Clinical trial NCT02048371
Conditions: Liposarcoma Osteogenic Sarcoma Ewing/Ewing-like Sarcoma Rhabdomyosarcoma Mesenchymal Chondrosarcoma
Sponsor: Sarcoma Alliance for Research through Collaboration
Start date: 2014-07-01; Completion date: 2022-05-01
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma.

Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents.

Detailed description:
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma.

Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents

Arms: arm 1: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off

Regorafenib arm 2: 21 days on and 7 days off

Placebo arm 3: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off

Regorafenib arm 4: 21 days on and 7 days off

Placebo arm 5: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off

Regorafenib arm 6: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off

Regorafenib arm 7: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off

Regorafenib
Interventions: intervention 1: Regorafenib intervention 2: Placebo
Intervention descriptions: intervention 1: Adults: 160 mg daily; 21 days on and 7 days off Pediatrics: 82mg/m2 (rounding to the nearest 20mg) daily; 21 days on and 7 days off intervention 2: 21 days on and 7 days off

Protocol documents:
Prot_SAP_000.pdf: 
 
Cover Page 
Clincialtrials.org 
 
Title: SARC024: A blanket protocol to study oral regorafenib in patients with selected 
sarcoma subtypes 
 
NCT: NCT02048371 
 
Document Date: 02DEC2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SARC Protocol: SARC024 
 
 
TITLE:  SARC024: A blanket protocol to study oral regorafenib in patients with selected 
sarcoma subtypes 
 
Sponsor:  Sarcoma Alliance for Research through Collaboration (SARC)  
 
Supporter: Bayer HealthCare 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially the unpublished data, has 
been generated by SARC and therefore provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff and 
applicable Independent Ethics Committee/Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written 
authorization from SARC except to the extent necessary to obtain informed consent 
from those persons to whom the drug may be administered. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND Status:  
 
Protocol Version: 
Final Version 1.0 14JAN2014 
Final Version 2.0 05MAR2014 
Final Version 3.0 25FEB2015 
Final Version 4.0 25JUN2015 
Final Version 5.0 10AUG2017 
DRAFT Version 6.0 02NOV2019 
Final Version 6.1 02DEC2019 
 
 


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Overall Principal Investigator: 
Robert G. Maki, MD, PhD 
 
 
 
 
 
 
Abramson Cancer Center 
University of Pennsylvania School of Medicine 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
 
Liposarcoma Cohort A 
Principal Investigator: 
 
Richard F. Riedel, MD 
 
 
 
 
 
Duke University Medical Center 
 
 
 
 
 
25178 Morris Bldg Duke S 
 
 
 
 
 
Box 3198 DUMC  
 
 
 
 
 
Durham, NC 27710 
 
 
 
 
 
  
 
Osteosarcoma Cohort B 
Principal Investigator: 
 
Christopher W. Ryan, MD 
Co-PI: Lara E. Davis, MD 
Oregon Health and Sciences University 
3303 SW Bond Ave CH14R 
Portland, OR 97239 
 
Ewing/Ewing-like sarcoma  
Cohort C Principal    
 
Steven Attia, DO 
Investigator:  
 
 
Mayo Clinic Florida 
4500 San Pablo Rd 
Jacksonville, FL 32224 
 
Rhabdomyosarcoma  
Cohort D Principal  
 
Leo Mascarenhas, MD MS 
Investigator:  
 
 
Children’s Hospital of Los Angeles 
 
 
 
 
 
4650 Sunset Blvd 
 
 
 
 
 
Los Angeles, CA  90027 
 
 
 
 
 
 
Mesenchymal Chondrosarcoma 
Cohort E Principle Investigator: 
Robert G. Maki, MD, PhD 
Abramson Cancer Center 
University of Pennsylvania School of Medicine 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
 
Principal Statistician: 
 
 
 
 
 
Karla Ballman, PhD 
 
 
Weill Cornell Medical College 
 
 
402 East 67th Street, LA-225 
 
 
New York, NY 10065 


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SARC Operations Office:     
24 Frank Lloyd Wright Drive 
 
 
 
 
 
Lobby A, Suite 3100; PO Box 406 
 
 
 
 
 
Ann Arbor, MI 48105 
 
 
 
 
 
Phone: (734) 930-7600 
 
 
 
 
 
Fax: (734) 930-7557                      
 
 
 
 
 
 
Email:  sarc024@sarctrials.org 
 
SARC Medical Officer:      
Scott Okuno, MD 
Mayo Clinic 
200 1st St SW 
Rochester, MN  55905 
 
 
 
 
 


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GLOSSARY OF ABBREVIATIONS 
 
AE          Adverse Event 
AJCC        American Joint Committee on Cancer 
ALT (SGPT) 
Alanine aminotransferase 
AST (SGOT) 
Aspartate aminotransferase 
BSC         Best Supportive Care 
CI 
Confidence interval 
CNS         Central Nervous System 
CR 
Complete Response 
CRF         Case Report Form 
CT          Computed Tomography 
CTCAE       Common Terminology Criteria for Adverse Events 
DCE         Dynamic Contrast Enhanced 
DSS         Disease-Specific Survival 
EDC         Electronic Data Capture  
FDA         Federal Drug Administration 
FISH        Fluorescence in situ hybridization 
G           Grade 
GCP         Good Clinical Practice 
GFR         Glomerular Filtration Rate 
GIST        Gastrointestinal Stromal Tumor 
GMP         Good Manufacturing Practice 
HFSR        Hand Food Skin Reaction 
HIV         Human Immunodeficiency Virus (HIV-1 or 2, HTLV-III) 
IB          Investigator’s Brochure 
ICF         Informed Consent Form 
ICH         International Conference of Harmonisation 
IHC 
Immunohistochemistry 
INR         International Normalized Ratio 
IRB         Institutional Review Board 
MDRD        Modified Diet in Renal Disease 
MRI         Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NYHA        New York Heart Association 
ORR 
Overall response rate 


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OS 
Overall survival 
PI          Principal Investigator 
PD 
Progressive disease  
PDGFR       Platelet Derived Growth Factors Receptor 
PET         Positron Emission Tomography 
PFS 
Progression free survival 
PTT         Partial thromboplastin time 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR          Response Rate 
SAE         Serious Adverse Event 
SARC        Sarcoma Alliance for Research through Collaboration 
SD 
Stable Disease 
SMOKI      Small Molecule Oral Kinase Inhibitor 
STBS        Soft Tissue and Bone Sarcomas 
SUSAR       Suspected Unexpected Serious Adverse Reaction 
TTP         Time to Tumor Progression 
VEGFR       Vascular Endothelial Growth Factor 
WHO         World Health Organization 
 
 


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SCHEMA: SARC024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Synopsis: SARC024 
 
Primary Objective 
 
Cohort A (liposarcoma): To compare the progression-free survival (PFS) of eligible subjects 
treated with regorafenib or placebo according to modified RECIST version 1.1. 
 
Cohort B (osteogenic sarcoma): To compare the progression-free survival (PFS) of eligible 
subjects treated with regorafenib or placebo according to RECIST version 1.1. 
 
Cohort C (Ewing/Ewing-like sarcoma): To estimate the RECIST 1.1 PFS rate of eligible 
subjects treated with regorafenib at 8 and 16 weeks. 
 
Cohort D (Rhabdomyosarcoma: Fusion-positive alveolar, Embryonal, Fusion-negative 
alveolar): To estimate the RECIST 1.1 PFS rate of eligible subjects treated with regorafenib at 8 
and 16 weeks. 
 
Cohort E (Mesenchymal chondrosarcoma): To estimate the RECIST 1.1 PFS rate of eligible 
subjects treated with regorafenib at 24 weeks. 
 
Secondary Objectives 
 
1. All cohorts: Calculate the incidence of reported CTCAE v 4.03 adverse events and 
abnormal laboratory test results 
 
2. All cohorts: Estimate the overall response rate (ORR) per RECIST version 1.1, time to 
tumor progression (TTP), PFS at 8 and 16 weeks, overall survival (OS), disease–specific 
survival (DSS)  
 
3. Cohorts A & B, after crossover: Assess PFS, RR, TTP, OS, and DSS following 
administration of regorafenib in the open label portion of the study.  
 
Exploratory endpoints 
 
1. Assess PFS and RR in these populations by Choi criteria 
 
2. Growth modulation index for treatment with regorafenib vs. prior line of therapy, defined 
as TTPregorafenib/TTPprior. 
 
Hypothesis and Rationale 
 
Inhibition of angiogenesis to slow or stop cancer growth is one mechanism under scrutiny as a 
therapeutic option for patients with metastatic cancers of all types. Some of the agents used to 
examine this issue in Soft Tissue and Bone Sarcomas (STBS) are multitargeted Small Molecule 


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Oral Kinase Inhibitors (SMOKIs). Imatinib, sunitinib, and regorafenib have all been approved 
for use in gastrointestinal stromal tumors (GISTs), one of the, if not the, most common form of 
sarcoma.  
 
After failure of standard cytotoxic chemotherapy, pazopanib was approved for use in patients 
with metastatic non-GIST metastatic soft tissue sarcomas other than liposarcoma by virtue of a 
phase III clinical trial in patients with metastatic soft tissue sarcoma1. Conversely, there are no 
randomized data to date regarding the activity of SMOKIs in bone sarcomas specifically, and 
although there are no randomized data regarding the activity of pazopanib in liposarcomas, there 
appears to be limited activity of SMOKIs based on the phase II study of pazopanib in soft tissue 
sarcomas2. 
 
Sorafenib, another multitargeted small molecule oral kinase inhibitor (SMOKI), demonstrated 
activity in a multi-arm phase II study, in which liposarcoma was also excluded. Small studies of 
sunitinib and anecdotes have shown at least minor activity in sarcomas3-6. In a phase II clinical 
trial of sorafenib in 35 patients with chemotherapy refractory osteogenic sarcoma, 3 patients had 
a partial response and 2 had a minor response, with 6 patients on treatment for more than 6 
months without worsening7. We also note anecdotal evidence of a patient with a Ewing sarcoma 
with a sustained RECIST partial response (S. Attia, DO, personal communication).  
 
Although regorafenib was approved for use in patients who had progressive GIST despite 
imatinib and/or sunitinib on the basis of phase II and phase III data8,9, it has not been examined 
in a systematic fashion in patients with other forms of sarcoma. 
 
Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of 
activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is 
precedent to examine SMOKIs such as regorafenib in sarcomas other than GIST. It is also 
recognized that SMOKIs such as regorafenib, sorafenib, pazopanib, and sunitinib have 
overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of 
these SMOKIs block vascular endothelial growth factor and platelet derived growth factors 
receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of 
these agents10. 
 
Since the protocol was developed, preclinical data from the laboratory of Raffaella Sordella at 
Cold Spring Harbor Laboratory indicate responsiveness to SMOKIs of mesenchymal 
chondrosarcoma primary tissue culture and of xenografted tumor to mice, with tumor shrinking 
seen of established tumors grown subcutaneously (unpublished results). As a result, this rare 
sarcoma subtype, typically with an HEY1-NCOA2 fusion, may be susceptible to imatinib, 
sorafenib, or regorafenib; studies with the agent are underway to confirm initial data are 
underway as of late 2019. 
 
We therefore propose parallel randomized phase II studies of regorafenib in patients with 
liposarcoma and osteogenic sarcoma to determine if there is significant activity of these agents, 
as has been observed with pazopanib in soft tissue sarcomas. In addition, we seek to determine 
the activity of regorafenib in Ewing/Ewing-like sarcoma, rhabdomyosarcoma, and mesenchymal 
chondrosarcoma, given anecdotal data of activity (or of promising preclinical data), planning to 


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examine individual cohorts of patients in a prospective phase II trial. We further note that since 
median time to progression with an active agent in advanced Ewing/Ewing-like sarcoma was 
only 1.3 months11, it is difficult to propose a randomized study design without single cohort data.  
 
Trial Design 
 
We seek to conduct parallel clinical trials of regorafenib in five different metastatic/local-
regionally recurrent STBS populations: (A) liposarcoma (pure well-differentiated liposarcoma is 
excluded); (B) osteogenic sarcoma; (C) Ewing/Ewing-like sarcoma; (D) fusion-positive alveolar 
rhabdomyosarcoma, embryonal rhabdomyosarcoma and fusion negative alveolar 
rhabdomyosarcoma; and (E) mesenchymal chondrosarcoma. 
 
For cohorts A and B, we will conduct parallel randomized phase II studies. Patients will be 
randomized 1:1 between regorafenib and placebo, and followed for disease progression. For 
those patients with progression of disease on placebo, crossover to active drug will be offered to 
patients if they remain eligible for the clinical trial in all other respects.  
 
Patients will be further stratified by number of prior lines of therapy (1 vs 2 or more), as well as 
WHO performance status (0-1 vs 2).  
 
Since PFS with active therapy was very short in advanced Ewing/Ewing-like sarcoma using an 
IGF1R inhibitor, for example, a single cohort phase II clinical design will be used for cohort C to 
obtain initial clinical experience with this very aggressive sarcoma subtype.  
 
For cohorts D & E, we will conduct single cohort phase II clinical designs to obtain initial 
clinical experience with these sarcoma subtypes in patients at least 5 years of age. 
 
Maximum Total Number of Subjects 
 
Cohort A: 48, seeking 42 events in 16 months 
Cohort B: 48, seeking 42 events in 16 months 
Cohort C: Single stage phase II design, n=30 
Cohort D: Singe stage phase II design, n ~ 12* 
Cohort E: Singe stage phase II design, n ~ 12* 
 
*These two arms will enroll a total of 24 patients, given the study funding for 24 patients. The 
number of people studied in each group will vary according to the ability to accrue either 
diagnosis.  
 
Number of enrolling centers: approximately 18 
 
Anticipated Length of Study (patient enrollment period, overall length including follow-up)   
 
We anticipate accrual of 4 subjects per month for Cohorts A and B and 0.5 subject per month for 
cohorts C, D and E.  
 


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Study Drug(s), Dosing and Administration 
 
Regorafenib starting dose of 160 mg oral daily (4 tablets of 40 mg), 3 weeks on, 1 week off. 
 
Patients under age 18 will start at 82 mg/m2/dose oral daily as the initial dose (rounding to 
nearest 20 mg, and capped at the adult dose of 160 mg oral daily). 
 
Efficacy Evaluations 
 
Tumor reimaging and tumor measurements by CT and-or MRI every 8 weeks for 32 weeks, then 
every 12 weeks. Scans may be done ± 7 days of planned date. 
 
Specific Safety Evaluations/ Concerns 
 
Skin toxicity 
Hypertension 
Congestive heart failure 
Proteinuria 
Fatigue, malaise 
Liver function test abnormalities 
Dehydration, prerenal azotemia 
 
Brief Statistical Design 
 
Cohorts A and B:  Randomized, double blinded, placebo-controlled, phase II design. 
 
Cohorts C, D and E:  Single stage, single arm, phase II design.  


 
TABLE OF CONTENTS 
 
SCHEMA: SARC024 .................................................................................................................... IX 
1. OBJECTIVES ............................................................................................................................. 3 
1.1 Primary Objective .................................................................................................................. 3 
1.2. Secondary Objectives ........................................................................................................... 3 
1.3. Exploratory objectives .......................................................................................................... 3 
2. BACKGROUND ......................................................................................................................... 4 
2.1 Soft tissue and bone sarcomas (STBS) .................................................................................. 4 
2.2 Regorafenib ........................................................................................................................... 5 
2.3 Preclinical data regarding regorafenib .................................................................................. 5 
2.4 Clinical experience with regorafenib .................................................................................... 6 
2.5 Rationale ................................................................................................................................ 9 
2.6 Study Design ....................................................................................................................... 10 
3. PATIENT SELECTION……………………………………………………………………….11 
3.1 Inclusion Criteria ................................................................................................................. 11 
3.2 Exclusion Criteria ................................................................................................................ 14 
3.3 Inclusion of Women and Minorities .................................................................................... 17 
4. REGISTRATION PROCEDURES ........................................................................................... 17 
4.1 General Guidelines .............................................................................................................. 17 
4.2 Registration Process ............................................................................................................ 17 
4.3 Treatment assignment .......................................................................................................... 18 
4.4 Screen Failures and Dropouts ............................................................................................. 18 
4.5 Replacement ........................................................................................................................ 18 
5. TREATMENT PLAN ............................................................................................................... 18 
5.1 Agent Administration .......................................................................................................... 18 
5.2 Regorafenib and placebo ..................................................................................................... 19 
5.3 Blinding and unblinding ...................................................................................................... 19 
5.4 Study drug administration ................................................................................................... 20 
5.5 General Concomitant Medication and Supportive Care Guidelines ................................... 21 
5.6 Duration of Therapy ............................................................................................................ 22 
5.7 Duration of Follow Up ........................................................................................................ 22 
5.8 Criteria for Removal from Study ......................................................................................... 22 
6. DOSING DELAYS/DOSE MODIFICATIONS ....................................................................... 23 
6.1 Dose Reduction Levels ........................................................................................................ 23 
6.2 Management of toxicity (other than hand-foot skin reaction, hypertension and LFT 
abnormalities) ............................................................................................................................ 24 
6.3 Management of hand-foot skin reaction .............................................................................. 25 
6.4 Hypertension ....................................................................................................................... 28 
6.5 Liver Function Abnormalities ............................................................................................. 32 
6.6 Prevention/management strategies for diarrhea .................................................................. 33 


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7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..................................... 33 
7.1 Adverse Event and Laboratory Abnormalities .................................................................... 34 
7.2 Handling of Safety Parameters ............................................................................................ 38 
8. PHARMACEUTICAL INFORMATION ................................................................................. 39 
8.1 Regorafenib: description of mechanism of action ............................................................... 39 
8.2  Administration of Study Drugs .......................................................................................... 39 
8.3 Formulation, Packaging and Labelling of Study Drugs ...................................................... 39 
8.4 Agent Ordering .................................................................................................................... 40 
8.5 Agent Accountability .......................................................................................................... 40 
8.6 Destruction of study drugs .................................................................................................. 41 
9. STUDY EVALUATIONS AND STUDY CALENDAR .......................................................... 41 
9.1 Screening Studies ................................................................................................................ 41 
9.2 On Study Evaluation ........................................................................................................... 42 
9.3 Off Study Evaluations ......................................................................................................... 44 
9.4 Study Calendar .................................................................................................................... 46 
10. MEASUREMENT OF EFFECT ............................................................................................. 47 
10.1 Antitumor Effect – Solid Tumors, with modifications for well differentiated-
dedifferentiated liposarcoma ..................................................................................................... 47 
10.2 Antitumor Effect – Solid Tumors: Choi criteria ............................................................... 54 
11. DATA REPORTING / REGULATORY CONSIDERATIONS............................................. 55 
11.1 Data Reporting .................................................................................................................. 55 
11.2 Multi-Institutional Guidelines ........................................................................................... 58 
11.3 Data and Participating Institution Monitoring ................................................................... 59 
11.4 Human Subjects Protection ............................................................................................... 59 
11.5 Premature termination of study ......................................................................................... 60 
12. STATISTICAL CONSIDERATIONS .................................................................................... 61 
12.1 Efficacy and safety variables ............................................................................................. 61 
12.2 Study Design/Endpoints .................................................................................................... 62 
12.3 Sample Size/Accrual Rate ................................................................................................. 64 
12.4 Stratification Factors ......................................................................................................... 65 
12.5 Analysis of Secondary Endpoints ...................................................................................... 65 
13. ETHICAL AND LEGAL CONDUCT OF THE STUDY....................................................... 65 
13.1 Subject information and consent ....................................................................................... 66 
13.2 Publication policy .............................................................................................................. 67 
13.3 Confidentiality ................................................................................................................... 67 
14. REFERENCES ........................................................................................................................ 68 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................ 70 
APPENDIX B.  SARC024 FAX/EMAIL COVERSHEET AND MEDWATCH FORM ............ 71 


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APPENDIX C. STUDY DRUG DIARY TEMPLATE ................................................................ 72 
APPENDIX D. STRONG CYP3A4 INDUCERS AND INHIBITORS ....................................... 74 
 


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1. OBJECTIVES 
 
1.1 Primary Objective  
 
A. Cohort A (liposarcoma): To compare the progression-free survival (PFS) of eligible 
subjects treated with regorafenib or placebo according to modified RECIST version 1.1. 
 
