Conditions: Esophageal Cancer Gastric Cancer
Keywords: BAY 73-4506 (REGORAFENIB) FLUOROURACIL LEUCOVORIN OXALIPLATIN
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effects, good and/or bad, of the drug regorafenib with chemotherapy regime (FOLFOX). This is a a Phase II trial that will study if this new treatment is effective and safe in patients with esophagus and stomach cancer.

Detailed description:

Arms:
arm 1: Regorafenib 160 mg daily on days 4 to 10 and days 18 to 24 as four 40 mg coprecipitate tablets + mFOLFOX on Day 1 and Day 15 of each cycle. Each cycle consists of 28 days. All patients will receive systemic chemotherapy with the mFOLFOX regimen and regorafenib. The specific version of the FOLFOX regimen used at MSKCC is mFOLFOX6. mFOLFOX6 will be given on Day 1 of each cycle. Patients will receive Oxaliplatin 85 mg/m2 IV (over 120 minutes), leucovorin 400 mg/m2 IV (over 120 minutes), 5-FU 400 mg/m2 IVP, and 5-FU 1200 mg/m2/day CIVI x 2 days, every two weeks. Treatment will be performed on the scheduled day ± 7 days. In case of discontinuation of FOLFOX due to cumulative toxicity and administration as a single agent during the study, regorafenib for patient convenience will be administered 160 mg daily for 3 weeks on/1 week off. The 3 weeks on/1 week off schedule is supported by the single agent regorafenib data in colon cancer and GIST.

Interventions: intervention 1: Regorafenib intervention 2: 5-Fluorouracil intervention 3: Leucovorin intervention 4: Oxaliplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 1 of 43
 
 
 
 
 
 
Phase II study of FOLFOX plus regorafenib in patients 
with unresectable or me tastatic e sophagogastric cancer 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Yelena Y. Janjigian, MD 
Medicine/GI Oncology Service 
Co-Principal Investigator(s)/Department: 
David Ilson, MD 
Medicine/GI Oncology Service 
Investigator(s)/Department: 
Geoffrey Ku, MD 
Marinela Capanu, PhD 
Robert Lefkowitz, MD 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
David P. Kelsen, MD 
Nancy Kemeny, MD 
Eileen O‘Reilly, MD 
Leonard Saltz, MD 
Zsofia Stadler, MD 
Diane Reidy, MD 
Neil Segal, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Maeve A. Lowery, MD 
Andrew Epstein, MD 
Anna Varghese, MD 
James Harding, MD 
Armin Shahrokni, MD 
Elizabeth Won, MD 
Han Xiao, MD 
Mila Gorsky, MD 
Audrey Hamilton, MD 
Tina Passalaris, MD 
Sree Chalasani, MD 
Stefan Berger, MD 
Avni Desai, MD 
John Fiore, MD Stuart 
Lichtman, MD Steven 
Sugarman, MD 
Kenneth K. Ng, MD 
Arlyn Apollo, MD 
Pamela  Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD 
Stephanie Smith- Marrone, MD 
Nancy Mills, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Patricia Gabriel, NP 
Erica Kaufmann, NP 
Medicine/GI Oncology Service 
Epidemiology/Biostatistics 
Radiology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Nursing 
Nursing 
Nurisng 
Nursing 
Consenting Professional(s)/Department: 
Yelena Y. Janjigian, MD 
Geoffrey Ku, MD 
Medicine/GI Oncology 
Medicine/GI Oncology 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 2 of 43
 
 
 
 
 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
David Ilson, MD 
David P. Kelsen, MD 
Nancy Kemeny, MD 
Eileen O‘Reilly, MD 
Leonard Saltz, MD 
Zsofia Stadler, MD 
Diane Reidy, MD 
Neil Segal, MD Rona 
Yaeger, MD Kenneth 
Yu, MD Maeve A. 
Lowery, MD Andrew 
Epstein, MD Anna 
Varghese, MD James 
Harding, MD Armin 
Shahrokni, MD 
Elizabeth Won, MD 
Han Xiao, MD 
Mila Gorsky, MD 
Audrey Hamilton, MD 
Tina Passalaris, MD 
Sree Chalasani, MD 
Stefan Berger, MD 
Avni Desai, MD 
John Fiore, MD Stuart 
Lichtman, MD Steven 
Sugarman, MD 
Kenneth K. Ng, MD 
Arlyn Apollo, MD 
Pamela  Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD 
Stephanie Smith- Marrone, MD 
Nancy Mills, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Patricia Gabriel, NP 
Erica Kaufmann, NP 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/GI Oncology 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Nursing 
Nursing 
Nurisng 
Nursing 
Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 3 of 43 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 4 
 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................................. 8 
 
4.1 
Design ................................................................................................................................. 8 
 
4.2 
Intervention.......................................................................................................................... 9 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .............................................................................. 9 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................ 13 
 
6.1 
Subject Inclusion Criteria .................................................................................................. 13 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 14 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 14 
 
8.0 
PRETREATMENT EVALU ATION........................................................................................ 15 
 
9.0 
TREATMENT/INTERVENTION  PLAN................................................................................. 15 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION....................................... 17 
 
11.0 TOXICITIES/SIDE EFFECTS............................................................................................... 19 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 28 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY........................................................................ 29 
 
14.0 BIOSTATISTICS................................................................................................................... 30 
 
15.0   RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 31 
 
15.1 Research Participant Registration .................................................................................... 31 
 
16.0 DAT A M AN AGEMENT ISSUES .......................................................................................... 31 
 
16.1 Quality Assurance............................................................................................................. 31 
 
16.2 Data and Safety Monitoring .............................................................................................. 32 
 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................. 33 
 
17.1 Privacy............................................................................................................................... 33 
 
17.2 Serious Adverse Event (SAE) Reporting .......................................................................... 33 
 
18.0 INFORMED CONSENT PROCEDURES ............................................................................. 40 
 
19.0 REFERENCES...................................................................................................................... 42 
 
20.0 APPENDICES....................................................................................................................... 43 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 4 of 43 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single-arm, Phase II study of regorafenib in combination with 5-Fluorouracil, Leucovorin 
and Oxaliplatin (FOLFOX) as first line therapy in patients with metastatic esophagogastric 
adenocarcinoma. 
 
Primar y Obje ctive: To determine the six months progression free survival (PFS) in the first-line 
treatment of patients with metastatic or unresectable esophagogastric  adenocarcinoma. With a 
total  of  36  esophagogastric   adenocarcinoma  patients ,  we  have  80%  power  to  detect  an 
improvement in the 6-month progression free survival (PFS) from a historical control of  40% to 
61% with type I error rate of 5%. 
 
Se condary Objective: To determine overall survival (OS), response rate, toxicity rates in the 
first-line treatment of patients with metastatic or unresec table esophagogastric adenocarcinoma. 
 
Study population: Patients with newly diagnosed metastatic or unresectable esophagogastric 
adenocarcinoma. Patients must be untreated for metastatic esophagogastric adenocarcinoma, 
except for perioperative therapy > 6 months prior to recurrence. 
 
Study de sign: Single institution, open-label, non-randomized, single-arm phase II 
 
Numbe r of patients: 36 
 
Study drugs: Regorafenib, administered orally 
 
Dose and regimen:   Regorafenib 160 mg daily on days 4 to 10 and days 18 to 24 as four 40 mg 
coprecipitate tablets + mFOLFOX on Day 1 and Day 15 of each cycle. Each cycle consists of 28 
days. Treatment will be administered on an outpatient basis.  All patients will receive systemic 
chemotherapy with the mFOLFOX regimen and regorafenib. There are several variations of the 
basic FOLFOX regimen. The specific version of the FOLFOX regimen used at MSKCC is 
mFOLFOX6. mFOLFOX6 will be given on Day 1 of each cycle.  Patients will receive Oxaliplatin 
85 mg/m2 IV (over 120 minutes), leucovorin 400 mg/m2 IV (over 120 minutes), 5-FU 400 mg/m2 
IVP, and 5-FU 1200 mg/m2/day CIVI x 2 days, every two weeks.  Treatment will be performed on 
the scheduled day ± 7 days.  In case of discontinuation of FOLFOX due to cumulative toxicity and 
administration as a single agent during the study, regorafenib for patient convenience will be 
administered 160 mg daily for 3 weeks on/1 week off.  The 3 weeks on/1 week off schedule is 
supported by the single agent regorafen ib data in colon cancer and GIST. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primar y Obje ctive: 
To determine if the addition if regorafenib to FOLFOX chemotherapy improves 6 month 
progression free survival (PFS) in the first-line treatment of patients with metastatic or 
unresectable esophagogastric adenocarcinoma. 
 
Se condary Obje ctives: 
Determine of the addition of regorafenib to FOLFOX chemotherapy affects: 
1)  Overall survival 
2)  Response rate 
3)  Toxicity rates 
. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 5 of 43 
 
 
 
 
 
Exploratory objective: 
To archive available unstained slides/tumor block and patient blood sample (normal DNA 
comparison) stored in tissue procurement service (TPS) for future correlative analysis. The 
patients will be asked to provide at least 15 unstained slides.  Tissue submission is encouraged, 
but not mandated for enrollment in the study. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Esophagogastric cancer 
 
In the United States, approximately  21,600 and 17,990 new cases  of gastric  and esophageal 
cancer respectively are diagnosed annually with ~26,200 deaths attributable to the disease.1  For 
locally advanced disease, outcome hinges on the ability to achieve complete resection and 
multidisciplinary treatment approaches include perioperative systemic chemotherapy and/or 
radiotherapy.  Most esophagogastric  cancers are locally advanced at the time of diagnosis, with 
the overall 5-year survival rate for distant or metastatic disease of ~ 3%.1 
 
Chemotherapy remains the mainstay of treatment for metastatic disease, improving survival when 
compared to best supportive care. Currently, there is no single standard of care chemotherapy 
regimen for advanced gastric carcinoma. Of the available treatments, combination chemotherapy 
provides increased response rates and overall survival at the cost of increased toxicity. 
Nonetheless, even with the most aggressive regimen, median survival is only 9.2 months.2 
 
3.2 5-Fluorouracil, Le ucovorin and Oxaliplatin (FOLFOX) in e sophagogastric cancer 
 
In advanced esophagogastric cancer, 5-fluoruracil has been the cornerstone of chemotherapy 
regimens and as a single agent results in response rates of 20-30%.
3  Studies have shown that 
when 5-fluorouracil is combined with other cytotoxics, there is a significant improvement in 
response rate and time to progression at the expense of increased toxicity.4  The addition of 
docetaxel to cisplatin and 5-flurouracil has demonstrated an improved overall survival in 
advanced esophagogastric cancer patients (9.2 vs 8.6 months).2 However, there is significantly 
more grade 3 and 4 neutropenia, complicated neutropenia, diarrhea and neurosensory toxicity, 
making this combination regimen suitable for only a carefully selected patient population treated 
by physicians familiar with its administration. 
 
