Clinical trial NCT02259725
Conditions: Gastrinoma Glucagonoma Insulinoma Metastatic Gastrointestinal Carcinoid Tumor Pancreatic Polypeptide Tumor Pulmonary Carcinoid Tumor Recurrent Gastrointestinal Carcinoid Tumor Recurrent Islet Cell Carcinoma Somatostatinoma
Sponsor: University of Southern California
Start date: 2016-08-16; Completion date: 2020-08-20
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that have spread from the primary site (place where it started) to other places in the body. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess progression-free survival (PFS) in advanced/metastatic in patients with carcinoid or pancreatic islet cell tumors.

SECONDARY OBJECTIVES:

I. To assess overall survival and response rate in advanced/metastatic poor prognosis in patients with carcinoid or pancreatic islet cell tumors.

II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors.

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: regorafenib intervention 2: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
0S-14-3 
0S-14-3: Phase II Study of Single Agent Regorafenib in Patients with Advanced/Metastatic 
Neuroendocrine Tumors 
NCT #: NCT02259725 
Principal Investigator: 
Syma Iqbal, MD, FACP 
USC/Norris Cancer Center 
1441 Eastlake Avenue, 
3454 Los Angeles, CA 
90033-9173 323-865-3900 
Fax 323-865-0061 
iqbal@usc.edu 
Co-Investigator(s): 
Heinz-Josef Lenz, MD, FACP 
Anthony El-Khoueiry, MD 
Afsaneh Barzi, MD, PhD 
William Harris, MD 
Seattle Cancer Care Alliance 
University of Washington 
Medicine and Oncology, Cancer Center Clinical Research 
Division 825 Eastlake Avenue East, G4830 
Seattle, WA 98109 
206.688.7175 
Fax: 206.288.2042 
wph3@u.washington.edu 
Thorvardur R. Halfdanarson, 
MD Department of Oncology 
Mayo Clinic 
13400 East Shea Boulevard 
Scottsdale, AZ 
Halfdanarson.Thorvardur@mayo.edu 
Biostatistician: 
Dongyun Yang, PhD 
Study Drug: 
Regorafenib (Stivarga) 
Funding Source: 
Bayer HealthCare Pharmaceuticals 
Initial version: 
6/25/14 
Amended: 
11/21/16, 3/13/18 
Research Office: 
CLINICAL INVESTIGATIONS SUPPORT OFFICE (CISO) 
1441 Eastlake Avenue, Room 
7310E Los Angeles, California 
90089-9177 
Telephone (323) 865-0451 
Email: 
ciso.clinical@med.usc.edu 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use 
except as authorized in writing by the study sponsor. 


0S-14-3 
 
 
 
 
 
0S-14-3: Phase II Study of Single Agent Regorafenib in Patients with Advanced/Metastatic 
Neuroendocrine Tumors 
 
 
Protocol Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:   
 
 
 
 
PI Signature:   
 
 
Institutional Name:   
 
 
Date:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use 
except as authorized in writing by the study sponsor. 


0S-14-3 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................1 
STUDY SCHEMA ..............................................................................................................2 
STUDY SUMMARY ..........................................................................................................2 
1.0 
BACKGROUND AND RATIONALE ...................................................................4 
1.1 
Disease Background........................................................................................................ 4 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 5 
1.3 
Correlative Studies .......................................................................................................... 7 
1.4 
Rationale .......................................................................................................................... 8 
2.0 
STUDY OBJECTIVES ...........................................................................................8 
2.1 
Primary Objectives ........................................................................................................... 8 
2.2 
Secondary Objectives ...................................................................................................... 8 
3.0 
PATIENT ELIGIBILITY .........................................................................................8 
3.1 
Inclusion Criteria .............................................................................................................. 8 
3.2 Exclusion Criteria ........................................................................................................... 10 
4.0 
TREATMENT PLAN ............................................................................................12 
4.1 Treatment Dosage and Administration .......................................................................... 12 
4.2 Toxicities and Dosing Delays/Dose Modifications ......................................................... 13 
4.3 Concomitant Medications/Treatments ........................................................................... 19 
4.5 Duration of Therapy ....................................................................................................... 21 
4.6 Removal of Patients from Protocol Therapy .................................................................. 21 
4.7 Duration of Follow Up .................................................................................................... 21 
5.0 
STUDY PROCEDURES ......................................................................................21 
5.1 Screening/Baseline Procedures .................................................................................... 21 
5.2 Procedures During Treatment ....................................................................................... 23 
5.3 Follow-up Procedures .................................................................................................... 24 
5.4 Study Calendar .............................................................................................................. 25 
6.0 
Measurement of Effect ......................................................................................26 
6.1 Antitumor Effect- Solid Tumors ...................................................................................... 26 
6.2 Safety/tolerability ........................................................................................................... 30 
7.0 
ADVERSE EVENTS ............................................................................................30 
7.1 
Adverse Event Monitoring .............................................................................................. 30 
7.2 
Definitions ...................................................................................................................... 30 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 32 
7.4 Reporting Requirements for Adverse Events ................................................................ 32 
7.5 Monitoring Rules for Safety ...........................................................................................35 
8.0 
DRUG INFORMATION .......................................................................................35 
8.1 
Agent XXX ..................................................................................................................... 35 
9.0 
CORRELATIVES/SPECIAL STUDIES ............................................................37 
9.1 
Archival Tissue .................................................................................................................... 37  
 
9.2 
Plasma Collection ........................................................................................................... 37 
10.0 
STATISTICAL CONSIDERATIONS..............................................................37 
10.1 Study Design/Study Endpoints ...................................................................................... 38 
10.2 Sample Size and Accrual............................................................................................... 38 
10.3 Data Analyses Plans...................................................................................................... 39 
10.4 Reporting and Exclusions .............................................................................................. 39 
11.0 
STUDY MANAGEMENT .................................................................................40 
11.1 Conflict of Interest ......................................................................................................... 40 
11.2 
Institutional Review Board (IRB) Approval and Consent Process ................................. 40 
11.3 Required Documentation (for multi-site studies) ........................................................... 41 
11.4 Registration Procedures ............................................................................................... 41 
11.5 RECORDS AND DATA SUBMISSION ....................................................................... 43 
11.6 Data Management and Monitoring/Auditing ................................................................ 43 


0S-14-3 
 
 
i 
11.7 Adherence to the Protocol ............................................................................................ 46 
11.8 Record Retention ........................................................................................................... 47 
11.9 
Obligations of Investigators ........................................................................................ 47 
12.0 
REFERENCES .................................................................................................49 
 
12.1 Appendix 1: Registration Request Form…………………………………………………...50 


0S-14-3 
 
1 
Protocol version 03.13.2018 
 
LIST OF ABBREVIATIONS 
Examples Include: 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CISO 
Clinical Investigations Support Office 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
MCC 
Multi-site Coordinating Center 
MTD 
Maximum Tolerated Dose 
NCCC 
Norris comprehensive Cancer Center 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 


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Protocol version 03.13.2018 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
 
Title 
Phase II Study of Single Agent Regorafenib in Patients with 
Advanced/Metastatic Neuroendocrine Tumors 
Short Title 
Phase II Study of Regorafenib in Advanced/Metastatic Neuroendocrine 
Tumors 
Protocol Number 
0S-14-3 
Phase 
II 
Methodology 
Open label 
Study Duration 
Estimate one patient per month accrual. If both cohorts accrue past the 
interim the study will take 4 years to complete accrual. 
Study Center(s) 
2 
Objectives 
1. 
To assess PFS in advanced/metastatic in patients with carcinoid 
or pancreatic islet cell tumors 
2. 
To assess OS, RR in advanced/metastatic poor prognosis in 
patients with carcinoid or pancreatic islet cell tumors 
3. 
To assess toxicity of patients treated with regorafenib 
4. 
To   explore   markers  of   angiogenesis  as   they  relate   to 
outcome in carcinoid and pancreatic islet cell tumors. 
Number of Subjects 
Cohort A (Carcinoid Tumors): 11+13=24 
Cohort B (Pancreatic Islet Cell Tumors): 11+13=24 
Signed Informed 
consent + Patient 
registered 
 Regorafenib 80 mg QD 
Week 1/120 mg QD 
Week 2/160 mg QD 
Week 3 then 1 week off 
followed by Cycle 2+ 160 
mg QD D1-21, of a 28 
day cycle 
PD Discontinue 
Protocol treatment 


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Protocol version 03.13.2018 
 
 
Diagnosis 
and 
Main 
Inclusion Criteria 
Advanced metastatic, progressing carcinoid or pancreatic islet cell 
cancers 
*Patients may have received one line of prior therapy with octreotide, 
locoregional therapy.  Continuation of concurrent octreotide is allowed. 
*No prior targeted tx or anti-angiogenic therapy. 
*Patients will be maintained on octreotide (sandostatin) for the duration of 
their treatment. 
*SWOG PS 0-1 
Study Product(s), Dose, 
Route, Regimen 
Regorafenib 80 mg QD Week 1/120 mg QD Week 2/160 mg QD Week 3 
then 1 week off followed by Cycle 2+ 160 mg QD D1-21, of a 28 day 
cycle. 
Duration of administration 
Patients may remain on study until the development of disease, 
development of intolerable toxicity, or any of the criteria for removal of the 
study as set forth in the protocol. 
Statistical Methodology 
The 6-month PFS rate will be the primary endpoint. Two parallel Simon’s 
2-stage phase II trials will be conducted to evaluate the efficacy of 
regorafenib in patients with advanced carcinoid (cohort A) or pancreatic 
islet cell tumors (cohort B). For cohort A, a 6-month PFS rate of 40% would 
be considered as disappointing and 65% or higher would be encouraging. 
For cohort B, a 57% rate would be considered as not interesting, and 80% 
or higher would be promising. We need a total of 24 patients with carcinoid 
tumors (cohort A) and 24 patients with pancreatic islet cell tumors 
(cohort B). 
The study design of both trials has 80% power to demonstrate the efficacy 
of regorafenib. The type I error rate is 5.1% and 5.3%, for cohort A and B, 
respectively. We designed the trials with type I error rate a little higher 
than 5% because the tumors are rare and the sample size should be as 
small as possible. 


