 
denominator). 
Pain progression at a given time point is defined as a ≥30% increase compared with baseline 
in the worst pain intensity score (BPI-SF “worst pain” item) or either a ≥30% increase in 
the average daily use of any type of opioid narcotic or the addition of a new opioid narcotic 
compared with baseline.  Time to pain progression is defined as the date of randomization 
to the earliest date that pain progression is observed.  Patients not reporting pain progression 
will be censored at their date of last pain and pain medication data reporting.  Time to pain 
palliation is defined as the date of randomization to the earliest date that confirmed pain 
palliation is observed.  Duration of pain palliation is defined for all patients who experience 
confirmed pain palliation and is the time from the earliest date that confirmed pain palliation 
is observed to the earliest date that pain progression is observed.  Patients not reporting pain 
progression will be censored at their date of last pain and pain medication data reporting.   
For the primary analysis, the rate of pain palliation at Week 8 confirmed as Week 12 will 
be compared between arms using a two-sided alpha=0.05 chi-squared tests at the time of the 
final analysis. 
For the exploratory hypotheses, median time to pain palliation, duration of response, and 
time to pain progression will be estimated for each arm using Kaplan-Meier estimates and 
will be compared between arms using a log- rank test.  All other items/questionnaires will 
be scored according to published scoring guidelines and statistical analysis will include all 
eligible and consented patients who provide data for the given outcome and who initiate 
treatment (i.e., the requirement for baseline pain to be >/=3 is not in effect for the other 
outcomes).  Descriptive statistics will include means, standard deviations, medians, and 
ranges for each continuous or ordinal scale/subscale/item by group at each time point.  
Descriptive graphical techniques will include mean plots by group for each continuous or 


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Update #06 
ordinal scale/subscale/item.  Relative frequencies of responses for each ordinal item will 
also be generated at each time point by group.   
Each patient-reported outcome will be compared between arms at each time point using two-
sample t-tests followed by analysis of covariance adjusting for the baseline value at each 
time point.  Finally, a linear mixed-effects model with random intercepts and slopes will 
also be used to compare each continuous/ordinal patient-reported outcome over time 
between arms.  In these linear mixed-effects models, the post-baseline score is the modeled 
outcome and the predictors are the baseline score of the given patient-reported outcome, 
arm, time (treated as a continuous variable and measured at the planned week of 
assessment), and treatment-by-time interaction. 
Missing data will be handled in a number of ways.  Baseline patient/disease characteristics 
will be compared between patients who provide data and patients who have missing data for 
each endpoint.  We will also graphically explore patterns of missing data.  All analyses will 
be completed using all available data, followed by analyses completed using imputed data 
using the arm minimum followed by the arm maximum.  Lastly, we will employ pattern 
mixture models for longitudinal analyses.  Output from all analyses will be compared to 
assess the degree to which missing data impacts study results. 
For all statistical analyses, p-values <0.05 will be considered statistically significant.  For 
interpreting the clinical significance of effects, 0.2, 0.5, and 0.8 SD effects will be 
considered as small, moderate, and large based on Cohen30 throughout. 
Power:  We anticipate ~70% of eligible patients who initiate treatment will be evaluable for 
the primary analysis of this companion study.  With 51 patients contributing data for the 
primary analysis, the primary analysis has 80% power to detect a 40% difference in the rate 
of pain palliation at Week 8 confirmed at Week 12 between arms (50% pain palliation in 
the sorafenib arm versus 10% in the placebo arm) using a two-sided alpha=0.05 chi-squared 
test. Power for a 45% difference (55% pain palliation in the sorafenib arm versus 10% in 
the placebo arm) is 87%. These power calculations assume 2:1 randomization.  This power 
calculation conservatively assumes that 10% of patients in the placebo arm will experience 
a “placebo effect” such that patients report improvement in pain despite being treated with 
a placebo. 
15.3.3 Statistical design for correlative study A091105-ST1 
See the note in Section 15.2, which will apply to all analyses for this section A091105-ST1. 
Statistics for Core #1: Archival FFPE and TMA studies: Associations among the possible 
predictors of response to sorafenib and CTNNBI mutations will be examined using Fisher’s 
exact test, Kruskal-Wallis test, or Spearman’s correlation coefficient as appropriate. 
Variables considered include CTNNB1 genotype, tumor size, tumor site, gender, age at 
initial diagnosis, and primary versus recurrent disease.  Strata will be compared by using the 
log-rank test. Multivariate models will be constructed by introducing all variables 
aforementioned simultaneously into the model and then eliminating variables using the 
backward selection method. P values will be two-tailed and considered significant at alpha 
0.05.   Analyses will be conducted using SAS for Windows (release 9.3; SAS Institute, Cary, 
NC). 
Statistics for Core #2: Microarray: A two-sided t-test will be used to identify differentially 
expressed genes on log transformed data and those with a twofold change. False discovery 
rate (FDR) will be assessed by permutation testing (n = 1000) of the sample group labels. 
The selection approach is to first compute two t -tests and fold changes for each comparison 
between pre- treatment and day 8 versus the normal skin biopsy.  Genes that have a nominal 
p value < 0.01 and fold > 2 for each comparison will be selected.  To assess FDR, 


