Clinical trial NCT03099486
Conditions: Colorectal Cancer
Sponsor: Fox Chase Cancer Center
Start date: 2017-10-06; Completion date: 2020-06-02
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm open label pilot phase II trial of Regorafenib PO plus 5-FU/LV infusion in 15 mCRC patients who progressed on prior Regorafenib monotherapy as well as 5-FU containing chemotherapy combinations.The study will enroll mCRC patients with prior progression on standard multi-agent combination chemotherapy and progression on regorafenib monotherapy.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Regorafenib intervention 2: 5-FU intervention 3: Leucovorin
Intervention descriptions: intervention 1: The dose of Regorafenib is 160 mg PO daily D1-D21 of 28-day cycle or last tolerated dose while on Regorafenib monotherapy. intervention 2: 5-FU dose D1 and D15 of 28 day cycle i400 mg/m2 bolus over 10 mins followed by 2400 mg/m2 continuous infusion over 46 hours intervention 3: D1 and D15 of 28 day cycle Leucovorin 400 mg/m2 over 2 hours,

Protocol documents:
Prot_SAP_001.pdf: 
 
 
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GI-094 A Pilot Phase II, single arm, open label, investigator-initiated clinical trial of 
Regorafenib plus 5-Fluorouracil/Leucovorin (5FU/LV) beyond progression on 
Regorafenib monotherapy in metastatic colorectal cancer (mCRC) 
 
Brief Title: Regorafenib plus 5-FU/LV beyond progression in mCRC 
 
Sponsor Investigator: 
Namrata Vijayvergia, MD 
Fox Chase Cancer Center  
333 Cottman Avenue 
Philadelphia, PA 19111 
Tel: (215) 214-1676 
 
Email: Namrata.Vijayvergia@fccc.edu  
 
Sub-Investigator:              Efrat Dotan, MD 
 
Michael Hall, MD 
 
Crystal Denlinger, MD 
 
Paul Engstrom, MD 
                                            Juhi Mittal, MD 
 
Statistician: 
Eric Ross, PhD 
Fox Chase Cancer Center 
333 Cottman Ave. 
Philadelphia, PA 19111 
Phone: (215) 728-2891 
Fax: (215) 728-2553 
Email: eric.ross@fccc.edu 
 
 
 
 
Protocol Version Date: 12/14/2018 
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Synopsis 
 
[Title] 
Regorafenib plus 5-FU/LV treatment beyond progression in mCRC 
patients 
Clinical study phase 
Pilot Phase II 
Study objective(s) 
The goal is to investigate PFS and OS in mCRC patients who 
progressed on regorafenib monotherapy and are treated with 
regorafenib/5-FU/LV combination therapy 
[Background treatment] 
Standard multi-agent combination chemotherapy and regorafenib 
monotherapy 
Indication 
Metastatic Colorectal Cancer including cancers with wild-type or 
mutant KRAS/NRAS/BRAF genes 
Diagnosis and main criteria 
for inclusion 
mCRC with prior progression on standard multi-agent combination 
chemotherapy and progression on regorafenib monotherapy. 
Study design 
Single arm open label pilot phase II trial of Regorafenib PO plus 5-
FU/LV infusion in mCRC patients who progressed on prior 
Regorafenib monotherapy as well as 5-FU containing chemotherapy 
combinations. Dose of Regorafenib is 160 mg PO daily D1-D21 of 
28 day cycle or last tolerated dose while on Regorafenib 
monotherapy. 5-FU dose D1 and D15 is 400 mg/m2 over 10 mins, 
Leucovorin 400 mg/m2 over 2 hours, 5-FU 2400 mg/m2 IV infusion 
over 46 hours (or last tolerated dose of infusional 5-FU).  
Type of control 
Historical control (no control arm for the single arm study) 
Number of subjects 
15 
Plan for statistical analysis 
Descriptive pilot study 
Institutional enrollment 
The study will be performed at Fox Chase Cancer Center and Fox 
Chase Cancer Center at Temple University Hospital 
Publications 
Results will be submitted by the PI and collaborating investigators to 
society meetings such as ASCO, GI ASCO, AACR and eventually 
the work will be submitted for publication in a journal as a full 
manuscript after the study is concluded. 
 
 


 
 
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Contents 
1. 
Introduction ...................................................................................................................4 
1.1 
Metastatic Colorectal Cancer ................................................................................5 
1.2 
Regorafenib ...........................................................................................................5 
1.3 
Preclinical ..............................................................................................................5 
1.4 
Clinical Experience ...............................................................................................6 
1.5 
Rationale for Combination ....................................................................................7 
1.6 
Preclinical ..............................................................................................................7 
1.7 
Clinical experience ................................................................................................8 
2 
Study objectives ..........................................................................................................10 
2.1 
Primary Objective: ..............................................................................................10 
2.2 
Secondary objective: ...........................................................................................10 
3 
Study design ................................................................................................................11 
4 
Patient Selection Inclusion & Exclusion ....................................................................11 
4.1 
Inclusion criteria ..................................................................................................11 
4.2 
Exclusion criteria .................................................................................................13 
4.3 
Inclusion of Women and Minorities ....................................................................14 
4.4 
Pregnancy ............................................................................................................15 
4.5 
Patient Registration .............................................................................................15 
5 
Treatment Plan ............................................................................................................16 
5.1 
Treatments to be administered ............................................................................16 
5.2 
Regorafenib .........................................................................................................16 
5.3 
Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions ..........................................................................................................17 
5.3.1 
Excluded therapies and medications ............................................................17 
5.3.2 
Prior and concomitant therapy .....................................................................17 
5.3.3 
Permitted concomitant therapy: ...................................................................18 
5.4 
Duration of Therapy ............................................................................................18 
5.5 
Duration of Follow-up .........................................................................................19 
6 
Dose Modifications .....................................................................................................19 
6.1 
Specific Toxicities and Modifications .................................................................21 
6.1.1 
The table below outlines dose adjustments for hematologic and non-
hematologic toxicities related to regorafenib except HFSR and 
hypertension. ................................................................................................21 
6.1.2 
Grading for Hand-Foot-Skin-Reaction ........................................................22 
6.1.3 
Suggested regorafenib dermatologic toxicity modification .........................22 
6.1.4 
Hypertension ................................................................................................24 
6.1.5 
Liver Function Abnormalities ......................................................................25 
6.1.6 
Prevention/management strategies for diarrhea ...........................................26 
7 
Study Agent Information ............................................................................................26 
7.1 
Regorafenib .........................................................................................................26 
7.2 
5FU ......................................................................................................................27 
7.3 
Destruction and Return of Regorafenib ..............................................................27 
7.4 
Records to be kept at Site; Dispensing and Accountability ................................27 
8 
Study Calendar ............................................................................................................28 


 
 
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9 
Adverse Events ...........................................................................................................29 
9.1 
Definitions ...........................................................................................................29 
9.1.1 
Severity Rating ............................................................................................29 
9.1.2 
Attribution/Relationship to regorafenib and 5FU ........................................30 
9.1.3 
Expectedness ................................................................................................30 
9.2 
Recording and Reporting Responsibilities ..........................................................30 
9.2.1 
Investigative Site Recording Responsibilities: ............................................30 
9.2.2 
Investigative Site Reporting Responsibilities: .............................................31 
9.2.3 
Sponsor Reporting Responsibilities:............................................................32 
9.2.4 
OCR Reporting Responsibilities to Bayer: ..................................................32 
9.2.5 
Expedited Reporting of Other Safety Information: .....................................33 
9.3 
Pregnancy ............................................................................................................34 
10 Measures of Effect ......................................................................................................34 
10.1 Definitions ...........................................................................................................34 
10.2 Disease Parameters ..............................................................................................35 
10.3 Methods for Evaluation of Measurable Disease .................................................36 
10.4 Response Criteria ................................................................................................37 
10.4.1 
Evaluation of Target Lesions .......................................................................37 
10.4.2 
Evaluation of Non-Target Lesions ...............................................................38 
10.4.3 
Evaluation of Best Overall Response ..........................................................38 
10.5 Duration of Response ..........................................................................................39 
10.6 Progression-Free Survival ...................................................................................40 
11 Statistical Considerations ............................................................................................40 
11.1 Study Design/Endpoints ......................................................................................40 
11.2 Sample Size/Accrual Rate ...................................................................................41 
11.3 Stratification Factors ...........................................................................................41 
11.4 Analysis of Secondary Endpoints .......................................................................41 
11.5 Reporting and Exclusions ....................................................................................41 
11.5.1 
Evaluation of toxicity ..................................................................................41 
11.5.2 
Evaluation of response .................................................................................41 
11.6 Planned interim analyses .....................................................................................42 
12 Data and Safety Monitoring Plan ................................................................................42 
12.1 Monitoring Plan ...................................................................................................42 
12.2 Data Safety Monitoring Committee ....................................................................43 
12.3 Administrative .....................................................................................................43 
12.4 Data Reporting ....................................................................................................43 
12.5 Retention of Records ...........................................................................................43 
12.6 Study Agents .......................................................................................................43 
12.7 Informed Consent ................................................................................................44 
14.0 Reference list .............................................................................................................45 
 