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Protocol version 03.13.2018 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Neuroendocrine tumors, which include carcinoid tumors and pancreatic islet cell tumors, are rare 
malignancies, occurring in only 1-2 people per 100,000 in the United States. As these cancers 
cause few symptoms and little pain, most patients are diagnosed with disseminated metastases. 
Patients with metastatic disease have a 5-year survival rate of only 18%.1 Carcinoid tumors and 
pancreatic islet cell tumors both arise from neuroendocrine cells and are histologically 
indistinguishable. Neuroendocrine tumors are usually made up of small cells containing regular, 
well-rounded nuclei with rare mitoses. These tumors often have a slow rate of progression, yet 
patients with metastatic disease eventually develop significant morbidity, including pain, 
diarrhea, constipation, anorexia, weight loss, fatigue, and sometimes episodic flushing, wheezing 
and right sided valvular heart disease. 
 
For patients with neuroendocrine tumors and localized disease, surgery has shown a survival 
benefit. For unresectable disease, however, no treatment with survival benefit has been found. 
Therefore, treatment in this population is currently palliative. Somatostatin analogs are effective 
in relieving the symptoms of both the carcinoid syndrome and the hormonal hypersecretion seen 
with pancreatic endocrine tumors.2 Octreotide may also led to an improvement in PFS as reported 
in a phase II study, although treatment is not necessarily associated with objective responses. 
Some patients benefit from interferon-, but the toxicity of this treatment frequently outweighs 
the small therapeutic benefit.3 Chemotherapy is of limited efficacy in the metastatic population, 
with streptozotocin being the only approved anticancer agent for patients with neuroendocrine 
tumors, only of the pancreatic islet cell type. The combination of streptozocin and doxorubicin has 
been investigated in patients with advanced pancreatic islet cell tumors, with a response rate of 
only 6%. The combination was found to have considerable toxicity, including myelosuppression, 
asthenia and renal insufficiency. Decreases in hormone secretion and improved physical 
examinations were seen in patients treated with this combination, however.4,5 Patients with 
metastatic carcinoid tumors have also shown resistance to chemotherapeutic regimens consisting 
of streptozocin and cyclophosphamide, streptozocin and 5-FU, as well as docetaxel and 
gemcitabine.6-8 Some single agents and drug combinations have shown limited activity 
(response rates of 30% or less) in carcinoid patients (fluorouracil, doxorubicin, dacarbazine, 
cyclophosphamide,fluorouracil plus strotozocin and etoposide plus cisplatin). Complete 
responses with these regimens are rarely seen. The responses that are seen do not usually last 
long.9 There is recent data supporting the role of antiangiogenic agents and mTOR inhibitors in 
this disease. 
 
Generally, NE tumors are hypervascular and VEGF and VEGF receptors have been found to play 
critical roles in angiogenesis in these tumors as expression has been demonstrated both in GI and 
pulmonary carcinoid. In pancreatic islet cell cancers, phase III trials of sunitinib and everolimus 
compared to placebo have now been reported. Both trials enrolled patients with progressive 
disease within the previous 12 months and demonstrated clinically and statistically significant 
improvements in PFS compared to placebo. Both agents have been approved by the US FDA and 
become standard therapy for pancreatic NET (islet cell carcinoma). For patients who participated 
in the sunitinib trial, the median progression-free survival was 11.4 months in the sunitinib group 
as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 


0S-14-3 
 
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Protocol version 03.13.2018 
 
95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of 
progression-free survival according to baseline characteristics favored sunitinib in all subgroups 
studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo 
group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 
deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The 
most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, 
and fatigue. 
 
For patients with pancreatic neuroendocrine tumors who participated in the everolimus study, 
The median progression-free survival was 11.0 months with everolimus as compared with 4.6 
months with placebo (hazard ratio for disease progression or death from any cause with 
everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% 
reduction in the estimated risk of progression or death. Estimates of the proportion of patients 
who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus 
as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly 
grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the 
placebo group), rash(49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections 
(23%vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent 
with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). 
The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 
weeks vs. 16 weeks). 
 
In addition, bevacizumab has demonstrated anti-tumor activity and is currently being evaluated 
in a recently closed SWOG trial, a randomized phase III trial with sandostatin versus interferon 
and sandostatin. 10,11 
 
In the recent, double-blind, placebo-controlled, phase 3 RADIANT-4 trial in advanced, progressive, 
well- differentiated, non-functional neuroendocrine tumors of lung or gastrointestinal origin 
patients were randomly assigned in a 2:1 ratio to receive everolimus 10 mg per day orally or 
identical placebo, both with supportive care. The primary endpoint was progression-free survival 
assessed by central radiology review, analyzed by intention to treat. Overall survival was a key 
secondary endpoint. A total of 302 patients were enrolled, of whom 205 were allocated to 
everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months 
(95% CI 9·2–13·3) in the everolimus group and 3·9 months (3·6– 7·4) in the placebo group. 
Everolimus was associated with a 52% reduction in the estimated risk of progression or death 
(hazard ratio [HR] 0·48 [95% CI 0·35–0·67], p<0·00001). Although not statistically significant, the 
results of the first pre-planned interim overall survival analysis indicated that everolimus might 
be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40–1·05], one-sided p=0·037, 
whereas the boundary for statistical significance was 0·0002). The drug was well tolerated the 
most common toxicities were stomatitis, diarrhea, anemia, fatigue and hyperglycemia. The FDA 
approved everolimus for progressive, well-differentiated non-functional, neuroendocrine tumors 
of gastrointestinal or lung origin in patients with unresectable, locally advanced or metastatic 
disease in February 2016. This has changed the approach and standard treatment options in this 
patient population.12 
 
1.2 
Regorafenib 


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Protocol version 03.13.2018 
 
 
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as 
measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI).13 
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 Ab1 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. 
 
1.2.1 
Preclinical 
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 growth in multiple xenograft models (breast, colon, renal, NSCLC, 
melanoma, pancreatic, thyroid, ovarian). 13 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 antibody.13 These data suggest that 
regorafenib can target the tumor cell MAPK pathway (tumor cell survival) and tumor 
vasculature in some but not all tumors. 
 
1.2.2 
Clinical experience 
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 therapies. 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 three weeks 
on / one 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 two 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 


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Protocol version 03.13.2018 
 
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, 0.418 to 0.581; 1-sided p< .000001). There 
was a substantial difference in disease control rate in the regorafenib and placebo groups 
(44% vs. 15%; p<.000001). Regorafenib demonstrated comparable efficacy benefits across 
patient subgroups analyzed including age, number of mets, 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. 
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 sunitinib. 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 <.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% 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. 
 
Recently data from a randomized Phase II study of regorafenib in refractory metastatic 
colorectal cancer was presented at ASCO GI 2018 by Bekaii-Saab et al.  This study 
randomized patients to Arm A: 80 mg regorafenib per day, with weekly dose escalation of 
40 mg, up to a dose of 160 mg per day if no significant drug-related toxicities were observed 
or Arm B: 160 mg regorafenib per day.  Arm A, the dose escalation arm had patients staying 
on regorafenib longer (43% initiating the 3rd cycle versus 25%, p=.028) and had longer 
overall survival, (9.0 months vs. 5.9 months, p=.094).  Progression free survival was not 
statistically significantly longer for Arm A (2.5 months versus 2.0 months, p=.553), but rates 
of overall grade 3/4 toxicity did favor Arm A (% palmar-plantar erythrodysethesia syndrome 
15 versus 16, hypertension 7 versus 15 and fatigue 13 versus 18).  
 
 
1.3 
Correlative Studies 
There are no validated biomarkers to predict efficacy to anti VEGF or anti VEGFR targeted therapy. 
There are promising markers identified such as VEGF or VEGFR mRNA expression or germline 


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Protocol version 03.13.2018 
 
polymorphisms in these genes which have been shown to be associated with outcomes, however 
no prospective clinical trial with sufficient patient samples has been tested. There is evidence that 
VEGF independent pathways may play a critical role in effectiveness of bevacizumab with data 
showing IL8, CXCR2, IL1beta, or IL6 are associated with outcome either measured by plasma levels 
or germline polymorphisms. 
 
We will obtain archival tumor tissue and plasma samples at baseline and at the time of 
progression to explore the biomarkers of benefit from regorafenib. 
 