Studies using combined 5-fluorouracil and oxaliplatin have demonstrated similar outcomes when 
compared to other reference regimens in advanced esophagogastric cancer. 5-9  The substitution 
of oxaliplatin for cisplatin has been shown to be non-inferior in terms of overall survival, with 
significantly less grade 3 and 4 neutropenia, nephrotoxicity, nausea, renal toxicity, 
thromboembolism and alopecia. 
5,10,11Aproximately 40% of the FOLFOX-treated patients were 
progression free at 6 months  with a trend toward improved median PFS and overall survival with 
5FU/Oxaliplatin versus 5FU/Cisplatin (5.8 v 3.9 months, respectively; P= .077) and  (10.7 v 8.8 
months, respectively). 5 
 
FOLFOX is well tolerated, has proven activity in advanced esophagogastric cancer12  and is safe in 
combination with other biologic agents. The tolerability and safety of mFOLFOX in 
esophagogastric cancer is well established and compares favorably to 5-Fu/Cisplatin 
regimen.5,13,14  This regimen is increasingly used as a chemotherapy backbone in studies exploring 
novel biologic agents (e.g.  NC I 8376 randomized Phase II study in gastric and gastroesophageal 
junction cancer of FOLFOX +/- hedgehog inhibitor GDC 0449). 
 
Because there are preliminary safety data combining regorafenib with FOLFOX in colon cancer, 
a phase I study is not required (Bayer data on file). FOLFOX is a well tolerated, effective regimen 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 6 of 43 
 
 
 
 
 
in advanced gastric cancer and is safe in combination with regorafenib. Adding a third cytotoxic 
agent (i.e. epirubicin or docetaxel) would necessitate phase I testing and most certainly add 
additional toxicities. 
 
3.3 Rationale of the study 
 
Regorafenib is of particular interest in esophagogastric cancer given the Phase III data 
demonstrating the increase in overall survival vs placebo in patients with metastatic colorectal 
cancer progressing after standard therapies.15   Furthermore regorafenib provides a significant 
improvement in progression-free survival compared with placebo in patients with metastatic 
gastrointestinal stromal tumors (GIST) after progression on standard treatments with imatinib and 
sunitinib.16  The efficacy and safety data supported FDA approval for colon and GIST (data 
described in Section 3.3.1.2). 
 
 
Regorafenib, the first small-molecule multi-kinase inhibitor with proof of efficacy in colorectal 
cancer15, is being studied in 1st  line setting in colorectal cancer combination with FOLFOX  and has 
a potential for new standard of care in patients with advanced esophagogastric cancer. MSKCC 
investigators have a track record over several decades in performing such trials, including two 
multicenter studies evaluating bevacizumab in metastatic disease.17,18    There is a clear rationale to 
study more than one VEGF targeted agent in esophageal cancer, as has been indicated by 
MSKCC experience in developing bevacizumab and the MSKCC initiated phase II study of single 
agent sorafenib in 2nd/3rd  line setting in patients with metastatic esophagogastric cancer. The 
phase II study of single agent sorafenib in patients with metastatic esophagogastric cancer 
finished accrual at MSKCC (IRB# 09-016, Janjigian et al manuscript in preparation).  Patients 
receive sorafenib 400mg daily BID x 28 day cycles in 2nd or 3r d line setting until disease 
progression or unacceptable toxicity or serious intercurrent illness. The primary endpoint of the 
trial is to assess progression free survival (PFS). Secondary endpoints include response and 
therapy tolerance.  Thirty-five patients have been accrued, with 34 evaluable; median number of 
prior therapies 2. One (3%) ongoing complete response (40+ months) was observed in a patient 
with Stage IV esophageal adenocarcinoma biopsy proven metastatic neck lymphadenopathy, 
recurrence after prior chemoradiotherapy and surgery. A second patient with GE junction 
adenocarcinoma had protracted stable disease in bulky celiac node disease (26+ months).  23 
patients (68%) had stable disease. Median PFS is 3.6 months (95% CI 1.8 to 3.9 months), with 
median overall survival 8.8 months (95% CI 5.9 to 11.1 months). Overall, sorafenib is well 
tolerated in this patient population. Significant grade 3 toxicities included hand foot reaction (3 
patients), rash (1 patient), dehydration (3 patients) and fatigue (2 patients). Twenty-seven of 33 
tumors (82%) tested positive for phospho-ERK by immunohistochemistry. 
 
Encouraging response and survival were observed in a phase II trial combining sorafenib with 
chemotherapy in patients with metastatic gastroesophageal junction cancer.19  Forty-four 
chemotherapy-naïve patients with Eastern Cooperative Oncology Group performance status 0 or 
1, of whom 80% had metastatic disease and two thirds had poorly differentiated gastric or GEJ 
adenocarcinoma were enrolled. The treatment regimen was sorafenib 400 mg orally twice a day 
for 21 days, docetaxel 75 mg/m2 intravenously on day 1, and cisplatin 75 mg/m2 intravenously on 
day 1, repeated every 21 days. The primary end point was response rate to the combination. 
Toxicity, overall survival, and progression-free survival were assessed as secondary end points. 
Eighteen of the 44 eligible and treated patients showed partial responses (41%; 90% C I, 28% to 
54%). The median progression-free survival was 5.8 months (90% CI, 5.4 to 7.4 months). The 
median overall survival was 13.6 months (90% CI, 8.6 to 16.1 month). The major toxicity of this 
regimen was neutropenia, which reached grade 3 to 4 in 64% of patients. One patient 
experienced hemorrhage at the tumor site. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 7 of 43 
 
 
 
 
 
Our underlying research paradigm is that simultaneous targeting of multiple relevant pathways 
may lead to a more efficacious oncologic therapy. Regorafenib is the next generation inhibitor that 
targets pathway beyond VEGF that drive esophagogastric cancer. FGFR2 and PDGFR 
alterations have been described in esophagogastric cancer, and are associated with high 
metastatic potential and aggressive tumor biology.20  Platelet-derived growth factor receptor 
(PDGFR) has a role in promoting angiogenesis, tumor growth and metastasis. Along with the 
fibroblast growth factor receptor (FGFR), PDGFR regulates the migration and adherence of 
pericytes and smooth muscle cells to endothelial cells, providing support and stability to vessel 
walls. Chemotherapy potentiates the effects of targeted agents, as suggested by promising 
overall survival in a recent Phase II study of sorafenib in combination with chemotherapy. 
Therefore the proposed study combines FOFLOX and regorafenib. 
 
3.3.1 Re gorafenib 
 
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 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, BR AFV600E, SAPK2, PTK5, and Ab1 at concentrations of 
regorafenib that have been achieved clinically.  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.
21
 
 
The rationale for the dose of regorafenib in this study is based upon the phase I data from 
Study 11650 (in which escalating doses from 10 mg to 220 mg per day of regorafenib was 
administered on a discontinuous schedule [3 weeks out of every 4]). Signs of antitumor 
activity were observed in subjects receiving doses from 60 mg to 220 mg per day on a 
discontinuous schedule (3 weeks out of every 4). However, of the 220 mg/day cohort, 8 of 
12 subjects required a dose reduction for toxicity, whereas only 1 subject of 12 on the 
160 mg/day cohort required such a dose reduction. Thus, based upon the efficacy and 
toxicity data, 160 mg was chosen as the dose for this study. 
Preliminary data from an ongoing phase I study, evaluating the safety, efficacy, and PK of 
regorafenib in combination with chemotherapy (mFOLFOX6 or FOLFIR I) in patients with 
metastatic CRC, support the feasibility of the combination therapy. From a clinical and PK 
perspective, the proposed combination of regorafenib with mFOLFOX6 (with 85 mg/m2 
oxaliplatin) is expected to be tolerable. A PK interaction is not expected. 
 
3.3.1.1 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). 21  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. 
21 These data suggest that regorafenib can target 
the tumor cell MAPK pathway (tumor cell survival) and tumor vasculature in some but not all 
tumors. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 8 of 43 
 
 
 
 
 
3.3.1.2 Clinical e xperience 
 
Two phase III global randomized studies have evaluated the efficacy of regorafenib. 1 5,16   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.15      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 clinical benefit. 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 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% C I, 
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.16  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.  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 GR ID study data supported FD A 
approval February 2013. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a single institution, single arm study of regorafenib 160 mg daily on days 4 to 10 and 
days 18 to 24 as four 40 mg coprecipitate tablets + FOLFOX on Day 1 and Day 15 of each cycle. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 9 of 43 
 
 
 
 
 
Each cycle consists of 28 days. Treatment will be administered on an outpatient basis.  All 
patients will receive systemic chemotherapy with the FOLFOX regimen and regorafenib. There 
are several variations of the basic FOLFOX regimen. The specific version of the FOLFOX 
regimen used at MSKCC is mFOLFOX6. mFOLFOX6 will be given on Day 1 of each cycle. 
Patients will receive Oxaliplatin 85 mg/m2 IV (over 120 minutes), leucovorin 400 mg/m2 IV (over 
120 minutes), 5-FU 400 mg/m2 IVP, and 5-FU 1200 mg/m2/day CIVI x 2 days, every two weeks. 
If oxaliplatin has been discontinued then leucovorin will be administered over 30 minutes. In an 
effort to prevent adverse events, all patients will be premedicated with antiemetics as per 
institutional guidelines prior to the first dose of treatment.  All other anti-emetics and supportive 
agents may be administered at the discretion of the primary oncologist. Treatment will be 
performed on the scheduled day ± 7 days.  In case of discontinuation of FOLFOX due to 
cumulative toxicity and administration as a single agent during the study, regorafenib for patient 
convenience will be administered 160 mg daily for 3 weeks on/1 week off.  The 3 weeks on/1 
week off schedule is supported by the single agent regorafenib data in colon cancer and GIST. 
 