 
1. Introduction 
 


 
 
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1.1 Metastatic Colorectal Cancer  
Colorectal cancer (CRC) is the third most common cancer diagnosis in the United States 
and the most prevalent malignancy of the digestive tract (1). Worldwide, approximately 
1.3million patients are diagnosed with CRC, and 694,000 deaths are attributed to the 
disease each year (2). Screening tests are both widely available and effective at detecting 
this disease at an early stage. As a result of screening efforts, fewer than 25% of patients 
diagnosed with CRC in the United States have evidence of metastatic spread at initial 
presentation (1). Unfortunately, 50 to 60% of patient diagnosed with CRC eventually 
develop metastases, and the majority of these patients have unresectable disease (3). 
Whenever possible, the standard of care for patients with CRC is complete surgical 
resection for possible cure. This is typically followed by adjuvant chemotherapy in patients 
with stage III disease, stage IV disease with resectable metastases or stage II disease with 
high-risk features (4). If complete resection is not possible, however, patients are offered 
systemic chemotherapy. Sometimes in this setting neoadjuvant therapy results in 
downsizing of disease, making surgical resection possible with improved long-term 
outcomes. The mainstays of first and second line treatment for patients with stage IV 
unresectable metastatic CRC (mCRC) consists of fluoropyrimidine-based combination 
chemotherapy with FOLFOX (leucovorin, 5-FU, oxaliplatin), Cape-Ox (capecitabine, 
oxaliplatin), or FOLFIRI (leucovorin, 5-FU, irinotecan). Patients with tumors that retain 
wild-type KRAS/NRAS can benefit from the addition of monoclonal antibodies that target 
the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab. 
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) 
receptor is generally offered to patients who develop progressive disease while undergoing 
treatment with an EGFR antagonist or as a component of initial therapy for KRAS/NRAS 
mutated tumors (4). 
 
 
1.2  Regorafenib  
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic 
activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging 
(MRI) (1). Regorafenib is a small molecule inhibitor of multiple membrane-bound and 
intracellular kinases involved in normal cellular functions and in pathologic processes such 
as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.  In 
in vitro biochemical or cellular assays, regorafenib or its major human active metabolites 
M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-
alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, 
BRAFV600E, SAPK2, PTK5, and Ab1 at concentrations of regorafenib that have been 
achieved clinically.  In in vivo models, regorafenib demonstrated anti-angiogenic activity 
in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in 
several mouse xenograft models including some for human colorectal carcinoma. 
 
 
1.3  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 


 
 
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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). (1)  Immunohistochemical ex-
vivo studies with a phospho –specific monoclonocal 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. (1) 
These data suggest that regorafenib can target the tumor cell MAPK pathway (tumor cell 
survival) and tumor vasculature in some but not all tumors.  
 
1.4 Clinical Experience 
Three phase III global randomized studies have evaluated the efficacy of regorafenib. The 
CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo 
after failure of standard therapy) trial is an international, multicenter, randomized, double-
blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has 
progressed after approved standard therapies. Metastatic colorectal cancer patients were 
randomized to regorafenib plus best supportive care (BSC) or placebo plus BSC. Treatment 
cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks 
on / one week off plus BSC. The primary endpoint of this trial was overall survival. 
Secondary endpoints included progression-free survival, objective tumor response rate and 
disease control rate. The safety and tolerability of the two treatment groups were also 
compared. 
 
At a preplanned second interim analysis, there was a statistically significant survival 
benefit for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% 
confidence interval [CI], 0.635 to 0.941; 1-sided p = .0051). Patients treated with 
regorafenib had a median overall survival of 6.4 months, compared with 5.0 months for 
placebo — a 29% increase in survival. In addition to improved overall survival, 
progression-free survival was superior; median progression-free survival was 1.9 months 
(95% CI, 1.88 to 2.17) for regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. 
The estimated hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 
0.581; 1-sided p< .000001). There was a substantial difference in disease control rate in 
the regorafenib and placebo groups (44% vs. 15%; p<.000001). Regorafenib 
demonstrated comparable efficacy benefits across patient subgroups analyzed including 
age, number of mets, number of lines of prior therapy, and kras status. 
The most frequent grade ≥ 3 adverse events in the regorafenib group were hand–foot skin 
reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension 
(7%).  The efficacy and safety from the CORRECT study supported FDA approval in 
September 2012.  
A second randomized international, double-blind, placebo-controlled study enrolled 
patients with mCRC whose disease progressed after approved standard therapies was 


 
 
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conducted in Asia Pacific (China, Hong Kong, Taiwan, Republic of Korea, and Vietnam). 
This multicenter phase III study randomly (CONCUR - A placebo CONtrolled, 
randomized, double blind Clinical study Using Regorafenib in Asian CRC patients after 
failure of standard therapies) assigned 136 Asian patients to regorafenib at 160 mg daily 
and 68 to placebo.The primary endpoint of the study was overall survival. Sixty percent of 
patients enrolled received previous targeted therapy. 
The study met its primary endpoint, with regorafenib demonstrating a median overall 
survival of 8.8 months compared to 6.3 months for placebo compared –and with 45% 
reduction in the risk of death compared with placebo ((hazard ratio 0.55, 95% CI 0.40-
0.77, one-sided p=0.00016 P = 0.0002). Adverse events in CONCUR were consistent with 
the known safety profile of regorafenib in metastatic colorectal cancer. 
The efficacy and safety of regorafenib were examined in the Phase III GRID trial in patients 
with gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment 
options. The study involved 199 patients with metastatic and/or unresectable GIST that had 
become resistant to imatinib and sunitinib. Patients were randomized 2:1 to regorafenib 
(160 mg orally once daily on a 3 weeks on/1 week off cycle) or placebo, plus best 
supportive care. 
The results showed that treatment with regorafenib led to a statistically significant 3.9-
month improvement in progression-free survival (PFS), compared with placebo (4.8 
months vs. 0.9 months; hazard ratio [HR] = 0.27;  p <.0001). Overall survival was 
statistically similar between groups as expected due to a trial design that allowed crossover 
to regorafenib for disease progression (85% for placebo and 31% regorafenib randomized 
patients). The median survival period without tumor growth among patients on regorafenib 
was 4.8 months while for the control group on placebo it was less than a month. The overall 
disease control rate combining partial responses with durable stable disease for at least 12 
weeks was 53% with regorafenib compared with 9% in the control group. The most 
common grade ≥3 adverse events associated with regorafenib were hand-foot skin reaction 
(56.1%), hypertension (48.5%), and diarrhea (40.9%).   The efficacy and safety of the 
GRID study data supported FDA approval February 2013. 
1.5   Rationale for Combination 
Our preclinical data support the concept that there is synergy between 5-FU and 
regorafenib in mCRC subtypes and anecdotal patient cases we have treated have suggested 
that there is disease control by combining regorafenib plus 5-FU beyond progression on 
regorafenib 
 
1.6  Preclinical 
We have observed synergistic effects with the addition of regorafenib to 5-FU in colorectal 
cancer cell lines with KRAS mutation, BRAF mutation, p53 mutation, p53 deletion or 
wild-type p53 status (Figure 1, Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015).  
 


 
 
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Figure 1: Regorafenib synergizes with chemotherapy. (Combination index (CI) values of regorafenib in 
combination with 5-fluorouracil for 48 h in various non-constant ratios against colon cancer cell lines. 
Combination index <1, D1 and >1 indicates synergism, additivity or antagonism, respectively. Red 
numbers indicate synergy (CI<1). Additional details of the case can be found in Marks et al., Cancer Biol. 
Ther. 16:1710-1719, 2015. 
 
 
Of note, while it is known that mismatch repair deficient colorectal cancers are generally 
more resistant to 5-FU than microsatellite stable tumors, the HCT116 mismatch repair 
deficient cells used in our study were sensitive to the regorafenib plus 5-FU combination 
regardless of whether p53 was wild-type or deleted (Marks et al., Cancer Biol. Ther. 
16:1710-1719, 2015). We performed cell culture experiments to assess alterations in 
specific biomarkers that may correlate with observed sensitivity patterns. Potent inhibition 
of Mcl-1 expression was observed in regorafenib-treated colorectal cancer cells and the 
reduced expression was still present when 5-FU was added in combination across the panel 
of cell lines tested (Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015). Reduced Mcl-1 
and Bcl-XL (although reduction of Bcl-XL was less robust and noted primarily in the 
combination therapy conditions) could be a contributing factor to the observed sensitivity 
patterns (Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015). 
 