B. Cohort B (osteogenic sarcoma): To compare the progression-free survival (PFS) of 
eligible subjects treated with regorafenib or placebo according to RECIST version 1.1. 
 
C. Cohort C (Ewing/Ewing-like sarcoma): To estimate the RECIST 1.1 PFS rate of eligible 
subjects treated with regorafenib at 8 and 16 weeks. 
 
 
D. Cohort D (Rhabdomyosarcoma: Fusion-positive alveolar, Embryonal, Fusion-
negative alveolar): To estimate the RECIST 1.1 PFS rate of eligible subjects treated with 
regorafenib at 8 and 16 weeks.  To estimate the RECIST 1.1 response rate (PR or better) of 
eligible patients treated with regorafenib at 8 weeks. 
 
 
E. Cohort E (mesenchymal chondrosarcoma): To estimate the RECIST 1.1 PFS rate of 
eligible subjects treated with regorafenib at 24 weeks.  To estimate the RECIST 1.1 response 
rate (PR or better) of eligible patients treated with regorafenib at 24 weeks. 
 
1.2. Secondary Objectives 
 
 
A.  All cohorts: Calculate the incidence of reported CTCAE v 4.03 adverse events and 
abnormal laboratory test results 
 
B. All cohorts: Estimate the overall response rate (ORR) per RECIST version 1.1, time to 
tumor progression (TTP), PFS at 8 weeks and 16 weeks, overall survival (OS), disease–
specific survival (DSS)  
 
C. Cohorts A and B, after crossover: Assess PFS, RR, TTP, OS, and DSS following 
administration of regorafenib in the open label portion of the study.  
 
1.3. Exploratory objectives 
 
 
A. Assess PFS and RR in these populations by Choi criteria 
 
B. Growth modulation index for treatment with regorafenib vs. prior line of therapy, defined 
as TTPregorafenib/TTPprior. 
 
 
 


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2. BACKGROUND 
 
2.1 Soft tissue and bone sarcomas (STBS) 
 
Soft Tissue and Bone Sarcoma (STBS) are malignant tumors of mesenchymal origin. 
Approximately 14,000 cases are diagnosed annually in the US, accounting for less than 1% of 
malignancies diagnosed12. Surgery, with or without adjuvant radiation therapy is the mainstay 
of treatment for early stage soft tissue sarcoma13; chemotherapy is routinely used in the 
adjuvant setting for osteosarcomas and Ewing/Ewing-like sarcomas of bone. Despite surgical 
excision, between 30-60% of patients develop recurrent and/or metastatic disease. Although 
preoperative chemotherapy may improve resectability of advanced STBS, the use of 
chemotherapy after resection of metastatic STBS has not been shown to improve overall 
survival13. 
 
Complete responses to chemotherapy for recurrent or metastatic sarcomas are rare and do not 
seem to translate into improved survival. Most tumors develop rapid drug resistance and 
patients develop progressive disease within months. The median survival time from diagnosis 
for patients with metastatic disease is 8 to 12 months.  Thus, in most patients with advanced 
and/or metastatic sarcoma, palliation is the main objective of treatment.  Given the toxicity 
and lack of efficacy of chemotherapy, typically doxorubicin, ifosfamide, dacarbazine and 
other agents such as gemcitabine (and combinations), patients with advanced and metastatic 
disease are appropriate candidates for investigational therapies. 
 
Other than cytotoxic agents, there are few options for treatment for patients with metastatic 
and-or local-regionally recurrent osteogenic sarcoma, liposarcoma, and Ewing/Ewing-like 
sarcoma. Trabectedin (ET743, Yondelis®) has been approved in Europe and the U.S. for 
treatment of metastatic sarcomas on the basis of a randomized phase II study14, as well as 
phase III trials data.   
 
Mifamurtide (Mepact®) has also been approved in Europe, in this case for the adjuvant 
treatment of osteogenic sarcoma. Eribulin, with at least some activity in a phase II study in 
soft tissue sarcomas, is now approved by virtue of a phase III study vs dacarbazine in 
advanced liposarcoma and leiomyosarcoma.   
 
Children with relapsed and refractory childhood rhabdomyosarcoma (RMS) have a poor 
prognosis when treated with chemotherapy15, 16 . Patients with embryonal histology fair better 
than patients with alveolar histology. Fusion-negative alveolar histology has a similar 
prognosis to embryonal histology17. Adult patients with RMS have a much poorer prognosis 
when compared with children18. A recently completed randomized phase 2 clinical trial in 
patients with first relapse or refractory RMS conducted by the Children’s Oncology Group 
selected the mTOR inhibitor for further investigation in newly diagnosed patients with 
intermediate risk RMS19. A randomized clinical trial of vincristine and irinotecan with or 
without temozolomide has been recently completed by the European Pediatric Sarcoma Study 
Group and results are pending. 
 


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     2.2 Regorafenib 
 
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity 
as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI)20.  
 
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular 
kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, 
tumor angiogenesis, and maintenance of the tumor microenvironment.  In in vitro biochemical 
or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited 
the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, 
FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, 
and Abl at concentrations of regorafenib that have been achieved clinically.  In in vivo 
models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition 
of tumor growth as well as anti-metastatic activity in several mouse xenograft models 
including some for human colorectal carcinoma. 
 
     2.3 Preclinical data regarding regorafenib 
 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in human colon 
and breast xenografts as demonstrated by a reduction in microvessel area, reduced Ki-67 
staining, and reduced pERK1/2 staining in tissue sections from tumor xenografts, and dose-
dependent inhibition of tumor growth in multiple xenograft models (breast, colon, renal, 
NSCLC, melanoma, pancreatic, thyroid, ovarian)20.  Immunohistochemical ex-vivo studies 
with a phospho –specific monoclonal anti-ERK 1/2 antibody demonstrated inhibition of the 
MAPK pathway five days after treatment with regorafenib in 2 of 3 tumor models examined 
(MDA-MB-231 and BxPC-3), but not in NSCLC (H460). 
 
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-3 and Colo-205) 
demonstrated a significant reduction in new blood vessels by histomorphometry as detected in 
tumor samples using a murine CD31 antibody20. These data suggest that regorafenib can 
target the tumor cell MAPK pathway (i.e., tumor cell survival) and tumor vasculature in some 
but not all tumors. 
 
2.3.1 Preclinical pediatric oncology data  
 
In vitro effects on cell proliferation were determined in 33 pediatric solid tumor cell lines of 
the Innovative Therapies for Children with Cancer (ITCC) panel covering five malignancies21.  
Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 
μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 
mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase 
(MEK) inhibitor refametinib against various tumor types, including patient-derived brain 
tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene.  
 
Regorafenib moderately inhibited the proliferation of the tested pediatric tumor cell line panel 
and was not indicative for the selection of a certain tumor indication.  In vivo, regorafenib 
demonstrated significant tumor growth delay in all models tested across the various 


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indications, which is consistent with the observations from a broad and diverse panel of adult 
tumor models. No partial or complete remissions were observed as single agent, except for the 
IGRM57 medulloblastoma model, which is PDGFRA amplified; inhibition of the PDGFR 
signaling pathway in tumors with amplified PDGFRA may be involved in its therapeutic 
efficacy.  Mechanistically the antitumor activity of regorafenib appears to be primarily 
mediated by its antiangiogenic mechanism, which is accompanied by a proapoptotic activity. 
Similar findings of tumor growth inhibition in culture and in a xenograft model using by 
regorafenib, sorafenib, and imatinib have been observed in testing of materials derived from a 
patient with mesenchymal chondrosarcoma (R. Sordella, Cold Spring Harbor Laboratory, 
unpublished observations).  
 
     2.4 Clinical experience with regorafenib 
 
2.4.1 Colorectal cancer 
 
Two phase III global randomized studies have evaluated the efficacy of regorafenib. The 
CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo 
after failure of standard therapy) trial is an international, multicenter, randomized, double-
blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has 
progressed after approved standard therapies23. Metastatic colorectal cancer patients were 
randomized to regorafenib plus best supportive care (BSC) or placebo plus BSC. Treatment 
cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for 3 weeks on, 1 
week off plus BSC. The primary endpoint of this trial was overall survival. Secondary 
endpoints included progression-free survival, objective tumor response rate and disease 
control rate. The safety and tolerability of the 2 treatment groups were also compared. 
 
At a preplanned second interim analysis, there was a statistically significant survival benefit 
for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% confidence 
interval [CI], 0.635 to 0.941; 1-sided p = .0051). Patients treated with regorafenib had a 
median overall survival of 6.4 months, compared with 5.0 months for placebo — a 29% 
increase in survival. In addition to improved overall survival, progression-free survival was 
superior; median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for 
regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated hazard ratio for 
progression-free survival was 0.493 (95% CI, 0.42 to 0.58; 1-sided p<0.0001). There was a 
substantial difference in disease control rate in the regorafenib and placebo groups (44% vs. 
15%; p<0.0001).  Regorafenib demonstrated comparable efficacy benefits across patient 
subgroups analyzed including age, number of metastases, number of lines of prior therapy, 
and KRAS status. 
 
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin 
reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension 
(7%).  The efficacy and safety from the CORRECT study supported FDA approval in 
September 2012. 
 
2.4.2 GIST (gastrointestinal stromal tumor) 
 


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The efficacy and safety of regorafenib were examined in the Phase III GRID trial in patients 
with gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment options. 
The study involved 199 patients with metastatic and/or unresectable GIST that had become 
resistant to imatinib and sunitinib9. Patients were randomized 2:1 to regorafenib (160 mg 
orally once daily on a 3 weeks on, 1 week off cycle) or placebo, plus best supportive care. 
 
The results showed that treatment with regorafenib led to a statistically significant 3.9 month 
improvement in progression-free survival (PFS), compared with placebo (4.8 months vs. 0.9 
months; hazard ratio [HR] = 0.27; p <0.0001). Overall survival was statistically similar 
between groups as expected due to a trial design that allowed crossover to regorafenib for 
disease progression (85% for placebo and 31% for regorafenib randomized patients).  The 
median survival period without tumor growth among patients on regorafenib was 4.8 months 
while for the control group on placebo it was less than a month. The overall disease control 
rate combining partial responses with durable stable disease for at least 12 weeks was 53% 
with regorafenib compared with 9% in the control group. The most common grade ≥ 3 
adverse events associated with regorafenib were hand-foot skin reaction (56.1%), 
hypertension (48.5%), and diarrhea (40.9%).   The efficacy and safety of the GRID study data 
supported FDA approval February 2013. 
  
2.4.3 Pediatric tumors: phase I clinical trial and RP2D determination 
 
Regorafenib was evaluated as a single agent in a multicenter, open-label, non-randomized, 
phase I dose-escalating study designed to define the safety profile, MTD, RP2D, PK, 
pharmacodynamics, preliminary tumor response, and acceptability/palatability of the 
formulations (tablets and granulates) in pediatric subjects with solid malignant tumors which 
are recurrent or refractory to standard therapy. Data from this trial is described below (all 
information were taken from the study interim report, dated 19 August 2016). 
 
A total of 55 pediatric subjects with advanced, histologically or cytological confirmed solid 
malignant tumors were enrolled at 4 different regorafenib dose levels. Forty-one subjects who 
received at least 1 dose of regorafenib were valid for the safety and PK analyses, 23 subjects 
were valid and included in the analysis of MTD, and 39 subjects were valid for the efficacy 
analysis. The median age of subjects was 13.0 years (range: 3 to 17 years of age).  
 
Safety: Regorafenib was tolerable at doses up to 82 mg/m2 in pediatric patients, and safety 
was consistent with the known safety profile of regorafenib in the adult population. All 41 
treated subjects had at least 1 TEAE.   
 
The most frequent TEAEs (≥ 10% of 41 treated subjects) were: vomiting (51.2%), pyrexia 
(48.8%), headache (43.9%), AST increased, fatigue and nausea (41.5% each), ALT increased 
(39.0%), palmar-plantar erythrodysaesthesia syndrome (HFSR) and blood bilirubin increased 
(31.7% each). (MedDRA preferred terms). The most common TEAEs of Grade 3 or above 
(Grades 3/4/5), irrespective of relationship to study drug, occurring in more than 5% of all 41 
treated subjects were death (12.2%), headache (9.8%), lymphopenia, neutropenia, 
thrombocytopenia, vomiting, ALT increased, hydrocephalus, dyspnoea, and rash maculo-
papular (7.3% each). 


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In total, 40 of all 41 treated subjects (97.6%) reported at least 1 regorafenib related TEAE and 
the majority were Grade 2 (22 subjects, 53.7%). Drug-related TEAEs occurring in ≥ 20% 
subjects in the safety analysis set were AST increased (34.1%), nausea, fatigue, ALT 
increased, blood bilirubin increased, and palmar-plantar erythrodysaesthesia syndrome 
(HFSR) (31.7% each), pyrexia (29.3%), decreased appetite (26.8%), neutropenia, and 
thrombocytopenia (24.4% each).  
 
Fifteen subjects (36.6%) experienced drug-related TEAEs of worst CTCAE severity Grade ≥ 
3, with 11 subjects (26.8% of 41) and 4 subjects (9.8%) having drug-related TEAEs of worst 
Grades 3 and 4, respectively. Drug-related TEAEs of CTCAE Grade 5 did not occur.  
Common drug-related TEAEs of CTCAE Grade 3 or above (Grades 3/4), occurring in ≥ 5% 
of all 41 treated subjects (by MedDRA preferred term) were thrombocytopenia and rash 
maculo-papular (7.3% each). 
 
Dose-limiting toxicities were thrombocytopenia at 60 mg/m2, rash maculopapular at 72 
mg/m2, fever at 82 mg/m2, and hypertension and erythroderma at 93 mg/m2. An increased 
incidence of Grades 3/4 hematological events was observed across dose levels; it appeared 
that subjects with a history of myelosuppressive therapies such as high dose chemotherapy 
with stem cell rescue or craniospinal irradiation were at a higher risk for such events. 
 
Overall, 27 out of 41 subjects (65.9%) had at least one dose modification, and the majority of 
dose modifications were due to AEs; 14 dose reductions (34.1%) were reported for the 41 
subjects treated. No subject had more than one dose reduction.  Three out of 6 subjects 
(50.0%), 10 out of 14 subjects (71.4%), 7 out of 14 subjects (50.0%), and 6 out of 7 subjects 
(85.7%) had AEs leading to dose interruptions in Dose Levels 1, 2, 3 and 4, respectively. The 
most commonly reported TEAEs (any grade) leading to interruption of study drug in at least 
5% subjects of any dose level were pyrexia, platelet count decreased, and rash maculo-papular 
(7.3% of each). The median duration of regorafenib treatment interruptions or delays 
(excluding the protocol defined 7 days rest period) was 4 days (range: 1-17 days). 
 
Pharmacokinetics: Regorafenib exposure at all dose levels (60, 72, 82 and 93 mg/m2) was 
comparable to that observed in adults; including high inter-subject variability. The observed 
geometric mean exposure for the 82 mg/m2 dose group of 50.1 and 47.8 (mg*h/L), based on 
nominal and actual dosing, is in the same range as that observed (48.4 mg*h/L) in adults at the 
dose level of 160 mg q.d. 
 