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permutation testing of the same selection will be performed 1000 times and the sample group 
labels switched around in each permutation.  Java TreeView color maps will be generated.  
To unravel a treatment-specific gene expression signature, the analysis will identify over- 
and under-expressed genes in pre- treatment and day 8 biopsies as compared to all control 
samples (germlineDNA extracted from whole blood).  Using Sigterms, sorafenib associated 
gene signature will search for Gene Ontology (GO) annotation terms, gene sets curated by 
the Molecular Signature Database (MSigDB, v2.5 and top enriched transcription factor 
sequence motifs.  Enrichment will be assessed by one-sided Fisher’s exact test with 
estimated FDR.  
Statistics for Core #3 and 4: For each paired sample, differences in protein levels will be 
compared by paired t-test. This sample size of 75 patients will allow 93% power to detect 1 
standardized difference.  Quantitative changes in IHC score of VEGF, PDGFR and β-
catenin cytoplasm/nuclear ratio will be correlated with disease status at 1 year by Fishers 
exact test. 
15.3.4 Pain Palliation  
See Section 15.3.2 for details. 
15.4 
Inclusion of Women and Minorities 
This study will be available to all patients regardless of race, gender, or ethnicity.   Total accrual 
is 83 patients.  The newly formed Alliance does not have a history of accrual to sarcoma trials 
in this population and we are basing our estimates on what has been observed at MSKCC.   Here, 
we expect at least 5% of patients to be Hispanic or Latino, 5% to be African American, and 65% 
to be female. 


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Update #06 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
5 
2 
0 
0 
7 
White 
39 
20 
5 
2 
66 
More Than One Race 
0 
0 
0 
0 
0 
Total 
44 
22 
5 
2 
73 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
7 
3 
0 
0 
10 
More Than One Race 
0 
0 
0 
0 
0 
Total 
7 
3 
0 
0 
10 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, 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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16.0 ADVERSE EVENT REPORTING 
16.1 
Solicited Adverse Events  
The following adverse events are considered "expected" and their presence/absence should be 
solicited, and severity graded, at baseline and for each cycle of treatment. 
 
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Fatigue 
General disorders 
Papulopustular rash 
Skin and subcutaneous tissue disorders 
Palmar-plantar erythodysesthesia 
syndrome 
Skin and subcutaneous tissue disorders 
Diarrhea 
Gastrointestinal disorders 
Anorexia 
Metabolism and nutrition disorders 
Nausea 
Gastrointestinal disorders 
Vomiting 
Gastrointestinal disorders 
Abdominal pain 
Gastrointestinal disorders 
Mucositis oral 
Gastrointestinal disorders 
Hypertension 
Vascular disorders 
Arthralgia 
Gastrointestinal disorders 
Myalgia 
Gastrointestinal disorders 
16.2 
Expedited Adverse Event Reporting 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below.  Investigators are required to notify the Alliance Protocol Operations 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 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 website http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
In the rare event when Internet connectivity is disrupted, a 24 hour notification is to be made to 
the NCI by telephone at 301-897-7497. An electronic report MUST be submitted upon re-
establishment of Internet connection. 
The Alliance requires investigators to route all expedited adverse event reports through 
the Alliance Protocol Operations 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 below.  Note that the table below and the Additional Instructions 
or Exclusions may conflict. The 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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Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE ≤ 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2 
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 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
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  


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• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
 
• Expedited AE reporting timelines defined: 
➢ 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS report 
within 5 calendar days of the initial 24-hour report. 
➢ 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event.  
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific expedited 
adverse event reporting exclusions (see below). 
• Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an agent 
under a CTEP IND. 
• Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be forwarded 
to your local IRB. 
• A091105 uses a drug under a CTEP IND. The reporting requirements for investigational agents 
under a CTEP IND should be followed for all agents (any arm) in this trial. 
• Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-AERS, 
but should be submitted as part of study results. All other grade 3, 4, or 5 adverse events that 
precipitate hospitalization or prolong an existing hospitalization must be reported via CTEP-AERS. 
• 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. 
• Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours.  
• Any death occurring greater than 30 days after the last dose of the investigational agent/intervention 
requires expedited reporting within 24 hours only if it is possibly, probably, or definitely related to 
the investigational agent/intervention. 
• Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be reported 
expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this event as a 
patient death. 
• A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the General 
disorders and administration SOC. 