All patients must be able to provide informed consent prior to enrollment. 
See Section 10 for treatment table. 
4.2 
Intervention 
 
Up to 36 patients will be enrolled on this clinical trial. Patients will receive regorafenib 160 mg daily 
on days 4 to 10 and days 18 to 24 as four 40 mg tablets + FOLFOX on Day 1 and Day 15 of each 
cycle until disease progression, unacceptable toxicity or serious intercurrent illness develops or if 
patient consent is withdrawn. Each cycle consists of 28 days.  Patients must have evaluable or 
measurable disease and will undergo a computerized tomography (CT) or magnetic resonance 
imaging (MRI) scan of the chest,  abdomen, and pelvis  within 28 days of start of therapy, at eight 
weeks, and every eight weeks thereafter (every 2 cycles), with a scheduling window of up to one 
to fourteen (1-14) days. Response assessment will be by RECIST 1.1 criteria22.The same imaging 
modality performed at baseline (CT or MRI) will be repeated at subsequent imaging. Intrapatient 
dose reduction to regorafenib will be allowed depending on the type and severity of toxicity 
encountered provided that criteria for patient withdrawal from study treatment have not been met. 
Once regorafenib is dose reduced, the patient should not go back to the starting dose. In case of 
discontinuation of FOLFOX due to cumulative to xicity and administration as a single agent during 
the study, regorafenib for patient convenience will be administered 160 mg daily for 3 weeks on/1 
week off.  The 3 weeks on/1 week off schedule is supported by the single agent regorafenib data 
in colon cancer and GIST. Therapy will be administered in the outpatient setting, with each cycle 
consisting of 28 days of continuous therapy. The cycle start date will coincide with the physician 
visit date. A study diary will be completed by patients to ensure compliance with the study drug 
(see APPENDIX A). 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
For dose modification and management of adverse events see Section 11.0 
5.1 
Re gorafenib (Bay 73-4506) 
Regorafenib 40-mg tablets contains regorafenib and the inactive excipients microcrystalline 
cellulose, croscarmellose sodium, magnesium stearate, povidone, colloidal anhydrous silica, 
polyvinyl alcohol-part hydrolyzed, talk, titanium dioxide E171 (color index 77891), Macrogol/PEG 
33350, lecithin (soy), iron oxide yellow – E172 (color index 77491), iron oxide red – E172. 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal.  Each bottle includes 30 tablets and a 3-gram desiccant.  The 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 10 of 43
 
 
 
 
 
bottles will have a label affixed containing study identification, product identification, and quantity 
of tablets.  Once the drug has been received it must be kept in a secure, dry location.  Study drug 
must be stored in its original bottle at a temperature not above 25°C (77°F). 
The study drug must be exclusively used for the investigation specified in this protocol and it will 
only be accessible to authorized staff. 
Dosage and administration 
Regorafenib will be provided by Bayer as 40-mg tablets, which are coated, not divisible, gray- 
orange-red, oval (length 16 mm, width 7 mm, thickness 4.9-5.6 mm), and 472 mg each in total 
weight.  Tablets are in an immediate-release dosage form with rapid dissolution characteristics 
under the in vitro test conditions. 
Four 40-mg regorafenib tables should be taken in the morning with approximately 8 fluid ounces 
(240 mL) of water after a low-fat (<30% fat) breakfast.   Some examples of low fat breakfasts are: 
 
•   Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 
ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat). 
 
•   One cup of cereal  8 ounces (240 mL) of skim milk, one piece of toast with jam (no butter or 
marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g of 
carbohydrate, 520 calories.)Patients with emesis should not take a replacement dose. A study 
diary will be completed by patients to ensure compliance with Regorafenib 
Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical Practice 
(GCP) and Good Manufacturing Practices (GMP) requirements and the instructions given by the 
clinical supplies department of the Institution and will be inaccessible to unauthorized personnel. 
Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug ac countability form. (See the CTEP 
website at http://ctep.cancer.gov/protocolDevelopment  for the ―Policy and Guidelines for 
Accountability and Storage of Investigational Agents‖ or to obtain a copy o f the drug accountability 
form.) 
De struction and Return 
At the end of the study, unused supplies of regorafenib (Bay 73-4506) 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 
Bayer HealthCare Pharmaceuticals 
6 West Belt 
Wayne, NJ  07470 
Tre atment compliance 
An adequate record of receipt, distribution, and return of all study drugs must be kept in the form 
of a Drug Accountability Form. 
 
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations.  At the discretion of 
the principal investigator, a subject may be discontinued from the trial for non-compliance with 
follow-up visits or study drug. 


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IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 11 of 43
 
 
 
 
 
Prior and concomitant therapy 
 
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 
CRDB (including start/stop dates, dose frequency, route of administration, and indication). 
Specific caution should be taken when considering or adm inistering a concomitant medication 
that is metabolized by the cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9.  Such 
concomitant medication should be avoided, if possible. 
 
There is no clinical information on the effect of CYP3A4 inhibitors on the PK of regorafenib. 
Substances that are inhibitors of CYP3A4 activity such as ketoconazole are expected to decrease 
metabolism of regorafenib and thus increase regorafenib plasma concentrations.  There are no 
clinical data evaluating the effect of chronically coadministered CYP3A4 inhibitor on regorafenib 
efficacy.  Since there is a possibility of increased regorafenib toxicity upon chronic 
coadministration of CYP3A4 inhibitors with regorafenib, chronic coadministration of CYP3A4 
inhibitors with regorafenib should be avoided, if possible. 
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 with in 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. 
•   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 
•   For subject receiving regorafenib in combination with chemotherapy consider adding the 
following: 
o A standard antiemetic regimen for the prophylaxis of acute emesis is recommended 
on the day of chemotherapy at least 30 minutes prior to the administration of 
chemotherapy.  Such a regimen may include a serotonin (5-HT3) antagonist (e.g. 
granisetron or ondansetron) with or without a corticosteroid (e.g. dexamethasone). 
The investigators should also consider providing subjects with a standard antiemetic 
regimen for treatment of delayed or breakthrough emesis as needed. 
5.2 5-FU, le ucovorin and oxaliplatin 
 
Qualified personnel who are familiar with procedures that minimize undue exposure to them and 
to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
The total administered dose of cytotoxic chemotherapy may be rounded up or down within a 
range of 5% of the actual calculated dose. 
It is not necessary to change the doses of 5-FU, leucovorin or oxaliplatin due to changes in weight 
unless the calculated dose changes by ≥10%. 
 
5.2.1 Oxaliplatin 
Oxaliplatin will prepared and administered as per MKSCC guidelines. Please refer to the FDA- 
approved package insert for additional information. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 12 of 43
 
 
 
 
 
Toxicity 
The most commonly observed oxaliplatin toxicities include neurotoxicity, GI toxicity, and 
myelosuppression. Three neurotoxicity syndromes have been seen: acute sensory neuropathy 
develops within hours to 2 days after oxaliplatin administration. Symptoms include paresthesias, 
dysesthesias, and hypothesia of the hands, feet and perioral region. Jaw spasm, abnormal 
tongue sensation, dysarthria, eye pain and a sensation of chest pressure have also been noted. 
Acute sensory neuropathy symptoms may be exacerbated by exposure to cold temperature or 
cold objects. Symptoms are reversible, usually resolving within 14 days and commonly recurr ing 
with further dosing. This syndrome has been observed in about 56% of patients receiving 
oxaliplatin with 5-FU and leucovorin. 
Acute pharyngolaryngeal dysesthesia is reported to occur in 1-2% of patients. This syndrome is 
characterized by a subjective sensation of difficulty breathing or swallowing without laryngospasm 
or bronchospasm or objective evidence of hypoxia. Avoidance of cold drinks, food and air is 
suggested in order to minimize pharyngolaryngeal dysesthesia. Antianxiety agents (e.g., 
lorazepam) may be used to treat pharyngolaryngeal dysesthesias once oxygen saturation has 
been documented to be normal. 
Peripheral neuropathy persisting > 14 days is characterized by paresthesias, dysesthesias, and 
hypothesia. Abnormalities in proprioception may also be seen. Symptoms of persistent 
neuropathy may improve upon discontinuation of oxaliplatin. 
Various agents have been used in an attempt to minimize neurotoxicity of oxaliplatin (e.g. 
carbamazepine, Mg+, Ca++). Calcium and magnesium infusions appear to be beneficial in 
preventing neurotoxicity. Contrary to preliminary findings described in 2007, calcium and 
magnesium do not appear to interfere with tumor response to FOLFOX. Calcium and magnesium 
infusions are generally given before and after oxaliplatin, and should not be prepared in the same 
infusion solution as FOLFOX components. 
Gastrointestinal toxicities include nausea, vomiting (oxaliplatin is considered to be moderately 
emetogenic) and diarrhea. 
Neutropenia is reported in 73% of patients receiving oxaliplatin with 5-FU and leucovorin (44% 
grade 3 or 4). Grade 3 or 4 thrombocytopenia is reported to occur in 4% of patients receiving the 
combination. 
Allergic reactions, similar to those seen with other platinum compounds, have also been observed 
in patients treated with oxaliplatin. Reactions range from rash to anaphylaxis. 
Rarely, oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. Oxaliplatin 
should be discontinued in the presence of unexplained pulmonary symptoms (e.g. nonproductive 
cough, dysphagia) or pulmonary infiltrates until interstitial lung disease or pulmonary fibrosis have 
been ruled out. 
Recent reports of oxaliplatin extravasation suggest that tissue necrosis may result and that 
oxaliplatin should be considered a vesicant. No standard treatment exists for oxaliplatin 
extravasation although heat and sodium thiosulfate have both been suggested. 
Veno-occlusive disease (VOD) of the liver is a rare complication associated with oxaliplatin and 5- 
FU. Clinical manifestations of VOD include hepatomegaly, ascites, and jaundice. Histologically, 
VOD is characterized by diffuse damage in the centrilobular zone of the liver. Sequelae of VOD 
include hepatomegaly, splenomegaly, portal hypertension, and esophageal varices. A rec ent 
analysis of resected liver metastases in 153 patients indicated histological findings consistent with 
VOD in 6/27 patients who received 5-FU alone, 4/17 patients who received 5-FU and irinotecan, 
20/27 patients who received 5-FU and oxaliplatin, and 14/16 who received 5-FU, oxaliplatin and 
irinotecan. The remaining 66 patients had not received chemotherapy prior to resection. There 
were no such findings in these patients. 
For more information on toxicities associated with oxaliplatin, please see the pac kage insert. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 13 of 43
 
 
 
 
 
5.2.2 5-Fluorouracil (5-FU; fluorouracil) 
 
5-FU will prepared and administered as per MKSCC guidelines. Please refer to the FDA- 
approved package insert for additional information. 
. 
Toxicity 
Nausea, diarrhea, vomiting (mild); stomatitis: 5-8 days after treatment initiation; 
myelosuppression: granulocytopenia (9-14 days); thrombocytopenia (7-14 days); Alopecia; loss of 
nails; hyperpigmentation; photosensitivity; maculopapular rash; palmar–plantar 
erythrodysesthesia: (42-82% receiving continuous infusion); C NS effects: cerebral ataxia (rare); 
cardiotoxicity: MI, angina; asymptomatic S–T changes 68%; ocular effects: excessive lacrimation 
and less commonly, tear duct stenosis. 
Drug Inte ractions 
Leucovorin enhances the cytotoxicity of 5-FU by forming a more stable tertiary complex with 
thymidylate synthase. Concomitant Adminstration of 5-FU with warfarin has been reported to 
result in increased INR/prolonged prothrombin time. Patients on warfarin should be converted to 
enoxaparin or rivaroxaban therapy. 
 