1.4 
Rationale 
Regorafenib is a multiple kinase inhibitor (MKI) targeting several receptor tyrosine kinases (RTKs) 
that are involved in tumor progression (VEGFR-2, VEGFR-3, TIE-2, PDGFR-ß, c-KIT, RET and FGFR- 
1) (VEGFR: vascular endothelial growth factor receptor) along with p38α, a member of the MAPK 
family. In cellular mechanistic assays, regorafenib reduced basal phosphorylation of the MAPK 
pathway in a panel of human breast, melanoma, and pancreatic tumor cell lines. In other cellular 
assays, regorafenib was found to be a potent inhibitor of human VEGFR-2, VEGFR-3, TIE-2, c-KIT, 
and PDGFR-ß receptor phosphorylation. In addition, regorafenib blocks VEGF dependent MAPK 
activation in human endothelial cells and PDGF dependent cell proliferation in primary human 
vascular smooth muscle cells.  (BAYER Regorafenib package insert) 
 
Given the potential treatment of neuroendocrine tumors with vegf inhibition, we are proposing a 
phase II study with regorafenib as a single agent in patients with advanced/metastatic NE tumors. 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
2.1.1 
To assess PFS in advanced/metastatic in patients with carcinoid or 
pancreatic islet cell tumors 
2.2 
Secondary Objectives 
 
2.2.1 
To assess Overall Survival and Response Rate in advanced/metastatic poor 
prognosis in patients with carcinoid or pancreatic islet cell tumors 
 
2.2.2 
To assess the toxicity of patients treated with regorafenib 
 
 
2.2.3 
To explore markers of angiogenesis as they relate to outcome in 
carcinoid and pancreatic islet cell tumors.” 
 
3.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. 
 
3.1 
Inclusion Criteria 
 


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Protocol version 03.13.2018 
 
3.1.1 Advanced metastatic, progressing carcinoid or pancreatic islet cell cancers 
 
3.1.2 
No prior chemotherapy or anti-angiogenic therapy. One prior mTOR inhibitor 
is allowed. Patients may have received one line of prior therapy with 
somatostatin analogue, locoregional therapy. Continuation of concurrent 
somatostatin analogue is allowed. Patients will be maintained on 
somatostatin analogue for the duration of their treatment. 
 
3.1.3 
Age ≥ 18 years. 
 
3.1.4 
Life expectancy of at least 12 weeks (3 months). 
3.1.5 Subjects must be able to understand and be willing to sign the written   informed 
consent form.  A signed informed consent form must be appropriately obtained prior 
to the conduct of any trial-specific procedure. 
 
3.1.6 All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF). 
Exceptions to this include alopecia. 
 
3.1.7 Adequate bone marrow, renal and liver function as assessed by the following 
laboratory requirements: 
 
• 
Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
 
• 
Alanine aminotransferase (ALT) and aspartate amino-transferease (AST) 
≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
 
• 
Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
 
• 
Lipase ≤ 1.5 x the ULN 
 
• 
Amylase ≤ 1.5 x the ULN 
 
• 
Serum creatinine ≤ 1.5 x the ULN 
 
• 
International normalized ratio (INR)/ Partial thromboplastin time (PTT) < 
1.5 x ULN. (Subjects who are 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. Close monitoring 
(day 5 of cycle 1 and day 1 of each cycle) is mandatory) will be performed 
until INR/PTT is stable based on a measurement that is pre-dose as defined by 
the local standard of care. 
) 
 
• 
Platelet count > 100,000 /mm3, hemoglobin (Hb) > 9 g/dL, absolute 
neutrophil count (ANC) > 1,500/mm3. Blood transfusion to meet the inclusion 
criteria will not be allowed. 


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3.1.8 
Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the 
Modified Diet in Renal Disease (MDRD) abbreviated formula. 
 
3.1.9 
Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of study drug. Post-menopausal 
women (defined as no menses for at least 1 year) and surgically sterilized 
women are not required to undergo a pregnancy test. The definition of 
adequate contraception will be based on the judgement of the investigator 
 
3.1.10 Subjects (men and women) of childbearing potential must agree to use 
adequate contraception beginning at the signing of the ICF until at least 3 
months after the last dose of study drug. The definition of adequate 
contraception will be based on the judgment of the principal investigator or 
a designated associate. 
 
3.1.11  Subject must be able to swallow and retain oral medication. 
3.1.12 SWOG Performance Status 0-1. 
 
3.1.13 Patients must have measurable disease. 
 
Exclusion Criteria 
 
3.1.14 Previous assignment to treatment during this study. Subjects permanently 
withdrawn from study participation will not be allowed to re-enter study. 
 
3.1.15 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic 
pressure > 90 mm Hg [NCI- CTCAE v4.0] on repeated measurement) despite 
optimal medical management. 
 
3.1.16 Active or clinically significant cardiac disease including: 
 
• 
Congestive heart failure – New York Heart Association (NYHA) > Class II. 
 
• 
Active coronary artery disease. 
 
• 
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
 
• 
Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months before randomization, or myocardial infarction within 6 months 
before randomization. 
 
3.1.17 Evidence or history of bleeding diathesis or coagulopathy. 
 
3.1.18 Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks 
prior to start of study medication. 
 


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Protocol version 03.13.2018 
 
3.1.19 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. 
 
3.1.20 Subjects with any previously untreated or concurrent cancer that is distinct in 
primary site or histology from carcinoid or pancreatic islet cancer except 
cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder 
tumor. Subjects surviving a cancer that was curatively treated and without 
evidence of disease for more than 3 years before randomization are 
allowed. All cancer treatments must be completed at least 3 years prior 
to study entry (i.e., signature date of the informed consent form). 
 
3.1.21 Patients with pheochromocytoma. 
 
3.1.22 Known history of human immunodeficiency virus (HIV) infection or current 
chronic or active hepatitis B or C infection requiring treatment with antiviral 
therapy. 
 
3.1.23 Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
 
3.1.24 Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
 
3.1.25 Renal failure requiring hemo-or peritoneal dialysis. 
 
3.1.26 Dehydration Grade >1 NCI-CTCAE v4.0. 
 
3.1.27 Patients with seizure disorder requiring medication. 
 
3.1.28 Persistent proteinuria  Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by 
urine protein: creatinine ratio on a random urine sample). 
 
3.1.29 Interstitial lung disease with ongoing signs and symptoms at the time of 
informed consent. 
 
3.1.30 Pleural effusion or ascites that causes respiratory compromise (≥ NCI-
CTCAE version 4.0 Grade 2 dyspnea). 
 
3.1.31 History of organ allograft (including corneal transplant). 
 
3.1.32 Known or suspected allergy or hypersensitivity to any of the study drugs, 
study drug classes, or excipients of the formulations given during the course 
of this trial. 
 
3.1.33 Any malabsorption condition. 
 
3.1.34 Women who are pregnant or breast-feeding. 
 
3.1.35 Any condition which, in the investigator’s opinion, makes the subject 


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Protocol version 03.13.2018 
 
unsuitable for trial participation. 
 
3.1.36 Substance abuse, medical, psychological or social conditions that may 
interfere with the subject’s participation in the study or evaluation of the 
study results. 
 
3.1.37 Patients with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and 
other adverse events. 
 
3.1.38 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to regorafenib or other agents used in study. 
 
3.1.39 Uncontrolled, intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.1.40 Excluded therapies and medications, previous and concomitant 
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study 
treatment (regorafenib). 
• Prior use of regorafenib. 
• Concurrent use of chemotherapy, radiotherapy or another investigational drug or 
device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial 
entry (signing of the informed consent form) 
 
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days before start of study medication. 
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 
 
4.1 
TREATMENT PLAN 
 
4.1 
Treatment Dosage and Administration 
 
Regorafenib 80 mg QD Week 1/120 mg QD Week 2/160 mg QD Week 3 then 1 week off 
followed by Cycle 2+ 160 mg QD D1-21, of a 28 day cycle. 
 
Regorafenib 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 (i.e. Special K), 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 


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Protocol version 03.13.2018 
 
protein, 93 g of carbohydrate, 520 calories. 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed for the development of toxicity according to the Study 
Calendar. Toxicity will be assessed according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made according 
to the system showing the greatest degree of toxicity. 
 
 
4.2.1.1 Dose Levels and Reductions 
Study medication will be administered on a 3 weeks on/1week off schedule [3 weeks 
out of every 4]. A new cycle of therapy can start when all toxicities, (except hand-
foot 
syndrome, 
alopecia, 
non- refractory nausea/vomiting, non-refractory 
hypersensitivity and nonclinical and asymptomatic laboratory abnormalities) have 
resolved to Grade 2 or less. Hand-foot syndrome must have resolved to Grade 0-1. 
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. 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. 
Strictly follow the modification in the following tables for the first two cycles until 
individual treatment tolerance can be ascertained.  Thereafter, these modifications 
should be regarded as guidelines to produce mild-to-moderate, but not debilitating, 
side effects.  If multiple adverse events are seen, administer dose based on greatest 
reduction required for any single adverse event observed.  Reductions or increases 
apply to treatment given in the preceding cycle and are based on adverse events 
observed since the prior dose.   
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol version 03.13.2018 
 
Dose Level 
 
 
If no SDRT 
If + SDRT** 
Dose level 
0*  
80 mg po qd 
Two 40-mg tablets of regorafenib 
Proceed to next 
dose level 
 
Dose level  1 120 mg po qd Three 40-mg tablets of regorafenib Proceed to next 
dose level 
Decrease to 80 mg 
Dose level  2 160 mg po qd Four 40-mg tablets of regorafenib 
 
Decrease to 120 mg 
* Starting Dose 
** SDRT=  Significant Drug Related Toxicities 
If a subject experience more than one toxicity, dose reduction should be according 
to the toxicity with the highest grade 
In the case of two or more toxicities of the same grade, the investigator may dose 
reduce according to that deemed most causally related to study treatment 
 
The following tables outline dose adjustments for toxicities related to study drug 
except hand-foot skin reaction, hypertension and liver function test abnormalities. 
 