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• All new malignancies must be reported via 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, myelodysplastic 
syndrome/acute myelogenous leukemia, and in situ tumors. 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
unless otherwise specified. 
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. 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
• 
Treatment expected adverse events include those listed in Section 9.0 and in the package insert. 
16.3 
CAEPR for Sorafenib 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Sorafenib (BAY 43-9006, NSC 724772) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2571 patients. Below is the CAEPR for 
Sorafenib (BAY 43-9006). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 


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Version 2.7, November 16, 20151 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 4.0 Term) 
[n= 2571] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome 
  
 
Chest pain - cardiac 
 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Ascites 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 Gastrointestinal hemorrhage2  
 Gastrointestinal hemorrhage2 (Gr 3) 
 
 
Gastrointestinal perforation3   
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time prolonged 
 
 Activated partial thromboplastin time 
prolonged (Gr 2) 
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase increased 
(Gr 3) 
Alkaline phosphatase 
increased 
 
 
 Alkaline phosphatase increased (Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase increased 
(Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased  
(Gr 3) 
Creatinine increased 
 
 
 Creatinine increased (Gr 3) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
 
GGT increased 
 
  
INR increased 
 
 
 INR increased (Gr 3) 
 
Investigations - Other 
(bicarbonate-serum low) 
 
  


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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 4.0 Term) 
[n= 2571] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Lipase increased 
 
 
 Lipase increased (Gr 3) 
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased (Gr 3) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
Serum amylase increased 
 
 
 Serum amylase increased (Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 3) 
 
Hypernatremia 
 
  
Hypoalbuminemia 
 
 
 Hypoalbuminemia (Gr 3) 
Hypocalcemia 
 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 3) 
Hyponatremia 
 
 
 Hyponatremia (Gr 3) 
Hypophosphatemia 
 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
 Back pain (Gr 3) 
 
Bone pain 
 
  
 
Musculoskeletal and 
connective tissue disorder -  
Other (muscle spasm) 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Treatment related secondary 
malignancy 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS  
  
 
Acute kidney injury 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Respiratory hemorrhage5 
 
  


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 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 4.0 Term) 
[n= 2571] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 3) 
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson syndrome   
 
 
Toxic epidermal necrolysis   
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation may include Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Respiratory hemorrhage may include bronchopulmonary hemorrhage, epistaxis, laryngeal hemorrhage, 
mediastinal hemorrhage, pharyngeal hemorrhage, and pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
6Febrile neutropenia is seen mostly in combination with other agents. 
 
Adverse events reported on sorafenib (BAY 43-9006; Nexavar) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that sorafenib (BAY 43-
9006; Nexavar) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(Thrombotic microangiopathy [e.g., TTP or HUS]); Febrile neutropenia6 


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CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Palpitations; Pericardial effusion; 
Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus tachycardia; Supraventricular 
tachycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Adrenal insufficiency; Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(color vision deficits); Eye disorders - Other (light to dark adaptation); Eye disorders - Other (retinal vein 
occlusion); Eye disorders - Other (retinal hemorrhage); Eye disorders - Other (visual field distortion); 
Flashing lights; Keratitis; Photophobia; Retinal detachment 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fistula; Anal mucositis; Anal pain; Anal 
ulcer; Cheilitis; Colitis; Colonic obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophageal pain; Esophagitis; Flatulence; Gastric ulcer; Gastritis; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (small bowel NOS fistula); Gastrointestinal fistula; Hemorrhoids; Ileal fistula; Ileus; Oral 
pain; Pancreatitis; Proctitis; Rectal fistula; Rectal mucositis; Rectal obstruction; Rectal pain; Small 
intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Facial pain; 
Flu like symptoms; Localized edema; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage; Hepatobiliary disorders - Other 
(biliary obstruction secondary to multiple biliary stones) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Cytokine release syndrome; Immune system 
disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Fall; Fracture; Hip 
fracture; Vascular access complication; Wound complication; Wound dehiscence 
INVESTIGATIONS - CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; 
Cholesterol high; Ejection fraction decreased; Fibrinogen decreased; Investigations - Other (blood urea 
nitrogen high) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; Hypermagnesemia; 
Hypertriglyceridemia; Hyperuricemia; Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Generalized muscle weakness; Joint range of motion decreased; Muscle weakness left-sided; Muscle 
weakness lower limb; Muscle weakness right-sided; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorders -  Other (cramping); Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Myelodysplastic syndrome; Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Hydrocephalus; Ischemia 
cerebrovascular; Lethargy; Leukoencephalopathy; Memory impairment; Neuralgia; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Stroke; Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Libido decreased; Personality 
change; Psychosis 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Proteinuria; Renal and 
urinary disorders - Other (focal segmental glomerulosclerosis); Renal and urinary disorders - Other 
(nephrotic syndrome); Renal and urinary disorders - Other (right ureter rupture); Renal calculi; Renal 
hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urine 
discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Gynecomastia; 
Hematosalpinx; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord hemorrhage; 
Testicular hemorrhage; Uterine hemorrhage; Vaginal fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchospasm; Hiccups; Hoarseness; Hypoxia; Laryngeal mucositis; Pharyngeal 
mucositis; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; 
Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other (nasal septal perforation); 
Tracheal mucositis 