1.7  Clinical experience 
Our clinical experience reported as clinical case reports showed that two patients diagnosed 
with metastatic colorectal cancer who exhausted all approved standard therapies had stable 
disease following treatment with the combination of regorafenib and either 5-FU or 
capecitabine (Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015). Both these patients 
showed disease progression despite treatment with first-line FOLFOX and second-line 
FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based 
regimens, both patients received additional cytotoxic and targeted therapies with eventual 
disease progression. These therapies included capecitabine plus dabrafenib and trametinib, 


 
 
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regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available 
options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or 
capecitabine. The first patient was transitioned to regorafenib 160 mg PO daily for days 1-
21 of a 28 day cycle with capecitabine 1000 mg PO twice daily for days 1-14 of a 21 day 
cycle while the second patient received 160 mg PO daily for days 1-21 of 28 day cycle plus 
infusional 5-FU every 2 weeks at 2400 mg/m2 over 46 hours, bolus 5-FU 400 mg/m2 on 
day 1 and leucovorin. This regimen produced stable disease in both patients with 
acceptable toxicity (Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015).  
 
The first patient had stable disease for at least one month after starting therapy with 
regorafenib and capecitabine. Disease control was reflected in both radiographic and 
serologic measures of CRC activity. The duration of the stable disease response to 
treatment was cut short, however, by severe pneumonia and pulmonary hemorrhage 
resulting in the patient’s demise. It remains uncertain whether this fatal bleed occurred as 
a treatment-related adverse event because the patient was concurrently receiving 
therapeutic-dose enoxaparin for her pulmonary embolus and otherwise had advanced 
metastatic disease. This patient did not experience toxicities commonly associated with 
regorafenib or capecitabine, therefore, did not require any dose reductions or delays during 
the short course of therapy.  
 
A more prolonged period of disease control following therapy was observed in the second 
patient, who received regorafenib with 5-FU for approximately 17 months. This patient 
had evidence of stable disease for at least 2 months before starting to accumulate new 
metastatic foci. Despite developing progressive disease, the patient opted to continue on 
this treatment, and for the next 11 months, his tumor markers remained largely suppressed. 
The patient ultimately passed away 17 months following his first dose of regorafenib with 
5-FU due to a disease-related complication. While on treatment with regorafenib and 5-
FU, this patient did experience modest treatment-associated toxicity and therefore required 
some dose reductions and several treatment delays. Of note the patient had disease control 
for many months on the regorafenib plus 5-FU combination as documented by a non-rising 
CEA while on therapy (Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015). CEA rose 
when patient had interruptions to therapy due to sepsis related to indwelling catheters but 
CEA became stable when the regorafenib plus 5-FU therapy was restarted (Figure 2). 
 


 
 
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Figure 2. Serologic response to prior systemic therapies and regorafenib plus capecitabine in a 
patient with metastatic colorectal cancer who had progressed on prior standard combination 
therapies. CEA (carcinoembryonic antigen) is displayed as a function of time in the patient’s treatment 
course. Additional details of the case can be found in Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015. 
 
Despite the multitude of clinical trials, there has not been active clinical investigation in 
the safety and efficacy of combining regorafenib with capecitabine or 5-FU in treatment 
refractory 
mCRC. 
This 
regimen 
holds 
considerable 
theoretical 
appeal, 
as 
fluoropyrimidines are the backbone of effective first and second-line therapy. Regorafenib, 
on the other hand, has been proven to prolong OS in patients who failed initial therapy and 
may blunt the side effects of cytotoxic chemotherapy. Further investigation into this 
possible later-line regimen is certainly warranted given the observation of stable disease 
from the combination of regorafenib and 5-FU or capecitabine despite progression on prior 
therapy with either agent alone. Our preclinical experiments support a rationale for the 
combination with evidence for synergy across a range of various CRC subtypes (KRAS 
mutant, BRAF mutant, KRAS/BRAF wild-type, MSI), and there is also reduction of 
prosurvival molecules such as Mcl-1 observed in CRC cells treated with combination 
(Marks et al., Cancer Biol. Ther. 16:1710-1719, 2015). 
2 Study objectives 
2.1 Primary Objective:  
The goal is to investigate PFS at 2 months in mCRC patients who progress on regorafenib 
monotherapy and are treated with regorafenib and 5-FU/LV combination therapy. 
 
2.2 Secondary objective: 
Characterize overall survival time, best overall response, duration of response, and disease 
control rate in mCRC patients who progress on regorafenib monotherapy and are treated 
with regorafenib and 5-FU/LV combination therapy. Safety profile of the combination 
therapy will also be assessed by frequencies and grades of toxcities due to the combination 
 


 
 
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therapy 
3 Study design 
This is a single arm open label pilot phase II trial of Regorafenib PO plus 5-FU/LV infusion 
in 15 mCRC patients who progressed on prior Regorafenib monotherapy as well as 5-FU 
containing chemotherapy combinations.The study will enroll mCRC patients with prior 
progression on standard multi-agent combination chemotherapy and progression on 
regorafenib monotherapy.  
 
All 15 patients will have response evaluation after every 2 cycles on therapy. The study 
will be terminated and the null hypothesis accepted if none (0) of the first 10 patients are 
both alive and progression free at 2 months. Alternatively, if one (1) or more of the first 10 
patients are alive and progression free an additional 5 patients will be accrued. 
 
There is no randomization in this single arm pilot study. There is no stratification although 
the study will collect demographic information, prior therapies, location of baseline 
metastasis (liver, lung, other) and information on genomic analysis of the CRCs including 
KRAS/NRAS/BRAF/MSI as standard of care. 
 
All patients are expected to have confirmed histologic diagnosis of metastatic colorectal 
cancer. Response assessment (radiologic tumor assessment) by RECISTv1.1 criteria will 
be done after every 2 cycles (8 weeks) while patients are on study. Tumor marker analysis 
(CEA, CA19.9) will be performed at the time of screening. For patients with elevated levels 
at screening,  analysis will be performed every 2 weeks while the patients are on study. 
 
The dose of Regorafenib is 160 mg PO daily D1-D21 of 28-day cycle or last tolerated dose 
while on Regorafenib monotherapy. 5-FU dose D1 and D15 is 400 mg/m2 over 10 mins, 
Leucovorin 400 mg/m2 over 30 min, 5-FU 2400 mg/m2 IV infusion over 46 hours (or last 
tolerated dose of infusional 5-FU).  
 
4 Patient Selection Inclusion & Exclusion  
4.1 Inclusion criteria 
 
4.1.1 mCRC with prior progression on standard multi-agent combination 
chemotherapy and regorafenib as a standard approved monotherapy. 
Progression on prior regorafenib is required for inclusion in this clinical study. 
Prior regimens may include FOLFOX -/+ bevacizumab, FOLFIRI -/+ 
bevacizumab or -/+ cetuximab (if KRAS wild-type) or panitumumab (if KRAS 
wilt-type). Other prior regimens may include 5-FU or capecitabine -/+ 
bevacizumab, irinotecan -/+ cetuximab or panitumumab, FOLFIRI -/+ ziv-
aflibercept or ramicirumab. 
 
4.1.2 Patients treated with oxaliplatin in an adjuvant setting should have progressed 
during or within 6 months of completion of adjuvant therapy. Patients who 


 
 
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progress more than 6 months after completion of oxaliplatin containing 
adjuvant treatment must be retreated. Patients who have withdrawn from 
standard treatment due to unacceptable toxicity warranting discontinuation of 
treatment and precluding retreatment with the same agent prior to progression 
of disease will also be allowed in the study. 
 
4.1.3 Patients previously treated with regorafenib, lonsurf or capecitabine as the last 
prior regimen can start on this study as long as there is at least 1 week of period 
between the last dose of previous treatment and day 1 in this study provded the 
patients are eligible. Patients who were on FOLFOX or FOLFIRI regimens  
must have at least 2 weeks period between the last dose and the first dose in this 
clinical study. Patients previously treated with Avastin, Zaltrap, cetuximab, 
pembrolizumab, panitumumab, nivolumab Erbitux, and Vectibix must have at 
least 4 weeks period between the last dose of previous chemotherapy and the 
first dose in this clinical study.  
 
4.1.4 Measurable metastatic disease that is refractory. 
 
4.1.5 ECOG performance status 0-2. 
 
4.1.6 Patients are included regardless of KRAS/NRAS, BRAF, p53, or MSI status 
 
4.1.7 Age ≥ 18 years. 
 
4.1.8 Life expectancy of at least 8 weeks (2 months). 
 
4.1.9 Subjects must be able to understand and be willing to sign the written informed 
consent form. A signed informed consent form must be appropriately obtained 
prior to the conduct of any trial-specific procedure. 
 