Table  1: 
Recommended  dose  modification  for  toxicities  except  hand-foot-skin    reaction, 
hypertension and ALT/ST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose 
Modificationb 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ 
Grade 2c 
Reduce by 1 
dose level 
If toxicity remains < 
Grade 2, dose re- 
escalation can be 
considered at the 
discretion of the 
treating 
investigator. If 
dose is re- 
escalated and 
toxicity (≥ Grade 3) 
recurs, institute 
permanent dose 
reduction. 
Grade 4 
Delay until ≤ 
Grade 2c 
Reduce by 1 
dose level. 
Permanent 
discontinuation 
can 
be 
considered at 
treating 
investigator’s 
discretion. 


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a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
version 4.0 
b. Excludes alopecia, non-refractory nausea/vomiting, lymphocyte count decreased, 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. 
 
The table above outlines dose adjustments for hematologic and non-hematologic toxicities related 
to regorafenib except HFSR and hypertension. 
 
In addition to these recommended dose modifications, subjects who develop diarrhea, 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 2: Grading for Hand-Foot-Skin-Reaction 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE 
v4.0 
Palmar-plantar 
erythrodysesthesia 
syndromea 
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 
changes 
Numbness, dysesthesia / 
paresthesia 
tingling, 
painless 
swelling, 
or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
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. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
Table 3  Recommended dose modification for hand-foot-skin reaction (HFSR)a 
Grade of event 
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain 
dose level and immediately 
institute 
supportive measures for symptomatic relief 


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Protocol version 03.13.2018 
 
Grade 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 Grade 0-1 b, c 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1.c 
When resuming treatment, treat at reduced dose  level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one dose 
level. b, d 
4th occurrence 
Discontinue therapy 
Grade 3 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves to 
Grade 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 
Grade 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 Grade 0-1 after dose reduction, dose re-escalation is not permitted.  
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued 
permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
 
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. 
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. 


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Protocol version 03.13.2018 
 
• 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 Grade 
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 
 
Hypertension 
Hypertension is a known AE associated with regorafenib treatment. Subject will have their blood 
pressure measured at least weekly at the study site during the first 6 weeks of treatment. 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 v4.0), 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 4 outlines suggested dose reductions. 
 
Table 4:  Management of Treatment-Emergent Hypertension 
Grade of event 
(CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
Grade 1 
Prehypertension (systolic 
BP  120  -  139  mmHg    or 
diastolic BP 80 - 89 mmHg) 
None 
• Continue regorafenib 
• Consider increasing blood pressure 
(BP) monitoring 
 


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Protocol version 03.13.2018 
 
Grade 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 
• If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 
90 mm Hga. When regorafenib is 
restarted, continue at the same dose 
level. 
Grade 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 until diastolic BP ≤ 90 
mm Hg, and if symptomatic, until 
symptoms resolve.a 
• When 
regorafenib 
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 level.b 
• If Grade 3 hypertension recurs despite 
dose reduction and antihypertensive 
therapy, reduce another dose level.c 
Grade 4 
Life-threatening 
consequences 
 
(eg, 
malignant hypertension, 
transient or permanent 
neurologic 
deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per investigator’s 
discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 
 
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 5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia 
may occur in patients with Gilbert’s syndrome. 
 
 
test abnormalities 
Observed 
elevations 
of ALT and/or AST 
Occurrence 
Recommended measures and dose modification 
Table 5: Recommended measures and dose modifications in case of drug-related liver function 


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19 
Protocol version 03.13.2018 
 
< 5 times upper limit of 
normal 
(ULN) 
(maximum Grade 2) 
Any 
occurrence 
Continue Regorafenib 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 
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 
treatment, 
reduce dose by 40 mg (one tablet), and monitor liver 
function weekly for at least 4 weeks. 
Re- 
occurrence 
Discontinue treatment with Regorafenib permanently. 
>20 times ULN 
(Grade 4) 
Any 
occurrence 
Discontinue treatment with Regorafenib permanently. 
>3 times ULN (Grade 2 
or 
higher) 
with 
concurrent bilirubin >2 
times ULN 
Any 
occurrence 
Discontinue treatment with Regorafenib permanently. 
Monitor liver function weekly until resolution or return 
to baseline. 
Exceptions: patients with Gilbert’s syndrome who 
develop elevated transaminases should be managed as 
per the above outlined recommendations for the 
respective observed elevation of ALT and/or AST. 
Weekly LFT monitoring for the first two cycles is required. 
 
4.2.1.2 
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-diarrheas and optimized hydration status). 
Anti-diarrhea 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. 
 
4.3 
Concomitant Medications/Treatments 
 
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 (including contrast media) taken within 2 weeks prior to the start of the 
study and during the study must be recorded in the subject’s source documentation and in the CRF 
(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 medication should be 


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Protocol version 03.13.2018 
 
avoided, if possible. 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga 
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 Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s Wort) 
Co administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160mg 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 Stivarga with strong inhibitors of CYP3A4 
activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazadone, posaconazole, 
telithromycin, and voriconazole). 
 
 
Permitted concomitant therapy includes: 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• Palliative radiation therapy is allowed if the target lesion(s) are not included within the 
radiation field and no more than 10% of the bone marrow is irradiated. 
• Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors may 
be used in the management of acute toxicity, such as febrile neutropenia, when clinically 
indicated or at the investigator’s discretion. However, they may not be substituted for a 
required dose reduction. Subjects are permitted to take chronic erythropoietin. 
• 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 
• Octreotide 
• 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. Close 
monitoring (day 5 of cycle 1 and day 1 of each cycle) is mandatory. If either of these 
values are above the therapeutic range, the doses should be modified and the assessments 
should be repeated weekly until they are stable. 
The following are not permitted: 
• Other investigational treatment during or within 30 days before starting study treatment 
• 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, cycloosporin, and digoxin). 
Warfarin is metabolized by the cytocrome enzyme CYP2C9 and it’s levels may be 


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Protocol version 03.13.2018 
 
especially affected by regorafenib 
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 
4.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
4.5 
Removal of Patients from Protocol Therapy 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation of treatment will 
be documented and may include: 
• 
Patient withdraws consent (follow-up); 
• 
Patient is unable to comply with protocol requirements; 
• 
Patient demonstrates disease progression (unless continued treatment with study 
drug is deemed appropriate at the discretion of the investigator); 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
• 
Treating physician determines continuation on the study would not be in the 
patient’s best interest; 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
• 
Development of second malignancy (except for basal cell carcinoma or squamous 
cell carcinoma of the skin) that requires treatment, which would interfere with this 
study; 
• 
Lost to follow-up. If a research subject cannot be located to document survival after 
a period of 2 years, the subject may be considered “lost to follow-up.” All attempts 
to contact the subject during the two years must be documented in CRF’s. 
 
 
4.6 
Duration of Follow Up 
Patients will be followed with phone calls every 3 months until death after removal from 
treatment. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
5.0 
STUDY PROCEDURES 
 
5.1 
Screening/Baseline Procedures 


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Protocol version 03.13.2018 
 
 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even 
if the studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 7 days prior to registration for labs, 
28 days for scans unless otherwise stated. The screening procedures include: 
 
5.1.1 
Medical history. Complete medical and surgical history, history of infections. 
 
5.1.2 
Demographics. Age, gender, race, ethnicity 
 
5.1.3 
Review subject eligibility criteria 
 
5.1.4 
Review previous and concomitant medications 
 
5.1.5 
Physical exam including vital signs (temperature, pulse,    respirations, blood 
pressure), height, weight 
 
5.1.6 
SWOG Performance status 
 
5.1.7 
Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. 
 
5.1.8 
Hematology, coagulation 
 
5.1.9 
Blood draw for correlative studies: 
 
Two purple top tubes to the Lenz lab, See Section 9.0 for details. 
 
5.1.10 
Serum chemistries: Phosphorus, Magnesium, LDH and Comprehensive 
metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin. 
 
5.1.11 
Urine Pregnancy test (for females of child bearing potential) 
 
5.1.12 
Tumor assessment 
 
5.1.13 
Thyroid Function (TSH, T3, T4), 5HIAA, Lipase 
 
5.1.14 
EKG 
 
5.1.15 
Serum Chromogranin 
 
5.1.16 
Ocreotide scan 
5.1.17 
Urinalysis for proteinuria 
 
5.1.18 
Archival tumor tissue 
 
5.1.19 
CXR if CT of chest is not done 
 


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Protocol version 03.13.2018 
 
5.2 
Procedures During Treatment 
 
5.2.1 
Prior to Each Treatment Cycle 
 
• Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure), height, weight 
• Hematology 
• Concomitant medications 
• Urine pregnancy test (if woman of childbearing potential) 
• EKG, PT/PT-INR, PTT, Thyroid Function (TSH, T3, T4) if clinically indicated 
• SWOG performance status 
• Urinalysis for proteinuria 
• Serum chemistries: Phosphorus, Magnesium, LDH and Comprehensive 
metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin. 
• Adverse event evaluation 
• 5HIAA 
• Pill Diary 
• Lipase 
 
5.2.2 
Day 8, 15 and 22 of Cycle 1 and 2 only 
 
• BP Monitoring 
• Liver Function Tests 
 
 
5.2.3 
Day 15 of all Cycles 
 
• Serum chemistries: Phosphorus, Magnesium, LDH and Comprehensive 
metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), glucose, and total bilirubin. 
• Hematology 
 
 
5.2.4 
One day of week 3 of Cycle 2 only 
 
• 
Octreotide scan 
 
5.2.5 
One Day of Week 3 of every other Cycle (starting with Cycle 2) 
 
• Serum Chromogranin 
• Tumor Assessment 
 
5.2.6 
Off Study 
• Pill Diary 
• SWOG Performance Status 
• Vital Signs 
• Blood draw for correlative studies - Two purple top tubes to the Lenz lab, See 
Section 9.0 for details 
 