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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Hyperhidrosis; Nail loss; Pain of 
skin; Purpura; Rash acneiform; Scalp pain; Skin and subcutaneous tissue disorders - Other (folliculitis); 
Skin and subcutaneous tissue disorders - Other (non-life threatening squamous cell carcinoma of skin: 
keratoacanthoma type); Skin hyperpigmentation; Skin hypopigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypotension; Phlebitis; Vascular disorders 
- Other (ruptured aortic aneurysm); Vascular disorders - Other (visceral arterial ischemia); Vasculitis 
 
 
Note: Sorafenib (BAY 43-9006; Nexavar) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 


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17.0 REFERENCES 
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individualized approach. Expert Rev Anticancer Ther. 2009 Apr;9(4):525-35. Review. 
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4. Smith AJ, Lewis JJ, Merchant NB, Leung DH, Woodruff JM, Brennan MF.  Surgical management 
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17. Guglielmi G, Cifaratti A, Scalzo G, Magarelli N. Imaging of superficial and deep fibromatosis. 
Radiol Med. 2009 Dec;114(8):1292-307. Epub 2009 Sep 30. 
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Curr Opin Oncol. 2009 Jul;21(4):352-9. Review. 
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somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol 151: 
329-334. 
22. W. A. Messersmith, P. LoRusso, J. M. Cleary, A. Dasari, X. Zhang, M. N. Shaik, R. D. Courtney, 
S. Randolph, G. ShapiroA phase I dose-escalation study of the novel gamma secretase inhibitor PF-
03084014 in patients (pts) with advanced solid tumors. J Clin Oncol 29: 2011 (suppl; abstr 3100)  
23.  Dodge ME, Lum L.  Drugging the cancer stem cell compartment: lessons learned from 
the hedgehog and Wnt signal transduction pathways.  Annu Rev Pharmacol Toxicol. 2011 Feb 
10;51:289-310. Review 
24.  Birgit Mosch, Bettina Reissenweber, Christin Neuber, and Jens Pietzsch.  Eph Receptors and 
Ephrin Ligands: Important Players in Angiogenesis and Tumor Angiogenesis.  Journal of Oncology 
Volume 2010 (2010)  
25. Vandevenne JE, De Schepper AM, De Beuckeleer L, Van Marck E, Aparisi F, Bloem JL, 
Erkorkmaz Z, Brijs S (1997) New concepts in understanding evolution of desmoid tumors: MR 
imaging of 30 lesions. European radiology 7(7): 1013-9 
26. Koh DM, Collins DJ (2007) Diffusion-weighted MRI in the body: applications and challenges in 
oncology. Ajr 188(6): 1622-35 
27. Pocock SL, Simon JR: Sequential treatment assignment with balancing for prognostic factors in 
the controlled clincal trial.  Biometrics 31:103-115, 1975.  
28.  Bretscher M, Rummans T, Sloan J, et al.  Quality of life in hospice patients: a pilot study.  
Psychosomatics. 1999; 40:309-313. 
29.  Cleeland CS, Ryan KM (1994 March). Pain Assessement: Global Use of the Brief  
Pain 
Inventory. Ann Acad Med. 23(2): 129-38. 
30.  Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, New Jersey: 
Lawrence Erlbaum Associates; 1988. 
31.  Grunberg SM, Groshen S, Steingass S, Zaretsky S, Meyerowitz B.  Comparison of conditional 
quality of life terminology and visual analogue scale measurements.  Quality of Life Res. 1996; 5:65-
72. 
32.  Gudex C, Dolan P, Kind P, Williams A.  Health state valuations from the general public using 
the visual analogue scale.  Quality of Life Res. 1996; 5:521-531. 
33. Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR; Clinical Significance Consensus 
Meeting Group. Methods to explain the clinical significance of health status measures. Mayo Clin 
Proc 2002; 77(4):371-83. 
34. Hyland ME, Sodergren SC.  Development of a new type of global quality of life scale and 
comparison and preference for 12 global scales.  Quality of Life Res. 1996; 5:469-480. 
35. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998; 16(1):139-44. 