4.1.10 Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements: 
o 
Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
o 
Alanine aminotransferase (ALT) and aspartate amino-transferease 
(AST)  ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement 
of their cancer) 
o 
Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects 
with liver involvement of their cancer) 
o 
Serum creatinine  ≤ 1.5 x the ULN 
o 
International normalized ratio (INR)/ Partial thromboplastin time 
(PTT)  ≤ 1.5 x ULN, unless patient is on therapeutic anticoagulation  
o 
Platelet count > 100000 /mm3, hemoglobin (Hb) > 9 g/dL, absolute 
neutrophil count (ANC) ≥ 1500/mm3.  Blood transfusion to meet the 


 
 
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inclusion criteria will not be allowed. 
4.1.11 
Subject must be able to swallow and retain oral medication. 
4.1.12 
Up to 5 of the 15 patients will be allowed to have had other approved or 
investigational drugs after prior progression of Regorafenib monotherapy. 
(all patients enrolled in this trial must have had prior progression on 
regorafenib therapy). This may include TAS102, off-label therapy that may 
have been prescribed based on tumor genomic profiling or any 
investigational agents on a clinical trial. 
4.1.13 
No more than grade 2 toxicity with last previous cycle of regorafenib mono 
therapy. 
 
4.2 Exclusion criteria 
 
4.2.1 Patients receiving any concurrent investigational agents 
4.2.2 Previous assignment to treatment during this study. Subjects permanently 
withdrawn from study participation will not be allowed to re-enter study. 
4.2.3 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic 
pressure > 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) 
despite optimal medical management. 
4.2.4 Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > 
Class II. 
o Active coronary artery disease. 
o Suspected Long QT syndrome defined as QTc interval > 500 
milliseconds at baseline. 
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. 
4.2.5 Evidence or history of bleeding diathesis or coagulopathy. 
 
4.2.6 Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks 
prior to start of study medication.  
4.2.7 Subjects diagnosed with thrombotic, embolic, venous, or arterial events, 
such as cerebrovascular accident (including transient ischemic attacks) deep 
vein thrombosis or pulmonary embolism within 3 months of start of study 
treatment. 
4.2.8 Patients with any previously untreated or concurrent cancer that is distinct 


 
 
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in primary site or histology except cervical cancer in-situ, treated ductal 
carcinoma in situ of the breast, curatively treated nonmelanoma skin 
carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder 
tumor. Subjects surviving a cancer that was curatively treated and without 
evidence of disease for more than 3 years before registration are allowed; 
all cancer treatments must be completed at least 3 years prior to registration. 
 
4.2.9 Patients with phaeochromocytoma. 
4.2.10 Known history of human immunodeficiency virus (HIV) infection or 
current chronic or active hepatitis B or C infection requiring treatment with 
antiviral therapy. 
4.2.11 Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
4.2.12 Symptomatic metastatic brain or meningeal tumors. 
4.2.13 Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
4.2.14 Major surgical procedure or significant traumatic injury within 28 days 
before start of study medication 
4.2.15 Renal failure requiring hemo-or peritoneal dialysis. 
4.2.16 Dehydration Grade >1 NCI-CTCAE v4.0. 
4.2.17 Patients with seizure disorder requiring medication. 
4.2.18 Persistent proteinuria  Grade 3 per NCI-CTCAE v4.0 (> 3.5 g/24 hrs, 
measured by urine protein: creatinine ratio on a random urine sample). 
4.2.19 Interstitial lung disease with ongoing signs and symptoms at the time of 
informed consent.  
4.2.20 Pleural effusion or ascites that causes respiratory compromise (≥ NCI-
CTCAE version 4.0 Grade 2 dyspnea). 
4.2.21  History of organ allograft (including corneal transplant). 
4.2.22 Known or suspected allergy or hypersensitivity to any of the study drugs, 
study drug classes, or excipients of the formulations given during the 
course of this trial. 
4.2.23  Any malabsorption condition. 
4.2.24  Women who are pregnant or breast-feeding. 
4.2.25 Any condition which, in the investigator’s opinion, makes the subject 
unsuitable for trial participation. 
4.2.26 Substance abuse, medical, psychological or social conditions that may 
interfere with the subject’s participation in the study or evaluation of the 
study results. 
4.3 Inclusion of Women and Minorities 


 
 
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Men and women, regardless of race, ethnic group or sexual orientation are eligible for this 
study.   
 
4.4 Pregnancy 
Women of child-bearing potential (WOCBP) and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, 
for the duration of treatment, and for at least 3 months after the completion of treatment. 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she must inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. In additional, men enrolled on this study should understand the risks to any 
sexual partner of childbearing potential. 
 
All WOCBP must have a negative pregnancy test within 72 hours prior to receiving the 
first dose of the investigational agent(s). If the pregnancy test is positive, the patient must 
not receive protocol treatment and must not be enrolled in the study. 
 
WOCBP is defined as follows: Any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma 
follicle-stimulating hormone (FSH) level > 35 mIU/ml). Even women who are using oral, 
implanted, or injectable contraceptive hormones or mechanical products (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g. vasectomy), should be considered to be WOCBP. 
 
4.5 Patient Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays 
by 
emailing 
the 
Investigator-Sponsored 
Research 
Unit 
(ISRU) 
at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study 
centrally once the following items have been received by email: 
 
 Completed registration form  
 Consent and HIPAA signature pages  
 Eligibility checklist 
 
Following registration, participants must begin protocol treatment within 14 
calendar days of registration.  Issues that would cause treatment delays must be 
discussed with the Sponsor-Investigator.  If a registered participant does not receive 
protocol therapy following registration, the participant will be recorded as 
withdrawn from study.  The Study Monitor must be notified as soon as possible if 
a participant does not begin protocol treatment as scheduled. For additional 


 
 
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registration questions, please email FCCC.MONITOR@fccc.edu or call (215) 
728-5544. 
 
The FCCC ISRU will notify the site by email once registration is confirmed and 
the sequence number has been assigned.  Participants must be registered and have 
received a sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
5 Treatment Plan 
5.1 Treatments to be administered 
 
5.2 Regorafenib 
Four 40-mg regorafenib tablets should be taken in the once a day with approximately 8 
fluid ounces (240 mL) of water after a low-fat (<30%) fat meal.  Some examples of low fat 
meals are: 
 Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon 
of jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g 
of fat). 
 One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of 
toast with jam (no butter or marmalade), apple juice, and one cup of coffee or tea 
(2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories. 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
Regorafenib 
 
160 mg 
Or 
last tolerated dose while on 
Regorafenib monotherapy 
(last tolerated dose has to 
be either 40, 80, 120 or 160 
mg to be included in the 
trial) 
 
 
PO 
 
 
 D1-D21, 
daily 
 
 
 
 
 
4 weeks (28 
days) 
5-FU 
400 mg/m2 bolus over 10 
mins 
followed by 
2400 mg/m2 continuous 
infusion over 46 hours 
Or 
last tolerated dose of 
infusional 5-FU 
 
 
IV 
D1 and D15 
of each 
cycle 
Leucovorin 
 
400 mg/m2 over 30 mins 
Or 
last tolerated dose of 
leucovorin 
 
IV 
D1 and D15 
of each 
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5.3 Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions 
5.3.1 Excluded therapies and medications 
 Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than the study 
treatment. 
 Concurrent use of another investigational drug or device therapy (i.e., outside of 
study treatment) during, or within 4 weeks of trial entry (signing of the informed 
consent form). 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days before start of study treatment. 
 Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 Systemic antitumor therapy, including cytotoxic therapy, signal transduction 
inhibitors, immunotherapy, and hormonal therapy. 
 Bone marrow transplant or stem cell rescue. 
 Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. warfarin, phenytoin, quinidine, carbamazepine, Phenobarbital, 
cycloosporin, and digoxin). Warfarin is metabolized by the cytocrome enzyme 
CYP2C9 and it’s levels may be especially affected by regorafenib 
5.3.2 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 CRF (including start/stop dates, dose frequency, route of 
administration, and indication). Specific caution should be taken when considering or 
administering a concomitant medication that is metabolized by the cytochrome enzymes 
CYP2C8, CYP2B6 and CYP2C9.  Such concomitant medication should be avoided, if 
possible. 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of 
the active metabolite M-5, and resulted in no change in the mean exposure of the active 
metabolite M-2.  Avoid concomitant use of regorafenib with strong CYP3A4 inducers 
(e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
Co administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160mg dose 
of regorafenib increased the mean exposure of regorafenib and decreased the mean 
exposure of the active metabolites M-2 and M-5. Avoid concomitant use of regorafenib 
with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, nefazadone, posaconazole, telithromycin, and voriconazole). 