5.2.3 Le ucovorin Calcium (Folinic Acid) (calcium folinate; citrovorum factor; N 5- 
formyltetrahydrofolate; 5-formyl-FH4; folinic acid) 
 
Leucovorin will beprepared and administered as per MKSCC guidelines. Please refer to the FD A- 
approved package insert for additional information. 
 
Toxicity 
The only adverse reactions associated with leucovorin are allergic reactions. These are extremely 
uncommon. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 Subject Inclusion Criteria 
 
• 
Patient must have histologically or cytologically confirmed metastatic or unresectable 
esophageal, gastroesophageal junction or gastric adenocarcinoma. 
• 
Patient must have disease that can be evaluated radiographically.  This may be measurable 
disease or non-measurable disease.  Minimum indicator lesion size = 10 mm by helical CT or 
= 20 mm by conventional techniques. Pathological nodes must be = 15 mm by the short axis 
to be considered measurable. 
• 
Subject must be able to swallow and retain oral medication 
• 
Age 18 years or older. 
• 
Karnofsky performance status > 70% 
• 
Peripheral neuropathy < grade 1 
• 
Hematologic (minimal values) 
White blood cell count > 3000/mm
3© 
Absolute neutrophil count > 1500 cells/ mm3 
Hemoglobin > 8.0 g/dl 
Platelet count > 90,000 / mm3 
•   Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
•   Alanine aminotransferase (ALT) and aspartate amino-transferase (AST)  ≤ 2.5 x ULN (≤ 5 x 
ULN for subjects with liver involvement of their cancer) 
•   Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their 
cancer). Patients with alkaline phosphatase elevation secondary to the bony m etastases rather 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 14 of 43
 
 
 
 
 
than liver dysfunction may proceed with treatment on protocol after discussion with the 
principal investigator. 
•   Serum creatinine  ≤ 1.5 x the ULN 
•   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. 
•   Patients with prior deep vein thrombosis (DVT) or pulmonary embolism (PE) currently on an 
anticoagulation regimen with low molecular weight heparin (LMWH)  or rivaroxaban will be 
permitted.. 
 
6.2 
Subject Exclusion Criteria 
 
•   Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg on repeated measurement) despite optimal medical management. 
•   Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or 
digoxin. 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 months 
before randomization, or myocardial infarction within 6 months before 
randomization. 
•   Evidence or history of bleeding diathesis or coagulopathy. 
• 
Any hemorrhage or bleeding event ≥ NC I CTCAE version 4.0 Grade 3 within 4 weeks 
prior to start of study medication. 
•   Unwillingness to give written informed consent, unwillingness to participate, or inability to 
comply with the protocol for the duration of the study. 
• 
Active hepatitis B infection, active hepatitis C infection or known HIV carrier. 
• 
Patient may not have received prior chemotherapy for metastatic or unresectable disease. 
Patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) 
if more than 6 months have elapsed between the end of adjuvant therapy and registration. 
• 
Patient may not have received prior 5-Fluorouracil, Leucovorin, Oxaliplatin or regorafenib. 
Patient may have received prior radiosensitizing doses of 5Fu if more than 6 months have 
elapsed between the end of adjuvant therapy and registration. 
• 
Patient may not have had major surgical procedure within 4 weeks of registration. 
• 
Patient may not have had radiation within 2 weeks of registration. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
This will be a single institution, phase II study. Patients with metastatic or recurrent esophageal, 
gastric and gastroesophageal (GE) junction cancer that are eligible will be identified for enrollment 
from MSKCC clinical practice and clinic lists. All patients with metastatic or recurrent disease that 
have not received prior chemotherapy for metastatic disease will be offered the study. The study 
information will be posted on clinicaltrials.gov and the MSKCC website. No additional measures, 
e.g. advertisement, payment to patients, will be employed to recruit patients. Patients will be 
accrued to this study without regard for gender or minority status. 
 
Inclusion of women and minorities 
The investigators take due notice of the NIH policy concerning inclusion of women and minorities 
in clinical research populations. There will be no limitation with regards to race or gender. 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 15 of 43
 
 
 
 
 
 
Our institutional demographics for accrual of patients on esophageal, gastric and GE junction 
cancer trials reflect the national incidence of this disease: 10-15% of our patients have been 
women; African-American males comprise 3-5% of patients treated on protocol. Given that our 
protocol accrual closely reflects the national incidence of this disease, no specific strategy will be 
undertaken to recruit women or persons of color on this trial. 
 
This protocol does not include children because the number of children with esophageal, gastric 
and GE junction cancer is very small and because the majority are already accessed by a nation- 
wide pediatric cancer research network. This statement is based on exclusion 4b of the NIH 
Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human 
Subjects. 
 
8.0 
PRETREATMENT EVALUATION 
 
Pretreatment evaluation will be performed within 2 weeks (14 days) of study entry and will 
include: 
• 
History, concomitant medications, and toxicity assessment. 
• 
Physical exam, vital signs (blood pressure, weight, heart rate, temperature), and 
performance status. 
• 
Serum pregnancy test for women of childbearing potential (WOCP) 
In addition, all WOCP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g. late or missed period) at any time during study 
participation. 
• 
Laboratory evaluation including complete blood count, and comprehensive chemistry 
panel (includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, calcium, 
bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase), , Thyroid 
function test (TSH, T3, T4)Urinalysis 
• 
Electrocardiogram 
• 
CT scan or MR I of all relevant disease sites within 28 days of study entry. 
 
Correlative studies 
 
The patients will be asked to consent to provide archived tissue (at MSKCC or an outside 
institution) and/or tissue from an upcoming clinically indicated biopsy for molecular analysis 
of their tumors, which will be stored for future correlative analysis. The patients will be asked 
to provide matched normal blood sample for normal DNA comparison. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
A standard antiemetic regimen for the prophylaxis of acute emesis is recommended on the day of 
chemotherapy, as per MSKCC guidelines. 
 
All patients that meet the eligibility criteria who have signed informed consent and have enrolled 
on the trial will be treated with regorafenib 160mg (flat dose), on days 4 to 10 and days 18 to 24 
as four 40 mg coprecipitate tablets + FOLFOX on Day 1 and Day 15 of each cycle (Table 1). Each 
cycle consists of 28 days. In case of discontinuation of FOLFOX due to cumulative toxicity and 
administration  as a single agent during the study, regorafeni b for patient convenience  will be 
administered 160 mg daily for 3 weeks on/1 week off.   The 3 weeks on/1 week off schedule is 
supported by the single agent regorafenib data in colon cancer and GIST. A given treatment or 
follow up visit may be moved +/- 4 days for specific administrative reasons, in particular clin ic 
closure for holidays. 


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IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 16 of 43
 
 
 
 
 
 
9.1 Modified FOLFOX-6 (mFOLFOX-6). 
 
Patie nts  ≤65  years  old: Oxaliplatin  85 mg/m
2  IV on  day 1, followed  by or  concurrent  with 
leucovorin 400 mg/m2  (or levoleucovorin 200 mg/m2) IV, followed by 5FU 400 mg/m2  IV bolus, 
followed by 5FU 2400 mg/ m2 IV infusion over 48 hours 
 
Patie nts  >  65  ye ars  old:  Oxaliplatin  70  mg/m2    on  day  1,  followed  by  or  concurrent  with 
leucovorin 300 mg/m2  (or levoleucovorin  150 mg/m2) IV, followed by 5FU 300 mg/m2  IV bolus, 
followed by 5-FU 2000 mg/m2  infusion over 48 hours. 
 
 
The patients will be seen weekly for the first three weeks on study. After first three weeks, weekly 
visits are no longer required and patients can be seen every 2 weeks. 
 
 
Table 1: Regorafenib + mFOLFOX6 Study Treatment 
 
 
Study Drugc 
Doses and Route of 
Administration 
 
1 
2 
3 
4- 
10 
 
11- 
14 
Day 
15 
16 
17 
18- 
24 
 
25- 
28 
Oxaliplatin 
85 mg/m
2 
2-hour i. v. infusion 
X 
X 
Folinic acid 
 
see 
footnotea 
2-hour i. v. infusion X 
X 
5-Fluorouracil 
400 mg/m
2 
i.v. bolus injection 
X 
X 
2400 mg/m2 
46-hour i. v. 
infusion 
X 
X 
X 
X 
X 
X 
Regorafeni b
b             160 mg od                 oral tabl ets                                X                                            X 
a Either D/L-folinic acid 400 mg/m2 or L-folinic acid 200 mg/m2. 
b If regorafenib is administered as a monotherapy during the study, 160 mg daily will be 
administered for 3 weeks on/ 1 week off 
cChemotherapy doses reduced for patients >65 years old: Oxaliplatin 70 mg/m
2  on day 1, 
followed by or concurrent with leucovorin 300 mg/m 2 (or levoleucovorin 150 mg/m2) IV, followed 
by 5FU 300 mg/m
2  IV bolus, followed by 5-FU 2000 mg/m
2  infusion over 48 hours. 
 
9.2 Re gorafenib 
 
Re gorafenib 160mg (flat dose), on days 4 to 10 and days 18 to 24 as four 40 mg coprecipitate 
tablets. Each cycle consists of 28 days. In case of permanent discontinuation of FOLFOX due to 
cumulative toxicity and administration as a single agent during the study, regorafenib for patient 
convenience will be administered 160 mg daily for 3 weeks on/1 week off.   The 3 weeks on/1 
week off schedule is supported by the single agent regorafenib data in colon cancer and GIST. 
Dose reductions described in section 11. 
 
The following assessments should be performed every 2 we eks (14 days) prior to receiving 
study tre atment (+/- 7 days) 
• 
Record concomitant medications 
• 
Vitals (temperature, HR, BP and RR), physical examination (including height and 
weight) and performance status assessment (KPS) 
• 
Laboratory evaluation including complete blood count, and comprehensive chemistry 
panel (includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, calcium, 
bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase) 
• 
Record Adverse Events (CTCAE v4.0) 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 17 of 43
 
 
FU 
d
 
FU e 
 
 
 
 
Radiological imaging studies to evaluate tumor status will be repeated every two cycles (8 
weeks) while on study regardless of treatment delays.  However, if a tumor response status of 
complete response (CR) or partial response (PR) is assigned from these studies, then a repeat 
scan(s) must be done no sooner than 4 weeks after the scan documenting CR or PR to confirm 
these findings.  A given CT or MRI assessment may be moved +/- 7 days for specific 
administrative reasons, in particular clinic closure for holidays or patient‘s preference. 
 