Tumor response: No clear relationship between dose level and best tumor response could be 
observed. None of the treated subjects achieved a CR and only 1 subject (alveolar 
rhabdomyosarcoma) had a transient PR. Fifteen subjects had stable disease and 1 subject with 
“CNS anaplastic ependymoma” completed 30 cycles of regorafenib treatment. 
 
Based on the overall safety profile and drug exposure across dose levels observed in this 
phase 1 study, 82 mg/m2 q.d. in a 3-weeks-on/1-week-off schedule is the selected RP2D to be 
studied in subsequent clinical trials of regorafenib when used as monotherapy in children and 
adolescents with solid tumors. The hematologic toxicity will continue to be followed closely 


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in the proposed expansion cohort phase of this study. For subsequent studies in combination 
with other anticancer agents, a dose finding and/or dose confirmation phase 1b study to 
determine the optimal dose of regorafenib when combined with chemotherapy is warranted. 
 
2.5 Rationale 
 
Inhibition of angiogenesis to slow or stop cancer growth is one mechanism under scrutiny as a 
therapeutic option for patients with metastatic cancers of all types. Some of the agents used to 
examine this issue in STBS are multitargeted Small Molecule Oral Kinase Inhibitors 
(SMOKIs). Imatinib, sunitinib, and regorafenib have all been approved for use in 
gastrointestinal stromal tumors (GISTs), which is perhaps the most common form of sarcoma.  
 
After failure of standard cytotoxic chemotherapy, pazopanib was approved for use in patients 
with metastatic soft tissue sarcomas other than liposarcoma by virtue of a phase III clinical 
trial in patients with metastatic soft tissue sarcoma1. Conversely, there are no randomized data 
to date regarding the activity of SMOKIs in bone sarcomas specifically, and although there 
are no randomized data regarding the activity of pazopanib in liposarcomas, there appears to 
be activity of SMOKIs based on the phase II study of pazopanib in soft tissue sarcomas2. 
 
Sorafenib, another multitargeted small molecule oral kinase inhibitor (SMOKI), demonstrated 
activity in a multi-arm phase II study, in which liposarcoma was also excluded. In a phase II 
clinical trial of sorafenib in 35 patients with chemotherapy refractory osteogenic sarcoma, 3 
patients had a partial response and 2 had a minor response, with 6 patients on treatment for 
more than 6 months without worsening7. Sunitinib shows minor activity in at least a subset of 
sarcomas in small phase II studies or as anecdotes3,4. We also note evidence of an anecdote of 
a patient with a Ewing sarcoma with a sustained RECIST partial response (S. Attia, MD, 
personal communication).  
 
Although regorafenib was approved for use in patients who had progressive GIST despite 
imatinib and/or sunitinib, it has not been examined in a systematic fashion in patients with 
other forms of sarcoma. 
 
Given the activity of sorafenib and pazopanib in soft tissue sarcomas, and evidence of activity 
of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is 
precedent to examine SMOKIs such as regorafenib in sarcomas other than GIST. It is also 
recognized that SMOKIs such as regorafenib, sorafenib, pazopanib, and sunitinib have 
overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of 
these SMOKIs block vascular endothelial growth factor and platelet derived growth factors 
receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of 
these agents10. 
 
We propose parallel randomized phase II studies of regorafenib in patients with liposarcoma 
(excluding purely well differentiated liposarcoma) and osteogenic sarcoma to determine if 
there is significant activity of these agents, as has been observed with pazopanib in soft tissue 
sarcomas. In addition, we seek to determine the activity of regorafenib in Ewing/Ewing-like 


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sarcoma, given anecdotal data of activity, planning to examine a single cohort of patients in a 
prospective phase II fashion.   
 
As of amendment 5, the Ewing sarcoma cohort (C) completed accrual. As of amendment 6, 
only the rhabdomyosarcoma cohort is open to accrual; the slow accrual to this arm of the 
study has led to opening another arm of the trial to obtain initial data with regorafenib in 
mesenchymal chondrosarcoma as a new cohort (E).  
 
In addition, given the completion of a pediatric phase I study of regorafenib, it is now possible 
to safely dose patients under age 18 with regorafenib. This allows both for including younger 
patients on study and investigating diagnoses that are far more common in children than 
adults. Osteogenic sarcoma, rhabdomyosarcoma, and Ewing sarcoma and its relatives all 
occur in the pediatric population, and a substantial majority of embryonal and alveolar 
rhabdomyosarcoma patients fall into the pediatric age group. The limiting factor for treatment 
with regorafenib is weight, given available tablet sizes. A minimum weight and body surface 
area is specified in the entry criteria to help ensure patient safety.  
 
Rhabdomyosarcoma has an incidence much greater in younger children, below the age of 10, 
compared to older children or adults. Patients with recurrence/metastatic rhabdomyosarcoma 
have a dismal prognosis and will die of disease, nearly universally within 24 months of 
diagnosis. Accordingly, one goal of this study is to ensure that the appropriate populations of 
patients can be treated with a novel therapeutic that may extend their survival. Since 
rhabdomyosarcoma is more common between the ages of 0-10 than in older children, it is 
reasonable to treat patients who can tolerate the therapy proposed in the protocol amendment, 
namely children ages 5 and older (as well as adults), to ensure that an appropriate population 
of patients with metastatic rhabdomyosarcoma are being treated. lastly, given the pediatric 
phase I data noted in the protocol, a dose and schedule of regorafenib have already been 
determined in pediatric patients, making the use of regorafenib more tenable for patients and 
families with this nearly uniformly fatal diagnosis. 
 
     2.6 Study Design 
 
We seek to conduct parallel clinical trials of regorafenib in five different metastatic/local-
regionally recurrent STBS populations: (A) liposarcoma (excluding purely well-differentiated 
liposarcoma); (B) osteogenic sarcoma; (C) Ewing/Ewing-like sarcoma; (D) 
rhabdomyosarcoma (only embryonal or alveolar subtypes); (E) mesenchymal 
chondrosarcoma.  
 
For cohorts A and B, we will conduct parallel randomized phase II studies. Patients will be 
randomized 1:1 between regorafenib and placebo, and follow for disease progression. For 
those patients with progression of disease on placebo, crossover to active drug will be offered 
to patients if they remain eligible for the clinical trial in all other respects. If patients are 
deemed to have disease that is too rapidly progressive to be considered for a randomized 
clinical trial, they should be excluded from consideration.  
 


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Since there are even fewer data regarding the small round blue cell tumor family characterized 
rhabdomyosarcoma, the Ewing sarcoma family of tumors, and mesenchymal chondrosarcoma, 
which are often more aggressive than either liposarcoma subtypes or osteogenic sarcoma, 
single stage phase II clinical designs will be used to obtain initial clinical experience with 
these very aggressive sarcoma subtypes. Patients will be further stratified by number of prior 
lines of therapy (1 vs 2 or more), as well as WHO performance status (0-1 vs 2).  
 
3. PATIENT SELECTION 
 
3.1 Inclusion Criteria 
 
3.1.1 Age ≥  10 year for Liposarcoma, Osteosarcoma, Ewing sarcoma, and 
Mesenchymal chondrosarcoma 
 
Age ≥ 5 years for Rhabdomyosarcoma cohorts 
 
 
3.1.2 Weight ≥ 15 kg (33 lb) 
 
3.1.3 Minimum BSA 0.65 m2 
 
3.1.4 Patients must have histologically or cytologically confirmed advanced/metastatic 
liposarcoma, osteogenic sarcoma, Ewing/Ewing-like sarcoma of soft tissue or 
bone, fusion-positive alveolar rhabdomyosarcoma, embryonal 
rhabdomyosarcoma/fusion-negative alveolar rhabdomyosarcoma, or mesenchymal 
chondrosarcoma. This study will accept the diagnosis made at the investigator’s 
center. 
 
 
Patients will be categorized into the following groups as follows:  
 
Cohort A: Liposarcoma (enrollment complete as of amendment 5) 
 
 
 
Specify one of the mutually exclusive categories: 
 
(1) Dedifferentiated liposarcoma. Patients with solely well-
differentiated liposarcoma (including atypical lipoma) are 
specifically excluded (see below) 
(2) Myxoid and/or round cell 
(3) Pleomorphic 
(4) Liposarcoma of unknown subtype/cannot determine. 
 
Cohort B: Osteogenic sarcoma (enrollment complete as of amendment 5) 
 
 
 
 
 
 
Specify tissue of origin & subtype: 
 
1. Bone 
a. Specify bone and laterality 
b. Specify location of primary sarcoma within bone 


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i. Central  
ii. Surface 
iii. Gnathic (maxilla, mandible) 
iv. Multifocal 
v. Unable to determine 
c. Specify predominant histology of primary 
 
i. Osteoblastic 
ii. Chondroblastic 
iii. Fibroblastic 
iv. Telangiectatic 
v. Small cell 
vi. Other histology or not indicated 
d. Specify other defining characteristics 
i. e.g. giant cell rich, surface dedifferentiated, change 
in histology over time, etc. 
2. Soft tissue (extraosseous osteosarcoma) 
a. Specify defining characteristics per AJCC staging criteria– 
primary site, primary size, superficial or deep location, 
metastatic sites. 
 
 
Cohort C. Ewing/Ewing-like sarcoma (enrollment complete as of 
Amendment 5) 
 
1. Specify soft tissue or bone primary site 
 2. Specify type:  
 
 
 
 
 
 
 
 
a.  Ewing/Ewing-like sarcoma family of tumors (includes 
Ewing sarcoma, Primitive neuroectodermal tumor (PNET), 
Askin tumor of chest wall) with evidence of translocation 
(e.g. by FISH, PCR) 
b. Ewing-like sarcoma with proof of novel translocation 
involving CIC-DUX4 or BCOR-CCNB3 or related genes 
c. Histological diagnosis of Ewing sarcoma family of tumors, 
but no proof of translocation. 
  
   
 
Cohort D.  Rhabdomyosarcoma 
1. Specify one of the mutually exclusive categories: 
• Fusion-positive alveolar rhabdomyosarcoma 
a. Indicate translocation, (e.g. PAX3-FOXO1, PAX7-
FOXO1) 
• Embryonal rhabdomyosarcoma 
• Fusion-negative alveolar rhabdomyosarcoma 
 
 
 
 
 
(Note: pleomorphic rhabdomyosarcoma and rhabdomyosarcoma,  
 
 
 
 
not otherwise specified (NOS) do not fall into these categories and are  
  
 
 
 
excluded) 
 


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2. Specify anatomic primary site 
 
 
 
 
 
Cohort E.  Mesenchymal chondrosarcoma 
 
 
 
 
 
 
1. Specify anatomic primary site  
 
3.1.5 WHO Performance Status 0, 1 or 2. To assess performance status for pediatric 
patients, Lansky (> 16 years) and Karnofsky (≥ 16 years)should be converted to 
WHO_ECOG in order to determine eligibility for patients under 18 years of age. 
 
3.1.6 At least one prior line of systemic therapy for the sarcoma diagnosis (neoadjuvant, 
adjuvant or metastatic disease).  
 
3.1.7 All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 4.03 
Grade 1 or less (except alopecia, grade 0-2 permitted, and anemia, grade 0-2 
permitted) at the time of signing the Informed Consent Form (ICF). 
 
3.1.8 Subject must be able to swallow and retain oral medication. 
 
3.1.9 At least one site of measurable disease on x-ray/CT/MRI scan as defined by 
RECIST 1.1.  Baseline imaging must be performed within 28 days of first study 
drug administration. 
 
3.1.10 Adequate organ function within 14 days of registration, defined as:  
 
Absolute neutrophil count (ANC) 
≥ 1,500/μL (microliter) 
 
 
 
 
 
≥1,000/μL (for patients < 18 yrs. old) 
Platelets 
 
 
≥ 100,000/μL  
 
 
 
 
 
≥75,000/μL (for patients < 18 yrs. old) 
Total bilirubin  
≤ 1.5 mg/dL 
INR*  
 
 
≤ 1.5 
AST(SGOT)/ALT(SGPT) 
all ≤ 2.5 × ULN (up to 5 × ULN 
 
 
 
 
for patients with liver involvement 
 
 
 
 
by tumor)  
Creatinine 
 
 
 
     ≤ 1.5 × ULN or GFR† > 30 ml/min 
 
 
 
 
Serum albumin 
≥ 3 g/dL 
 
 
 
 
Amylase  
 
<1.5 x the ULN 
 
 
 
 
Serum lipase  
≤ 1.5 × ULN 
 
*International normalized ratio (INR): Subjects who are prophylactically treated 
with an agent such as warfarin or heparin will be allowed to participate provided 
that no prior evidence of underlying abnormality in coagulation parameters exists, 
according to the written documentation of the treating physician. Close monitoring 
of at least weekly evaluations will be performed until INR/PTT is stable based on a 
measurement that is pre-dose as defined by the local standard of care. 
 
†Glomerular filtration rate (GFR): according to the Modified Diet in Renal 


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Disease (MDRD) abbreviated formula23, GFR (mL/min/1.73 m2) = 175 × (SCr)-
1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American). 
 
Adequate hematological function assessed by the following laboratory 
requirements conducted within 7 days before starting study treatment: 
 
Peripheral ANC 
 
 
 
≥ 1.0 x 109/L 
Platelet count 
≥ 100 x 109/L (>75 x 109/L for 
patients < 18 years of age at 
enrollment (transfusion independent) 
Hemoglobin  
 
 
 
≥ 8.0 g/ dL 
 
Lipase  
 
 
 
 
≤ 1.5 x ULN 
AST/ALT  
 
 
 
 
≤ 3.0 x ULN 
Bilirubin (sum of conjugated + unconjugated)  ≤ 1.5 ULN 
 
Adequate renal function defined as creatinine clearance based on Schwartz 
Estimate ≥ 70 ml/min/1.73 m2  
 
International normalized ratio (INR) ≤ 1.5 x upper limit of normal (ULN) and 
partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) 
≤ 1.5 x ULN 
 
Alkaline phosphatase limit ≤ 2.5 x ULN for age (≤ 5 x ULN for subjects with bone 
tumors or metastases to bone) 
 
3.1.11 Written, voluntary informed consent. 
 
3.1.12 Fertile men and women of childbearing potential must agree to use an effective 
method of birth control from Day 1 of study and for 3 months after last study drug 
administration in both sexes, as assessed by the investigator. Women of 
childbearing potential include pre-menopausal women and women within the first 
2 years of the onset of menopause. Women of childbearing potential must have a 
negative pregnancy test ≤ seven days prior to Day 1 of study. The definition of 
adequate contraception will be based on the judgment of the investigator. 
 
3.1.13 Evidence of progression of disease as defined by RECIST 1.1 (i.e. new disease 
sites or 20% growth of target lesions) within 6 months of registration.  
 
3.1.14 Patients with central nervous system disease are eligible for enrollment if they 
have received prior radiotherapy or surgery to sites of CNS metastatic disease and 
are without evidence of clinical progression for at least 12 weeks after therapy. 
 
     3.2 Exclusion Criteria 
 
3.2.1 Patients with documentation of well differentiated liposarcoma only (of the well 


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differentiated/dedifferentiated liposarcoma family) are specifically excluded, 
owing to its characteristically slow growth. If high grade areas are suspected 
(dedifferentiation), but not proved by pathology analysis (e.g. after primary 
resection of a well-differentiated liposarcoma), a biopsy must be performed to 
demonstrate the high-grade dedifferentiated disease. If there is a question 
regarding the diagnosis, the Cohort PI should be consulted. 
 
3.2.2 Prior systemic therapy with a small molecule oral kinase inhibitor, including but 
not limited to: pazopanib, sunitinib, sorafenib, everolimus, sirolimus, vemurafenib, 
dasatinib and trametinib. 
 
3.2.3 Previous assignment to treatment during this study.  Subjects permanently 
withdrawn from study participation will not be allowed to re-enter study. Patients 
who progress on placebo are specifically allowed to enroll on the treatment arm of 
the study if they meet all other entry criteria. 
 
3.2.4 Concurrent, clinically significant, active malignancies within 12 months of study 
enrollment. 
 
3.2.5 Patients with severe and/or uncontrolled concurrent medical disease that in the 
opinion of the investigator could cause unacceptable safety risks or compromise 
compliance with the protocol. 
 
3.2.6 Major surgery within 28 days prior to study registration or those patients who have 
not recovered adequately from prior surgery. 
 
3.2.7 Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of 
volume of pelvis bones or equivalent) or limited field radiation for palliation < 14 
days prior to study registration or those patients who have not recovered 
adequately from side effects of such therapy. 
 
3.2.8 Patients who have received prior systemic therapy < 14 days prior to study 
registration or have not recovered adequately from toxicities to CTCAE v. 4.03 
grade 1 or less (except alopecia); prior investigational therapy may not have been 
given < 5 half-lives of last dose of treatment, or < 14 days, whichever is greater. 
 
3.2.9 Patients who have had prior autologous, or allogeneic bone marrow transplant. 
 
3.2.10 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v 4.03] on repeated measurement) despite optimal 
medical management. Uncontrolled hypertension for this study will be defined as 
greater than 95th percentile for age on two anti-hypertensives. 
 
3.2.11 Active or clinically significant cardiac disease including: 
 


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1) Congestive heart failure–New York Heart Association (NYHA) > 
class II. 
2) Active coronary artery disease. 
3) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
4) Unstable angina (anginal symptoms at rest), new onset angina within 3 
months before randomization, or myocardial infarction within 6 
months before randomization. 
 
3.2.12 Evidence or history of bleeding diathesis. Patients on warfarin, heparinoids, or 
factor X inhibitors are permitted on study.  
 
3.2.13 Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to 
study registration.  
 
3.2.14 Subjects with thrombotic, embolic, venous, or arterial events, such as 
cerebrovascular accident (including transient ischemic attacks) deep vein 
thrombosis or pulmonary embolism within 6 months of start of study treatment. 
 