 
 
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5.3.3 Permitted concomitant therapy: 
 Standard therapies for concurrent medical conditions. 
 Supportive care for any underlying illness. 
 Palliative radiation therapy is allowed if the target lesion(s) are not included within 
the radiation field and no more than 10% of the bone marrow is irradiated. 
 Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth 
factors may be used in the management of acute toxicity, such as febrile 
neutropenia, when clinically indicated or at the investigator’s discretion. However, 
they may not be substituted for a required dose reduction. Subjects are permitted to 
take chronic erythropoietin. 
 Treatment with nonconventional therapies (such as acupuncture), and 
vitamin/mineral supplements are permitted provided that they do not interfere with 
the study endpoints, in the opinion of the investigator. 
 Bisphosphonates or danusumab 
 Therapeutic or prophylactic anticoagulation 
Subjects who are treated with an agent such as warfarin or heparin require close 
monitoring (day 1 and day 15 of each cycle) of their INR/PTT. If either of these 
values are above the therapeutic range, the doses should be modified and the 
assessments should be repeated weekly until they are stable. 
 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. 
5.4 Duration of Therapy 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
 Subject withdraws consent from study treatment and study procedures. A subject 
must be removed from the trial at his/her own request or at the request of his/her 
legally acceptable representative. At any time during the trial and without giving 
reasons, a subject may decline to participate further. The subject will not suffer any 
disadvantage as a result. 
 Disease Progression 
 Pregnancy. (Note: subjects who have been withdrawn from treatment with study 
drug because of pregnancy should not undergo CT scans or MRI or bone scans 
while pregnant) 
 If, in the investigator's opinion, continuation of the trial would be harmful to the 


 
 
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subject's well-being. 
 Subject is lost to follow-up. 
 Death. 
Subjects may be withdrawn from the study for the following reasons: 
 The subject is non-compliant with study drug, trial procedures, or both; including 
the use of anti-cancer therapy not prescribed by the study protocol. 
 Severe allergic reaction to regorafenib or 5-FU (such as exfoliative erythroderma 
or Grade 3 or 4 hypersensitivity reaction). 
 The development of a second cancer.  
 Development of an intercurrent illness or situation which would, in the judgment 
of the investigator, significantly affect assessments of clinical status and trial 
endpoints. 
 Deterioration of ECOG performance status to 4. 
 Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial 
result. 
 
5.5 Duration of Follow-up 
 
Safety follow-up will be performed 30 days (+/-3 days) after discontinuation from the 
study.  Patients removed from the study for unacceptable toxicity would move into safety 
follow-up and would be followed 30 days (+/-3 days) after discontinuation or until 
resolution or stabilization of the adverse events, whichever occurs last.  
Survival follow-up:  For patients who discontinued the study for reasons other than 
disease progresson, radiologic tumor evaluation must be done every 6 to 9 weeks. 
Patients will be followed-up every every 3 months for 2 years, every 6 months for next 2 
years and annually until death. Telephone call is appropriate if patient is unable to be 
seen in clinic for survival follow-up.  
6 Dose Modifications 
The starting dose of regorafenib is 160 mg once daily or the last tolerated dose of 
regorafenib monotherapy. Study medication will be administered on a 3 weeks on/1week 
off schedule (3 weeks out of every 4). The strating dose of 5FU is 2400mg/m2 or the last 
tolerated dose of 5-FU 
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. 


 
 
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The modifications of regorafenib and 5FU will follow the following predefined dose levels*: 
 
Regorafenib 
5-FU 
Leucovorin 
Dose level 0  
160 mg po daily Four 40-mg tablets 
of regorafenib 
2400mg/m2 
400mg/m2 
Dose level - 1 
120 mg po daily  Three 40-mg tablets 
of regorafenib 
 
No bolus administration 
and 1920mg/m2 
 
320 mg/m2 
Dose level - 2 
80 mg po daily  Two 40-mg tablets of 
regorafenib 
No bolus  
administration 
1536mg/m2 
256 mg/m2 
Dose level -3 
40mg po daily 
One 40-mg tablets of 
regorafenib 
No bolus  
administration 1229 
mg/m2 
205 mg/m2 
* except for those starting at the last tolerated dose.  
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 3 dose reductions are required for subjects starting  at 160 mg po daily 
of regorafenib, 400mg/m2 of leucovorin and 2400mg/m2 of 5FU, subjects would come 
off protocol therapy. For patients who start at 120mg po daily dose two dose reduction 
are allowed. For patients who start at 80mg po daily dose one dose reduction is 
allowed while patients who start at 40mg po daily, no dose reduction is allowed. If a 
dose reduction has been performed, dose re-escalation can be considered (up to the 
maximal 160 mg daily dose for regorafenib, 400mg/m2 of leucovorin and 2400mg/m2 for 
5FU) at the discretion of the treating physician provided that the toxicity(ies) has resolved 
to baseline. 
 
Similar to regorafenib patients will start 5FU and leucovorin at the last tolerated dose 
level. Patients who start treatment at 2400mg/m2 of 5FU and 400mg/m2 of leuvovorin, 
3 dose reductions will be allowed as shown in the table above. Patients who start at 
dose lower than 2400mg/m2  of 5FU and 400mg/m2 of leuvovorin, their dose would be 
reduced by 20% from the last dose for every dose reduction. If  dose reductions are 
required beyond dose level -3, the patient will be off-treatment.  
 
The exact combination of administered dose may depend upon the last tolerated dose. For 
example it is possible that a patient would start on 80mg po daily regorafenib dose, 
400mg/m2 of leucovorin and 2400mg/m2 of 5FU if these were the last tolerated doses. If a 
dose reduction is required in this case 5 FU and leucovorin will be reduced by 20% 
(1920mg/m2 ; 320mg/m2 respectively), and regorafenib will be reduced to 40mg po daily. 
If further dose reduction is required this patient will be off-treatment unless treating 


 
 
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physician thinks that the toxicity can be alleviated by just reducing the 5FU and leucovorin 
dose. Similarly when the lowest allowed dose in the study, which is 40mg daily for 
regorafenib, 205mg/m2 for leucovorin and 1229mg/m2 for 5-FU is reached for one drug 
while the lowest allowed dose for the other drugs is not reached and further dose reduction 
is warranted, patient will be off-treatment unless the treating physician thinks that the 
toxicity can be alleviated by reducing the dose of the drug that has not reached the lowest 
dose level. Maximum 3 dose reductions are allowed for both the drugs. If a third dose 
reduction is needed the patient will be off-treatment 
 
When treatment is delayed due to toxicities both drugs will be held and the treatment will 
be restarted with appropriate dose modification of both drugs. 
 
6.1 Specific Toxicities and Modifications 
The following tables outline dose adjustments for toxicities related to study drug except 
hand-foot skin reaction, hypertension and liver function test abnormalities.  
 
Hematological toxicities will be addressed through standard dose modifications for 5-FU 
at the investigator’s discretion. At the beginning of any cycle, treatment will be delayed for 
ANC < 1000, platelet count < 75,000, or Hgb < 7.0. A 20% reduction in 5-FU dose will be 
done for grade 3 toxicity. 
6.1.1 The table below outlines dose adjustments for hematologic and non-
hematologic toxicities related to regorafenib except HFSR and 
hypertension. 
 
Table 6-1:  Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/AST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose  
Modificationb 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 2c 
Reduce by 1 dose level 
If toxicity remains < 
Grade 2, dose re-
escalation can be 
considered at the 
discretion of the 
treating investigator. If 
dose is re-escalated and 
toxicity (≥ Grade 3) 
recurs, institute 
permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 1 dose level. 
Permanent 
discontinuation 
can be considered at 
treating investigator’s 
discretion. 
 
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
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b. Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity and nonclinical 
and asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless subject is 
deriving clinical benefit. 
 
 
 
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. 
 
6.1.2 Grading for Hand-Foot-Skin-Reaction 
 
Table 6-2: Grading for Hand-Foot-Skin-Reaction 
 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndromea 
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters  
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
changes 
Numbness, dysesthesia / 
paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting instrumental 
activities of daily life 
(e.g., preparing meals, 
shopping for groceries 
or clothes, using the 
telephone, managing 
money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, dressing 
and undressing, 
feeding self, using the 
toilet, taking 
medications) and not 
bedridden 
a. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
 
6.1.3 Suggested regorafenib dermatologic toxicity modification 
 
Table 6.3 Recommended dose modification for hand-foot-skin reactiona 
Grade of event  
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute supportive 
measures for symptomatic relief 
Grade 2 
 
1st occurrence 
Consider decreasing dose by one dose level and immediately 
institute supportive measures.  If no improvement, interrupt 
therapy for a minimum of 7 days, until toxicity resolves to 
Grade 0-1 b, c 


 
 
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No improvement within 
7 days or 2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1.c 
When resuming treatment, treat at reduced dose level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one dose level. b, 
d 
4th occurrence 
Discontinue therapy 
Grade 3 
 
1st occurrence 
Institute supportive measures immediately. Interrupt therapy 
for a minimum of 7 days until toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one dose level. b, 
d 
2nd occurrence 
Institute supportive measures immediately. Interrupt therapy 
for a minimum of 7 days until toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one additional 
dose level b, d  
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the discretion of the 
investigator if subject has completed one cycle at reduced dose without recurrence of event. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
Recommended prevention/management strategies for skin toxicities consistent with 
HFSR are summarized below: 
Control of calluses 
Before initiating treatment with regorafenib: 
 Check condition of hands and feet. 
 Suggest a manicure/pedicure, when indicated. 
 Recommend pumice stone use for callus or ‘rough spot’ removal. 
During regorafenib treatment: 
 Avoid pressure points. 
 Avoid items that rub, pinch or create friction. 
Use of creams 
 Non-urea based creams may be applied liberally. 
 Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used 
sparingly and only to affected (hyperkeratotic) areas. 
 Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day.  
Approximately 5% to 8% provides gentle chemical exfoliation. 