End of Tre atment Visit 
 
• 
Record concomitant medications 
• 
Vitals (temperature, HR, BP and RR) 
• 
Laboratory evaluation including complete blood count, and comprehensive chemistry 
panel (includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, calcium, 
bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase) 
• 
Record Adverse Events (CTCAE v. 4) 
 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
Table 2: Study Flow Chart 
 
Procedure 
Screen a
Cycle 1 (28 days ) 
Cycle 2 (28 days ) 
Sub- 
sequent 
Cycles 
EOT c 
Safety 
Survival 
1 
2 
3 
4- 
1 
0 
1 
5 
1 
6 
1 
7 
18- 
24 
2 
8 
1 
2 
3 
4- 
1 
0 
1 
5 
1 
6 
1 
7 
18- 
24 
2 
8 
Medical 
hx/demographics X 
Urine/serum 
pregnancy test 
X 
Tumor biopsy 
samples for 
biomarkersf 
Physical exam  b 
X X g 
X 
X 
X 
X 
X 
X 
X h 
X 
Perform ance 
status 
X X 
X 
X 
h
 
X 
X 
Toxicities/AE 
assessment 
Reported from screening throughout all subsequent cycles 
X 
X 
I,J
 
TS H, FT3, F T4 
X 
TS H, T3/4 testing shoul d be performed during treatm ent if clinically inidicated 
Hem atology b 
X X g 
X 
X 
X 
X 
X 
X 
X 
X h 
X 
Chemistry b 
X X g 
X 
X 
X 
X h 
X 
Urinalysis 
X 
MRI/ CT 
assessment 
m 
X 
X
n
 
X 
h
 
X 
X 
o
 
Conc omitant 
medication 
X
p 
All medications taken during the study will be docum ented 
X 
X 
12-l ead ECG 
X 
ECHO/ MUGA 
X 
LVEF assessment should be perform ed i f clinically indicated 
mFOLF OX6 q 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X h 
Regorafeni b r 
X 
X 
X 
X 
X h 
BP monitoring 
Weekly for the first 3 weeks of 
treatment 
Regorafeni b 
dispensing 
X 
X 
X 
X 
X 
h
 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 18 of 43
 
 
 
 
 
Regorafeni b 
compliance 
Com pliance will be assessed at every cycle 
X 
h
 
BP = blood pressure; chem o = chemotherapy; ECG = electrocardiogram; ECHO = echocardiogram; EOT = 
end of treatment; FU = follow-up; LVEF = left ventricular ejection fraction; h = hour(s); hx = history; MUGA = 
multiple gated acquisition scan; 1° = primary. 
a 
Radi ological imagi ng studies withi n 28 days of start of study treatment, other screening eval uation 
within 2 weeks pri or to start of study treatment. 
b 
Physical  exam (vital signs [BP, heart rate, temperature],  wei ght, and a revi ew of body system s ), 
chemistry,  Hematol ogy and physical exam  will be done weekly  for the fi rst 3 weeks  and on th e 
intended days 1 and days 15 of each cycle prior to the chem o or ≤ 72 h pri or to dosing there a fter. 
After the end of the cytotoxic regimen (mF OLF OX6 or 5-FU/ folinic acid alone), day 15 assessments  
can be done at the discretion of the investigator. 
c 
Within 1-14 days of tum or progression or study treatment discontinuation. 
d 
Assessment by treating medical oncologist 
e 
For those  patients  no longer followed  by MSKCC M D, the study  res earch  assistant  will make a 
follow up phone call every 3 months to assess patient‘s vital status. 
f 
A  sample  of  archi val  tumor  biopsy,  or  other  avail able  tum or  biopsy,  should  be  submitted  fo r 
biomarker analysis duri ng screening.  Tumor bi opsy samples may als o be submitted for biom arke r 
analysis at any other time duri ng the course of the clinical study. 
g 
For physical exam/lab assessments,  not required if screening assessments  were done within 7 2 
hours of first dose. For E CG, not requi red if screening ECG was done withi n 7 days of first dose. 
h 
Cycles ≥3: Procedures will be performed identical to cycle 2 radi ologic tumor assessment will be at 
the end of every second cycle (cycles 4, 6, etc) before the next cycle (cycles 5, 7, etc). For subjects 
on monotherapy regorafeni b, no day 15 visit after the fi rst 4 cycles is required. 
i 
AE monitoring shoul d continue for at least 4 weeks following the last dose of study treatm ent. 
j 
 Only appli es to AEs that occur within 30 days following the last study treatment. Those AEs will b e  
followed until resolution. 
l 
Proteinuri a has to be assessed with lab value at screening and continue only if clinically indicated. 
Urinalysis must not show 1+ or more protei n in uri ne or the subject will requi re a repeat urinalysis. 
m   The  baseline  and  subs equent  scans  to  assess  response  must  be  perform ed  using  identical 
technique. Radiol ogical im aging studies to evaluat e tumor status will be repeated every 2 Cycles  (8 
weeks)  whil e on study  regardless  of treatment  delays.   However,  i f a  tum or response status  o f 
complete response (CR) or partial  response (P R) is assigned from these studies,  then a r ep eat 
scan(s) must be done no sooner than 4 weeks  after the scan documenti ng CR or PR to confirm  
these findings. 
n 
Starting in cycle 2, done at the end of every 2nd cycle (cycles 2, 4, 6, etc) before t he next cycle 
(cycles 3, 5, 7, etc). 
o 
 For subjects  who have entered the survi val  follow -up peri od and have not yet experience d  PD, 
every effort should be m ade to follow-up for tumor eval uation (by  CT or MRI) until progression o f 
their mali gnancy every 8 weeks, or until a new anticancer treatment is started. 
p 
All medication gi ven within 2 weeks pri or to the start of study treatment. 
q 
Doses  of chem otherapy  regim en should be recalculated  pri or to each cy cle if there has been a 
change of ≥ 10% in body weight. Use actual wei ght. 
r 
 Regorafenib  as a monotherapy  will be administered  for 3 weeks  on/ 1 week off and should b e 
dispensed on day 1 of every cycle. 
s 
If screening evaluations are done within 14 days of st art of treatment, Cycle 1 Day 1 evaluations need not 
be repeated 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 Re gorafenib 
 
The starting dose of regorafenib is 160 mg once daily on days 4 to 10 and days 18 to 24 as 
four 40 mg coprecipitate tablets + FOLFOX on Day 1 and Day 15 of each cycle. Each cycle 
consists of 28 days. In case of discontinuation of FOLFOX due to cumulative toxicity and 
administration as a single agent during the study, regorafenib for patient convenience will be 
administered 160 mg daily for 3 weeks on/1 week off.  The 3 weeks on/1 week off schedule is 
supported by the single agent regorafenib data in colon cancer and GIST. 
 
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. 
 
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level 0 (standard 
starting dose) 
160 mg by 
mouth daily 
Four 40-mg tablets of regorafenib 
Dose level - 1 
120 mg by 
mouth daily 
Three 40-mg tablets of regorafenib 
Dose level - 2 
80 mg by mouth 
daily 
Two 40-mg tablets of regorafenib 
 
If a subject experiences 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. 
 
If more than 2 dose reductions are required, regorafenib only will be discontinued and the rest of 
the study treatment may be continued.  The following tables outline dose adjustments for toxicities 
related to study drug except hand-foot skin reaction, hypertension and liver function test 
abnormalities. 


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Table 11.1.1:  Recommended dose modification for toxicities except hand-foot-skin 
reaction, hypertension and ALT/ST/bilirubin 
NCI-CT CAE v4.0
a 
Do se Interruption 
Do se 
Modification 
b 
Do se for 
Sub sequent Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 2
c
 
Reduce by 1 dos e 
level 
Grade 4 
Delay until ≤ Grade 2
c 
Reduce by 1 dos e 
level. 
Permanent 
discontinuati on 
can be considered at 
treating i nvestigator‘s  
discretion. 
a. NCI-CTCAE = National Cancer Institute - Common Terminol ogy Criteri a for Adverse E vents, 
version 4.0 
b. Excludes alopecia, non-refractory nausea/ vomiting, non -refractory hypersensiti vity and 
nonclinical and asymptom atic laboratory abnorm alities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless 
subject is deri vi ng clinical benefit. 
*   Modify accordi ng to study specific cycle length 
Table 11.1.2 : Grading for Hand-F oot-Skin-Reaction 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4. 0 
Palmar-plantar 
erythrodysesthesia 
syndrom e 
Minimal skin changes or 
derm atitis 
(e.g., erythem a, edem a, 
or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeli ng, blisters 
bleeding, edem a, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeli ng, 
blisters, bleedi ng, 
edem a, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
changes 
Num bness, dysesthesia 
/ paresthesia tingling, 
painl ess swelling, or 
erythem a of the hands 
and/or feet 
Painful erythema and 
swelling of the hands  
and/or feet 
Moist desquam ation, 
ulceration, blistering, 
or severe pai n of the 
hands and/or feet 
Effect on acti vities 
Does not disrupt norm al 
activities 
Limiting instrum ental 
activities of daily life 
(e.g., preparing 
meals, shoppi ng 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. 
 
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. 


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Page 21 of 43
 
 
Grade of event 
(NCI-CTCAE v 4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief 
Grade 2 
1
st 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 
2
nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0- 
1.c 
When resuming treatment, treat at reduced dose 
level b 
3
rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0- 
1. c 
When resuming treatment, decrease dose by one 
dose level. b, d 
4
th 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 
2
nd 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 
3
rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the 
investigator. 
b. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued 
permanently. 
c. Subjects requiring > 2 dose reductions should go off protocol therapy. 
d. The maximum daily dose is 160 mg. 
 
 
 
 
Suggested re gorafenib (Bay 73-4506) dermatologic toxicity modification 
 
Table 11.1.3   Re commended dose modification for hand-foot-skin re action
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(For studies with combination therapy, consider including the following statement ―The other 
study treatment may be continued‖). 
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
me asures such as topical e mollients, 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: 


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•   Avoid pressure points. 
•   Avoid items that rub, pinch or create friction. 
Use of cre ams 
•   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. 


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Table 11.1.4:  Management of Treatment-Emergent 
Hyperten sion 
 
Grade ( CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
Prehypertension 
(systolic BP 
120 - 139 mm Hg or 
diastolic 
BP 80 - 89 mm Hg) 
None 
• Conti nue regorafeni b 
• Consi der inc reasing blood pressure 
(BP) monitoring 
 
2 
Systolic BP 140 - 
159 mm Hg 
or diastolic BP 90 - 
99 mmHg, 
OR 
Symptomatic 
increase by 
> 20 mmHg 
(diastolic) if 
previously within 
norm al limits 
• Treat wit h the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
• If BP previously within normal 
limits, start anti-hypertensi ve 
monotherapy 
• If patient al ready on anti- 
hypertensi ve medication, titrate 
up the dose. 
• Conti nue regorafeni b 
 
• If symptom atic, hold regorafeni b 
until symptoms resol ve AND 
diastolic BP ≤ 90 mm Hga. When 
regorafenib is restarted, continue at 
the same dos e level. 
 