3.2.15 Known history of human immunodeficiency virus (HIV) infection or current 
chronic or active hepatitis B or C infection requiring treatment with antiviral 
therapy. 
 
3.2.16 Ongoing infection > Grade 2 NCI-CTCAE v 4.03. 
 
3.2.17 Presence of a non-healing wound, non-healing ulcer, or benign bone fracture 
(patients with stress insufficiency fractures e.g. from osteoporosis or pathological 
fracture from tumor are eligible for study). 
 
3.2.18 Patients with seizure disorder requiring medication. 
 
3.2.19 Proteinuria > 100 mg/dl on urine analysis.  
 
3.2.20 Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent.  
 
3.2.21 Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE 
version 4.03 Grade 2 dyspnea). 
 
3.2.22 History of organ allograft (including corneal transplant). 
 
3.2.23 Known or suspected allergy or hypersensitivity to regorafenib, or excipients of the 
formulations given during the course of this trial. 
 
3.2.24 Any malabsorption condition. 
 


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3.2.25 Women who are pregnant or breast-feeding. 
 
3.2.26 Any condition which, in the investigator’s opinion, makes the subject unsuitable 
for trial participation. 
 
3.2.27 Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
 
3.2.28 Inability to comply with protocol required procedures, including swallowing 
tablets. 
 
3.2.29 Use of any herbal remedy (e.g. St. John's wort [Hypericum perforatum]). 
 
3.3 Inclusion of Women and Minorities 
 
Men, women, children (at least age 5 years) and members of all ethnic and racial groups may 
be eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
     4.1 General Guidelines 
 
Subjects enrolling on this clinical trial must meet all inclusion and exclusion criteria. 
Exceptions will not be granted.  
 
Data will be entered via a web portal into a SARC study specific database.  While all study 
evaluations must be performed by the Investigator as described in Section 9, Study 
Evaluations and Study Calendar, only data related to the primary and secondary endpoints, as 
well as safety data, will be captured in the eCRFs. 
 
     4.2 Registration Process 
 
Prior to beginning patient registration, the site clinical research associate should review all the 
eligibility criteria with the site Principal Investigator as well as the follow-up requirements for 
the study to ensure that the patient to be enrolled meets all the eligibility requirements.  A 
patient failing to meet all the eligibility requirements should not be registered for the study 
and should not be enrolled in the study database.  Once the data has been entered into the 
study database for enrollment of the patient, a unique patient identification number will be 
assigned by the computer and will be used for the patient throughout trial participation.  
 
SARC024 uses a web based electronic data capture system (EDC) for data submission.  All 
sites must complete training prior to using the web based EDC system.  Data managers and 
other authorized users will be provided with a unique user identification number and password 
to access the EDC system.   
 


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All eligible subjects must be registered prior to the start of treatment.  All subject registrations 
and case report forms will be submitted electronically via the EDC system. 
 
Any problems accessing the EDC system or questions regarding the registration process 
should be directed to the SARC Operations Office via phone (734-930-7600) or via email, at 
sarc024@sarctrials.org. 
 
 
 
4.3 Treatment assignment 
 
Eligible patients will be registered by the site personnel and randomized at time of registration 
by the SARC operations office. For patients on substudies requiring randomization, subjects 
will be randomly assigned to receive either regorafenib 160 mg once daily or placebo (1:1), 3 
weeks on, 1 week off.     
 
Patients, investigators who give the treatment, those assessing outcomes, and those who will 
perform outcome analyses are blinded as to the allocation. Treatment allocation will remain 
masked until the time of disease progression, at which time assignment will be unblinded, so 
that patients on placebo may be crossed over to active treatment.  
 
     4.4 Screen Failures and Dropouts 
 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” and withdrawn from study participation.  Situations in which a subject is defined as 
a “dropout” include: if the subject has already been registered, randomized, assigned to 
treatment/run-in/wash-out or administered at least one dose of study drug.  
 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see above) is regarded a 
“screening failure”. 
 
     4.5 Replacement 
 
No withdrawn subjects (i.e. dropouts) will be replaced.  
 
5. TREATMENT PLAN 
 
5.1 Agent Administration 
 
Cohorts A and B: patients with liposarcoma or osteosarcoma will be randomized 1:1 to 
receive regorafenib or placebo. Crossover of the placebo group is permitted if patients still 
meet all entry criteria to continue on treatment. (Accrual completed as of amendment 5)  
 
Cohort C: patients with Ewing sarcomas will all receive regorafenib from the start of the 
study. (Accrual completed as of amendment 5) 
 


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Cohort D: patients with rhabdomyosarcoma (fusion-positive alveolar, embryonal, and fusion-
negative alveolar) will all receive regorafenib from the start of the study 
 
Cohort E: patients with mesenchymal chondrosarcoma will all receive regorafenib from the 
start of the study 
 
In all cases the length of one cycle of therapy is 28 days (3 weeks on, 1 week off). If a patient 
experiences toxicity and is not due to resume therapy until the 1 week of the cycle off 
treatment, the subsequent cycle of therapy may start after a minimum of 1 week off 
regorafenib.  
 
Example 1:  A patient experiences toxicity at the day 8 visit of a cycle and treatment is held 
until day 15. After resuming treatment from day 15 until day 22, the patient is off treatment 
from days 22-28, and starts again on day 29, which is day 1 of the new cycle of therapy. 
 
Example 2:  A patient experiences toxicity at day 17 and treatment is held through day 24, 
which is after the expected end of treatment that cycle on day 22. The patient may resume 
therapy with a new cycle of therapy as early as day 25, or may stay off therapy through day 
28, resuming treatment cycle day 29/day 1 of the new cycle.  
 
Conversely, imaging studies will be performed as outlined in the protocol and no changes in 
the scheduled scans are permitted. However, patients with clinical deterioration may have 
imaging studies earlier than scheduled, which may take the patient off study earlier than 
expected. 
 
     5.2 Regorafenib and placebo 
 
For the randomized cohorts of the study, regorafenib and placebo tablets will be packaged in 
high density polyethylene bottles with a white child resistant closure and induction seal. Each 
bottle includes 30 tablets and a 3 gram desiccant. The bottles will have a label affixed 
containing study identification, product identification, and quantity of tablets.  Once the drug 
has been received it must be kept in a secure, dry location. Study drugs must be stored in their 
original bottles at a temperature of 20-25 °C (68-77 °F); provisional temperature limits 
permitted to 15-30 °C (59-86 °F). 
 
The study drugs must be exclusively used for the investigation specified in this protocol and 
they will only be accessible to authorized staff. 
 
     5.3 Blinding and unblinding 
 
 
5.3.1 Blinding 
 
In compliance with applicable regulations, in the event of a SUSAR, the patient’s treatment 
code will usually be unblinded before reporting to the health authorities, ethic committees and 
investigators if the SUSAR was related to the blinded treatment. 


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5.3.2 Emergency unblinding by the investigator, and unblinding at progression 
 
Unblinding may occur in the randomized portion of the study for emergency purposes only.  
Patients who have disease worsening on study who were on placebo will be offered crossover 
to active treatment if they otherwise meet all entry criteria for the study.  
 
The local pharmacist will be the data source regarding blinding of a specific patient. If 
unblinding is necessary for the treatment of a subject for a serious adverse event, every 
attempt should be made to contact the Cohort PI prior to unblinding. If this is not feasible, 
then the overall Principal Investigator must be contacted within 24 hours of unblinding.  
 
If SARC does not receive a response from the Cohort PI or designee within 3 hours, SARC 
will notify the person that initiated the unblinding request and state that the treatment 
assignment will not be unblinded at that time and treatment of the patient should proceed as if 
the blinded drug is regorafenib. 
 
     5.4 Study drug administration 
 
Regorafenib (or placebo) is administered as monotherapy during the study. For adults on the 
study, the starting dose is 160 mg daily for 3 weeks on, 1 week off, taken in the morning with 
a low-fat meal each day.  
 
The medication should be taken within 8 hours of the same time each day, otherwise should 
be marked as a missed dose. One cycle is 28 days.  
 
For adults, four 40 mg regorafenib or placebo tablets should be taken in the morning with 
approximately 8 fluid ounces (240 mL) of water after a low-fat (< 30% fat) breakfast. Some 
examples of low-fat breakfasts are: 
 
• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of 
fat). 
 
• One cup of cereal, 8 ounces (240 mL) of skim milk, one piece of toast with jam (no 
butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 
93 g of carbohydrate, 520 calories). 
 
The medication will be taken in a similar fashion in pediatric patients (< 18 years). … 
Pediatric patients on trial will receive tablets according to the dosing table below (Table 5.4). 
The starting dose is 82 mg/m2 daily with the same 3 week on, 1week off schedule as for adult 
patients. The regorafenib dose will be rounded to the nearest 20 mg and capped at 160 mg as 
with adult patients.  The lowest permissible dose is 20 mg.  The  minimum body surface area 
to participate is 0.65m2 and minimum weight is 15 Kg. (33 lbs.) 
 
Table 5.4 – Pediatric Doses 


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BSA > 0.65m2 
Dose level 0 (standard starting dose) 
82 mg/m2 oral daily 
 
For dose modifications, for adult and pediatric patients, refer to tables in Section 6 of the 
protocol. 
 
Patients, or their guardians, should be instructed to record daily regorafenib or placebo dose 
on the Study Drug diary which will be provided to them (Appendix C). 
 
     5.5 General Concomitant Medication and Supportive Care Guidelines 
 
All medication that is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the discretion 
of the investigator.  All medications taken within 2 weeks prior to the start of the study and 
during the study must be recorded in the subject’s source documentation, including start/stop 
dates, dose frequency, route of administration, and indication.  Specific caution should be 
taken when considering or administering a concomitant medication that is metabolized by the 
cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9.  Such concomitant medications 
should be avoided, if possible. 
 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the 
active metabolite M-5, and resulted in no change in the mean exposure of the active 
metabolite M-2.  Avoid concomitant use of regorafenib with strong CYP3A4. A listing of 
strong CYP3A4 inducers is provided in Appendix D. 
 
Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of 
regorafenib increased the mean exposure of regorafenib and decreased the mean exposure of 
the active metabolites M-2 and M-5.  Avoid concomitant use of regorafenib with strong 
inhibitors of CYP3A4 activity. A listing of strong CYP3A4 inhibitors is provided in 
Appendix D. 
 
Permitted concomitant therapy includes: 
 
• Standard therapies for concurrent medical conditions 
• Supportive care for any underlying illness 
• Hematopoietic growth factors: subjects are permitted to take chronic erythropoietin. If 
a patient develops neutropenia, patients should have doses reduced, and not use 
growth factors such as filgrastim to artificially elevate the neutrophil count. Use of 
pegfilgrastim or related growth factors for an episode of febrile neutropenia is 
permitted 
• Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided that they do not interfere with the study endpoints, 
in the opinion of the investigator 
• Bisphosphonates 


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• Subjects who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT are stable, 
as determined by the investigator.   
 
 
 
 
The following are not permitted while the patient is on study: 
 
• Other investigational treatment during or within 14 days (or 5 half-lives, whichever is 
longer) before starting study treatment 
• Radiation therapy: any need for radiation therapy will be defined as clinical (if not 
radiographic) worsening of disease, and represent a progression event 
• Systemic antitumor therapy, including cytotoxic therapy, signal transduction 
inhibitors, immunotherapy, and hormonal therapy 
• Bone marrow transplant or stem cell rescue 
• Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine, and digoxin).  Warfarin is metabolized by the cytochrome enzyme 
CYP2C9 and warfarin levels may be especially affected by regorafenib 
• Use of any herbal remedy (e.g. St. John's Wort [Hypericum perforatum]). 
 
     5.6 Duration of Therapy 
 
Treatment may continue until one of the following criteria applies: 
 
• Disease progression as defined by RECIST 1.1 
• Greater than 28 days have elapsed since the last dose of study drug 
• Patient decides to withdraw from the study during the treatment phase of the study 
• Patient decides to withdraw from the study during the follow up phase after 
completion of treatment on the study 
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
     5.7 Duration of Follow Up 
 
Subjects will be contacted by phone once between 30 and 45 days after termination of study 
treatment or until death, whichever occurs first.  Patients removed from study for adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
     5.8 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.6 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
eCRF including death or lost to follow up. 


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Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
 
• Subject withdraws consent from study treatment and study procedures.  A subject must 
be removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative.  At any time during the trial and without giving reasons, a 
subject may decline to participate further.  The subject will not suffer any 
disadvantage as a result 
• Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not undergo 
CT scans [with contrast]/MRI or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being 
• Subject is lost to follow-up 
• Death. 
 
Subjects may be withdrawn from the study for the following reasons: 
 
• The subject is non-compliant with study drug (regorafenib or placebo), trial 
procedures, or both; including the use of anti-cancer therapy not prescribed by the 
study protocol 
• Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 
4 hypersensitivity reaction) 
• Development of a second cancer  
• Development of an intercurrent illness or situation which would, in the judgment of 
the investigator, significantly affect assessments of clinical status and trial endpoints 
• Deterioration of WHO performance status to 4 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. In all cases, the reason for withdrawal must be recorded in 
the eCRF and in the subject's medical records. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS  
 
6.1 Dose Reduction Levels 
 
In adults, the starting dose of regorafenib is 160 mg once daily for Cohorts C, D and E.  
The starting dose for Cohorts A and B is 4 tablets of regorafenib or placebo daily.  
 
For pediatric patients (< 18 years of age), the starting dose is 82 mg/m2 (rounding to 
nearest 20 mg), with a maximum daily dose capped at 160 mg. Please refer to dosing 
table in Section 5.2. 


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Study medication will be administered on a 3-weeks on, 1-week off schedule (3 weeks out of 
every 4). 
 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows.  In general, this will mean clinically 
meaningful G 3 or worse toxicity, although clinically significant G 2 toxicity may qualify, 
according to the treating physician. Dose modifications will follow predefined dose levels. 
Dose adjustments for hematologic toxicity are based on the blood counts obtained in 
preparation for the day of treatment. 
 
     Table 6.1.1 Dose reduction levels – adult patients 
The modifications of regorafenib or placebo dosing will follow the following 
predefined dose levels: 
Dose level 0 (standard 
starting dose) 
160 mg oral daily 
Four 40 mg tablets of regorafenib or 
placebo 
Dose level -1 
120 mg oral daily 
Three 40 mg tablets of regorafenib or 
placebo 
Dose level -2 
80 mg oral daily 
Two 40 mg tablets of regorafenib or 
placebo 
 
 
     Table 6.1.2 Dose reduction levels – pediatric patients 
The modifications of regorafenib or placebo dosing will follow the following 
predefined dose levels: 
Dose level 0 (standard 
starting dose) 
82 mg/m2 oral daily, rounding to nearest 20 mg 
Dose level -1 
72 mg/m2 oral daily, rounding to nearest 20 mg 
Dose level -2 
60 mg/m2 oral daily, rounding to nearest 20 mg 
 
If a subject experiences more than 1 toxicity, dose reduction should be according to the 
toxicity with the highest grade. 
 
In the case of 2 or more toxicities of the same grade, the investigator may dose reduce 
according to that deemed most causally related to study treatment. 
 
6.2 Management of toxicity (other than hand-foot skin reaction, hypertension and LFT 
abnormalities) 
 
The table below outlines dose adjustments for most hematologic and non-hematologic 
toxicities related to regorafenib except hand-foot skin reaction (HFSR) and hypertension 
and LFT abnormalities. 
 
In addition to these recommended dose modifications, subjects who develop diarrhea (see 


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Section 6.6), mucositis, anorexia or other events predisposing to fluid loss or inadequate fluid 
intake should be carefully monitored and rehydrated as clinically necessary.  This is in order 
to minimize the risk of postural hypotension and renal failure. 
 
Table 6.2 Recommended dose modification for most toxicities, except hand-foot  
 
skin reaction, hypertension and ALT/AST/bilirubin 
NCI-CTCAE v 
4.03a 
Dose Interruption 
Dose 
Modification b 
Dose for Subsequent 
Cycles 
Grade (G) 0-2 
Treat on time 
No change 
No change 
G 3 
Delay until ≤ G 2c 
Reduce by 1 dose 
level 
If toxicity remains < G2, 
dose re-escalation can be 
considered at the discretion 
of the treating investigator. 
If dose is re-escalated and 
toxicity (≥ G3) recurs, 
institute permanent dose 
reduction. 
G 4 
Delay until ≤ G 2c 
At a minimum, 
reduce by 1 dose 
level. 
 
Strongly consider 
permanent 
discontinuation for 
G4 events such as: 
gastrointestinal 
perforation/fistula, 
severe or life-
threatening 
hemorrhage, 
reversible posterior 
leukencephalopathy 
syndrome, or wound 
dehiscence. 
 
a. G: Grade; NCI-CTCAE = National Cancer Institute - Common Terminology   Criteria for Adverse 
Events, version 4.03 
b. Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity and nonclinical and 
asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay, treatment should be permanently discontinued unless subject is 
deriving clinical benefit and is discussed with the SARC Medical Officer. 
 
 
6.3 Management of hand-foot skin reaction  
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
 


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Grading and dose alterations are noted in Tables 6.3 and 6.4 below.  
 
Recommended prevention/management strategies for skin toxicities consistent with HFSR are 
summarized below: 
 
Control of calluses 
 
Before initiating treatment with regorafenib: 
• Check condition of hands and feet 
• Suggest a manicure/pedicure, when indicated 
• Recommend pumice stone use for callus or ‘rough spot’ removal. 
 
During regorafenib treatment: 
 
• Avoid pressure points 
• Avoid items that rub, pinch or create friction. 
 
Use of creams 
 
Non-urea based creams may be applied liberally 
 
• Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly 
and only to affected (hyperkeratotic) areas 
• Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day.  
Approximately 5% to 8% provides gentle chemical exfoliation 
• Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control 
• Topical corticosteroids like clobetasol 0.05% should be considered for subjects with G 
2 or 3 HFSR.  Avoid systemic steroids. 
 