 
 
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 Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control. 
 Topical corticosteroids like clobetasol 0.05% should be considered for subjects 
with Grade 2 or 3 HFSR.  Avoid systemic steroids. 
Tender areas should be protected as follows: 
 Use socks/gloves to cover moisturizing creams 
 Wear well-padded footwear 
 Use insole cushions or inserts (e.g. silicon, gel) 
 Foot soaks with tepid water and Epson salts 
6.1.4 Hypertension 
Hypertension is a known AE associated with regorafenib treatment.  Subject will have their 
blood pressure measured at least weekly at the study site during the first 6 weeks of 
treatment. If additional blood pressure measurements are done outside the study site, and 
the blood pressure is > 140 mm Hg systolic or > 90 mm Hg diastolic (NCI CTCAE v4.0), 
then the subject must contact study personnel. The management of hypertension, including 
the choice of antihypertensive medication, will be performed according to local standards 
and to the usual practice of the investigator. Every effort should be made to control blood 
pressure by medical means other than study drug dose modification. If necessary, Table 6-
4 outlines suggested dose reductions. 
 
Table 6-4:  Management of Treatment-Emergent Hypertension 
Grade  
 
(CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
 
Prehypertension (systolic BP 
120 - 139 mmHg or diastolic 
BP 80 - 89 mmHg) 
None 
 Continue regorafenib 
 Consider increasing blood pressure (BP) 
monitoring 
2 
 
Systolic BP 140 - 159 mmHg 
or diastolic BP 90 - 99 
mmHg, 
OR 
Symptomatic increase by 
> 20 mmHg (diastolic) if 
previously within normal 
limits 
 Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
 If BP previously within normal 
limits, start anti-hypertensive 
monotherapy 
 If patient already on anti-
hypertensive medication, titrate 
up the dose. 
 Continue regorafenib 
 
 If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 90 
mm Hga. When regorafenib is restarted, 
continue at the same dose level. 
 


 
 
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3 
 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
OR 
More than one drug or more 
intensive therapy than 
previously used indicated 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive medication  
 
AND/OR 
Increase current anti-hypertensive 
medication 
 
AND/OR  
Add additional anti-hypertensive 
medications.   
 Hold regorafenib until diastolic BP ≤ 90 
mm Hg, and if symptomatic, until 
symptoms resolve.a 
 
 When regorafenib is restarted, continue at 
the same dose level. 
 
 If BP is not controlled with the addition of 
new or more intensive therapy, reduce by 
1 dose level.b 
 
 If Grade 3 hypertension recurs despite 
dose reduction and antihypertensive 
therapy, reduce another dose level.c 
4 
 
Life-threatening 
consequences 
(eg, malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per investigator’s discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 
6.1.5 Liver Function Abnormalities 
For patients with observed worsening of serum liver tests considered related to regorafenib 
(i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease 
progression), the dose modification and monitoring advice in Table 6-5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia 
may occur in patients with Gilbert’s syndrome. 
 
Table 6.5: Dose Modification/interruption for alanine aminotransferase and/or 
aspartate aminotransferase increases related to study drug 
Increases in 
ASL/ALT (per 
NCI-CTCAE v 
4.0) 
1st Occurrence 
Restart 
Recurrence 
AST and/or ALT < 
5 X ULN (<Grade 
3) 
Continue dosing, 
with weekly 
monitoring of liver 
function until 
transaminases return 
to < 3 X ULN (< 
Grade 1) or baseline. 
 
 
ALT and/or AST > Interrupt dosing, with If the potential 
Discontinue 


 
 
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6.1.6 Prevention/management strategies for diarrhea 
Diarrhea can be a common side effect of regorafenib. The preventive/management 
strategies for diarrhea should be consistent with local standards (e.g., anti-diarrheals and 
optimized hydration status). 
Anti-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. 
7 Study Agent Information 
7.1 Regorafenib 
Regorafenib will be supplied by Bayer. Regorafenib tablets will be packaged in high 
density polyethylene bottles with a white child resistant closure and induction seal. Each 
bottle will contain  28 tablets  and a 3-gram desiccant. The bottles will have a label affixed 
containing study identification, product identification, and quantity of tablets. Once the 
5 X ULN (> Grade 
3) 
weekly monitoring 
until transaminases 
return to < 3 X ULN 
or baseline. 
benefit of 
reinitiating 
regorafenib is 
considered to 
outweigh the risk 
of hepatotoxicity: 
reduce 1 dose level 
and measure serum 
transaminases 
weekly for at least 
4 weeks. 
ALT and/or AST > 
20 X ULN (> 
Grade 4) 
Discontinue 
 
 
ALT and/or AST > 
3 X ULN (> Grade 
2) with concurrent 
bilirubin > 2 X 
ULN 
Discontinue 
treatment and 
measure serum 
transaminases weekly 
until resolution. 
Exception: subjects 
with Gilbert's 
syndrome who 
develop elevated 
transaminases should 
be managed as per 
the recommendations 
outlined above for 
ALT/AST elevations. 
 
 


 
 
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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). 
 
7.2 5FU 
5FU is a commercially availabile drug and will be procured as such by FCCC. See 5-FU 
package insert for most up-to-date information on 5FU. 
 
7.3 Destruction and Return of Regorafenib 
At the end of the study, unused supplies of regorafenib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. The certificate of destruction should be sent to Bayer. Patient returned study 
medication may be destroyed on site, as per institutional SOPs after documentation on the 
drug accountability document. Expired study medication may be destroyed on site, as per 
institution SOPs, during the study. 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 
Mail: (VP of Medical Affairs named in contract) at 
Bayer HealthCare Pharmaceuticals 
100 Bayer Boulevard 
Whippany, NJ 07981 
 
7.4 Records to be kept at Site; Dispensing and Accountability 
It is the responsibility of the Site Principal Investigator to ensure that a current record 
of investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed.  Records or logs must comply 
with applicable regulations and guidelines, and should include: 
 
 Amount received and placed in storage area. 
 Amount currently in storage area.  
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 
 
 
 


 
 
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8 Study Calendar 
 
 
Cycle 1 
Cycle 2k 
 
 
 
 
Screening 
(within  
-28 days of 
C1D1)  
 
D1l 
 
D8 
 
D15 
 
D22 
 
D1 
 
D8 
 
D15 
 
D22 
End  
of  
Treatment 
Saftey 
follow-
upi 
Survival
Follow 
Upf 
Regorafenib (Days 
1-21 of each 
cycle) 
 
--------------X------------- 
 
 
-------------X-------------- 
 
 
 
 
 
5-FU/LV (Q2 
weeks) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------------------------------X 
X 
X 
 
Physical examd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsc,d  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, pltsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistrya,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
INR/PTTd 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urinalysisd,g 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
CEA & CA 19-9e 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
AE evaluation 
X 
X-------------------------------------------------------------------------------X 
X 
X 
 
Radiologic 
evaluation 
X 
Radiologic measurements should be performed after every 2 cycles (8 
weeks, +/- 1 week). It could be scheduled for the first day of the next 
cycle but must be done before the drugs administration. 
Documentation (radiologic) must be provided for patients removed 
from study for progressive disease. 
 
 
XJ 
β-HCGb 
X 
 
 
 
 
 
 
 
 
 
 
 
Overall Survival 
 
X 


 
 
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FOOTNOTES 
 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus,potassium, total protein, SGOT[AST], SGPT[ALT], sodium.  
b: Serum pregnancy test (women of childbearing potential only) must be performed 72 hours prior to beginning 
therapy.  
c: Vital Signs: Heart Rate, Blood Pressure, Respiration rate, Temperature. 
d: After cycle 2, these assessments will be performed at D1 and Day15 of every cycle.  
e: if CEA and CA 19-9 are elevated at screening, CEA and CA 19-9 will be performed every 2 weeks. 
f: Follow every 3 months for 2 years, every 6 months for next 2 years and annually until death. Telephone call is 
appropriate if patient is unable to be seen in clinic.  
g: Color and appearance, pH and specific gravity, bilirubin, glucose, ketones, leukocytes, Nitrite, Occult blood, Protein, 
Urobilinogen 
h: AE evaluation beyond cycle 2 will be only on day 1 and day 15 of every cycle. 
i. 30 days after the End of treatment  
j. every 6-9 week until disease progression. 
k. Beyond cycle 2 cycles will be repeated as per cycle 2 schedules until end of treatment. Beyond cycle 2 labs would 
not be performed on day 8 and day 22 and no visit is necessary. 
l. Each  scheduled visit has a window of +/-1 week 
 
9 Adverse Events 
9.1 Definitions 
Adverse Events (AE) are any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (NCI CTEP Guidelines March 28, 2011). All 
AEs including those due to due to regorafenib and 5FU will be recorded.  
 