 
3 
Systolic BP ≥ 160 
mmHg or 
diastolic BP ≥ 100 
mmHg 
OR 
More than one drug 
or more 
intensi ve therapy 
than 
previously used 
indicated 
Treat wit h the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensi ve 
medication 
 
AND/OR 
Increase current anti- 
hypertensi ve medication 
 
AND/OR 
Add additional anti-hypertensi ve 
medications. 
• Hold regorafeni b until diastolic BP ≤ 
90 mm Hg, and i f symptomatic, 
until symptoms resol ve.a 
 
• When regorafenib is restarted, 
continue at the same dose l evel. 
 
• If BP is not controll ed with the 
addition of new or m ore int ensi ve 
therapy, reduce by 1 dose level.b 
 
• If Grade 3 hy pert ension recurs 
despite dose reduction and 
antihypertensi ve therapy, reduc e 
another dose level.c 
 
4 
Life-threatening 
consequences 
(eg, mali gnant 
hypertension, 
transient or 
perm anent 
neurol ogic deficit, 
hypertensi ve crisis) 
 
Per institutional guidelines 
Discontinue therapy 
a.  Patients requiring a del ay of >4 weeks shoul d go off protocol therapy 
b.  Patients requiring >2 dose reductions shoul d go off protocol therapy. 


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•   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. 
Te nder 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 
Hype rtension 
 
Hypertension is a known AE associated with regorafenib treatment.  Subject will have their blood 
pressure measured  at MD visits weeks 1 to 3 and additional BP monitoring per investigator 
discretion.  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 11.1.4outlines suggested 
dose reductions. 
Live r 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 below should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may 
occur in patients with Gilbert‘s syndrome. 
 
 
Table 11.1.5:  Do se modification s/interruption fo r ALT and/or AST and/or bilirubin increases 
related to study dr ug 
Ob served elevations 
1
st Occur rence 
Restart 
Re-occurrence 
AST and/or ALT ≤ 5 X 
ULN (< G3) 
  
 
 
 
ALT and/ or AS T >5 X 
ULN (≥ G3) 
 
 
 
 
 
 
 
ALT and/ or AS T > 20 X 
ULN (≥ G4) 
Conti nue dosing, wit h 
weekly monit oring of 
li ver function until 
transami nases return 
to <3 X ULN (≤ G1) or 
baseline. 
Interrupt dosing, with 
weekly monit oring until 
transami nases return 
to < 3 X ULN or 
baseline. 
 
 
 
Discontinue 
 
 
 
 
 
 
 
If the potential benefit for 
reinitiating regorafenib is 
considered to outwei gh 
the risk of hepatotoxicity: 
Reduce one dos e level 
and measure serum li ver 
tests weekly for at least 4 
weeks. 
 
 
 
 
 
 
 
Discontinue 


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ALT and/ or AS T > 3 X 
ULN (≥ G2) wit h 
concurrent bilirubi n > 2 X 
ULN 
Discontinue treatm ent 
and measure serum 
li ver tests weekly until 
resolution.  Exception: 
patients with Gil bert‘s 
syndrom e who 
develop elevated 
transami nases shoul d 
be managed as per 
the recomm endations 
outlined above for 
ALT/AS T el evations. 
 
Duri ng the first 2 cycles of treatment, ALT, AS T and bilirubin m ust be monitored weekly. 
 
Prevention/management strategies for diarrhea 
 
Diarrhea can be a common side effect of regorafenib (Bay 73-4506).  The same dose- 
modification algorithm used for skin toxicities can be used to address these toxicities.  However, 
the preventive/management strategies for diarrhea should be consistent with local standards 
(e.g., anti-diarrheals 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. 
 
11.2 FOLFOX 
 
Initiation of the next cycle of therapy may be delayed by no more than 4 weeks to allow recovery 
from toxicity.  Treatment delay of > 4 weeks due to toxicity may lead to removal from study. 
 
Dose reduction of oxaliplatin or 5-FU/folinic acid should be based on the worst toxicity 
demonstratedduring the preceding cycle.. Subjects who require more than 2 dose-reduction steps 
must permanently discontinue either oxaliplatin, or 5-FU/folinic acid, or both depending 
on the specific toxicity.  Regorafenib may continue at investigator‘s discretion. 
 
If cycle start date is delayed due to toxicity related to FOFLOX, regorafenib will be held and 
resume on Day 4 of the cycle.  In case of discontinuation of FOLFOX due to cumulative toxicity 
and administration as a single agent during the study, regorafenib for patient convenience will be 
administered 160 mg daily for 3 weeks on/1 week off. 
 
11.2.1 Dose Modifications of FOLFOX 
11.2.1.1 He matologic Toxicity 
Colony stimulating factors:  Patients should not routinely receive prophylactic colony stimulating 
factors (e.g., G-CSF, GM-CSF) during cycle 1. Subsequent use will be at the discretion of the 
treating physician. 
Neutropenia 
For ≥ grade 3 ANC on the day of treatment, delay treatment until ANC improves to ≤ grade 
2, then resume treatment with: 
• 
One dose level reduction of oxaliplatin for all subsequent cycles. 
• 
One dose level reduction of 5-FU (bolus & infusion) and leucovorin for all 
subsequent cycles. 
• 
If treatment is delayed for neutropenia for 4 consecutive weeks, discontinue all 
protocol treatment. 
Thrombocytopenia 


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For platelets 74,000 to 50,000 on day of treatment, delya treatment until platelets improve 
≥75K then resume treatment as follows: 
• 
One dose level reduction of oxaliplatin for all subsequent cycles. 
• 
One dose level reduction of 5-FU (bolus & infusion) and leucovorin for all 
subsequent cycles. 
• 
For platelets 74 – 50,000 persisting > 7 days, resume treatment with oxaliplatin 
with two dose level reductions when platelets improve to ≥ 75,000. 
For platelets 49,000– 25,000 on day of treatment, delay treatment until platelets improve 
to ≥ 75,000, then resume treatment as follows: 
• 
One dose level reduction of oxaliplatin for all subsequent cycles. 
• 
One dose level reductions of 5-FU (bolus & infusion) and leucovorin for all 
subsequent cycles. 
• 
For platelets < 49,000 - 25,000 persisting > 7 days, resume treatment with 
oxaliplatin with 2 dose level reductions when platelets improve to ≥ 75,000. 
For platelets < 25,000 on day of tre atment, delay treatment until platelets improve to ≥ 
75,000, then resume treatment as follows: 
• 
Two dose level reductions of oxaliplatin for all subsequent cycles. 
• 
Two  dose  level  reductions  of  5-FU  (bolis  &  infusion)  and  leucovorin  for  all 
subsequent cycles. 
• 
For platelets < 25,000 persisting > 7 days, resume treatment with oxaliplatin with 2 
dose level reductions when platelets improve to ≥ 75,000. 
 
 
11.2.1.2 Ne urologic Toxicities 
 
For  grade  2 peripheral  sensory  neuropathy  (moderate  paresthesia  or  dysesthesia,  or 
limiting instrumental activities of daily living) 
 
Skip oxaliplatin. When toxicity resolves to ≤ grade 1, resume oxaliplatin with one dose 
level reduction, for all subsequent cycles. Continue 5-FU and leucovorin. 
 
If oxaliplatin is skipped for 4 weeks (2 consecutive doses) for neurologic toxicity, 
discontinue oxaliplatin. Continue 5-FU and leucovorin. 
 
For grade 3 or greater peripheral sensory neuropathy (severe paresthesia or dysesthesia, 
or limiting self-care activities of daily living) 
 
Discontinue oxaliplatin. Continue 5-FU/leucovorin. 
 
11.2.1.3 Gastrointestinal Toxicities 
 
For grade ≥ 2 diarrhea, skip mFOLFOX6 until diarrhea improves to ≤ grade 1. 
 
• 
Following  grade  3  or  4  diarrhea  at  any  time  during  a  cycle:  continue 
mFOLFOX6 with one dose level reduction of 5-FU for all subsequent cycles 
and the previous dose level of oxaliplatin. 
• 
If  FOLFOX is  skipped  for  diarrhea  for  4 weeks  (2 consecutive  cycles), 
discontinue mFOLFOX6. 
For ≥ grade 2 oral mucositis present on Day 1 of a cycle: delay mFOLFOX6 until mucositis 
improves to < grade 2. Decrease 5-FU by 1 dose level for all subsequent cycles. 


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If a subject requires a dose delay of oxaliplatin/5-FU/folinic acid > 4 weeks from the 
intended next dose, then treatment of the specific drug will be permanently discontinued. 
 
Subjects who have had their treatment cycle delayed must be evaluated by those evaluations 
defined for the intended day 1 of that cycle ≤ 72 hours prior to actual dosing. 
 
Subjects may also discontinue oxaliplatin following multiple cycles if in the investigator's 
judgment cumulative toxicity is likely to increase over time and become problematic. 
If oxaliplatin treatment only should be discontinued in the investigator‘s judgment, the 
subjects should continue to receive other protocol-specified treatments. 
General dose reductions for mFOLFOX6 are outlined in Table 11.2.1 
 
Table 11.2.1 
 
Drug 
Age 
(Ye a r s) 
Sta rting Do se 
Do se Modifica tion 
Dose Level - 1 
Dose Level -2 
Oxaliplatin 
< 65 
85 mg/m
2 
70 mg/m
2 
50 mg/m
2 
≥ 65 
70 mg/m2 
50 mg/m2 
35 mg/m2 
5 FU 
< 65 
Bolus 5FU: 400 
mg/m2 
Leucovorin: 400 
mg/m2 
Infusion 5F U: 2400 
mg/m2/48 hours 
Bolus 5FU: 300 
mg/m2 
Leucovorin: 
300 mg/m
2 
Infusion 5F U: 
2000 mg/m2/48 
hours 
Bolus 5FU: 200 
mg/m2 
Leucovorin: 200 
mg/m2 
Infusion 5F U: 1600 
mg/m2/48 hours 
≥ 65 
Bolus 5FU: 300 
mg/m2 
Leucovorin: 300 
mg/m2 
Infusion 5F U: 2000 
mg/m2/48 hours 
Bolus 5FU: 200 
mg/m2 
Leucovorin: 
200 mg/m
2 
Infusion 5F U: 
1600 mg/m2/48 
hours 
Bolus 5FU: 150 
mg/m2 
Leucovorin: 150 
mg/m2 
Infusion 5F U: 1300 
mg/m2/48 hours 
 
 
 
11.3 FOFLOX and Re gorafenib 
 
The expected toxicities of FOLFOX and Regorafenib are fatigue, mucositis, myelosuppression, 
diarrhea, neuropathy,  liver function abnormalities, hand foot syndrome,  hypertension 
 
11.4 De finitions of Adv erse Ev ents. 
 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation 
of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment. 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately life- 
threatening, results in persistent or significant disability / incapacity, requires or prolongs patient 
hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other 
reason if it is an important medical event when based upon appropriate medical judgement which 


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may jeopardise the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions. 
 Severity of adverse event 
The severity of the AE should be judged based on the following: 
The severity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4 in the CRDB. 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Assessment 
of causal relationship must be recorded for each adverse event. 
 