Tender areas should be protected as follows: 
 
• Use socks/gloves to cover moisturizing creams 
• Wear well-padded footwear 
• Use insole cushions or inserts (e.g. silicon, gel) 
• Foot soaks with tepid water and Epson salts. 
 
Table 6.3.1 Grading for Hand-Foot Skin Reaction 
 
 
G 1 
G 2 
G 3 
NCI-CTCAE v 4.03  
Palmar-plantar 
erythrodysesthesia 
syndrome(a) 
Minimal skin changes or 
dermatitis 
(e.g., erythema, edema, 
or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters  
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
Numbness, dysesthesia / 
paresthesia tingling, 
Painful erythema and 
swelling of the hands 
Moist desquamation, 
ulceration, blistering, 


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Table 6.3.2 Recommended dose modification for hand-foot-skin reactiona 
 
changes 
painless swelling, or 
erythema of the hands 
and/or feet 
and/or feet 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting 
instrumental 
activities of daily life 
(e.g., preparing 
meals, shopping for 
groceries or clothes, 
using the telephone, 
managing money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, dressing 
and undressing, 
feeding self, using the 
toilet, taking 
medications) and not 
bedridden 
(a) Palmar-plantar erythrodysesthesia syndrome is a disorder characterized by redness, marked discomfort, 
swelling, and tingling in the palms of hands or the soles of the feet. 
G: grade 


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Grade of event 
(NCI-CTCAE v 
4.03) 
Occurrence 
Suggested Dose Modification 
Grade (G) 1 
Any 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief 
G 2 
 
1st occurrence 
Consider decreasing dose by one dose level and 
immediately institute supportive measures.  If no 
improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to G 0-1 b, c 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to G 0-1.c 
When resuming treatment, decrease dose by one dose 
level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to G 0-1. c 
When resuming treatment, decrease dose by one dose 
level. b, d 
4th occurrence 
Discontinue therapy 
G 3 
 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity 
resolves to G 0-1. c When resuming treatment, 
decrease dose by one dose level. b, d 
2nd occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity 
resolves to G 0-1. c When resuming treatment, 
decrease dose by one additional dose level b, d 
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to G 0-1 after dose reduction, dose re-escalation is permitted at the discretion of the 
investigator if subject has completed one cycle at reduced dose without recurrence of event. 
c. If there is no recovery after a 4 week delay, treatment with regorafenib or placebo will be discontinued 
permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg 
 
6.4 Hypertension 
 
Hypertension is a recognized AE associated with regorafenib treatment.  Subject will have 
their blood pressure measured at least weekly at the study site on weeks 1, 2, 3, 5, and 7.  If 
additional blood pressure measurements are done outside the study site, and the blood 
pressure is > 140 mm Hg systolic or > 90 mm Hg diastolic (NCI CTCAE v 4.03), then the 
subject must contact study personnel.  The management of hypertension, including the choice 
of antihypertensive medication, will be performed according to local standards and to the 
usual practice of the investigator.  Every effort should be made to control blood pressure by 
medical means other than study drug dose modification.  If necessary, Table 6.5 below 
outlines suggested dose reductions. 
 


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Table 6.4.1 Management of Treatment-Emergent Hypertension 
 
Grade   
(CTCAE v 4.03) 
Antihypertensive Therapy 
Regorafenib or placebo Dosing 
G 1 
Prehypertension (systolic BP 
120 - 139 mmHg or diastolic 
BP 80 - 89 mmHg) 
None 
• Continue regorafenib or placebo 
• Consider increasing blood pressure (BP) 
monitoring 
G 2 
Systolic BP 140 - 159 mmHg 
or diastolic BP 90 - 99 mmHg, 
OR 
Symptomatic increase by 
> 20 mmHg (diastolic) if 
previously within normal 
limits 
• Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
• If BP previously within normal 
limits, start anti-hypertensive 
monotherapy 
• If patient already on anti-
hypertensive medication, titrate 
up the dose. 
• Continue regorafenib or placebo 
 
• If symptomatic, hold regorafenib or placebo until 
symptoms resolve AND diastolic BP ≤ 90 mm 
Hga. When regorafenib or placebo is restarted, 
continue at the same dose level. 
 
G 3 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
OR 
More than one drug or more 
intensive therapy than 
previously used indicated 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive medication 
 
AND/OR 
Increase current anti-hypertensive 
medication 
 
AND/OR 
Add additional anti-hypertensive 
medications. 
• Hold regorafenib or placebo until diastolic BP ≤ 
90 mm Hg, and if symptomatic, until symptoms 
resolvea. 
• When regorafenib or placebo is restarted, 
continue at the same dose level. 
• If BP is not controlled with the addition of new 
or more intensive therapy, reduce by 1 dose 
levelb. 
• If Grade 3 hypertension recurs despite dose 
reduction and antihypertensive therapy, reduce 
another dose levelc. 
G 4 
Life-threatening consequences 
(e.g. malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of > 4 weeks should will discontinue regorafenib or placebo and stop participation in the study. 
b. If BP remains controlled for at least one cycle, dose re-escalation is permitted per investigator’s discretion. 
c.   Patients requiring > 2 dose reductions should go off protocol therapy. 
G: Grade 
  
 
 
  Table 6.4.2 Management of Treatment Emergent Hypertension for pediatric  
 
  
 
patients  
 
  
 
Please refer to appendix: 
 
Grade 
(CTCAE v 4.03) 
Antihypertensive 
Therapy 
Regorafenib or placebo Dosing 
Grade 1 If age ≤ 17 years: 
Asymptomatic, transient 
(< 24 hrs) BP increase > 
ULN; intervention not 
indicated. If age > 17 
Consider increased BP 
monitoring; start anti-
hypertensive medication if 
appropriate 
No modification 


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years: (SBP 120-139 
mmHg or DBP 80-89 
mmHg) 
Grade 2 asymptomatic If 
age ≤ 17 years: Recurrent 
or persistent (≥ 24 hrs) 
BP > ULN; If age > 17 
years: (SBP 140-159 
mmHg or DBP 90-99 
mmHg) 
-If age ≤ 17 years: 
monotherapy indicated, 
-If age > 17 years: As in 
Table 6.5 
Continue Study drug 
Grade 2 symptomatic OR 
Grade 3: (> 17 years: 
SBP > 160 mmHg or 
DBP > 100 mmHg) 
requiring more than one 
drug or more intensive 
therapy than previously 
(all ages) 
• Start or adjust anti-
hypertensive medication as 
in table 6.5 
 
• Hold study drug until symptoms 
resolve AND BP < 95th percentile ULN 
for age, height, and gender, if age ≤ 17 
years; or BP < 160/90 mmHg if age > 17 
years. Resume study at 100% (full) dose. 
If similar toxicity recurs, discontinue 
study drug. 
Grade 4 (all ages) life 
threatening (eg, 
hypertensive crisis or 
malignant hypertension) 
Per institutional guidelines 
Discontinue study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90th  and 95th  PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN  
GIRLS AGE 1-17 YEARS 
 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
90th 
97 
97 
98 
100 
101 
102 
103 
52 
53 
53 
54 
55 
55 
56 
95th 
100 
101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
2 
90th 
98 
99 
100 
101 
103 
104 
105 
57 
58 
58 
59 
60 
61 
61 
95th 
102 
103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
3 
90th 
100 
100 
102 
103 
104 
106 
106 
61 
62 
62 
63 
64 
64 
65 
Age
BP
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
(Year) 
Percentile 
Percentile of Height 
Percentile of Height 


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95th 
104 
104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
4 
90th 
101 
102 
103 
104 
106 
107 
108 
64 
64 
65 
66 
67 
67 
68 
95th 
105 
106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
5 
90th 
103 
103 
105 
106 
107 
109 
109 
66 
67 
67 
68 
69 
69 
70 
95th 
107 
107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
6 
90th 
104 
105 
106 
108 
109 
110 
111 
68 
68 
69 
70 
70 
71 
72 
95th 
108 
109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
7 
90th 
106 
107 
108 
109 
111 
112 
113 
69 
70 
70 
71 
72 
72 
73 
95th 
110 
111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
8 
90th 
108 
109 
110 
111 
113 
114 
114 
71 
71 
71 
72 
73 
74 
74 
95th 
112 
112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
9 
90th 
110 
110 
112 
113 
114 
116 
116 
72 
72 
72 
73 
74 
75 
75 
95th 
114 
114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
10 
90th 
112 
112 
114 
115 
116 
118 
118 
73 
73 
73 
74 
75 
76 
76 
95th 
116 
116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
11 
90th 
114 
114 
116 
117 
118 
119 
120 
74 
74 
74 
75 
76 
77 
77 
95th 
118 
118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
12 
90th 
116 
116 
117 
119 
120 
121 
122 
75 
75 
75 
76 
77 
78 
78 
95th 
119 
120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
13 
90th 
117 
118 
119 
121 
122 
123 
124 
76 
76 
76 
77 
78 
79 
79 
95th 
121 
122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
14 
90th 
119 
120 
121 
122 
124 
125 
125 
77 
77 
77 
78 
79 
80 
80 
95th 
123 
123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
15 
90th 
120 
121 
122 
123 
125 
126 
127 
78 
78 
78 
79 
80 
81 
81 
95th 
124 
125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
16 
90th 
121 
122 
123 
124 
126 
127 
128 
78 
78 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
17 
90th 
122 
122 
123 
125 
126 
127 
128 
78 
79 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in 
Children and Adolescents; NIH Publication No. 05-5267. 
 
 
90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT  
IN BOYS AGE 1-17 YEARS 
Age
BP
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
(Year) 
Percentile 
Percentile of Height 
Percentile of Height 
↓ 
5th 
10th     25th     50th    75th 
90th 
95th 
5th 
10th     25th     50th    75th    90th    95th 
1 
90th 
95th 
94 
98
95 
99
97 
101
99 
103
100 
104
102 
106
103 
106
49 
54
50 
54
51 
55
52 
56
53 
57
53 
58
54 
58
2 
90th 
95th 
97 
101 
99 
102 
100 
104 
102 
106 
104 
108 
105 
109 
106 
110 
54 
59 
55 
59 
56 
60 
57 
61 
58 
62 
58 
63 
59 
63 
3 
90th 
95th 
100 
104 
101 
105 
103 
107 
105 
109 
107 
110 
108 
112 
109 
113 
59 
63 
59 
63 
60 
64 
61 
65 
62 
66 
63 
67 
63 
67 


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4 
90th 
95th 
102 
106 
103 
107 
105 
109 
107 
111 
109 
112 
110 
114 
111 
115 
62 
66 
63 
67 
64 
68 
65 
69 
66 
70 
66 
71 
67 
71 
5 
90th 
95th 
104 
108 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
112 
116 
65 
69 
66 
70 
67 
71 
68 
72 
69 
73 
69 
74 
70 
74 
6 
90th 
95th 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
113 
117 
113 
117 
68 
72 
68 
72 
69 
73 
70 
74 
71 
75 
72 
76 
72 
76 
7 
90th 
95th 
106 
110 
107 
111 
109 
113 
111 
115 
113 
117 
114 
118 
115 
119 
70 
74 
70 
74 
71 
75 
72 
76 
73 
77 
74 
78 
74 
78 
8 
90th 
95th 
107 
111 
109 
112 
110 
114 
112 
116 
114 
118 
115 
119 
116 
120 
71 
75 
72 
76 
72 
77 
73 
78 
74 
79 
75 
79 
76 
80 
9 
90th 
95th 
109 
113 
110 
114 
112 
116 
114 
118 
115 
119 
117 
121 
118 
121 
72 
76 
73 
77 
74 
78 
75 
79 
76 
80 
76 
81 
77 
81 
10 
90th 
95th 
111 
115 
112 
116 
114 
117 
115 
119 
117 
121 
119 
122 
119 
123 
73 
77 
73 
78 
74 
79 
75 
80 
76 
81 
77 
81 
78 
82 
11 
90th 
95th 
113 
117 
114 
118 
115 
119 
117 
121 
119 
123 
120 
124 
121 
125 
74 
78 
74 
78 
75 
79 
76 
80 
77 
81 
78 
82 
78 
82 
12 
90th 
95th 
115 
119 
116 
120 
118 
122 
120 
123 
121 
125 
123 
127 
123 
127 
74 
78 
75 
79 
75 
80 
76 
81 
77 
82 
78 
82 
79 
83 
13 
90th 
95th 
117 
121 
118 
122 
120 
124 
122 
126 
124 
128 
125 
129 
126 
130 
75 
79 
75 
79 
76 
80 
77 
81 
78 
82 
79 
83 
79 
83 
14 
90th 
95th 
120 
124 
121 
125 
123 
127 
125 
128 
126 
130 
128 
132 
128 
132 
75 
80 
76 
80 
77 
81 
78 
82 
79 
83 
79 
84 
80 
84 
15 
90th 
95th 
122 
126 
124 
127 
125 
129 
127 
131 
129 
133 
130 
134 
131 
135 
76 
81 
77 
81 
78 
82 
79 
83 
80 
84 
80 
85 
81 
85 
16 
90th 
95th 
125 
129 
126 
130 
128 
132 
130 
134 
131 
135 
133 
137 
134 
137 
78 
82 
78 
83 
79 
83 
80 
84 
81 
85 
82 
86 
82 
87 
17 
90th 
95th 
127 
131 
128 
132 
130 
134 
132 
136 
134 
138 
135 
139 
136 
140 
80 
84 
80 
85 
81 
86 
82 
87 
83 
87 
84 
88 
84 
89 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in 
Children and Adolescents; NIH Publication No. 05-5267. 
 
 
6.5 Liver Function Abnormalities 
 
For patients with observed worsening of serum liver tests considered related to regorafenib 
(i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease 
progression), the dose modification and monitoring advice in Table 6.6 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may 
occur in patients with Gilbert syndrome. Note in Table 6.6 that hyperbilirubinemia itself is not 
a reason for dose reduction. Patients with Gilbert syndrome who develop elevated 
transaminases should be managed as per the recommendations outlined for ALT/AST 
elevations.  
 


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Table 6.5.1  Recommended measures and dose modification in case of drug-related liver 
function test abnormalities  
 
Observed elevations of 
ALT and/or AST 
Occurrence 
Recommended measures and dose 
modification 
 
 ≤ 5 times upper limit of 
normal ULN  
(maximum Grade 2) 
Any occurrence 
Continue regorafenib or placebo treatment.  
 
Monitor liver function weekly until transaminases 
return to < 3 times ULN (Grade 1) or baseline.  
>5 times ULN to  
≤ 20 times ULN  
(Grade 3) 
1st occurrence 
Interrupt regorafenib or placebo treatment. 
 
Monitor transaminases weekly until return to < 3 
times ULN or baseline. 
 
Restart: If the potential benefit outweighs the risk of 
hepatotoxicity, re-initiate regorafenib or placebo 
treatment, reduce dose by 40 mg (one tablet), and 
monitor liver function weekly for at least 4 weeks.  
Re-occurrence 
Discontinue treatment with regorafenib or placebo 
permanently. 
> 20 times ULN  
(Grade 4) 
Any occurrence 
Discontinue treatment with regorafenib or placebo 
permanently. 
> 3 times ULN  
(Grade 2 or higher)  
with concurrent 
hyperbilirubinemia 
 > 2 times ULN 
 
Discontinue treatment with regorafenib or placebo 
permanently. 
 
Monitor liver function weekly until resolution to < 3 
times ULN or return to baseline. 
 
Exception: patients with Gilbert syndrome who 
develop elevated transaminases should be managed as 
per the above outlined recommendations for the 
respective elevation of ALT and/or AST. 
6.6 Prevention/management strategies for diarrhea 
 
Diarrhea can be a common side effect of regorafenib.  The preventive/management strategies 
for diarrhea should be consistent with local standards (e.g., anti-diarrheals and optimized 
hydration status). 
 
Anti-diarrheal medications may be introduced if symptoms occur.  Previous trials have shown 
that the diarrhea could be managed with loperamide.  The recommended dose of loperamide 
is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. 
 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 


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Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) 
will determine whether the event requires expedited reporting in addition to routine reporting.  
For routine reporting it is expected that all adverse events grade 3 or greater are recorded.  
 
     7.1 Adverse Event and Laboratory Abnormalities 
 
7.1.1 Clinical AEs   
 
7.1.1.1 Definition of Adverse Events 
Per the International Conference of Harmonisation (ICH), an AE is any 
untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have 
a causal relationship with the treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product.  Pre-existing conditions which worsen 
during a study are to be reported as AEs. 
 
7.1.1.2 CTCAE term (AE description) 
The descriptions found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.  
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.03.  A copy of the CTCAE version 4.03 can be downloaded from 
the CTEP web site (http://ctep.cancer.gov). 
 
7.1.1.3  Intensity  
Intensity of all adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events v 4.03 (CTCAE) on a 
five-point scale (grades 1 to 5) and all grade 3 and above will be reported in 
detail on the eCRF.  Adverse events not listed on the CTCAE should be 
graded as follows:   
Table 7.1 CTC AE version 4.03 adverse event grading 
 


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CTC 
Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; 
no treatment or medical intervention is indicated 
although this could improve the overall well-being or 
symptoms of the patient 
Grade 3 
Severe 
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in order 
to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the 
survival of the patient at direct risk. 
Grade 4 
Life 
threatening/ 
disabling 
An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or 
performing normal daily activities; treatment or 
medical intervention is required in order to maintain 
survival. 
Grade 5 
Death 
AE resulting in death 
 
 
7.1.1.4 Drug-Adverse Event relationship 
 
The causality relationship of study drug to the adverse event will be assessed 
by the investigator as either: 
Yes or No 
 
If there is a reasonable suspected causal relationship to the study medication, 
i.e. there are facts (evidence) or arguments to suggest a causal relationship, 
drug-event relationship should be assessed as Yes. In other studies, the terms 
that qualify for a “Yes” assignation include “Definite”, “Probable”, or 
“Possible”. 
 