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36. Sloan JA, Mahoney MR, Sargent DJ, et al. Was it worth it (WIWI)? Patient satisfaction with 
clinical trial participation: Results from North Central Cancer Treatment Group (NCCTG) phase III 
trial N0147. J Clin Oncol 29: 2011 (suppl; abstr 6122) 
37. Sloan JA, O'Fallon JR, Suman VJ, Sargent DJ.  Incorporating quality of life measurement into 
oncology clinical trials.  Proc Am Stat Assoc. 1998:282-287. 
38. Sriwantanakul K, Kelvie W, Lasagna L, Calimlim JF, Weis OF, Mehta G.  Studies with different 
types of visual analog scales for measurement of pain.  Clin Pharmacol Ther. 1983; 34:234-239. 
39. Tan AD, Novotny PJ, Kaur JS, Buckner JC, Schaefer PL, Stella PJ, Kuebler JP, Sloan JA.  A 
patient-level meta-analytic investigation of the prognostic significance of baseline quality of life 
(QOL) for overall survival (OS) among 3,704 patients participating in 24 North Central Cancer 
Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. J Clin 
Oncol. 2008; 26(May 20 suppl; abstr 9515). 
40. Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  New 
response evaluation criteria in solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer 
45(2):  228-247, 2009. 
 41. Sloan JA, Liu H, Sargent DJ, Satele D, Schaefer PL, Halyard MY, Grothey A, Garces YI, Brown 
PD, Loprinzi CL, Buckner JC.  A patient-level pooled analysis of the prognostic significance of 
baseline fatigue for overall survival (OS) among 3,915 patients participating in 43 North Central 
Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials.  
J Clin Oncol 2009; 27(507s) 
 
 


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APPENDIX I- 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 Assessment 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. 
 
A translator may be used to administer the assessment. Additionally, since NCIC is participating in 
A091105, a French version of the assessment has been provided on the following page. 
 
 
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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Fatigue/Uniscale Évaluation 
 
Instructions: S'il vous plaît, pour chaque article ci-dessous, encerclez le numéro (0-10) qui vous 
décrit le mieux. 
 
Comment décririez-vous : 
 
 
1. Votre niveau de fatigue moyen au cours de la dernière semaine, aujourd'hui inclus? 
  
0  
1  
2  
3  
4  
5  
6  
7 
 8  
9  
10  
Aucune fatigue  
 
La pire fatigue possible 
 
 
 
 
 
 
 
2. Votre qualité de vie globale dans la semaine écoulée, y compris aujourd'hui? 
 
 0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
Aussi mauvaise  
 
 
 
 
 
 
Aussi bonne 
que possible   
 
 
 
 
 
 
que possible 


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APPENDIX II- QOL QUESTIONNAIRE 
QOL booklets can be ordered by sites through the CTSU Help Desk. CTSU ask sites to allow 7-10 
business days for the processing and mailing of supply requests.  CTSU only send booklets via US Mail, 
unless the site provides a FedEx account number. 
 
CTSU Help Desk 
1600 Research Blvd, WB384S 
Rockville, MD 20850-3195 
(240) 453-5641 
 
Sites in need of QOL booklets must submit a Supplier Request Form to CTSU Help Desk operations. 
That form can be accessed in the CTSU protocol folder document folder under site registration. 
Completed Supplier Request forms can be faxed (888 691 8039) or emailed (ctsucontact@westat.com) to 
CTSU. 
 
 


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Patient Information Sheet 
Patient Completed Quality of Life Booklet 
You have been given a booklet to complete for this study.  The booklet contains some questions about your 
‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
 
1.  The booklet contains 3 sets of questions: 
a. Brief Pain Inventory Short Form (3 questions) 
 
  
b. PRO-CTCAE (19 questions) 
 
  
c. LASA Overall Quality of Life Item (1 question) 
 
  
 
 
2.  Directions on how to complete each set of questions are written on the top of each set. 
 
3.  If you were given this booklet during a clinical visit, please complete the booklet during your 
clinical visit and return it to your physician. 
 
4.  If you received this booklet in the mail, please return the completed booklet in the provided 
envelope. 
 
 
5.  It is very important that you return the booklet to us, whether you finish the study or not.  
 
If any questions make you feel uncomfortable, you may skip those questions and not give an answer. 
 
Thank you for taking the time to help us. 
 
 


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1.  Please rate your pain by circling the one number that best describes your pain at its WORST 
in the last 24 hours. 
 
 0 
1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain As Bad 
As You Can 
Imagine  
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Circle the one number that describes how, during the past 24 hours, pain has interfered with your:  
A. General Activity 
          0 
 1 
 2 
 3 
 4 
5 
 6 
 7 
 8 
 9 
 10 
Does not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes  
 
B.   Sleep 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes  
 
(PRO-CTCAE questions) 
In the past 7 days… 
3.  What was the SEVERITY of your insomnia (including difficulty falling asleep, staying asleep, or 
waking up early) at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
Please answer the following questions about your symptoms and quality of life:  
(Brief Pain Inventory Short Form questions) 


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In the past 7 days… 
4.  How much did insomnia (including difficulty falling asleep, staying asleep, or waking up early) 
INTERFERE with your usual or daily activities?  
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
5.  What was the SEVERITY of your constipation at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
 
6.  How OFTEN did you have pain?  
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost Constantly 
 
7.  What was the SEVERITY of your pain at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
8.  How much did pain INTERFERE with your usual or daily activities?  
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 