Causality will be reported as either ―Yes‖ or ―No‖. 
 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No: 
There is no reasonable causal relationship between the investigational product 
administered and the  AE. 
 
 
11.5 Malignant disease progression 
 
Expected fluctuations or expected deterioration of the underlying disease should not be recorded 
as an AE unless at least one of the following criteria is met: 
− 
Worsening of the disease constitutes an SAE, 
− 
Additional treatment is required, i.e. concomitant medication is added or changed. 
− 
An unexpected deterioration from baseline has occurred in the opinion of the 
investigator. 
 
11.6 Worsening of pre-existing conditions 
 
A pre-existing condition present at baseline, which remains unchanged during the trial, does not 
need to be recorded as adverse event. Any worsening of any pre-existing baseline condition 
should be reported as an adverse event. Examples of worsening of a preexisting condition that 
should be recorded as an AE are given below; 
• 
Worsening of condition meets the criteria for an SAE 
• 
Action is taken with the investigational drug (i.e. dose is reduced or treatment is 
discontinued) 
• 
Treatment is required (concomitant medication is added or changed) 
• 
The investigator believes a patient has shown a clear deterioration from baseline 
symptoms 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one dose of FOLFOX and began regorafenib therapy will be 
evaluable for toxicity and response. Patients who are did not begin regorafenib therapy will not be 
evaluated for toxicity or response and will be replaced by a new patient. 
 
The primary endpoint of the study is the efficacy of the combination of FOLFOX and regorafen ib 
in terms of progression free survival (PFS) at 6 months. Secondary endpoints include best overa ll 
clinical benefit defined as stable disease (SD), complete response (CR), or partial response (PR). 
Confirmatory scans should be obtained no less than four weeks following initial documentation of 


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objective response. This is defined as the percentage of patients who have achieved either an 
objective complete or partial target lesion response that is confirmed on the RECIST 1.1 criteria. 
Complete or partial responses will be confirmed with repeat CT evaluation after 4 weeks. Target 
lesions must have a minimum size of at least one diameter of 10mm for liver, soft tissue lesions, 
lung, and skin. Pathological  nodes  must be at least 15mm  in the short axis to be considered 
target lesions. The primary tumor is not considered measurable disease. Recurrent or metastatic 
lesions  within a prior radiation fie ld are acceptable as long as disease has progressed in the 
radiation field by RECIST 1.1 criteria. The same imaging modality performed at baseline (CT or 
MR I) will be repeated at subsequent imaging. 
 
Secondary endpoints include toxicity, safety and tolerability. The type, frequency, severity, timing, 
and relationship of each adverse event will be determined as per the NC I Common Toxicity 
Criteria, version 4.0. Toxicity during cycle 1 and subsequent cycles will be reported. 
Assessment of stable disease will be based on RECIST 1.1 criteria. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease he/she will be taken off study and referred 
for alternative therapy. If at any time the patient develops unacceptable toxicity that fails to 
resolve after a maximum treatment delay of 4 weeks, he/she will be removed from study. Before 
being removed from the study, patients will be scanned to assess the response. If the off study 
scan shows progression of disease then the patient will be considered as a non responder, while 
a CR or PR will be considered as response. 
 
A patient will be withdrawn from the study treatment in the following circumstances: 
 
● the patient is no longer able to participate in the study (e.g., AE, surgery, concomitant 
diagnoses, concomitant therapies or administrative reasons); in such a case the Investigator‘s 
reason for a patient‘s removal must be recorded in CRDB. 
● Patient withdrawal of consents or election to discontinue participation in the trial 
● Significant deviation from the protocol or eligibility criteria; such patients will be considered 
protocol violations and removed from study 
● Non-compliance with study or follow-up procedures 
● Drug related AE(s) have not resolved after 4 weeks of treatment interruption. Exception to this 
in patients who derive obvious clinical benefit according to the investigator‘s judgment could be 
considered upon discussion with Principal Investigator. The dose reduction scheme provided 
should be followed in this case. 
● repeated episodes of drug related toxicity despite dose reduction as indicated in Section 11. 
● documented progressive disease 
 
As soon as a patient is withdrawn from the study treatment, the End of Treatment (EOT) visit 
has to be performed within 1-14 days after off study date. Every effort should be made to follow- 
up patients in case an adverse event has still ongoing at the time of withdrawal. Patients who 
show a clinical benefit from treatment with regorafenib (i.e., with either an objective tumor 
response or the absence of disease progression), may continue to receive additional treatment 
courses. Patients with radiologically documented progressive disease should be removed from 
the study unless the investigator judges it to be of clinical benefit for the patient to continue on trial 
therapy. 


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IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 30 of 43
 
 
Toxicity 
# of toxicities needed to stop 
the study 
Toxicity 
rate 
Probability 
boundary 
is crossed 
Gr 4+ Neutropenia 5 within the first 10 patients 
7 within the first 20 patients 
11 within 36 patients 
.19 
.11 
.45 
.98 
Gr 3+ Diarrhea 
4 within the first 10 patients 
6 within the first 20 patients 
8 within 36 patients 
.12 
.08 
.35 
.97 
Gr 3+ Neuropathy 2 within the first 10 patients 
3 within the first 20 patients 
5 within 36 patients 
.05 
.13 
.25 
.98 
Gr 4+ LFT 
5 within the first 10 patients 
8 within the first 20 patients 
11 within 36 patients 
.19 
.09 
.4 
.92 
Gr 3+ HFS 
4 within the first 10 patients 
6 within the first 20 patients 
8 within 36 patients 
.12 
.08 
.3 
.9 
Gr 3+ persistent 
hypertension 
2 within the first 10 patients 
3 within the first 20 patients 
4 within 36 patients 
.04 
.1 
.2 
.96 
 
 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint is progression free survival (PFS), as measured from the start of the 
treatment to the date of either documentation of disease progression or death.  W e will define 
progression of disease as per RECIST 1.1 criteria.  Patients with measurable disease and with 
evaluable radiographically but non-measurable disease will be eligible for study entry.  As per 
RECIST 1.1 criteria, any evidence of progression in non-measurable lesions, measurable lesions, 
or the development of new lesions, would qualify as disease progression.  Using an exact single 
stage binomial design, we will accrue 36 Stage IV or unresectable esophagogastric 
adenocarcinoma patients to differentiate between 6-month PFS of 40% and 61% with type I of 5% 
and power of 80%.  If 20 or more patients are progression free at 6 months, FOLFOX 
+Regorafenib will be considered worthy of further investiagaion.  Patients who come off study 
before 6 months without documented progression will be considered as events for the primary 
endpoint of 6 months PFS. We anticipate enrollment to be 2-3 patients/ months with completion of 
accrual in approximately 18 months. Patients that come off study due to toxicity before 6 months 
without documented progression will continue to be scanned to obtain 6 months assessment of 
progression. Patients that were lost to follow up or withdrew consent before 6 months without 
documented progression will be counted as events for the primary endpoint; however this is 
expected to be a rare occurrence. The patients who completed at least one cycle of FOFLOX and 
regorafenib will be considered evaluable. 
  
 
Previous clinical trial has reported the frequency of adverse events attributable to treatment 
with 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFOX.5  A similar frequency of adverse events will be considered attributable to the FOLFOX 
plus Regorafenib used in this trial and therefore acceptable. In order to reduce patient risk, the 
study design includes early termination of the trial in the event of excessive grade 4+ 
neutropenia, grade 3+ diarrhea despite adequate antidiarrheal management (loperamide and 
diphenoxylate/atropine) or grade 3+ neuropathy. In addition, the safety analysis will assess the 


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Page 31 of 43
 
 
 
 
 
toxicity rates that may arise related to regorafenib of grade 4+ LFT abnormality, grade 3 hand 
food syndrome (HFS)  (despite adequate skin management) or persistent grade 3+ 
hypertension despite adequate medical management. Furthermore, presence of grade 3+ 
events which in the clinical judgment of the principal investigator are felt to be serious, 
unexpected, and a side effect likely due to regorafenib, will give evidence to reduce the dose 
as well.  Only adverse events (possibly, probably, or definitely) related to the study treatment in 
the first 2 cycles (i.e. 8 weeks) will count towards the excessive toxicity boundaries below. The 
stopping rules are derived using repeated significance testing are given in the table below. 
  
 
Secondary endpoints: Overall survival will be measured from the start of treatment to death or 
last follow-up and will be estimated using the Kaplan- Meier method. Response rate will be 
estimated using binomial proportions along with 95% confidence intervals. Toxicity will be 
summarized using descriptive statistics. 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Re search Participant Re gistration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/).  The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
 
 
 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
The data collected for this study will be entered into MSKCC‘s Clinical Research 
DataBase (CRDB), a secure database. Source documentation will be available to support 
the computerized patient record. Anonymization will take place at the point of entry into 
the database. Subsequent laborator y analysis will take place on the anonymized samples. 
 
Tumor slides will be stored in the MSKCC pathology laboratory. Results from laboratory 
studies will include photomicrographs of IHC studies, computer files of sequencing data, 
and computer files from microarray analyses. These files will be stored on the D epartment 
of Medicine server. Documentation linking patient identifiers and patient samples results 
will be securely maintained in the CRDB with access limited to study investigators. 
 
 
 
16.1 
Quality Assurance 


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Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the new policies set forth by the 
NCI in the document entitled ―Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials‖ which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center‘s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 


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Page 33 of 43
 
 
 
 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Priv acy 
 
MSKCC‘s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Se rious Adverse Event (SAE) Re porting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject‘s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI‘s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FD A assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FD A by the 
SAE staff through the IND Office. 
 
 
 
 
 
 
 
 
17.3 


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Definitions 
 
The following standard text should be used: 
 
 
De finition of adverse event (AE) 
 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
 
A surgical procedure that was planned prior to the start of the study by any physician treating the 
subject should not be recorded as AE (however, the condition for which the surgery is required may 
be an AE if worsens compared to baseline). 
 
The clinical manifestation of any failure of expected pharmacological action (lack of efficacy) is not 
recorded as an AE if it is already reflected as a data point captured in the CRF.  If, however, the 
event fulfills any of the criteria of an SAE, it must be recorded as and AE and reported as an SAE. 
 
 
•   Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical his tory (e.g. 
seasonal allergy without acute complaints). 
 
•   Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are recorded 
as medical history (e.g. allergic pollinosis). 
 
•   Conditions that started or deteriorated after signing of informed consent will be documented 
as adverse events. 
 