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5.3 
Follow-up Procedures 
Patients will be followed with phone calls every 3 months until death after removal from 
treatment. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
 


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Protocol version 03.13.2018 
 
 
5.4 
Study Calendar 
Cycles will be 28 Days. Regorafenib will be taken orally Days 1-21 of each Cycle. 
For first cycle all labs and EKG should be done within 7 days of first receiving 
study drug. For the first cycle, Imaging studies should be done within 28 days of 
first receiving study drug. 
Table 6 
Parameter 
Pre- 
Treatment8 
Day 1 of 
All 
Cycles1
2 
Day 8, 
Day 15 
And 22 
of Cycle 
1 and 
2 only12 
Day 15 
of all 
Cycles1
2 
One 
Day of 
Week 3 
Of every 
other 
Cycle 
(starting 
with Cycle 
2) 
Off 
study 
Follow-up 
Informed Consent 
X 
Pill Diary 
X 
X 
History & Physical Exam 
X 
X 
Weight, SWOG Performance Status, 
Con Meds 
X 
X 
X 
Adverse Event/Toxicity Evaluation 
X 
X 
WBC (differential), Hgb, Platelets 
X 
X 
X 
Complete Metabolic Panel, Phosphorus, 
Magnesium, LDH 
X 
X 
Liver 
function 
X 
Lipase 
X 
X 
Thyroid Function (TSH, T3, T4) 
X 
X3 
PT/PT-INR, PTT 
X 
X3,9 
Urinalysis for proteinuria 
X 
X 
5HIAA 
X 
X 
Serum Chromogranin 
X 
X 
Octreotide scan 
X 
Cycle 2 only 
EKG 
X 
X3 
CXR (if CT of chest not done) 
X7 
X7 
BP Monitoring 
X 
X 
Radiology, x-ray or Scans for disease 
measurement2 
X8 
X 
X10 
Archival tumor tissue 
X8 
Plasma 
X8 
X8 
Urine Pregnancy Test 
X5 
X5 
Survival Follow-up 
X11 
 
1 
If used to follow measurable disease. 
2 
Within 28 days of Cycle 1, Day 1. 
3 
As clinically indicated. 
4 
Paraffin embedded tissue must be available for review. 
5 
For women of childbearing potential 
6 
Confirm response within 4 weeks. 
7 
Not required if CT scan of the chest is done. 
8 
See section 9. For plasma two purple top tubes to the Lenz lab. 
9 
Close monitoring (day 5 of cycle 1 and day 1 of each cycle) of PT/PT-INR and PTTis mandatory for 
patients on agents such as warfarin and heparin. 
10 Patients that come off for reasons other than disease progression will have their standard of care scans 
measured via RECIST until progressive disease, to determine date of disease progression 
11 Patients will be followed up via phone call, medical records or database search until death to determine survival time 
12 All study visits allow a +/ - 7 day window  
 
 


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6.0 
Measurement of Effect 
 
6.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 
criteria. 
 
6.1.1 
Definitions 
Evaluable for toxicity. All patients will be included in the toxicity summaries, 
from the time of their first treatment with study drug. 
 
All patients must be accounted for in the summary of objective response 
(see Section 10.4 for more details). To formally classify a patient as RECIST-
evaluable, only those patients who have measurable disease present at 
baseline, and have had their disease re-evaluated will be considered 
evaluable. 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.) 
 
 
6.1.2 
Disease Parameters (RECIST 1.1) 
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 with conventional techniques (CT, MRI, x-ray) or as >10 
mm with spiral CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation 
therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including 
small lesions (longest diameter <20 mm with conventional techniques or <10 
mm using spiral CT scan), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
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) and their suitability for accurate repeated measurements (either 
by imaging techniques or clinically). A sum of the longest diameter (LD) for all 


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Protocol version 03.13.2018 
 
target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
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-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 or absence of each should 
be noted throughout follow-up. 
 
6.1.3 
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 28 days 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 when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 
5 mm contiguous reconstruction algorithm. This applies to tumors of the chest, 
abdomen, and pelvis. 
 
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. 
 
6.1.4 
Response Criteria 
 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined 
by two separate observations conducted not less than 4 weeks apart. 


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Protocol version 03.13.2018 
 
There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. 
There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD recorded since the 
treatment started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): 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 
 
6.1.4.3 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 7 
Target 
Lesions 
Non- 
Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response 
for 
this 
Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 
wks. 
confirmation 
CR 
Non- 
CR/Non- 
PD 
No 
PR 
>4 
wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at   
least once 
>4 wks. from 
baseline 


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Protocol version 03.13.2018 
 
PD 
Any 
Yes or No 
PD 
no prior SD, PR 
or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation 
of treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
6.1.5 
Confirmation of Response: 
Confirmation of response is not required in this trial as response is not the 
primary endpoint. 
 
6.1.6 
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 recurrent 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. 
 
6.1.7 
Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death on study whichever comes first. 
Patients who go off treatment for reasons other than disease progression or 
death will be censored at the time of the last CT scan. 
 
6.1.8 
Time to Treatment Failure (TTF) 
Time to treatment failure is defined as from start of treatment until time to 
progression, death, start of alternate therapy or development of secondary 
malignancy, whichever comes first. 


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Protocol version 03.13.2018 
 
 
6.1.9 
Overall Survival (OS) 
Overall survival is defined as from start of treatment until death due to any cause. 
Otherwise OS is censored on the last day patients are known to be alive. 
 
6.1.10   The primary endpoint: 
 
 
 
The 6-month PFS rate is the primary endpoint. The 6-month PFS is dichotomous, 
yes or no. Radiographic scan for disease measurement that is done within ±14 
days of the 6-month landmark (Day 182 since first receiving study drug) will be 
counted to determine the 6-month PFS status. Patients who are alive and 
progression-free at 6 months (182 days) since first starting regorafenib will be 
counted as ‘yes’ for the 6-month PFS. Patients who progress or die within 6 
months of starting regorafenib will be counted as ‘no’ for the 6-month PFS. 
Patients whose status of progression or death at 6 months is unknown due to 
early withdrawal, loss-of-follow-up, or other reasons will be also counted as ‘no’ 
for 6-month PFS. 
 
6.2 
Safety/tolerability 
Analyses of safety/ toxicity will be performed for all patients having received at least 
one dose of study drug. The study will use the CTCAE version 4 for reporting of non-
hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified 
criteria for hematologic adverse events. 
 
7.1 
ADVERSE EVENTS 
 
7.1 
Adverse Event Monitoring 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of Subjects enrolled in the studies as well as 
those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care. 
 
All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until: 
➢ the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline; 
➢ any abnormal laboratory values have returned to baseline; 
➢ there is a satisfactory explanation other than the study drug for the 
changes observed; or 
➢ death. 
 
7.2 
Definitions 
 
7.2.1 
Definition of Adverse Event 


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Protocol version 03.13.2018 
 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this 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 an experimental 
intervention, whether or not related to the intervention. 
 
7.2.2 
Severity of Adverse Events 
 
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
 
7.2.3 
Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
 
7.3.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
 
7.3.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it 
were more severe). 
 
7.3.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
 
7.3.3.4 
Results in persistent or significant disability or incapacity. 
 
7.3.3.5 
Is a congenital anomaly/birth defect 
 
7.3.3.6 
Is an important medical event 


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Protocol version 03.13.2018 
 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4). 
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy 
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely—The AE is unlikely related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
 
7.4 
Reporting Requirements for Adverse Events 
 
7.4.1 
Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or within 30 
days of the last administration of the study drug. 
• 
Study Chair/USC PI: Syma Iqbal, MD (iqbal_s@med.usc.edu) 
• 
Multi-site Coord./DSMC Coord.: Grace Kim (Grace.Kim@med.usc.edu)_ 
• 
SAE occurring after consent but before first dose will not require reporting. 
 
• 
The Investigator may report serious adverse drug reactions (SADRs) using either: 


0S-14-3 
 
33 
Protocol version 03.13.2018 
 
 
A MedWatch form available at http://www.fda.gov/medwatch/ 
 
All reports shall be sent electronically to: 
 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only: 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 915 
Whippany, NJ 07981-0915 
 
Address: 
100 Bayer Boulevard, Whippany, NJ 07981 
FDX or UPS only 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
 
Phone: 
1-888-842-2937 
The investigator must report to Bayer 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. 
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 to Bayer 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 Bayer and record the cause of death in detail (within 24 hours. 
 
All non-USC sites are required to notify the study chair, Dr. Iqbal and the multi-site 
coordinator of all SAE submissions. Investigators should also report events to their IRB as 
required. 
SAE notification to the FDA: 
• 
USC: study team to work with CISO QA to submit to the FDA using MedWatch 3500A form 
in accordance within the FDA required timelines 
 


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34 
Protocol version 03.13.2018 
 
• 
Non-USC site: study team to notify USC PI within 24hrs of site becoming aware of the event 
by completing a MedWatch 3500A form. USC will review and submit applicable reports to 
the FDA and notify Bayer of the FDA submission. 
The study sponsor, USC, will be responsible for notifying FDA of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible but in no case later than 7 
calendar days after the sponsor's initial receipt of the information. 
 