Serious Adverse Event (SAE) is an AE that results in the following outcomes- 
 
 Death 
 Life threatening adverse event 
 Requires inpatient hospitalization or prolongation of existing hospitalization (for > 24 
hours),  
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
 Congenital anomaly/ birth defect.  
 
A “life-threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor. 
 
NOTE: Important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent any of the above outcomes.   
9.1.1 Severity Rating 


 
 
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The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions: 
1. Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2. Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL. 
3. Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. Grade 5: Death related to AE 
9.1.2 Attribution/Relationship to regorafenib and 5FU  
 Definite – clearly related 
 Probable – likely related 
 Possible – may be related 
 Unlikely – doubtfully related 
 Unrelated – clearly not related 
9.1.3 Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 
 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event 
is related to participation in the research is not consistent with either: 
 
1. The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol-related documents, 
such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package inserts: or 
 
2. The expected natural progression of any underlying disease, disorder, or condition 
of the subject (s) experiencing the adverse event and the subject (s) predisposing 
risk factor profile for the adverse event. 
 
9.2 Recording and Reporting Responsibilities 
9.2.1 Investigative Site Recording Responsibilities: 
1. Upon identification of an AE or SAE, the site investigator will utilize the above 
definitions to properly classify the event.  Each category listed above must be 
recorded for each event. 


 
 
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2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and in 
progress reports with details about the grade and attribution of each episode, action 
taken with respect to regorafenib and 5FU, and the patient’s outcome will be 
recorded in the CRF.  All events will be recorded on case report forms for the 
duration of the study until they resolve. 
3. The attribution and expectedness must be recorded on the MedWatch form. If this 
information is not available at the time of initial reporting, a final report must be 
documented with attribution and expectedness.  It may be necessary to submit 
follow up reports to the Sponsor should the event require further investigation. All 
subsequent SAEs must be recorded for up to 30 days after the last treatment. 
 
9.2.2 
Investigative Site Reporting Responsibilities: 
1.  The investigator/ site is responsible to report all SAEs that occur on or after the 
first day of study treatment to the sponsor within 24 hours of becoming aware of 
the event.  All subsequent SAEs must be reported for up to 30 days after the last 
treatment. 
 
 
Each investigator is responsible to report all AEs/SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC OCR reserves the right to request an event 
be reported to the IRB at their discretion.  Copies of events reviewed by the IRB 
must be sent by email to SAE.FCCC@fccc.edu. 
 
2. If the investigator or IRB feels the event warrants a revision to the informed consent 
that was not already initiated by the ISRU, draft revisions will be made in track 
changes and submitted to the ISRU for consideration.  Any consent revisions must 
receive ISRU approval prior to submission to the IRB. 
 
3. Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call the Study Monitor for confirmation with the Sponsor-Investigator 
 
4. If the results of an investigator or ISRU investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report the 
event following the above guidelines based on the date the determination is made. 
 
5. Investigative site should report Reportable New Information (RNI) to their local 
IRB. This information should also be sent to ISRU. Unexpected events during the 
clinical study that are considered to be reportable should be reported to IRB as RNI. 
Serious unexpected events that are associated with the treatment are considered to 
be reportable. Expected AEs that are experienced multiple times such that the 
frequency or severity of the AEs are more than expected in the patient population 
according to the investigator brochure are considered to be reportable. 
6. Copies of all related correspondence and reporting documents must be submitted 
to the ISRU and will be maintained in the trial master file.  
 


 
 
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Participating sites should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
  
           Fox Chase Cancer Center 
SAE.FCCC@fccc.edu 
 
9.2.3 
Sponsor Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the 
event.   
a. Unexpected (in terms of nature, severity, or frequency) given  
i. (a) the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and  
ii. (b) the characteristics of the subject population being studied; 
b. Possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
c. Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized. 
2. If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the form 
of an amendment from the OCR for each site’s IRB of record along with the report 
of the adverse event. 
3. All participating sites must be notified of all amendments approved by FCCC IRB; 
or if the study is suspended such that the participating sites cannot accrue patients 
in the study until further notification. 
4. All participating sites must be notified when the study is closed by IRB.   
5. Copies of all related correspondence and reporting documents will be maintained 
in a centralized regulatory file for this study at OCR. 
6. SAEs in this study are not reportable to FDA but will be collected by ISRU in 
MedWatch3500a form for Data safety 
7. Reportable New Information: Unexpected events during the clinical study that are 
considered to be reportable should be reported to IRB as RNI. Serious unexpected 
events that are associated with the treatment are considered to be reportable. 
Expected AEs that are experienced multiple times such that the frequency or 
severity of the AEs are more than expected in the patient population according to 
the investigator brochure are considered to be reportable. All participating sites 
should be made aware of any RNI. 
 
 
9.2.4 OCR Reporting Responsibilities to Bayer: 


 
 
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The following will be reported to BAYER by fax and/or email within 24 hours of 
becoming aware of any Serious Adverse Reactions with a potential relationship to 
Regorafenib.   
(1) any other relevant safety information including but not limited to: 
a. reports of drug exposure via mother / father with and without adverse events 
(exposure during conception, pregnancy, childbirth and breastfeeding) 
including their outcome; 
b. if linked to a serious adverse event, reports of misuse, abuse,  overdose , 
medication error and other uses outside what is foreseen in the protocol, 
drug dependency, occupational exposure, suspected transmission of an 
infectious agent, withdrawal syndrome, drug interactions with respect to the 
STUDY DRUG;  
 
(2) any communication concerning safety related information to regulatory 
authorities or ethics committees including but not limited to: 
o Development Safety Update Reports / relevant parts of IND reports for the 
STUDY; 
o Any other safety related reports, issues and queries that are either raised by 
or communicated to regulatory authorities or ethics committees (e.g. 
reportable non-serious cases); 
9.2.5 Expedited Reporting of Other Safety Information: 
The Investigator/ Sponsor shall report to Bayer within 24 hours of the investigator’s 
awareness of other events such as:   
 Any new and important event related to treatment with the study drug(s). 
 Any pregnancy during which a female patient was exposed to the study 
drug(s) 
 Any pregnancy in the partner of a male patient, where the male patient was 
exposed to study drug at the time of conception or conception occurred 
within two weeks of the last dose of study drug(s) 
 Any other relevant safety information including but not limited to reports 
on drug interaction, overdose, drug abuse or misuse, drug dependency, 
withdrawal syndrome, medication error, occupational exposure and lack of 
drug effect (LODE) occurring at any time during the treatment phase; 
 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform Bayer and record the cause of death in detail within 24 hours. 
 
All reports shall be sent electronically to: 
 
Electronic Mailbox: DrugSafety.GPV.US@bayer.com  
 


 
 
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Facsimile:                  (973) 709-2185  
 
Address:                 Global Pharmacovigilance - USA  
Mail only        
Bayer HealthCare         
                         
P.O. Box 915  
                         
Whippany, NJ 07981-0915  
 
Address: 
 
100 Bayer Blvd., Whippany, NJ 07981 
FDX or UPS only 
67 Whippany Road, Whippany NJ 07981 for UPS 
 
Reports for all Bayer products can also be phoned in via our Medical 
Communications Department 
 
Phone:                  
1-888-842-2937 
 
 
9.3 Pregnancy  
 
All WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
The outcome of any 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. 
In the event of a confirmed pregnancy in a patient participating in the study, the site 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor who 
will notify Dr. Vijayvergia.  
10 Measures of Effect 
For the purposes of this study, patients should be re-evaluated for response after every 2 
cycles. In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
10.1  Definitions 
Evaluable for adverse events: All patients who received any on-study treatment with 
Regorafenib and 5-FU/LV will be evaluable for adverse events from the time of their first 
treatment with Regorafenib and 5-FU/LV. 
 


 
 
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Evaluable for objective or best overall response:  Only those patients who have 
measurable disease present at baseline, have received any on-study treatment with 
Regorafenib and 5-FU/LV, and have had their disease re-evaluated will be considered 
evaluable for response.   
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, received any on-study 
treatment with Regorafenib and 5-FU/LV, and have had their disease re-evaluated will be 
considered evaluable for non-target disease. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
10.2  Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline, during study treatment 
and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
'Cystic lesions' thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 


 
 
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may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
10.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions - Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
CT and MRI - This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is variable globally.  
As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope 
of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if possible. 
 