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In the past 7 days… 
9.  What was the SEVERITY of your fatigue, tiredness, or lack of energy at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
10.  How much did fatigue, tiredness, or lack of energy INTERFERE with your usual or daily 
activities?  
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
 
 
 
11.  How OFTEN did you have nausea?  
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost Constantly 
 
12.  What was the SEVERITY of your nausea at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
13.  How OFTEN did you have vomiting?  
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost Constantly


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In the past 7 days… 
14.  What was the SEVERITY of your vomiting at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
 15.  How OFTEN did you have loose or watery stools (diarrhea)? 
 Never 
 Rarely 
 Occasionally 
 Frequently 
 Almost Constantly 
 
 
 
16.  Did you have any rash?  
 No 
 Yes 
 
17.  What was the SEVERITY of your hand-foot syndrome (a rash of the hands or feet that can cause 
cracking, peeling, redness, or pain) at its WORST?  
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
18.  In the past 7 days, how much did hand-foot syndrome (a rash of the hands or feet that can cause 
cracking, peeling, redness, or pain) INTERFERE with your usual or daily activities?  
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 


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In the past 7 days… 
19.  What was the SEVERITY of your decreased appetite at its WORST?   
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
20.  How much did decreased appetite INTERFERE with your usual or daily activities?  
 Not at all 
 A little bit 
 Somewhat 
 Quite a bit 
 Very much 
 
21.  What was the SEVERITY of your mouth or throat sores at their WORST?   
 None 
 Mild 
 Moderate 
 Severe 
 Very Severe 
 
(LASA Overall Quality of Life Item) 
 
Please check the number (0-10) best reflecting your response to the following that describes your 
feelings during the past week, including today. 
 
How would you describe:  
22.  Your overall Quality of Life? 
 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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Pain Medication Diary 
Subject Name:  _________________________                              
To be completed by study site 
Subject ID:    __ __ __ __               Assessment Period:  __ __                   Research Staff Signature: __________________________________      Date:_________________ 
 
Study Site Staff: Prior to each 7-day period, write in pain 
medication names, routes, and strengths in the columns 
below.  
• 
List only one type of medication on each row. 
Include all medications the patient is taking for 
pain or that may alleviate pain symptoms 
• 
Please write in the dates where indicated 
(Month/Day/Year). 
 
 
Study Participant: Please record the number of units you have taken of each medication over the prior 
24 hours. If you are wearing a patch, mark a “1” for every day the patch is worn. 
 
During this 7-day period, if you start a new medication for pain or change the strength of the pills, 
write the new information on a new row. (Do not change the information about the medication you 
have already taken.) 
 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Date:  
___/___/___ 
(mm/dd/yy) 
Medication Name  
(write in name) 
Route  
(check one box) 
Strength  
(example:50 mg) 
# Taken 
# Taken 
# Taken 
# Taken 
# Taken 
# Taken 
# Taken 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 
 
  Oral    
  Patch   
  Other 
 
 
 
 
 
 
 
 


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APPENDIX III- DRUGS WITH RISK OF TORSADES DE POINTES 
  
This list contains medications that are generally accepted (and documented in published data) as having 
an increased risk of QT prolongation and/or torsades de pointes. Concomitant administration of sorafenib 
and a medication on this list is prohibited. 
  
Generic Name 
Brand Name 
Comments 
Amiodarone 
Cordarone®, Pacerone® 
Low risk torsades de 
pointes 
Arsenic trioxide 
Trisenox® 
Torsades de pointes 
Bepridil 
Vasocor® 
  
Chloroquine 
Aralen® 
  
Chlorpromazine 
Thorazine® 
  
Cisapride 
Propulsid® 
Restricted availability in 
U.S. 
Clarithromycin 
Biaxin® 
  
Disopyramide 
Norpace® 
Torsades de pointes 
Dofetilide 
Tikosyn® 
Torsades de pointes 
Dolasetron 
Anzemet® 
  
Droperidol 
Inapsine® 
Torsades de pointes 
Erythromycin 
Erythrocin®, E.E.S. ® 
IV > PO 
Halofantrine 
Halfan® 
  
Haloperidol 
Haldol® 
IV > PO, high doses 
increase QT 
prolongation and 
torsades de pointes 
Ibutilide 
Corvert® 
Torsades de pointes, 
female > male, non-
Caucasian > Caucasian 


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Levomethadyl 
Orlaam® 
  
Mesoridazine 
Serentil® 
  
Methadone 
Dolophine®, Methadose® 
  
Pentamidine 
Pentam®, Nebupent® 
  
Pimozide 
Orap® 
  
Procainamide 
Pronestyl®, Procan®, Procanbid® 
N-acetylprocainamide 
causes torsade de 
pointes, not parent 
compound 
Quinidine 
Cardioquin®, Quinaglute® 
Torsades de pointes 
Sotalol 
Betapace® 
Torsade de pointes 
female > male 
Sparfloxacin 
Zagam® 
  
Thioridazine 
Mellaril® 
  
Note: the above list is not all-inclusive. 
  