IRB reporting 
• 
The Institutional IRB must be notified of “any unanticipated problems 
involving risk to subjects or others” in accordance with the Institutional 
policy. Such policies will be provided to the CISO QA prior to enrolling 1st 
patient. The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
• 
The USC NCCC Data and Safety Monitoring Committee (DSMC) must be 
notified within 24 hours of submission of such reportable event to the IRB. 
The patient ID and the study number as well as identifier of the SAE report 
should be submitted to the DSMC Coordinator via email or Fax to the 
attention of the DSMC Coordinator at 323-865-0089. 
• 
The FDA should be notified within 7 business days of any unexpected fatal 
or life-threatening adverse event with possible relationship to study drug, 
and 15 business days of any event that is considered: 1) serious, 2) 
unexpected, and 3) at least possibly related to study participation. 
 
7.4.2 
Routine Reporting 
• 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually 
as part of regular data submission. This report should also be forwarded to 


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Protocol version 03.13.2018 
 
the DSMC Coordinator. A list of all toxicities will be included in the IND 
annual report. 
 
7.5 
Stopping Rules (Monitoring rules for safety) 
Although we expect that regorafenib be well tolerated, the guidelines listed below will be used to 
raise a flag if the number of patients who experience unacceptable toxicity is large enough to 
strongly suggest that the true probability of unacceptable toxicity is 33% or higher. 
 
Unacceptable toxicity will be defined as 
• 
Any Grade 3 non-hematologic toxicity not reversible to Grade 1 or less within 96 hours with 
the exception of Grade 3 diarrhea or 
• 
Any Grade 4 non-hematologic toxicity or 
• 
Any Grade 4 hematologic toxicity not resolving to Grade 1 or less within 5 days, despite 
supportive care or 
• 
Grade 4 neutropenia associated with fever or 
• 
Grade 4 thrombocytopenia. 
 
An unacceptable toxicity, regardless of attribution, observed during any course, will be used in 
the decision to suspend accrual. Two cohorts will be monitored separately. 
To be evaluable for excessive toxicity a patient must complete a minimum of 2 courses of 
treatment or have experienced unacceptable toxicity. Patients who do not complete 2 courses 
and who do not experience any unacceptable toxicity will not be used in the decision to continue 
or suspend accrual to the trials, for reasons for excessive toxicity. Every time unacceptable toxicity 
is observed, the number of patients (X) who have experienced unacceptable toxicity will be 
compared to the number of patients (N) who are evaluable for excessive toxicity. If the number 
of patients, N, is greater than NX, the number given in column 2 of the Table XX, below, then 
accrual will not be suspended. If N is less than or equal to NX, then accrual will be suspended for 
review of the data. 
 
Table XX: Criteria for continuing accrual 
 
X: # pts who experienced a DLT in a cohort 
3 
4 
5 
6 
≥7 
Nx: Suspend trial of # evaluable pts. (N) is  Nx  in a cohort 
5 10 
15 
20 
suspend 
 
Using this rule with 24 patients, the probability of correctly suspending this regimen for 
review toxicities is 0.79 if the true chance of unacceptable toxicity is 33%. The probability 
of falsely suspending this regimen for review toxicities is 0.030, if the true chance of 
unacceptable toxicity is 10%. Estimations of the probabilities of suspending this regimen are 
based on 10,000 simulations. 
 
8.0 
DRUG INFORMATION 
 
8.1 
Regorafenib 
• 
Other names for the drug(s): Stivarga 
 
• 
Classification - type of agent: Tyrosine Kinase Inhibitor 


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Protocol version 03.13.2018 
 
 
• 
Mode of action: Stivarga (regorafenib) is a potent oral multi-kinase inhibitor with 
a kinase inhibition profile targeting angiogenic, stromal and oncogenic receptor 
tyrosine kinases (TK). This distinct anti-angiogenic profile includes inhibition of 
both VEGFR2 and TIE2 TK. 
 
• 
Storage and stability: Store Stivarga at 25°C (77°F); excursions are permitted from 
15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature]. Store tablets 
in the original bottle and do not remove the desiccant. Keep the bottle tightly 
closed after first opening. 
 
Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused 
tablets in accordance with local requirements. 
 
• Protocol dose: 160 mg qd will be administered for 3 weeks on /1 week off. One 
cycle is 28 days. 
 
• Preparation: None 
 
• Route of administration for this study: P.O. 
• Incompatibilities: See 4.3 
 
• Availability: Provided by sponsor free of charge. 
• Side effects: asthenia/fatigue, decreased appetite and food intake, hand-foot 
skin reaction (palmar-plantar erythrodysesthesia), diarrhea, mucositis, weight 
loss, infection, hypertension, dysphonia, gastrointestinal and abdominal pain, rash, 
fever and nausea. See the package insert for a comprehensive list of adverse 
events. 
8.1.1  Return and Retention of Study Drug 
 
Destruction and Return 
At the end of the study, unused supplies of regorafenib should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. The certificate of destruction should be sent to 
Bayer. 
A completed “Unused Study Drug Disposition Form Destruction or Return 
Confirmation” should be sent to Bayer at the following address: 
E-mail: Karen.marini@bayer.com 
OR 
Fax: 973-709-2193 
OR 
Mail: (VP of Medical Affairs named in contract) at 


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37 
Protocol version 03.13.2018 
 
Bayer HealthCare Pharmaceuticals 
6 West Belt 
Wayne, NJ  07470 
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. 
 
The study pharmacist at each participating site will be responsible for maintaining 
a record of shipment, receipt and dispensation of study medication(s). The study 
pharmacist will utilize an NCI drug accountability template for documenting 
dates, and amounts/doses received from the sponsor and dates, patient initials 
and doses dispensed to the patient. 
 
8.1.2 
Treatment compliance 
 
The study Research Coordinator(s) and Data Manager(s) will be responsible for 
drug accountability of dispensed and returned drug in accordance with the CISO 
SOP 8.0.  The CISO standard pill diary in English and Spanish will be used. 
 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
All correlative studies are mandatory. The samples will be collected for correlative studies 
which will be determined by current scientific knowledge available at the end of the study. For 
sites not at USC, store all samples for batch shipping. 
 
9.1 Archival Tissue 
 
Slides require 10 slides of unstained tumor 10 um thick from paraffin embedded tumor blocks 
or fresh frozen tissue. In lieu of slides, a tumor block may be sent. If possible, the tumor 
block should be large enough to provide the slides described above. 
 
9.2 Plasma Collection 
 
The blood will be collected prior to initiation and at time of progression/off study. The 
blood collection will require 2 tubes of blood (two purple top tubes). 
 
Dr. Lenz’s laboratory will receive and process 
information. Heinz-Josef Lenz, MD Laboratory 
USC Norris Cancer Center 
1441 Eastlake Avenue, Laboratory Room 
#5410 Los Angeles, CA 90033 
323-865-0572 
 
10.0 
STATISTICAL CONSIDERATIONS 


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10.1 
Study Design/Study Endpoints 
The 6-month PFS rate will be the primary endpoint (see definition at section 6.1.10). Two 
parallel Simon’s 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib 
in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B).14 Two 
randomized phase III trials [refs 10-11] that were completed for advanced pancreatic islet cell 
tumors observed the median PFS was about 11 months and 6-month PFS rate was 71% in 
arm of the anti-VEGF therapy. Two small phase II trials of anti-VEGF agents that were 
conducted among patients with advanced carcinoid tumor [refs 14-15] showed that the 
median PFS was about 6 months and 6- month PFS rate was 45%. Therefore 6-month PFS rate 
of 65% for patients with advanced carcinoid and 80% for patients with advanced pancreatic 
islet cell tumors would be promising for further investigation. Otherwise observation of 40% 
and 60% 6-month PFS rate would be considered ineffective in the setting of advanced 
carcinoid and pancreatic islet cell tumors, respectively. 
 
For cohort A, a 6-month PFS rate of 40% (under the null hypothesis) would be considered as 
disappointing and 65% or higher (under the alternative hypothesis) would be encouraging. For 
cohort B, a 57% rate (under the null hypothesis) would be considered as not interesting, and 80% or 
higher (under the alternative hypothesis) would be promising. The 6-month PFS rates under 
the null and alternative hypotheses were chosen based on a phase II consortium trial in the similar 
settings (NCI Protocol #: 8233). We need a total of 24 patients with carcinoid tumors (cohort A) and 
24 patients with pancreatic islet cell tumors (cohort B). 
 
10.2 
Sample Size and Accrual 
In cohort A, 11 patients will be enrolled in stage I. If 5 or more patients remain alive and 
progression-free at 6 months, we will continue to enroll until a total of 24 patients are enrolled. 
If 4 or fewer patients out of the first 11 patients remain alive and progression-free at 6 months, 
we will suspend the accrual. If we observe 14 or more patients are alive and progression-free at 
6 months, regorafenib would be considered promising for cohort A as long as it is tolerable. 
 
In cohort B, 11 patients will be enrolled in stage I. If 7 or more patients remain alive and 
progression-free at 6 months, we will continue to enroll until a total of 24 patients are enrolled. 
If 6 or fewer patients out of the first 11 patients remain alive and progression-free at 6 months, 
we will suspend the accrual. If we observe 18 or more patients are alive and progression-free at 
6 months, regorafenib would be considered promising for cohort B as long as it is tolerable. 
 
We will not suspend accrual when the number of patients enrolled meets the goal for the number 
of patients required for stage I in each trial but the decision of suspending the accrual during stage 
I cannot be reached due to the insufficient follow-up. 
 