The following criteria should be considered in order to assess the relationship 
as Yes: 
 
– 
Reasonable temporal association with drug administration 
– 
Known response pattern to suspected drug 
– 
Disappears or decreases on cessation or reduction in dose 
– 
Reappears on rechallenge. 
 


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The following criteria should be considered in order to assess the relationship 
as No; in other studies, the terms that qualify for a “No” assignation include 
“Unlikely”, or “Unrelated”: 
 
– 
It does not follow a reasonable temporal sequence from administration 
 
of the drug 
– 
It may readily have been produced by the subject’s clinical state, 
 
environmental or toxic factors, or other modes of therapy administered 
 
to the subject 
– 
It does not follow a known pattern of response to the suspected drug 
– 
It does not reappear or worsen when the drug is re-administered. 
 
7.1.1.5 Definition of Serious Adverse Events 
 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any Adverse Event that at 
any dose fulfils at least one of the following criteria: 
 
- 
Is fatal; (results in death; NOTE: death is an outcome, not an event) 
- 
Is Life-Threatening (NOTE: the term "Life-Threatening" refers to an 
 
event in which the patient was at immediate risk of death at the time 
 
of the event; it does not refer to an event which could hypothetically 
 
have caused a death had it been more severe) 
- 
Requires in-patient hospitalization or prolongation of existing 
 
hospitalization 
- 
Results in persistent or significant disability/incapacity 
- 
Is a congenital anomaly/birth defect 
- 
Is medically significant or requires intervention to prevent one or 
 
other of the outcomes listed above. 
 
7.1.1.6  Progression of Underlying Malignancy  
 
Progression of underlying malignancy is not reported as an adverse event if 
it is clearly consistent with the suspected progression of the underlying 
cancer as defined by RECIST 1.1. Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as a serious 
adverse event.  Clinical symptoms of progression may be reported as adverse 
events if the symptom cannot be determined as exclusively due to the 
progression of the underlying malignancy, or does not fit the expected 
pattern of progression for the disease under study. 
 
Symptomatic deterioration may occur in some patients.  In this situation, 
progression is evident in the patient’s clinical symptoms, but is not supported 
by the tumor measurements.  Or, the disease progression is so evident that 
the investigator may elect not to perform further disease assessments.  In 
such cases, the determination of clinical progression is based on 


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symptomatic deterioration. These determinations should be a rare exception 
as every effort should be made to document the objective progression of 
underlying malignancy. 
 
If there is any uncertainty about an adverse event being due only to the 
disease under study, it should be reported as an AE or SAE. 
 
7.1.2 Treatment and Follow-up AEs   
 
After the discontinuation of therapy with regorafenib continue to follow up AEs 
as follows: 
 
Related AEs:  Follow until one of the following occurs: 
- 
Resolved or improved to baseline 
- 
Relationship is reassessed as unrelated 
- 
Start of new anti-cancer regimen 
- 
Investigator confirms that no further improvement can be expected 
- 
Clinical or safety data will no longer be collected, or final database closure 
- 
Death. 
 
Unrelated severe or life threatening AEs:  Follow until one of the following 
occurs: 
- 
Resolved or improved to baseline 
- 
Severity improved to grade 2 
- 
Start of new anti-cancer regimen 
- 
Investigator confirms that no further improvement can be expected 
- 
Clinical or safety data will no longer be collected, or final database closure 
- 
Death. 
 
The final outcome of each adverse event must be recorded on the CRF. 
 
Unrelated Grade 1 or Grade 2 AEs:  Follow as clinically indicated  
 
7.1.3 Laboratory Test Abnormalities   
 
Any laboratory result abnormality fulfilling the criteria for a serious adverse 
event (SAE) should be reported as such. 
 
Any treatment-emergent abnormal laboratory result that is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded on the 
adverse event eCRF: 
- 
Accompanied by clinical symptoms 
- 
Leading to a change in study medication (e.g. dose modification, 
interruption or permanent discontinuation) 
- 
Requiring a change in concomitant therapy (e.g. addition of, interruption 
of, discontinuation of, or any other change in a concomitant medication, 


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therapy or treatment). 
 
7.1.4 Follow-up of Abnormal Laboratory Test   
 
In the event of medically significant unexplained abnormal laboratory test 
values, the test should be repeated and followed until it has returned to the 
normal range, baseline value and/or an adequate explanation of the abnormality 
is found. If a clear explanation is established it should be recorded in the eCRF. 
 
     7.2 Handling of Safety Parameters 
 
7.2.1  Reporting of Adverse Events  
 
All adverse events (related and unrelated) Grade 3 or worse occurring during 
the study and up to 30 days after the last dose of study medication must be 
reported.  Reporting the specific time of onset of a given AE is only necessary 
when it occurs in relation to study drug administration.   
   
7.2.2  Reporting of Serious Adverse Events (immediately reportable) 
 
Any clinical adverse event or abnormal laboratory test value that is serious and 
which occurs during the course of the study (as defined in section 7.1 above), 
regardless of the treatment arm, must be reported to SARC within 24 hours of 
the Principal Investigator becoming aware of the event (expedited reporting). 
SARC will then forward MedWatch data form(s) to the overall study PI and 
Cohort Principal Investigators and the supporter upon receipt. If only limited 
information is initially available, follow-up reports are required. The original 
SAE Form must be kept on file at the study site. 
 
SAEs must be reported on the MedWatch Form 3500A along with the completed 
Fax Coversheet and faxed or sent electronically to SARC as listed. (See 
Appendix B). 
 
Related Serious Adverse Events MUST be collected and reported regardless of 
the time elapsed from the last study drug administration, even if the study has 
been closed.  
 
Unrelated Serious Adverse Events must be collected and reported during the 
study and for up to 30 days after the last dose of study medication. 
 
7.2.3  Pregnancy  
 
Females must be instructed to stop taking the study medication and immediately 
inform the investigator if pregnancy occurs during the study. Pregnancies 
occurring up to 3 months after the completion of the study medication must also 


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be reported to the investigator.  The investigator should report all pregnancies 
within 24 hours to the sponsor. 
 
The investigator should counsel the patient; discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy. 
 
Pregnancy occurring in the partner of a male patient participating in the study 
should also be reported to the investigator and the sponsor. The partner should 
be counseled and followed as described above. 
 
8. PHARMACEUTICAL INFORMATION  
 
     8.1 Regorafenib: description of mechanism of action 
 
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular 
kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, 
tumor angiogenesis, and maintenance of the tumor microenvironment.   
 
     8.2  Administration of Study Drugs 
 
Regorafenib or placebo will be administered as monotherapy during the study. The starting 
dose of regorafenib on study is 160 mg daily for 3 weeks on, 1 week off.  The pediatric 
starting dose is 82 mg/m2, rounding to the nearest 20 mg, and capping at 160 mg as with adult 
patients. One cycle is 28 days. Dose reduction levels are noted elsewhere in this protocol 
document (see Section 6.1.2). 
 
Four 40 mg regorafenib or four placebo tablets should be taken in the morning with 
approximately 8 fluid ounces (240 mL) of water after a low-fat (< 30% fat) breakfast.   Some 
examples of low fat breakfasts are: 
 
• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat) 
 
• One cup of cereal, 8 ounces (240 mL) of skim milk, one piece of toast with jam (no 
butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g 
of carbohydrate, 520 calories). 
 
     8.3 Formulation, Packaging and Labelling of Study Drugs  
 
     Tablets: 
 
Regorafenib 40 mg tablets contains regorafenib and the inactive excipients microcrystalline 
cellulose, croscarmellose sodium, magnesium stearate, povidone, colloidal anhydrous silica, 
polyvinyl alcohol-part hydrolyzed, talk, titanium dioxide E171 (color index 77891), 
Macrogol/PEG 33350, lecithin (soy), iron oxide yellow – E172 (color index 77491), iron 


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oxide red – E172.  
 
Where applicable, placebo control tablets without regorafenib will be provided by Bayer. 
 
Regorafenib or placebo tablets will be packaged in high density polyethylene bottles with a 
white child resistant closure and induction seal.  Each bottle includes 30 tablets and a 3 gram 
desiccant.  The bottles will have a label affixed containing study identification, product 
identification, and quantity of tablets.  Once the drug has been received it must be kept in a 
secure, dry location.  Study drugs must be stored in their original bottles at a temperature of 
20-25 °C (68-77 °F); provisional temperature limits permitted to 15-30 °C (59-86 °F). 
The study drugs must be exclusively used for the investigation specified in this protocol and 
they will only be accessible to authorized staff. 
 
     8.4 Agent Ordering  
 
Regorafenib and placebo tablets for this trial will be provided by Bayer, and distributed by a 
third party pharmaceutical distribution firm to the individual sites. Details will be provided in 
the Operations Manual. 
 
     8.5 Agent Accountability 
 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the instructions 
given by the clinical supplies department of the Institution and will be inaccessible to 
unauthorized personnel. 
 
Accountability and patient compliance will be assessed by maintaining adequate drug 
dispensing and return records.  
 
Accurate records must be kept for each study drug provided by the sponsor. The drug dispensing 
log must be kept current and contain the following information: 
 
• Documentation of drug shipments received from the sponsor (date received and 
quantity) 
• Disposition of unused study drug not dispensed to patient 
• The identification of the patient to whom the study medication was dispensed 
• The date(s) and quantity of the study medication dispensed to the patient. 
 
All supplies, including partially used or empty containers must be returned to the treating 
institution at the end of the study, and destroyed as required by local or institutional 
regulations (Section 8.7). Copies of the dispensing & inventory logs must be sent to SARC (use 
the address in Section 8.7). 
 
Patients will also keep a Study Drug diary to indicate their compliance with therapy and 
adverse events they experience. These diaries will be reviewed and collected at each patient 
visit.  


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     8.6 Destruction of study drugs 
 
All unused and expired supplies of regorafenib and placebo should be destroyed according to 
institutional policies. A completed “Unused Study Drug Disposition Form Destruction 
Confirmation” should be sent to SARC by email to:   
 
eantalis@sarctrials.org or SARC024@sarctrials.org 
 
OR faxed to: 734-930-7557. 
 
9. STUDY EVALUATIONS AND STUDY CALENDAR 
  
9.1 Screening Studies 
 
The patient must sign the informed consent form before proceeding with screening. 
 
The following procedures will be performed during the screening period (within 14 days of 
protocol registration): 
 
• History/demographics 
• Physical exam 
• Vital signs, to include height, weight, WHO performance status 
• Concomitant medications, including herbal and other homeopathic remedies 
• Hematology: complete blood count, platelet count, differential, PT (INR), PTT 
• Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase  
• Urinalysis 
• Serum or urine pregnancy test (for women of childbearing potential) 
• Baseline radiologic imaging 
• The same modalities should be used throughout the study as this baseline, unless 
allergies or other adverse events intervene) 
• Images must be obtained within 28 days of the 1st day of therapy on study 
• Baseline tumor measurements from physical exam 
• ECG. 
 
 
The screening period will be up to 14 days prior to study registration.  Laboratory baseline 
evaluations are to be conducted within 14 days prior to study registration.  Radiologic imaging 
must be done within 28 days of the first day of study treatment. For patients for whom there 
are 14 days or fewer between registration and the start of treatment, the day 1 laboratory data 
may be omitted.   
 
Study treatment (day 1) should begin no later than 21 days (and within 28 days of baseline 
images) after patient enrollment into the study.   


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     9.2 On Study Evaluation 
 
The following procedures will be performed during the treatment period. Please note that 
visits may occur ± 2 days of the scheduled date, ± 3 days for weeks of bank holidays. Tumor 
measurements and reimaging may be done ± 7 days of the anticipated date.  Tumor imaging 
may be performed at other times as clinically indicated.  These will be considered non-
protocol standard of care scans.    
 
Cycle 1, Week 1 day 1 
 
• Demographics, interval history 
• Concurrent medications 
• Physical Exam 
• Vitals signs 
• Weight 
• WHO performance status 
• Hematology: complete blood count, platelet count, differential 
• Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase 
• For patients for whom there are 14 days or fewer between registration and the start of 
treatment, the day 1 blood chemistries and hematology may be omitted   
• Adverse event evaluation 
•  Dispense study drug 
•  Distribute study drug diary, if not already done. 
 
Cycle 1 Week 1, between days 4-6 
 
A phone call will be made to the patient during this period to review adverse events. 
 
Cycle 1 Week 2, day 1 
 
• Demographics, interval history 
• Concurrent medications 
•  Physical Exam 
• Vitals signs 
• Weight 
•  WHO performance status 
•  Hematology: complete blood count, platelet count, differential 
• Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose,  ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total  
protein, calcium, magnesium, phosphorus, lipase, amylase 
•  Adverse event evaluation. 
 
 


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Cycle 1 Week 3, day 1 
 
• Demographics, interval history 
•  Concurrent medications 
•  Physical Exam 
•  Vitals signs 
•  Weight 
•  WHO performance status 
•  Hematology: complete blood count, platelet count, differential 
• Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase 
•  Adverse event evaluation. 
 
Cycle 1 Week 4 
 
Off week from treatment. 
 
• The same modalities should be used throughout the study as baseline, unless allergies 
or other adverse events intervene. 
 
Cycle 2 Week 1, day 1 (Week 5 overall) 
 
• 
Demographics, interval history 
• 
Concurrent medications 
• 
Physical Exam 
• 
Vitals signs 
• 
Weight 
• 
WHO performance status 
• 
Hematology: complete blood count, platelet count, differential 
• 
Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase 
• 
Adverse event evaluation 
• 
Dispense study drug 
• 
Distribute study drug diary 
• 
Collect study drug diary for previous cycle. 
 
Cycle 2 Week 3, day 1 (Week 7 overall) 
 
• 
Demographics, interval history 
• 
Concurrent medications 
• 
Physical Exam 
• 
Vitals signs 
• 
Weight 


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• 
WHO performance status 
• 
Hematology: complete blood count, platelet count, differential 
• 
Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase 
• 
Adverse event evaluation. 
 
Week 8 
 
Off week from treatment. 
Imaging studies for comparison to baseline to be conducted this week. 
 
• 
The same modalities should be used throughout the study as baseline, unless allergies 
or other adverse events intervene). 
 
Cycle 3 Week 1, day 1 (Week 9 overall) and later 
 
Treatment continues 3 weeks on, 1 week off. 
Visits every 2 weeks until end of cycle 4, then every 4 weeks.  
 
• 
Tumor measurements and imaging every 8 weeks for 32 weeks, then every 12 weeks. 
Scans may be done ± 7 days of expected date. 
 
 
At each visit: 
 
• 
Demographics, interval history 
• 
Concurrent medications 
• 
Physical Exam 
• 
Vitals signs 
• 
Weight 
• 
WHO performance status 
• 
Hematology: complete blood count, platelet count, differential 
• 
Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase 
• 
Adverse event evaluation 
• 
Dispense study drug 
• 
Distribute study drug diary 
• 
Collect study drug diary for previous cycle. 
 
 
9.3 Off Study Evaluations 
 
Off study 
 
• 
Demographics, interval history 


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• 
Concurrent medications 
• 
Physical Exam 
• 
Vitals signs 
• 
Weight 
• 
WHO performance status 
• 
Hematology: complete blood count, platelet count, differential, if not done as part of 
end of cycle evaluation 
• 
Serum Chemistry: electrolytes, chloride, bicarbonate, BUN, creatinine, glucose, ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, total 
protein, calcium, magnesium, phosphorus, lipase, amylase, if not done as part of end 
of cycle evaluation 
• 
Serum or urine chemistry pregnancy test (for women of childbearing potential) 
• 
Tumor measurements and imaging, if not done as part of end of cycle evaluation 
• 
Adverse event evaluation 
• 
Collect study drug diary. 
 
Follow up phone call 30-45 days after off study visit date 
 
• 
Interval history 
• 
Concurrent medications. 
 
NOTE: Patients removed from study for adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
To reiterate:  Visits may occur ± 2 days of the scheduled date, ± 3 days for weeks of bank 
holidays. Tumor measurements and reimaging may be done ± 7 days of the anticipated date. 
 


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     9.4 STUDY CALENDAR  
 
 
Pre 
study 
Wk 
1, d1 
Wk 
1, d 
4-6 
Wk 
2, 
d1 
Wk 
3, 
d1 
Wk 
4 
Wk 
1, 
d1 
Wk 
2,  
Wk 
3, 
d1 
Wk 
4 
Wk 
1 
 
d1 
Off 
study 
30-
45d 
F/U  
CYCLE 
-- 
Cycle 1 (2) 
Cycles 2-4 (3) 
5+ 
(4)   
-- 
-- 
Regorafenib or 
placebo (1) 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
interval history, 
concurrent 
medications, 
adverse event 
evaluation 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Phone contact 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Physical exam 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Vital signs, 
weight, WHO 
performance 
status 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff, 
plts; 
Comprehensive 
serum chemistry 
(includes LFTs) 
(6); lipase, 
amylase 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT(INR), PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Study drug 
diary 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Radiological 
evaluation and 
tumor 
measurements 
X 
 
 
 
 
 
 
 
 
X(5) 
X(5) 
X(5) 
 
Beta HCG (7) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
(1) Therapy schedule consists of 3 weeks on and 1 week off for all cycles, until off study.  
(2) For cycle 1 only, visits are weekly for the first 3 weeks, and may occur ± 2 days of the 
scheduled date, ± 3 days for weeks of bank holidays. 
(3) For cycles 2-4, visits are every 2 weeks, and may occur ± 2 days of the scheduled date, ± 3 
days for weeks of bank holidays. 
(4) For cycle 5 and beyond, visits are every 4 weeks and may occur ± 2 days of the scheduled 
date and ± 3 days for weeks of bank holidays. 