Drugs with Possible or Conditional Risk of Torsades de Pointes 
This list contains medications that, in some reports, have been associated or weakly associated with 
causing torsades de pointes and/or QT prolongation. There is insufficient data that these medications 
alone may cause torsades de pointes and/or QT prolongation, however when sorafenib is given 
concomitantly with a medication on this list (or other risk factors are present such as bradycardia, 
electrolyte disturbances, congenital long QT syndrome, or concomitant drugs that inhibit metabolism), 
there may be possible or conditional risk of torsades de pointes and/or QT prolongation. Extreme caution 
and careful monitoring should be instituted with concomitant administration of sorafenib and a 
medication on this list. 
  
Generic Name 
Brand Name 
Comments 
Alfuzosin 
Uroxatral® 
  
Amantadine 
Symmetrel® 
Low 


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Amitriptyline 
Elavil® 
Nonspecific 
ECG changes 
reported. 
Atazanavir 
Reyataz® 
  
Azithromycin 
Zithromax® 
  
Chloral hydrate 
Noctec® 
  
Ciprofloxacin 
Cipro® 
  
Citalopram 
Celexa® 
  
Clomipramine 
Anafranil® 
  
Desipramine 
Pertofrane® 
QT 
prolongation, 
VF/sudden death 
reported 
Diphenhydramine 
Benadryl®, Nytol® 
  
Dolasetron 
Anzemet® 
Granisetron < 
Ondansetron < 
Dolasetron 
Doxepin 
Sinequan® 
  
Dronedarone 
Multaq® 
  
Escitalopram 
Lexapro®, Cipralex® 
  
Felbamate 
Felbatrol® 
  
Flecainide 
Tambocor® 
  
Foscarnet 
Foscavir® 
  
Fosphenytoin 
Cerebyx® 
  
Fluconazole 
Diflucan® 
IV > PO 
Fluoxetine 
Prozac®, Sarafem® 
1 in 10,000 
ventricular 
arrhythmias 
reported 


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Galantamine 
Reminyl® 
  
Gatifloxacin 
Tequin® 
  
Gemifloxacin 
Factive® 
  
Granisetron 
Kytril® 
Granisetron < 
Ondansetron < 
Dolasetron 
Imipramine 
Norfranil® 
Nonspecific 
arrhythmias 
reported 
Indapamide 
Lozol® 
  
Isradipine 
Dynacirc® 
  
Itraconazole 
Sporanox® 
  
Ketoconazole 
Nizoral® 
  
Lapatinib 
Tykerb® 
  
Levofloxacin 
Levaquin® 
Lower risk than 
that of similar 
agents 
Lithium 
Lithobid®, Eskalith® 
  
Moexipril/HCTZ 
Uniretic® 
  
Moxifloxacin 
Avelox® 
  
Nicardipine 
Cardene® 
  
Nilotinib 
Tasigna® 
  
Nortriptyline 
Pamelor® 
Nonspecific 
arrhythmias 
reported 
Octreotide 
Sandostatin® 
  
Ofloxacin 
Floxin® 
  
Ondansetron 
Zofran® 
Granisetron 
< 
Ondansetron 
< 


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Dolasetron 
Oxytocin 
Pitocin® 
  
Paliperidone 
Invega® 
  
Paroxetine 
Paxel® 
Lower risk than 
TCA’s 
Perflutren lipid microspheres 
Definity® 
  
Protriptyline 
Vivactil® 
  
Quetiapine 
Seroquel® 
QT prolongation 
Ranolazine 
Ranexa® 
  
Risperidone 
Risperdal® 
QT prolongation, 
sudden 
death 
reported 
Ritonavir 
Norvir® 
  
Sertraline 
Zoloft® 
Lower risk than 
TCA’s 
Solifenacin 
VESIcare® 
  
Sunitinib 
Sutent® 
  
Tacrolimus 
Prograf® 
  
Tamoxifen 
Nolvadex® 
  
Telithromycin 
Ketek® 
  
Tizanidine 
Zanaflex® 
  
Trazodone 
Desyrel® 
  
Trimethoprim-Sulfa 
Sulfa®, Bactrim®, Bactrim DS® 
Low 
Trimipramine 
Surmontil® 
  
Vardenafil 
Levitra® 
  
Venlafaxine 
Effexor® 
1 :1000 risk of 
arrhythmia 


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reported 
Voriconazole 
VFend® 
  
Ziprasidone 
Geodon® 
QT 
prolongation, 
1:1000 risk of 
arrhythmia 
Note: The above list is not all-inclusive. 
  