The study design of both trials has 80% power to demonstrate the efficacy of regorafenib. The 
type I error rate is 5.1% and 5.3%, for cohort A and B, respectively. We designed the trials with 
type I error rate a little higher than 5% because the tumors are rare and the sample size should 
be as small as possible. The sample size calculation was based on a single-arm 2-stage Simon’s 
Minimax phase II Design. An online program (Clinical Trial Design Systems) developed by Duke 
Cancer 
Institute 
was 
used 
to 
perform 
the 
calculation 
(http://www.dukecancerinstitute.org/research/shared-resources/biostatistics/clinical-trial- 


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design-systems/). 
 
 
10.3 
Data Analyses Plans 
Two cohorts will be analyzed separately. The primary data analysis set will include all patients 
who enroll the study and start to receive regorafenib for decision making in accrual and 
warranting further studies. Patients who withdraw the study, are lost to follow-up, or start 
another therapy before the status of 6-month PFS is determined will be counted as ‘no’ for the 
primary endpoint and be included in the primary data analysis set. Patients who drop out the trial 
before starting regorafenib will be replaced and excluded from the primary data analysis set. 
 
The primary endpoint, 6-month PFS rate will be summarized as a proportion of patients who are 
alive and progression-free among all patients in the primary data analysis set. The 95% confidence 
intervals of the 6-month PFS rate will be calculated using the Wilson method. We chose 6-month 
as the cut-off point because it would be easier to compare with the historical data. The tumor 
response will be evaluated by CT scans every 2 cycles starting with week 3 of cycle 2. Six-months 
since starting treatment are 182 days, may not be on the CT scan date. CT scans will not on the 
strict schedules. Additional scans may be conducted to confirm a complete or partial response. 
Patients whose systems deteriorate clinically will be counted as progression event without 
confirmation of CT scans. CT scans that are conducted within ±14 days of the landmark Day 182 
will be used to determine the 6-month PFS status if there are no other scans available to 
determine the status. The detailed status of 6-month PFS will be counted as follows: alive and 
progression-free, disease progression within 6 months, death within 6 months, and progression 
at 6 months unknown due to early withdrawal, toxicities, or other reasons. 
 
A sensitivity analysis of PFS at week 24 will be conducted. The PFS rate at week 24 may provide 
the impact of CT scheduling on estimating the 6-month PFS rate. 
 
In addition, progression-free survival (see definition at section 6.1.7) will be analyzed using 
Kaplan-Meier curves. The median PFS and 95%CIs will be calculated. The probability of 6-month 
PFS will be estimated from the KM curve too. 
 
The secondary endpoints including tumor response rate and OS (see definition at section 6.1.9) 
will be analyzed descriptively. 
 
Tumor response rate will be calculated as a proportion of patients who have either a complete or 
partial response among all patients in the primary data analysis set. The 95% confidence intervals 
will be given. 
 
OS will be analyzed in the same way as PFS. 
 
Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: 
cycle 1 and all cycles, type, and grade: grade 1-2, 3-4, and 5. 
 
10.4 
Reporting and Exclusions 
 
10.4.1 
Evaluation of toxicity. All toxicities experienced by patients who receive 


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any treatment of the study drug(s) will be reported. 
 
10.4.2 
Evaluation of response. All patients included in the study must be 
assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible. Each patient will be assigned 
one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 9) unknown (not assessable, insufficient data). 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who never received any study drug) should be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure. Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate. 
 
The primary analysis will be based on all eligible patients and who received any amount 
of study drug. 
 
10.5 
Data analysis plan for the exploratory objective 
Biomarkers such as mRNA levels or germline variations of genes related to angiogenesis will 
be measured once the study is completed and regorafenib is recommended for further studies 
in the setting. The associations between biomarkers and clinical outcomes (6-month PFS, 
response, PFS, and OS) will be analyzed in univariate analysis first using appropriate 
methods. Multivariable analyses will be conducted to evaluate the independent effect of a 
marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values 
will be adjusted for multiple comparisons. The purpose of the correlative study is to generate 
hypotheses that will be examined for future clinical trials. 
 
 
11.1 
STUDY MANAGEMENT 
 
11.1 Conflict of Interest 
 
All investigators will follow the University conflict of interest policy. Any USC 
investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must 
complete a “Statement of Outside Interests Related to Research” Form. The 
application is reviewed and approved by the Conflict of Interest Review Committee 
(CIRC) USC conflict of interest policy is available at 
http://ooc.usc.edu/conflict-interest-research 
 
11.2 
Institutional Review Board (IRB) Approval and Consent Process 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the consent 
form and protocol and all study related documents used in the study (e.g. QOL 
questionnaire, pill diary, brochure, advertisement etc). 


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In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required by 
the FDA Regulations and local or state regulations. Once this essential information 
has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked 
to give consent to participate in the study by signing a dated IRB-approved consent 
form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the patient and by the person authorized to obtain 
the informed consent 
 
11.3 Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Investigation Support Office (CISO) 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• 
Protocol signature page with Investigator signature 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
 
11.4 Registration Procedures 
Multi-Site Registration: 
All participants in the multi-site trial are subject to central registration, which is used for 
tracking study accrual, checking eligibility, and monitoring adequate participation of 
women and minorities. Subject registration will be conducted through the coordinating 
center at the NCCC-CISO. External sites will identify eligible subjects and verify enrollment 
availability with the MCC prior to consenting patients. The external site is required to 
notify the MCC of a new signed informed consent within 48 business hours and note the 
basic consent information on the screening log. A copy of the consent will accompany the 
complete eligibility packet for verification. The MCC will enter the patient, demographic, 
and consent information in the applicable USC database. The MCC will assign a study 
patient sequence ID and communicate this to the external site. 
 
The Coordinating Center Program Hours are 8 am to 4 pm, Monday through Friday, based 


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Protocol version 03.13.2018 
 
on the PST zone. The MCC will be closed on official government holidays unless otherwise 
indicated. The contact number for the MCC is 323-865-3122. A copy of the registration 
sheet is located in the Appendix. 
 
External sites will verify eligibility prior to submitting documents to the MCC for central 
registration. External sites must submit registration requests to the MCC at least one full 
business day prior to the planned treatment start date. Registration will require the 
external site to submit to the MCC all of the following: 
 
• 
A completed registration form with patient demographics: 
• 
Zip code 
• 
Age 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Initials 
• 
Date of Birth (DOB) 
• 
A completed Eligibility Checklist signed by the investigator 
• 
A copy of the most recently IRB-approved, patient signed informed consent form 
• 
All required screening tests, within the time parameters specified by the protocol study 
calendar 
• 
All other de-identified source documents needed to verify all points of eligibility 
• 
Any On-Study forms for registration specified by protocol 
 
These documents must be securely emailed to the MCC staff. With advance notice 
documents will also be accepted faxed to 323-865-0457. The MCC will verify completeness 
of documents and confirm eligibility. The MCC will enter the registration information in 
the USC OnCore® database. The MCC will then fax or securely email the completed 
Registration Form with the assigned study sequence ID to the external site as confirmation 
of patient registration. 
An external site must maintain a log of all subjects who sign informed consents. The log 
must also document an explanation for exclusion due to screen failure. The MCC will 
provide sites with a Patient Tracking Log at the time of site activation. In the event of 
screen failure, external sites must submit the Screen Failure form to the MCC within one 
business day of determining screen failure. 
 
Participating sites are required to retain, in a confidential manner, sufficient information 
on each subject so that the subject may be contacted should the need arise. 
 
All documents, investigative reports, or information relating to the patient are strictly 
confidential. Any patient specific reports (i.e. Pathology reports, MRI reports, Operative 
reports, etc.) submitted to the CISO-MCC must have the patient’s full name and social 
security number redacted (blacked out) and the assigned CISO-MCC patient ID number, 
protocol number, and site number written in. Patient initials only may be included or 
retained for cross verification of identification. 
 


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A registration verification letter will be emailed (preferred) or faxed to the registering 
site within one working day for patients registered to CISO-MCC multi-site trials. 
Treatment may not be initiated until the site receives this faxed or emailed verification. 
 
USC Registration: 
For patients enrolled at USC, the Research Coordinator must complete the protocol 
eligibility form to ensure that the patient is eligible. The PI will review the patient eligibility 
(with assistance from the Research Coordinator- who will assemble the required source 
documents, and do an initial review) prior to registering the patient on study. 
 
The Research Coordinator or data manager will then register the patient into the Cancer 
Center database, Café, by accessing the Registration forms. Likewise, after the patient has 
completed the study, the Off Study forms in cafe will need to be completed, for Off 
Treatment and Off Study. 
 
11.5 RECORDS AND DATA SUBMISSION 
A. Confidentiality of Records 
The original data collection forms will be kept in secure file cabinets, for USC patients 
forms will be kept in the Clinical Investigations Support Office (CISO). 
 
B.  Patient Consent Form 
At the time of registration, signed and dated copies of the patient Informed Consent with 
the Human Rights and the HIPAA authorization must be given to the patient. Institutional 
policy regarding distribution and location of original consent documents should be 
followed. When a study is opened at two or more institutions, a copy of the signed 
consent and HIPAA should be sent to USC CISO QA team as soon as possible, and not later 
than within 5 business days of obtaining consent. For patients consented at USC/LAC, 
institutional policy should be followed: a copy of ICF and HIPAA should be uploaded 
through True to USC CRO and to CISO QA Team. The original will be kept in the patient 
research chart maintained by the study assigned Data Manager. 
 
C. 
Registration Eligibility Worksheet 
At the time of registration, the completed Eligibility Worksheet will be submitted to the 
QA Monitor at CISO for review of eligibility compliance. 
 