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(5) Tumor measurements and reimaging occurs every 8 weeks for the first 32 weeks, then 
every 12 weeks. Scans may be performed ± 7 days of the anticipated date.  Tumor imaging 
may be performed at other times as clinically indicated; however, these will be considered 
non-protocol standard of care scans.  The cycle length may not be the same as the time 
between imaging studies depending on toxicity on treatment.   
(6) See above in Section 9 for details of blood collection requirements 
(7) For women of childbearing potential within 7 days of day 1 of study treatment. 
 
10. MEASUREMENT OF EFFECT 
 
10.1 Antitumor Effect – Solid Tumors, with modifications for well differentiated-
dedifferentiated liposarcoma 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks for 
the first 32 weeks, then every 12 weeks thereafter. At the discretion of the treating physician, 
additional imaging should be obtained if the patient has symptoms consistent with potential 
progression of disease. If progression is confirmed, the treatment will be unblinded as outlined 
in section 5.3. Scans may be done up to ± 7 days of the scheduled dates. 
 
Response and progression will be evaluated in this study using the international criteria of the 
revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur 
J CA 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in 
RECIST. We will modify choice of target lesions on this study to focus on the most 
aggressive component of well-differentiated-dedifferentiated liposarcoma, i.e. the 
dedifferentiated components, since the well differentiated component often cannot be 
distinguished from normal fat.  
 
10.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with regorafenib. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
 


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10.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as > 20 mm 
by chest x-ray or as > 10 mm with CT scan, MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable.  If the investigator thinks it appropriate to 
include them, the conditions under which such lesions should be considered must 
be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘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. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be used as 


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reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
For patients with well-differentiated dedifferentiated liposarcoma (WD-DDLS), 
the well differentiated component often does not change in size over a period of 
months to years, or if it does, it does not change in size quickly. For this reason, we 
will examine specifically in WD-DDLS patients the dedifferentiated components 
of the tumor. These can be identified as having a CT density of > 0 Hounsfield 
units, or have increased signal on T2-weighted images and/or less intense in T1-
weighted series than the fatty T1-intense well-differentiated components of well-
differentiated liposarcoma. By the same token, any lesions that are deemed to be 
sarcoma but not the dedifferentiated component will be considered non-target 
lesions, and their evaluation will be as with other non-target lesions as describe 
immediately below. Significant worsening of the well differentiated component in 
a WD-DDLS patient will be considered non-target lesion progression.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
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 is 
preferable.  
 
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 


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scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  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.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  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: At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, 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.  Note, however, that the PET portion of the 
CT introduces additional data which may bias an investigator if it is not routinely 
or serially performed.   
 
Ultrasound: Ultrasound is not an accepted standard for the assessment of lesion 
size and should not be used as a method of measurement.  Ultrasound 
examinations cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be guaranteed that 
the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection 
is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  Specific guidelines for both 


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CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 
3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer [JNCI 92:1534-1535, 2000]. This criterion is generally not germane for 
sarcoma patients, since there are no sarcoma-specific tumor markers in common 
use. 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
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. 
 
FDG-PET:  FDG-PET will not be used for tumor evaluation on this study. If an 
FDG-PET scan is done as part of routine monitoring of the patient, then scans of 
metastatic sites should be done with diagnostic quality images of those sites.  
 
10.1.4 Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to < 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
 


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Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All 
lymph nodes must be non-pathological in 
size (< 10 mm short axis). 
 
Note:  If tumor markers are initially above 
the upper normal limit, they must normalize 
for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD:  
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions.  Unequivocal progression 
should not normally trump target lesion 
status.  It must be representative of overall 
disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
Table 10.1 Tumor Time Point Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions Overall Response 
CR* 
CR 
No 
CR 
CR 
CR 
Non-CR/non-PD 
Not Evaluated 
No 
No 
PR 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
 
Not all evaluated 
Non-PD or not all 
evaluated 
Non-PD 
No 
 
No 
SD 
 
NE 
PD 
Any 
Yes or No 
PD 


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Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*CR = complete response; PR = partial response; SD = stable disease; and  
PD = progressive disease, NE = inevaluable. See text for more details. 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Table 10.2 Best Overall Tumor Response when confirmation of CR and PR required 
 
Overall response  
First time point 
Overall 
Response 
Subsequent 
time point 
Best Overall Response  
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
CR = Complete Response, PR = Partial Response, SD = Stable Disease,  
PD = Progressive Disease, and NE = inevaluable. 
 
a If a CR is truly met at first time point, then any disease seen at a subsequent time 
point, even disease meeting PR criteria relative to baseline, makes the disease PD at 
that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
 


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10.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
10.1.6 Progression-Free Survival (PFS), Time to progression (TTP) 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. TTP is defined as the duration of time 
from start of treatment to time of progression, omitting death.  
 
10.1.7 Response Review 
 
A post hoc central radiology review will be conducted and data regarding PFS and 
TTP will be recalculated based on these measurements as an additional endpoint. 
However, the interpretation of the images from the individual site will be used for 
the primary endpoint of PFS. De-identified images will be stored in a SARC 
designated centrally located bank. 
 
10.2 Antitumor Effect – Solid Tumors: Choi criteria 
 
As an exploratory endpoint we will examine alternate criteria and their relationship to 
RECIST overall response rate, progression free survival and overall survival24.  
 
Parameters to characterize a radiological outcome are indicated in Table 10.3 below. The 
central radiology review will calculate Choi criteria response and relationship to RECIST. 
 
 
 
 
 
 
 


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Table 10.3 Evaluation of radiological response by Choi criteria 
 
Parameter 
RECIST 
Choi 
PD 
↑20% SLD (min 5 mm ↑) OR 
new lesion OR 
non target lesion progression 
↑10% SLD (↓<15% MLD) OR 
new Lesion OR 
new or ↑ tumor within tumor 
SD 
↓< 30% SLD to  ↑< 20% SLD; 
no new lesions; no obvious 
progression of non-target 
lesions 
↓10% SLD to ↑10% SLD (↓<15% 
MLD); no symptomatic deterioration 
attributed to tumor progression 
PR 
↓at least 30% SLD; no new 
lesions; no  obvious progression 
of non-target lesions 
↓10% SLD (+ ↓at least 15% MLD); no 
new lesions; no  obvious progression of 
non-measurable disease 
CR 
Disappearance of all lesions; no 
new lesions 
Disappearance of all lesions; no new 
lesions 
SLD: Sum of longest diameters  
MLD: median lesion density 
 
 
11. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 Data Reporting 
 
 
11.1.1 Method 
 
Electronic case report forms (eCRFs) will be created by SARC, the overall Principal 
Investigator and reviewed by the statistician.  The database will be built within the 
MEDIDATA RAVE system for data collection for this study.  
 
The definition of serious adverse events (SAEs) is given in Section 7.1. Each serious 
adverse event must be followed up until resolution or stabilization, by submission of 
updated reports to the designated person. For purposes of this study, a laboratory 
abnormality that is assigned grade 3 or 4, according to CTCAE version 4.03 is reportable 
as an SAE.  CTCAE v 4.03 grade 3 or 4 baseline laboratory abnormalities that are part of 
the disease profile should not be reported as an SAE, specifically when they are allowed 
or not excluded by the protocol inclusion / exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the IRB and Regulatory Authorities.  


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All serious adverse events should be reported to SARC within 24 hours.  In the event of 
such an event, the investigator should refer to the Adverse Reporting section of the 
Operations Manual for reporting procedures. 
 
The Investigator will report serious adverse events (SAEs) using the MedWatch 
3500A form, which is attached in Appendix B. 
 
All reports shall be sent electronically to SARC:  
 
SARC:  
 
 
sarc@sarctrials.org 
 
 
SARC will send the SAE reports and coversheets to Bayer within 1 working day. 
 
 
Bayer Electronic Mailbox:  DrugSafety.GPV.US@bayer.com  
 
Facsimile:   
 
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare Pharmaceuticals Inc. 
 
 
 
P.O. Box 1000  
 
 
 
Montville, NJ 07045-1000  
 
Address:   
 
 
340 Changebridge Road  
FDX or UPS only    
Pine Brook, NJ  07058  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept.:  
 
Phone:  
 
 
1-888-765-3203 
 
11.1.2 Expected serious adverse events 
 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB)/summary of product characteristics. 
 
The expectedness of SAEs will be determined by the SARC overall Principal Investigator. 
 
11.1.3 Adverse events of special safety interest 
 
As with any new chemical entity, there is always potential for unexpected adverse events, 
including hypersensitivity reactions. 
 
Based on data from prior studies with regorafenib and from current knowledge of the 
pharmacological properties of other small molecule tyrosine kinase inhibitors in this drug 


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class, as soon as there is reasonable suspicion of any of the following AEs, the investigator 
should immediately notify the sponsor as outlined in Section 11.1.1.  
 
These events include: 
 
• 
Acute renal failure (NCI-CTCAE version 4.03 ≥ G3) or severe proteinuria 
(NCI-CTCAE version 4.03  ≥  G3) 
• 
Interstitial lung disease 
• 
Acute cardiac failure 
• 
Clinically significant bleeding (NCI-CTCAE version 4.03 ≥ G3) 
• 
Stevens-Johnson syndrome and erythema multiforme 
• 
Hepatic failure 
 
11.1.4 Pregnancies 
 
The investigator must report to SARC any pregnancy occurring in a study subject, or in 
his partner, during the subject’s participation in this study.  The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an 
SAE.   
 
For a study subject, the outcome of the pregnancy should be followed up carefully, and 
any abnormal outcome of the mother or the child should be reported. 
 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
 
11.1.5 Further safety documentation 
 
Progressive disease 
 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE (i.e., 
hospitalization, disability, death, or important medical event), the signs and symptoms 
should be reported as an SAE and not the underlying progressive disease. 
 
Death 
 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform SARC and record the cause of death in detail (using the SAE 
Form) within 24 hours. 
 
11.1.6 Data Safety Monitoring 
 
11.1.6.1  Data Safety Monitoring 
 
An Independent Data Monitoring Committee will be formed to monitor safety and 
efficacy.  The IDMC will be comprised of two oncologists and a statistician experienced 


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in clinical trials.   
 
 
11.1.6.2  Additional Data Safety Monitoring 
 
The SARC Clinical Trials Review Committee convenes monthly and will provide safety 
oversight for this trial.  The purpose of the Clinical Trials Review Committee is to review 
the status of the ongoing SARC studies, which includes but is not limited to:  
 
• Review of all safety data (Serious Adverse Events reported) 
• Review of any protocol violations 
• Review of study progress/accrual 
• Discussion of statistical aspects of protocol as appropriate. 
 
The committee is chaired by the SARC Medical Officer, who is responsible for leading 
the meeting and providing medical oversight.  Attendance includes all Principal 
Investigators on active SARC studies, SARC Research Project Managers, SARC President 
and a biostatistician.  
 
Safety oversight for this trial is also supported by the SARC Clinical Research Committee, 
which is made of senior sarcoma investigators.  This committee reviews the findings of 
the Clinical Research Committee on a monthly basis.  This committee provides an 
additional level of medical oversight for this trial.  
 
11.1.7 Patient Accrual and Participating Centers 
 
There will be approximately 18 SARC centers collaborating to accrue patients to this 
study.  We anticipate accrual will take approximately 18-24 months.  
 
This trial will be posted at the www.clinicaltrials.gov website. 
 
  11.2 Multi-Institutional Guidelines 
 
The trial coordinating center (Operations Center) will be SARC.  Patients will be registered 
electronically via the study website and adverse events (as defined in section 7.0) will be 
reported to the SARC Operations Center.   
 
IRB approvals: 
 
The protocol must be approved by the treating institution prior to enrolling patients.  
Documentation of individual IRB approval for the current protocol must be provided to the 
SARC Operations Center prior to enrolling patients on the trial.  In addition, documentation of 
approval of all protocol amendments and of yearly continuing review must be provide to the 
Research Project Manager either electronically or via mail to the following address: 
 
 
 


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SARC 
24 Frank Lloyd Wright Drive, PO Box 406 
Ann Arbor, MI 48105 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
Patient Registration 
 
Patient registration will be centrally managed electronically via the study website (see section 
4.2). 
 
Data Collection and Toxicity Reporting 
 
Registration reports will be generated by the Operations Center to monitor patient accruals 
and completeness of registration data.  Routine data quality reports will be generated to assess 
missing data and inconsistencies by the SARC. Any potential problems will be brought to the 
attention of the study Principal Investigator(s) for discussion and action. 
 
Access to the password protected study website will be limited to individuals involved in the 
clinical trial including: SARC staff, overall Study and Cohort PIs, participating site PIs, 
research nurse and data managers responsible for this trial.   
 
Shipment and receipt of specimens and imaging studies sent for correlative studies will be 
entered and tracked on the study website.  Details regarding handling and shipping will be 
outlined in the study operations manual. 
 
11.3 Data and Participating Institution Monitoring 
 
Data monitoring for this trial will be managed remotely.  A data monitoring and site 
monitoring plan will be developed for this trial.  Should areas of concern be identified through 
the remote monitoring process, an on-site monitoring visit may be warranted.  Findings will 
be discussed with the overall study PI and Cohort PIs, participating site PIs, Clinical Trials 
Review Committee and the SARC medical officer. 
 
11.4 Human Subjects Protection 
 
11.4.1 Rationale for Subject Selection 
 
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if 
they meet the eligibility criteria as outlined in section 3.1.  No groups will be excluded 
from participation in the trial.  
 
11.4.2 Evaluation of the Benefits and Risks/Discomforts  
 
The primary risk to patients participating in this research study is from toxicity associated 
with regorafenib, which has been approved by the FDA for the treatment of metastatic 


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renal cancer and gastrointestinal stromal tumors.  The primary objectives of this phase 2 
study are for Cohorts A & B to compare PFS of subjects treated with regorafenib or 
placebo and for Cohort C to estimate PFS at 8 and 16 weeks. A crossover option will be 
available for patients who progress on placebo as outlined in Section 5. 
 
11.4.3 Management of Patient Data 
 
All patient data will be captured and maintained in a study specific database with 
password-protected access.  Data is entered using an assigned study subject identification 
number.   
 
The data provided to those reviewing the results, for example the study statistician will 
include the subject identification numbers but will not include patient identifiable data. 
 
The research samples obtained on this study will only be sent using the study subject 
identification number, which can only be linked to the patient at a given institution by the 
treating physician. 
 
All documentation that contains personal health information that may include patient 
identifiable information will be maintained at the site to preserve patient confidentiality.  
 
11.5 Premature termination of study 
 
This study may be closed prematurely for any of the following reasons: 
 
• If risk-benefit ratio becomes unacceptable owing to, for example: 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; head 
of study center) must be informed as applicable according to local law. 
• In case of a partial study closure, ongoing subjects, including those in post study follow-
up, must be taken care of in an ethical manner. 


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Details for individual subject's withdrawal can be found in Section 5.8. 
 
 
12. STATISTICAL CONSIDERATIONS  
 
12.1 Efficacy and safety variables 
 
12.1.1 Efficacy variables 
 
Efficacy variables to analyze include: 
• 
Progression free survival (PFS, as assessed by RECIST 1.1), defined as time from 
randomization (or 1st day of treatment, cohort C, D and E) to site determined 
radiographic tumor progression or death from any cause (whichever occurs first).  For 
patients alive without progression, censoring occurs at the date of last tumor 
assessment. In PFS analyses, if the exact progression date is unknown, the date of 
progression is taken to be the date the first time at which progression can be declared 
• 
Proportions of patients who are progression-free (and alive) 
• 
Proportions of patients without progression or death at landmark times (in particular at 
8 and 16 weeks) 
• 
Overall survival is defined as the time from randomization (or 1st day of treatment, 
cohorts C, D and E) until death from any cause.  Censoring occurs at the date of last 
contact. 
• 
Disease-specific survival is defined as the time from randomization (or 1st day of 
treatment cohorts C, D and E) until death from sarcoma  
• 
Time to progression (as assessed by RECIST 1.1), defined as time from randomization 
(or 1st day of treatment, cohort C) to centrally-determined radiographic tumor 
progression, censoring for death without progression.  Progression is defined, 
according to RECIST 1.1, as a 20% increase from nadir and a minimum of 5 mm 
increase over the lowest sum, the appearance of one or more new target or non-target 
lesions, or unequivocal progression of existing non-target lesions determined by 
radiographic assessment.  In TTP analyses, the exact progression date is unknown.  
Date of progression is taken to be the date the first time at which progression can be 
declared   
• 
Change in target lesion size.  Target lesion size will be measured by imaging methods.  
Tumor size will be measured as a unidimensional tumor measurement per RECIST 
1.1. 
• 
Overall response rate (ORR as assessed by RECIST 1.1) defined as the portion of 
patients evaluable for response who achieved partial response or better and stable 
disease or better 
 
12.1.2 Safety variables 
 
A treatment-associated adverse event (TAAE) is defined as an AE that was not present at 
baseline, or an exacerbation of a pre-existing AE.  For laboratory data, a treatment-
associated abnormal laboratory value (TAAV) represents an abnormal value that was 
normal at baseline. 


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Safety variables of analysis include the following: 
 
• 
Proportions of patients with any TAAEs 
• 
Proportions of patients with serious TAAEs 
• 
Proportions of patients with Grade 3 or greater TAAEs 
• 
Proportions of patients with severe TAAE 
• 
Proportions of patients with TAAEs leading to study drug discontinuation 
• 
Proportions of patients with TAAEs leading to dose modifications  
• 
Proportions of patients with drug-related TAAEs 
• 
Proportions of patients with TAAVs 
• 
Mean and median changes from baseline in vital signs  
• 
Mean and median changes from baseline in clinical laboratory measures 
• 
Mean and median changes from baseline in measures from electrocardiography. 
 