References:  
1.     Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About 
the QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
2.     Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT 
Interval Prolongation.  Pharmacotherapy 2003;23:887-908. 
3.     Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. 
Anesthesiology 2005;102:204-210 
4.     Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval 
Prolongation:  Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
5.     Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
6.     Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About 
the QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
7.     Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT 
Interval Prolongation.  Pharmacotherapy 2003;23:887-908. 
8.     Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. 
Anesthesiology 2005;102:204-210 
9.     Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval 
Prolongation:  Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
10.  Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
 
 


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APPENDIX IV- AGENT ACCOUNTABILITY 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as Collaborator(s) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s 
family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 


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comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed for 
up to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary 
data, in addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as 
soon as possible and preferably at least three (3) days prior to submission, but in any case, prior 
to presentation at the meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
FAX 301-402-1584 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator(s) confidential/ 
proprietary information.


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APPENDIX V- BRIEF PAIN INVENTORY QUESTION #1 FOR STRATIFICATION 
All patients are stratified according to baseline level of pain.  
• 
For patients who consented to the A091105-HO1 study: The baseline level of pain question 
already appears as question #1 in the QOL questionnaire booklet (see Appendix II). 
Therefore, you do not need to administer this Appendix, and will enter the value circled for 
question #1 onto the OPEN Registration Form (Step 1). 
• 
For patients who do not consent to the A091105-HO1 study: Administer this appendix within 
28 days prior to registration. The baseline level of pain may also be administered verbally as 
long as a source document is maintained at the institution. French and Spanish versions of 
the question are provided on the following page. 
1.  Please rate your pain by circling the one number that best describes your pain at its 
WORST in the last 24 hours. 
 
 0 
1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain As Bad 
As You Can 
Imagine  
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Level of Pain 


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Español 
 
Clasifique su dolor hacienda un cículo alrededor del número que mejor describe la intensidad 
máxima de dolor sentido en las últimas 24 horas. 
 
 0 
1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
Ningún 
Dolor 
 
 
 
 
 
 
 
 
 
El Peor Dolor 
Imaginable 
 
 
 
 
 
Français 
 
SVP, entourez d’un cercle le chiffre qui décrit le mieux la douleur la plus intense que vous ayez 
ressentie pendant les dernières 24 heures. 
 0 
1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
Pas de 
douleur 
 
 
 
 
 
 
 
 
 
Douleur la plus 
horrible que vous 
puissiez imaginer 
 
 


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APPENDIX VI – A091105 OPTIONAL MEDICATION DIARY 
PATIENT MEDICATION DIARY – Sorafenib 
 
Today’s date ______________________________ 
Agent: Sorafenib 
Patient Name__________________ (initials acceptable) Patient Study ID ________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each 4 week-period while you take sorafenib. After cycle 14 you will 
complete one form for each 8 week period.  
2. 
Sorafenib should be taken once daily on an empty stomach one hour before or two hours 
after eating. These tablets should be swallowed whole and cannot be crushed or chewed. 
3. 
Record the date, the number of capsules you took, and when you took them. Record doses as soon 
as you take them; do not batch entries together at a later time. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
If you make a mistake while you write, please cross it out with one line, put your initials next to it, 
and then write the corrected information next to your initials.  Example: 10:30 am SB 9:30 am 
5.    If you miss a dose of sorafenib, you should take it as soon as you remember, as long as it is on the 
same day.  
6. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of daily 
dose 
# of capsules taken 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 


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Day 
 
Date 
Time of daily 
dose 
# of capsules taken 
Comments 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Beginning with Cycle 14 (i.e. after 1 year of treatment) 
29 
 
 
 
 
 
30 
 
 
 
 
 
31 
 
 
 
 
 
32 
 
 
 
 
 
33 
 
 
 
 
 
34 
 
 
 
 
 
35 
 
 
 
 
 
36 
 
 
 
 
 
37 
 
 
 
 
 
38 
 
 
 
 
 
39 
 
 
 
 
 
40 
 
 
 
 
 
41 
 
 
 
 
 
42 
 
 
 
 
 
43 
 
 
 
 
 
44 
 
 
 
 
 
45 
 
 
 
 
 
46 
 
 
 
 
 
47 
 
 
 
 
 
48 
 
 
 
 
 
49 
 
 
 
 
 
50 
 
 
 
 
 
51 
 
 
 
 
 
52 
 
 
 
 
 
53 
 
 
 
 
 
54 
 
 
 
 
 
55 
 
 
 
 
 
56 
 
 
 
 
 
 
Physician’s Office will complete this section: 
 
1. Date patient started protocol treatment 
___________________________________________________ 
 
2. Date patient was removed from study 
____________________________________________________ 
 


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3. Total number of capsules taken this month (each size) 
_________________________________________ 
 
4. Physician/Nurse/Data Manager’s Signature 
_________________________________________________ 
 
Patient’s signature 
______________________________________________________________________________