D. Data Collection Forms and Submission Schedule 
If a treatment trial, protocol data will be entered into eCRFs in Café. 
Within two weeks of registration, the data manager will complete the initial set of On 
Study forms and baseline Toxicities 
Within two weeks of completion of each course of treatment, the data manager must 
complete the Course Assessment, Toxicities, and if appropriate Response data. 
• After Off Treatment, within two weeks of each follow up, complete the Follow Up 
forms. 
 
11.6 Data Management and Monitoring/Auditing 
 
11.6.1  Active Monitoring Program Details 


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a. 
Adherence to Protocol/Per Patient: It is the responsibility of the USC Principal 
Investigator (PI) to ensure that patient recruitment and enrollment, treatment, follow-up 
for toxicities and response, and documentation and reporting at USC are all performed as 
specified in the protocol. When a study is opened at two or more institutions, the PI at 
each institution will assume the responsibilities for the day-to-day monitoring of the trial, 
as described below. 
b. 
Day-to-Day Monitoring – Eligibility: At USC, the Study Coordinator will assist the 
Investigator in reviewing eligibility and will assemble the required source documents, and 
do a final review by completing an Eligibility Registration Worksheet. When a study is 
opened at two or more institutions, the PI at each institution will review the patient 
eligibility in accordance with that institution’s policy. For all institutions, the Eligibility 
Registration Worksheet with a copy of Informed Consent and supporting source 
documents will be submitted to CISO QA via email or Fax for verification prior to 
registering the patient on study. 
c. 
Day-to-Day Monitoring – Informed Consent: Prior to registering the patient on study, the 
Study Coordinator will review the informed consent, to ensure that the patient has signed 
and dated the most current IRB-approved form, and that the form has been signed and 
dated by the person obtaining the consent as well as appropriate witnesses. A copy of the 
ICF will also be provided to CISO QA for review. CISO SOP 3.3 will be followed. 
Day-to-Day Monitoring – Treatment: The PI and co-investigators are responsible for 
ensuring that treatment is given per protocol. The Study Coordinator will review the 
treatment orders with the treating investigator. Regardless of who the treating physician 
is, there will be only one responsible Study Coordinator for each study at each of the 
hospitals affiliated with the USC Norris Cancer Center. The treating investigator will 
review the status of each patient on-study, with the Study Coordinator and treating 
physicians, on an on-going basis. When a study is opened at two or more institutions, 
CISO QA will periodically audit medical records for the subjects on study at other 
institutions to ensure compliance and adherence to the protocol. 
d. 
Data Management – Patient Charts: When a study is opened at two or more institutions, 
the policy in place at each institution will be followed for maintaining medical and 
research related records. Such policies will be provided to the CISO QA prior to enrolling 
1st patient. At USC, all written source documents not associated with the study research 
are maintained in the patient chart, which is stored in the Department of Medical Records 
at the appropriate hospital. At the Norris Hospital, the official medical record is the 
Electronic Patient File (EPF). Radiographical images are stored in the Department of 
Radiology and in an electronic system called Synapse. At Los Angeles County General 
Hospital the official medical record is called Affinity. These are the permanent, official 
documents for each patient on-study. A copy of the signed informed consent, physician’s 
notes, orders, test results and pathology notes are maintained in the patients’ hospital 
charts. It is the responsibility of the research staff to ensure that the patient chart contains 
the required documents and work closely with treating investigators to ensure all 
protocol-related assessments are carefully documented. 
e. 
Data Management – Research Charts: When a study is opened at two or more 
institutions, the policy in place at each institution will be followed for maintaining medical 


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Protocol version 03.13.2018 
 
and research related records. Such policies will be provided to the CISO QA prior to 
enrolling 1st patient. At USC, to facilitate adherence to the protocol schedule and data 
management, research charts are created to collect copies of the relevant notes, orders 
and results, that are in the Patient Chart. In Addition, all source documents related to the 
research, such as original informed consent forms, HIPAA Forms, AE assessment 
worksheets, disease response worksheets and NTFs are maintained in the Research 
Charts. Protocol calendars, worksheets, and checklists, are also kept in the research chart. 
These are maintained in the Clinical Investigation Support Office until the study is 
completed and the results are published and no further need is anticipated. These are 
then stored off-site. It is the responsibility of the Data Manager to ensure that the 
research chart contains all the required documents. 
f. 
Data Management – Case Report Forms: It is the responsibility of the Data Manager to 
complete the required case report forms. For in-house trials, case report forms are 
developed for each trial; these are used to finalize the data entry screens in the Cancer 
Center clinical trials database. It is the responsibility of the PI to review the Off-Study 
Summary form which summarizes pertinent toxicity, response and adherence 
information, once the patient has completed treatment. 
 
11.6.2 Quality Assurance Monitoring Committee (QAMC) Oversight 
 
The Quality Assurance and Monitoring Committee (QAMC) of the NCCC has the 
responsibility for study auditing and monitoring for protocol compliance, data accuracy, 
performance of audits and monitoring of accrual. QAMC procedures are detailed in the 
NCCC Data Safety and Monitoring Plan available on CISO Website. 
 
11.6.2.1 QAMC Annual Patient Audits 
The QAMC is responsible for conducting audits and providing the initial review of the 
audits, for all open institutional (i.e. USC initiated), CCCP-sponsored trials, and any trials 
identified by the CIC. These trials are audited by the QAMC once a year. Faculty and staff 
at the Cancer Center involved in clinical research – but not directly involved in the 
research under evaluation – are asked to serve as auditors. Twenty percent of patients 
accrued during the past 12 months – and a minimum of 2 patients – are selected at 
random; however, additional patients may be selected for audit if there is some indication 
that there might have been a problem or unusual circumstance (possibly related to 
compliance, toxicity, response or some indication of an irregularity). The audit involves a 
review of the research chart, hospital medical record (i.e., source documentation) and 
evaluates the following: documentation of eligibility (including failure to obtain 
appropriate informed consent) and baseline status of the patient; documentation of 
adherence to protocol-specified treatment and follow-up; evaluation of toxicity; and 
evaluation of response or other outcome. In addition, for investigative agents, a drug 
audit is also performed for these patients by the Research Pharmacist. In addition, for 
Institutional, Investigator Initiated Trials, Data in the CAFÉ database are compared to the 
information in the medical record. 
 
11.6.2.2 
QAMC Annual Protocol Review 
All open trials are reviewed at least once a year by the QAMC (or more often if stipulated 
by the CIC). This annual review includes the following: evaluation of the current accrual 


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relative to the planned total accrual; examination of gender and minority accrual; 
examination of all reported violations; review of past audits and correspondence with the 
PI; review of results of current audit (by an outside agency or by the NCCC QAMC); review 
of previous correspondence between the PI and the QAMC/DSMC. The QAMC review 
process is detailed in USC NCCC DSM Plan available on the CISO website. 
 
11.6.3 Data and Safety Monitoring Committee (DSMC) Oversight 
The Data and Safety Monitoring Committee (DSMC) is an independent body responsible 
for the safety of study subjects through the review of new protocols to ensure an 
adequate adverse event assessment/reporting plan, study stopping rules and through the 
real-time and periodic monitoring of severe adverse events (SAEs) or those AEs that 
require expedited reporting. The DSMC performs quarterly and annual safety reviews as 
well as interim efficacy/futility analyses on institutional trials. DSMC procedures are 
detailed in USC NCCC DSM Plan available on the CISO website. 
 
11.7 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
 
11.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
 
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change. 
 
11.7.2 Non-Emergency departures from protocol 
A protocol deviation is any variance from an IRB approved protocol. 
If the deviation meets all of the following criteria, it is considered a minor protocol 
deviation that: 
• 
Is generally noted or recognized only after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected 
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
 
If the deviation meets any of the following criteria, it is considered a protocol 
violation: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious noncompliance with federal regulations, State laws, or 
University policies. 


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Protocol Deviations: personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. 
 
Protocol Violations: All protocol violations will be entered in the clinical trial 
database by the Research Coordinator. In addition, Research Coordinator and 
Investigator should report all protocol violations within one (1) week of the 
knowledge of the event using iStar. 
 
 
11.7.3 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required. 
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB as well as to all the sponsoring agencies (FDA, NCI, etc.) for review and for approval 
prior to implementation. It is the responsibility of the study PI to ensure that the 
appropriate agencies have been informed of the proposed amendments and that these 
have been reviewed and approved. 
 
11.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of 
a study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 
11.9 Obligations of Investigators 
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 


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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 entered onto the Case Report Forms. 
Periodically, monitoring visits will be conducted and the Principal Investigator will provide 
access to his/her original records to permit verification of proper entry of data. At the 
completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data.


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12.0 
REFERENCES 
1. 
Kulke, M.H. and R.J. Mayer, Carcinoid tumors. N Engl J Med, 1999. 340(11): p. 858-68. 
2. 
Arnold, R., M. Frank, and U. Kajdan, Management of gastroenteropancreatic endocrine tumors: 
the place of somatostatin analogues. Digestion, 1994. 55 Suppl 3: p. 107-13. 
3. 
Oberg, K., Advances in chemotherapy and biotherapy of endocrine tumors. Curr Opin Oncol, 1998. 
10(1): p. 58-65. 
4. 
Moertel, C.G., et al., Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the 
treatment of advanced islet-cell carcinoma. N Engl J Med, 1992. 326(8): p. 519-23. 
5. 
Cheng, P.N. and L.B. Saltz, Failure to confirm major objective antitumor activity for streptozocin 
and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer, 1999. 
86(6): p. 944-8. 
6. 
Engstrom, P.F., et al., Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic 
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