It is noted that patients who cross over from placebo to receive open-label regorafenib will 
have treatment-related derivations from first dose of placebo during the double-blind 
period and treatment-related derivations from first dose of regorafenib during the open-
label portion of the study. 
 
12.2 Study Design/Endpoints 
 
Cohorts A and B (liposarcoma and osteosarcoma) 
 
Each of cohorts A and B will be studied using a randomized placebo controlled phase II 
design with a progression free survival endpoint. Outcomes will be determined on an intention 
to treat analysis.  
 
Each cohort substudy will be powered to detect a difference of at least 3 months in median 
PFS, which has been discussed among expert sarcoma oncologists as a clinically meaningful 
difference in outcome. This corresponds to a median control group PFS of 2 months, median 
treatment group PFS of 5 months, and hazard ratio of 0.4 for treatment/control groups.  
 
42 events are needed to detect a targeted difference with 90% power and 5% one-sided 
significance level. The final analysis of the primary PFS endpoint will be conducted when at 
least 42 patients had disease worsening. 48 eligible patients are expected to be randomized, to 
achieve the 42 expected events with an enrollment rate of 4 eligible patients per month per 
substudy. With the predicted accrual rate and PFS parameters, the 42 events are expected to 
occur in 16 months.  
 
We will limit to a maximum of 16 patients per substudy A & B with WHO performance status 
of 2. There is no such limitation for substudy C.    
 
Survival will be estimated by the Kaplan-Meier method. The treatment groups will be 
compared with a one-sided stratified log rank test. All analyses will be done in the intention-
to-treat population. 


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We will conduct a prognostic factor analysis for PFS using a univariate Cox model; 
significant factors subsequently will be included in a multivariable Cox regression model 
(cutoff p<0·05). For a predictive analysis of PFS, Cox models will be generated with the 
investigated factor, treatment, and their interaction, with a significance value of p<0·05. P-
values will not be adjusted for multiple comparisons. 
 
Cohort C (Ewing/Ewing-like sarcoma): 
 
Since progression free survival is so short in Ewing/Ewing-like sarcoma, even with an active 
agent such as an IGF1R inhibitor (1.3 months in one study), a single-stage design examining 
PFS at 8 and 16 weeks will be employed for this cohort.   
 
 
We will take median PFS of 0.5 at 8 weeks as evidence of activity for this cohort, in 
comparison to an uninteresting median PFS (8 weeks) of 0.25. For this 30 patient cohort with 
these parameters, this yields a false positive rate of 0.05 (alpha) and power (1-beta) of 0.91.  
 
The response rate will be estimated and a confidence interval will be constructed.  A sample 
size of 30 patients and 50% PFS rate at 8 weeks yields a 95% binomial confidence interval of 
(31%, 69%).   
 
Cohort D (Rhabdomyosarcoma: Fusion-positive alveolar, Embryonal, Fusion-negative 
alveolar): 
 
Since published estimates of progression free survival in rhabdomyosarcoma patients after 
more than one relapse are scarce, we will estimate the RECIST 1.1 Response rate (PR or 
better) at 8 weeks.  Cohort D will accrue separately to approximately 12 patients with either of 
(1) fusion-positive alveolar rhabdomyosarcoma and (2) embryonal rhabdomyosarcoma/fusion 
negative alveolar rhabdomyosarcoma, and will be analyzed as a combined cohort.  We will 
consider a disease control rate (CR+PR+stable disease at 8 weeks) of 30% to be evidence of 
activity, in comparison to a disease control rate of 10% as not useful to pursue further.   
 
A total of ~ 12 patients will be accrued to Cohort D and ~ 12 to Cohort E, below. Since 
funding is available for 24 patients in Cohorts D and E, the below are estimates of accruals, 
and the actual accrual will be used to define success vs failure for each cohort based on final 
accrual, maintaining similar disease control rates at 8 weeks (30% [active] vs 10% [not 
active]) for Cohort D, regardless of final accrual total. 
 
For a 12-patient cohort with a type I error of 0.10 and a power of 0.90, if 2 or fewer patients 
have disease control, then regorafenib will be determined to be unworthy of further study in 
this setting.  If 3 or more patients have disease controlled at 8 weeks, regorafenib will be 
considered worthy of further investigation in Cohort D.  A sample size of 12 patients will 
permit determination of disease control rate of 30% with 95% binomial confidence interval of 
(10%, 57%). 
 
 


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Cohort E (Mesenchymal chondrosarcoma): 
 
Published estimates of progression free survival on chemotherapy for patients with metastatic 
mesenchymal chondrosarcoma patients are also unavailable. However, existing data indicate 
the overall survival of patients with metastatic mesenchymal chondrosarcoma is similar to 
those with unselected soft tissue sarcomas, in the 18 month range (Amer et al. J Orthop Res 
2019, https://doi.org/10.1002/jor.24463), so we will estimate the RECIST 1.1 response rate 
(PR or better) at 24 weeks. Cohort E will accrue to ~ 12 patients with metastatic mesenchymal 
chondrosarcoma. We will consider a disease control rate (CR+PR+stable disease) at 24 weeks 
of 50% to be evidence of activity, as is the case with 1st line doxorubicin or gemcitabine in 
unselected STS (GEDDiS study) in comparison to a disease control rate of 25%, as not useful 
to pursue further.   
 
A total of ~ 12 patients will be accrued to Cohort E,. Since funding is available for 24 patients 
in Cohorts D and E, the estimates of accruals, and the actual accrual will be used to define 
success vs failure for each cohort based on final accrual, maintaining similar disease control 
rates at 24 weeks (50% [active] vs 25% [not active]) for Cohort E, regardless of final accrual 
total. 
 
The design is based on a Simon’s two-stage using only the first stage. A 12-patient cohort 
with a type I error of 0.10 and a power of 0.80, yields a decision rule that if 3 or fewer patients 
have disease control at 24 weeks, then regorafenib will be determined to be unworthy of 
further study in this setting.  If 4 or more patients have disease controlled at 24 weeks, 
regorafenib will be considered a worthy of further investigation in Cohort E.  A sample size of 
12 patients will permit determination of 24-week disease control rate of 50% with 95% 
binomial confidence interval of (21%, 79%). 
 
12.3 Sample Size/Accrual Rate 
 
Enrollment in cohorts A & B is expected to be 4 patients per month per cohort, with a total of 
48 patients per cohort enrolled 1:1 between regorafenib: placebo. Enrollment is expected to be 
completed in 12 months with a minimum follow-up period of 6 months.  
 
For cohort C, enrollment is expected to be 3 per month for a total enrollment of 30 patients 
over 10 months.  (Enrollment for this cohort is complete.) 
 
For cohort D, enrollment is expected to be 0.5 per month (1 each fusion positive, fusion 
negative types) for a total enrollment of 12 patients over 24 months. 
 
For cohort E, enrollment is expected to be 0.5 per month (1 each fusion positive, fusion 
negative types) for a total enrollment of 12 patients over 24 months. 
 
 
 
 
 


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12.4 Stratification Factors 
 
Patients will be stratified by WHO performance status ([0 or 1] vs 2) and by number of prior 
lines of therapy (1 vs 2 or more). No more than 1/3 of patients will be permitted on cohorts A 
and B with WHO performance status 2.  
 
12.5 Analysis of Secondary Endpoints 
 
Descriptive statistics will be generated for secondary endpoint variables. 
Methodologies for variables that are proportions will include construction of confidence 
intervals for each group and for the difference between groups.  For example, a Fisher exact 
test will be used for single-population analyses, while a Mantel-Haenszel test will be used for 
analyses combining data across strata.  
 
Methodologies for time-to-event variables will include construction of 95% confidence 
intervals for each group separately and for the difference between groups.  For analysis, a log-
rank test will be used.  Logistic regression and analysis of covariance methods on measured 
variables with baseline measures as covariables. Kaplan Meier curves will be displayed for 
time-to-event data.   
 
13. ETHICAL AND LEGAL CONDUCT OF THE STUDY 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by Good 
Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
 
Documented approval from appropriate IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations.  When 
necessary, an extension, amendment or renewal of the IRB approval must be obtained and 
also forwarded to SARC. 
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
 
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by SARC and the sponsor, Bayer.  However, the investigator may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/SARC/Bayer approval/favorable opinion.  As soon 
as possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution.  Any deviations from the protocol must be explained and documented by the 
investigator. 
 


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The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients.  The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
Subjects will not be paid to participate in this study. 
  
13.1 Subject information and consent 
 
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 
 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  
The subject / legal representative or proxy consenter will receive a copy of the signed and 
dated form. 
 
The signed informed consent statement will be uploaded into the database and will remain in 
the investigator site file or, if locally required, in the patient’s note/file of the medical 
institution. 
 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of Bayer and the investigator).  
This is to be documented by a signature from the informing physician as well as by a 
signature from the witness. 
 
2. For minors or adults under legal protection, consent shall be given by the legal 
guardian(s).  The consent of a minor or adult under legal protection shall also be requested 
where such a person is able to express his/her own will.  His/her refusal or the withdrawal of 
his/her consent may not be disregarded. 
 
3. In emergency situations, when prior consent of the patient is not possible, the consent of 
the patient’s legal representative(s) or proxy consenter, if present, should be requested.  The 
patient should be informed about the study as soon as possible and his/her consent to continue 


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the study should be requested. 
 
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form.  The investigator will inform the subject / legal representative 
or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use. 
 
     13.2 Publication policy  
 
Timely publication is central to SARC’s mission.  A manuscript should be prepared and 
submitted for publication within one year of availability of the study results. Authorship will 
align with the SARC publication policy. 
 
     13.3 Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual. 
 
 


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14. REFERENCES 
 
 
1. 
van der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue 
sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. 
Lancet 379:1879-86, 2012 
 
2. 
Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis 
inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II 
study from the European organisation for research and treatment of cancer-soft tissue and 
bone sarcoma group (EORTC study 62043). J Clin Oncol 27:3126-32, 2009 
 
3. 
George S, Merriam P, Maki RG, et al: Multicenter phase II trial of sunitinib in the 
treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 27:3154-60, 2009 
 
4. 
Hensley ML, Sill MW, Scribner DR, Jr., et al: Sunitinib malate in the treatment of 
recurrent or persistent uterine leiomyosarcoma: a Gynecologic Oncology Group phase II 
study. Gynecol Oncol 115:460-5, 2009 
 
5. 
Stacchiotti S, Tamborini E, Marrari A, et al: Response to sunitinib malate in 
advanced alveolar soft part sarcoma. Clin Cancer Res 15:1096-104, 2009 
 
6. 
Stacchiotti S, Grosso F, Negri T, et al: Tumor response to sunitinib malate 
observed in clear-cell sarcoma. Ann Oncol 21:1130-1, 2010 
 
7. 
Grignani G, Palmerini E, Dileo P, et al: A phase II trial of sorafenib in relapsed 
and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an 
Italian Sarcoma Group study. Ann Oncol 23:508-16, 2012 
 
8. 
George S, Wang Q, Heinrich MC, et al: Efficacy and safety of regorafenib in 
patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and 
sunitinib: a multicenter phase II trial. J Clin Oncol 30:2401-7, 2012 
 
9. 
Demetri GD, Reichardt P, Kang YK, et al: Efficacy and safety of regorafenib for 
advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): 
an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 
381:295-302, 2013 
 
10. 
Davis MI, Hunt JP, Herrgard S, et al: Comprehensive analysis of kinase inhibitor 
selectivity. Nat Biotechnol 29:1046-51, 2011 
 
11. 
Pappo AS, Patel SR, Crowley J, et al: R1507, a monoclonal antibody to the 
insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing 
sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through 
Collaboration study. J Clin Oncol 29:4541-7, 2011 
 
12. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 
63:11-30, 2013 
 
13. 
Brennan MF, Antonescu CR, Maki RG: Management of soft tissue sarcoma. New 
York, Springer, 2013  
 
14. 
Demetri GD, Chawla SP, von Mehren M, et al: Efficacy and safety of trabectedin 
in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of 
prior anthracyclines and ifosfamide: results of a randomized phase II study of two 
different schedules. J Clin Oncol 27:4188-96, 2009 
 
15. 
Pappo AS, Anderson JR, Crist WM, et al: Survival after relapse in children and 
adolescents with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma 
Study Group. J Clin Oncol 17:3487-93, 1999 
 
16. 
Mascarenhas L, Lyden ER, Breitfeld PP, et al: Randomized phase II window trial 


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of two schedules of irinotecan with vincristine in patients with first relapse or progression 
of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 
28:4658-63, 2010 
 
17. 
Missiaglia E, Williamson D, Chisholm J, et al: PAX3/FOXO1 fusion gene status is 
the key prognostic molecular marker in rhabdomyosarcoma and significantly improves 
current risk stratification. J Clin Oncol 30:1670-7, 2012 
 
18. 
Sultan I, Qaddoumi I, Yaser S, et al: Comparing adult and pediatric 
rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 
2005: an anlysis of 2,600 patients. J Clin Oncol 27:3391-7, 2009 
 
19. 
Mascarenhas L, Meyer WH, Lyden E, et al: Randomized phase II trial of 
bevacizumab and temsirolimus in combination with vinorelbine (V) and 
cyclophosphamide (C) for first relapse/disease progression of rhabdomyosarcoma (RMS): 
a report from the Children's Oncology Group (COG). J Clin Oncol 32:5s, 2014 (suppl; 
abstr 10003) 
 
20.  
Wilhelm SM, Dumas J, Adnane L, et al: Regorafenib (BAY 73-4506): a new oral 
multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with 
potent preclinical antitumor activity. Int J Cancer 129:245-55, 2011 
 
21. 
Daudigeos-Dubus E, Le Dret L, Lanvers-Kaminsky C, et al: Regorafenib: 
antitumor activity upon mono and combination therapy in preclinical pediatric malignancy 
models. PLoS One 10: e0142612, 2015 
 
22. 
Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for 
previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. Lancet 381:303-12, 2013 
 
23. 
Levey AS, Coresh J, Greene T, et al: Using standardized serum creatinine values 
in the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med 145:247-54, 2006 
 
24. 
Choi H, Charnsangavej C, Faria SC, et al: Correlation of computed tomography 
and positron emission tomography in patients with metastatic gastrointestinal stromal 
tumor treated at a single institution with imatinib mesylate: proposal of new computed 
tomography response criteria. J Clin Oncol 25:1753-9, 2007 
 
 
 
 


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APPENDIX A: Performance Status Criteria 
 
 
WHO Performance Status Scale 
Grade 
Descriptions 
0 
Asymptomatic (Fully active, able to carry on all pre-disease activities 
without restriction) 
1 
Symptomatic but completely ambulatory (Restricted in physically 
strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature. For example, light housework, office work) 
2 
Symptomatic, <50% in bed during the day (Ambulatory and capable of 
all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours) 
3 
Symptomatic, >50% in bed, but not bedbound (Capable of only limited 
self-care, confined to bed or chair 50% or more of waking hours) 
4 
Bedbound (Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair) 
5 
Deceased 
 
 
 
 
 


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APPENDIX B.  SARC024 Fax/Email Coversheet and MedWatch form 
 
 
 
24 Frank Lloyd Wright Dr. 
Ann Arbor, MI 48105 
Tel.  734-930-7600 
Fax. 734-930-7557 
sarc024@sarctrials.org 
 
Fax or email to the following within 24 hours of PI becoming aware of event:  
sarc024@sarctrials.org; Fax: (734) 930-7557 
 
Study Title 
SARC024: A blanket protocol to study oral 
regorafenib in patients with selected sarcoma 
subtypes 
Site PI Name 
 
Patient Unique Study # 
 
Adverse Event (CTCAE v4.03) 
 
Adverse Event Grade 
 
Adverse Event Causality 
Relationship 
 Yes                              
 No                  
Type of Report (Check one) 
 Initial         Follow-up 
All serious adverse events will be reported and documented on Form FDA 3500 A (MedWatch 
Form) Please fax completed MedWatch Form along with this Fax Coversheet. 
 
Completed by: 
 
Date: 
 
 
 
 


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APPENDIX C. Study Drug Diary Template 
 
(See subsequent page) 
 


73 
 
SARC024 Study Drug Diary 
ONLY TAKE STUDY DRUG FOR 3 WEEKS (21 DAYS).  DO NOT TAKE ANY STUDY DRUG DURING WEEK 4 OF EACH CYCLE. 
*  If you are 8 hours or more late from your scheduled dose, do not take the dose, and please write “M” in the box. 
** Check blood pressure every week. 
*** Rate nausea “1” if you are able to eat and drink a reasonable amount, “2” if you can eat and drink but the amount is decreased significantly, or “3” if you can’t eat and 
drink. 
Note: Try to take the study drug daily at the same time, if possible, and consistently with or without food. Do not retake if vomiting occurs. 
Grapefruit/grapefruit juice must be avoided while on study 
Your initials/Parent or guardian initials: __________________ 
To be completed by the site: Patient ID: ____________________________          Cycle number: ______             Cycle Start Date __________   
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug  
Number of tablets taken* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for missed dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Watching for Side Effects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea*** 
(see scale below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting  
(number of times) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea  
(number of times) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Watching for Other Side 
Effects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


74 
 
APPENDIX D. Strong CYP3A4 inducers and inhibitors 
 
Listing of strong CYP3A4 inducers to avoid while on study 
 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifampin 
St. John’s wort 
 
Listing of strong CYP3A4 inhibitors to avoid while on study 
 
Clarithromycin 
Grapefruit juice 
Itraconazole 
Ketoconazole 
Posaconazole 
Telithromycin 
Troleandomycin 
Voriconazole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: U.S. Food and Drug Administration: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm 
Accessed - 04/04/2017