 
De finition of serious adverse event (SAE) 
 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the following 
criteria (a – f): 
 
a.  Results in death. 
b.  Is life-threatening. 
The term ‗life-threatening‘ in the definition refers to an event in which the patient was at risk 
of death at the time of the event, it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at least 
one of the following exceptions is met: 
 
- The admission results in a hospital stay of less than 12 hours. 
 
- The admission is pre-planned. 
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
 
- The admission is not associated with an AE. 
(e.g. social hospitalization for purposes of respite care). 
 
However, it should be noted that invasive treatment during any hospitalization may fulfill the 
criterion of ‗medically important‘ and as such may be reportable as an SAE dependent on 


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IRB Number: 13-080 A(4) 
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Page 35 of 43
 
 
 
 
 
clinical judgment.  In addition, where local regulatory authorities specifically require a more 
stringent definition, the local regulation takes precedence. 
 
d.  Results in persistent or significant disability / incapacity. 
 
Disability means a substantial disruption of a person‘s ability to conduct normal life‘s functions. 
 
e.  Is a congenital anomaly / birth defect. 
 
f. Is another medically important serious event as judged by the investigator. 
 
Serious adverse events 
In addition to the SAE criteria specified in the standard text above, further criteria may be defined; 
e.g. all Grade-4 laboratory toxicities according to the Common Terminology Criteria for Adverse 
Events (CTCAE, version to be specified) may have to be recorded as SAEs. 
 
Classifications for adverse event assessment 
 
The following classifications should be used: 
• Seriousness 
 
• Intensity 
As an alternative to the grading system described in the standard text below (mild, 
moderate, severe), other systems for intensity may be used (e.g. CTCAE, Grade 1 to 
Grade 5).  If used, this needs to be stated and definitions of the grades should be 
provided.  If applicable, a “translation” between the CTCAE system and the standard 
system of intensity grading may have to be provided. 
 
• Causal relationships to study drug: 
To be assessed separately for concomitant agents 
 
Example 1 
Doxorubicin (open 
regorafenib  (blinded) 
Versus 
Doxorubicin (open label) 
+ matching placebo 
(blinded) 
The relationship to study drug will assume that both 
active entities (regorafenib or doxorubicin) are suspect 
drugs if both drugs are given in combination.  Due to 
regorafenib, regorafenib and placebo being blinded, the 
assumption is that both compounds could be in causal 
relationship as long as doxorubicin and regorafenib 
/placebo (blinded) are given in combination.  In 
exceptional cases, the investigator can state in the 
comment field that he/she believes that the event is more 
likely to be caused by doxorubicin. 
Example 2 
Dose-escalation trial, 
open-label study 
regorafenib  + 
bevacizumab 
The assessment of the relationship of an AE to the 
administration of study drug is the investigator’s clinical 
decision based on all available information at the time of 
the completion of the CRF.  Study drug refers to 
regorafenib and/or bevacizumab and the assessment of 
relationship to study drug will be done for each drug 
separately.  If the investigator feels such a distinction 
cannot be made (e.g. due to a suspected underlying 
interaction) the same assessment will be documented for 
both drugs 
 
• Study treatment action 
 
• Other specific treatment of AE 


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IRB Number: 13-080 A(4) 
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Page 36 of 43
 
 
 
 
 
 
• Causal relationship to protocol-required procedures(s) 
 
• Outcome 
 
 
All AEs will be assessed and documented by the investigator according to the categories detailed 
below. 
 
Seriousness 
 
For each AE, the seriousness must be determined according to the criteria given in Section 0. 
 
Intensity 
 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to the severity 
(intensity) of the AE: 
 
CTCAEv 4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention is not indicated. 
 
CTCAEv 4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; limiting to 
age-appropriate instrumental activities of daily living (ADL; instrumental ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc). 
CTCAEv 4 Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self care 
ADL (self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden). 
 
CTCAEv 4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
 
CTCAEv 4 Grade 5: death due to an AE. 
 
Causal relationship 
 
The assessment of the causal relationship between an AE and the administration of treatment is a 
clinical decision based on all available information. 
 
If applicable for trials with more than one study agent, the following sentence should be included. 
 
The causality assessment should be done separately for each study treatment. 
 
The assessment is based on the question whether there was a ―reasonable causal relationship‖ to 
the study treatment in question. 
 
Possible answers are ―yes‖ or ―no‖. 
An assessment of ―no‖ would include: 
1.  The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical site. 
or 
2.  Non-plausibility, e.g. the subject is struck by an automobile when there is no indication that 
the drug caused disorientation that may have caused the event; cancer developing a few 
days after the first drug administration. 


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IRB Number: 13-080 A(4) 
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Page 37 of 43
 
 
 
 
 
An assessment of ―yes‖ indicates that there is a reasonable suspicion that the AE is associated with 
the use of the study treatment. 
 
Factors to be considered in assessing the relationship of the AE to study treatment include: 
 
- The temporal sequence from drug administration:  The event should occur after the drug is 
given.  The length of time from drug exposure to event should be evaluated in the clinical 
context of the event. 
 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re- 
challenge): 
 
- Subject‘s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question. 
 
- Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have. 
 
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them may be suspected to cause the event in question. 
 
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the study 
treatment, coupled with the individual subject‘s pharmacodynamics should be considered. 
 
 
[Causal relationship to protocol-required procedure(s)] 
 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a ―reasonable causal relationship‖ to 
protocol-required procedure(s). 
 
Possible answers are ―yes‖ or ―no‖. 
 
Action taken with study treatment 
 
Any action on study treatment to resolve the AE is to be documented using the categories listed 
below. 
 
 
If applicable for trials with more than one study agent, the following sentence should be included. 
 
The study treatment action should be recorded separately for each study treatment. 
 
־ 
Drug withdrawn 
 
־ 
Drug interrupted 
 
־ 
Dose reduced 
 
־ 
Dose not changed 
 
־ 
Dose increased 
 
־ 
Not applicable 
 
־ 
Unknown 


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IRB Number: 13-080 A(4) 
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Page 38 of 43
 
 
 
 
 
Other specific treatment(s) of adverse events 
 
־ 
None 
 
־ 
Remedial drug therapy 
 
Outcome 
 
The outcome of the AE is to be documented as follows: 
 
־ 
Recovered/resolved 
 
־ 
Recovering/resolving 
 
־ 
Recovered/resolved with sequelae 
 
־ 
Not recovered/not resolved 
 
־ 
Fatal 
 
־ 
Unknown 
 
Assessments and documentation of adverse events 
 
Reporting of serious adverse events 
 
Each serious adverse event must be followed up until resolution or stabilization, by submission of 
updated reports to the designated person. An isolated laboratory abnormality that is assigned grade 
4, according to CTC definition, is not reportable as an SAE; unless the investigator assesses that the 
event meets standard ICH criteria for an SAE.  CTC grade 4 baseline laboratory abnormalities that 
are part of the disease profile should not be reported as an SAE, specifically when they are allowed 
or not excluded by the protocol inclusion/exclusion criteria. 
 
When required, and according to local law and regulations, serious adverse events must be reported 
to the Ethics Committee and Regulatory Authorities. 
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an 
event, the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures. 
 
The Investigator may re port serious adverse drug reactions (SADRs) using e ither: 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html 
 
OR 
 
A MedWatch form available at http://www.fda.gov/medwatch/ 
 
All reports shall be sent electronically to: 
 
Ele ctronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Addre ss: 
Global Pharmacovigilance - USA 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 39 of 43
 
 
 
 
 
Mail only: 
Bayer HealthCare Pharmaceuticals Inc. 
 
P.O. Box 1000 
 
Montville, NJ 07045-1000 
  
 
 
Addre ss: 
340 Changebridge Road 
 
FDX or UPS only 
Pine Brook, NJ 07058 
 
Re ports for all Bayer products can also be phoned in via our Clinical Communications De pt: 
Phone: 
1-888-842-2937 
Expected adverse events 
 
For this study, the applicable reference document is the most current version of the investigator‘s 
brochure (IB) / summary of product characteristics. 
 
 
If applicable, the following sentence should be included. 
 
Overview listings of frequent events that have occurred so far in the clinical development are shown 
in the current IB.  If relevant new safety information is identified, the information will be integrated 
into an update of the IB and distributed to all participating sites. 
 
The expectedness of AEs will be determined by Bayer according to the applicable reference 
document and according to all local regulations. 
 
Adverse events of special safety interest 
 
This optional subsection may be used to pre-define certain AEs that are of particular interest for a 
given drug development program.  All pertinent details (e.g. reporting procedures) are to be 
specified as appropriate. 
 
If not needed, this subsection should be deleted. 
 
As with any new chemical entity, there is always potential for unexpected adverse events, including 
hypersensitivity reactions. 
 
Based on data studies with regorafenib and from current knowledge of the pharmacological 
properties of other small molecule tyrosine kinase inhibitors in this drug class, as soon as there is 
reasonable suspicion of any of the following AEs, the investigator should immediately notify the 
sponsor. 
 
Reportable adverse events include: 
 
•   Acute renal failure (NC I-CTCAE version 4.0 ≥ grade 3) or severe proteinuria (NCI-CTCAE 
version 4.0 ≥ grade 3) 
 
•   Interstitial lung disease 
 
•   Acute cardiac failure 
•   Clinically significant bleeding (NC I-CTCAE version 4.0 ≥ grade 3) 


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IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
Page 40 of 43
 
 
 
 
 
•   Stevens-Johnson Syndrome and erythema multiforme 
 
•   Hepatic failure 
 
•   Reversible posterior leukoencephalopathy syndrome 
 
•   Gastrointestinal perforation or fistula 
 
 
 
Pre gnancies 
 
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 c onsidered 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. 
 
For all reports, the forms provided are to be used. 
 
Further safety 
 
Consider adding following additional language: 
 
 
Progressive disease 
 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE 
(i.e., hospitalization, disability, death, or important medical event), the signs and symptoms should 
be reported as an SAE and not the underlying progressive disease. 
 
De ath 
 
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 (using the SAE Form) within 24 hours. 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


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IRB Number: 13-080 A(4) 
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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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IRB Number: 13-080 A(4) 
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19.0 
REFERENCES 
 
1. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63:11- 
30, 2013 
2. 
Van Cutsem E, Moiseyenko VM, Tjulandin S, et a l: Phase III Study of Docetaxel and 
Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for 
Advanced Gastric Cancer: A Report of the V325 Study Group, 2006, pp 4991-4997 
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Journal of Clinical Oncology 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-080 A(4) 
Approval date: 18-Apr-2017 
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20.0 
APPENDICES 
 
Appendix A: Pill Diary For Regorafenib Days 4 through 10 and 18 through 24 
 
Appendix B: Pill Diary For Regorafenib Days 1 through 21