 
 
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Cytology, Histology - These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion.   
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
10.4 Response Criteria 
10.4.1 Evaluation of Target Lesions 
 


 
 
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Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
10.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
10.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 


 
 
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For  
 
 
 
 
 
 
 
 
 
 
 
 
 
     For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
 
10.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


 
 
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for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
10.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
  
11 Statistical Considerations 
11.1 Study Design/Endpoints 
We will conduct a single-arm, Simon’s optimal two-stage phase II clinical trial, two-stage 
phase II clinical trial to evaluate the efficacy of the combination therapy in patients who 
progressed on prior Regorafenib monotherapy as well as 5-FU containing chemotherapy 
combinations. The primary outcome variable is progress-free survival at two months or 
greater. The treatment will be of no interest if the proportion of patients who are both 
alive and progression free at 2 months (p) is less than 5% (the null hypothesis). 
Alternatively, the  combination therapy will be of interest if the proportion of patients 
who are alive and progression free at 2months is at least 30%.  Fifteen patients would be 
needed to test the null hypothesis at the 3.6% level of significance with 87% power.   
 
The study will be terminated and the null hypothesis is accepted if none (0) of the first 10 
patients are alive and progression free at 2 months. Alternatively, an additional 5 patients 
will be accrued if one (1) or more of the first 10 patients are alive and progression free 
after 2 months on the combination therapy. Accrual will pause after 10 patients are 
enrolled for interim analysis unless the criteria for accruing next 5 patients is already 
met.The probability of early stopping under the null hypothesis is 60% and there is a 
2.8% chance of early stopping in error. If the trial progresses until 15 patients are 
evaluated and 3 or more patients are alive and progression free at 2 months, then the null 
hypothesis will be rejected and the combination therapy deemed worthy of further 
consideration.   
 
We have established rules to terminate study accrual in the case of an excess number of 
patients with a severe drug related toxicity (SDRT) using the methods of Ivanova et al. 
(2005).  We anticipate that the true probability of a patient experiencing at least one 
SDRT will not exceed 30%. SDRT will be defined as any grade 3 or 4 drug related 
toxicity that is not resolved within 30 days such that the patient cannot be treated during 
this time due to the toxicity. Accrual will be halted if the number of observed patients 
with SDRTs is equal to, or exceeds, Sn out of n patients (see table 11.1). The chance of 
early study suspension is 64% if the true SDRT probability is 50% and 14.0% if it is 
30%.The probability of early study termination under several true SDRT probabilities is 
presented in Table 11.2. 
 


 
 
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Table 11.1. Stopping rules for Toxicity 
Number 
of 
Patients, n 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Boundary, 
Sn 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
8 
 
 
 
Table 11.2. Probability of study 
termination due to excess 
toxicity under a number of 
scenarios. 
True Severe 
Toxicity 
Probability 
Probability of 
early stopping 
0.30 
0.14 
0.50 
0.64 
0.70 
0.97 
 
In secondary analyses we will use standard descriptive statistics (e.g., means, medians, 
frequencies, proportions and 95% confidence intervals) to characterize best overall 
response (BOR) and disease control rate (CR, PR or stable disease at two-months). 
Kaplan-Meier methods will be used to analyze progression free survival time, overall 
survival time, and duration of response. Toxicity data will be compiled in frequency 
tables by cateogory and grade to evaluate the safety profile of the combination therapy. 
 
11.2  Sample Size/Accrual Rate 
The study will enroll 15 patients. It is expected to enroll 1 patient per 2 months. 
 
11.3  Stratification Factors 
There is no stratification although demographic information will be collected.  
  
11.4 Analysis of Secondary Endpoints 
Samples will be collected as indicated above  
 
11.5 Reporting and Exclusions 
11.5.1  Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Regorafenib and 5-FU/LV. 
11.5.2 Evaluation of response 
All patients included in the study must be assessed for response to treatment, even if there 


 
 
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are major protocol treatment deviations.  Each patient will be assigned one of the 
following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, insufficient data).  
[Note:  By arbitrary convention, category 9 usually designates the “unknown” status of 
any type of data in a clinical database.] 
 
Evaluable for adverse events: All patients who received any on-study treatment with 
Regorafenib and 5-FU/LV will be evaluable for adverse events from the time of their first 
treatment with Regorafenib and 5-FU/LV. 
 
Evaluable for objective response:  Only those patients who have measurable disease 
present at baseline, have received any on-study treatment with Regorafenib and 5-
FU/LV, and have had their disease re-evaluated will be considered evaluable for 
response. The best overall response (BOR) is the best response recorded from the start of 
the study treatment until the end of treatment taking into account any requirement for 
confirmation. 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, received any on-
study treatment with Regorafenib and 5-FU/LV, and have had their disease re-evaluated 
will be considered evaluable for non-target disease. The response assessment is based on 
the presence, absence, or unequivocal progression of the lesions.  
 
Evaluable for primary efficacy analyses:  Patients who (1) were evaluable for objective 
response, and (2) either had had their disease re-evaluated at the two month follow-up or 
died or progressed before two months will be included in the primary efficacy analysis 
for PFS.  Individuals who are lost to follow-up before two months and were alive and 
progression-free at last observation will be considered failures. 
 
11.6 Planned interim analyses 
Interim monitoring will be performed. The study will be terminated if none (0) of the first 
10 patients are both alive and progression free at 2 months on the combination therapy. 
Stopping rules for excess toxicity are described in section 12.1.  
12 Data and Safety Monitoring Plan 
12.1 Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the ISRU will collect and report data to 
the study Sponsor-Investigator who will review the data on a regular basis at a rate 
dependent on subject accrual.  All serious adverse events (SAEs) will be reviewed on a 
real time basis first by the study site PI and subsequently by the ISRU and Sponsor-
Investigator as applicable. 
 


 
 
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12.2  Data Safety Monitoring Committee   
Interim analysis of toxicity, outcome and ongoing scientific investigations may be 
performed by the Fox Chase Cancer Center Data & Safety Monitoring Board (FCCC 
DSMB).  In this capacity the FCCC DSMB will serve as an advisory committee to the 
Sponsor-Investigator.  The FCCC DSMB will review those aspects of this trial that are 
outlined in the responsibilities section of the Data & Safety Monitoring Plan (DSMP).  If 
the committee decides that changes should be made to this trial, it will make 
recommendations in writing to the Sponsor-Investigator, the Associate Director of 
Clinical Research, and the Protocol Management Executive Committee, which, in turn, 
have the authority to approve or disapprove these recommendations.  These changes will 
be discussed with the Sponsor-Investigator before they are implemented.  These changes 
may include early termination of accrual.  Other changes might include altering the 
accrual goals or changing the eligibility criteria for the trial. 
 
12.3 Administrative  
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
12.4 Data Reporting 
The FCCC Study Monitor will request case report forms to be completed within 2 weeks 
of the protocol visit.  Participating sites are responsible to respond to queries prior to the 
next scheduled monitoring visit 
 
The ISRU is responsible for compiling and submitting data to the Sponsor-Investigator 
and statistician on an ongoing basis for monitoring as described in the DSMP and 
reporting to the Data and Safety Monitoring Board. 
 
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, 
such as case report files, produced will be stored in a secure location.  
 
The ISRU is responsible for distributing and tracking review of all IND Action Letters, 
Safety Reports, study specific Serious Adverse Events 
 
12.5 Retention of Records   
Time points for the retention of records are described in detail in the contract between the 
grantor and the OCR and passed on to the participating site.  Please refer to the study 
specific terms for specific time points.  In all cases the Study Monitor must be notified of 
any plans to move records to an offsite location prior to doing so. 
 
12.6 Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol. The agent 
may not be transferred to any party not participating in the clinical trial. 
 


 
 
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12.7 Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  
The case history for each patient shall document that informed consent was obtained 
prior to participation in the study. A copy of the informed consent documents must be 
provided to the patient or the patient’s legally authorized representative. If applicable, 
they will be provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file. 
 
 


 
 
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14.0 Reference list 
1) Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH, 
Zopf D.  Regorafenib : A new oral multikinase inhibitor of angiogenic, stromal, and 
oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J 
Cancer. 2010 Dec 17. [Epub ahead of print]. 
2) Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002 
Oct;2(10):795-803. 
3) Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting 
both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin 
Invest. 2003 May;111(9):1287-95. 
4) Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, et al. 
Response to imatinib mesylate in patients with chronic myeloproliferative diseases with 
rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002 
Aug 15;347(7):481-7. 
5) Frost A et al. Phase I study of , an inhibitor of oncogenic and angiogenic kinases in 
patients with advanced solid tumors: final results of a dose-escalation study. J Clin Oncol 
(meeting abstracts) 2008;26:2558. 
8) Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial. 
Grothey A, Van Cutsem E, Sobrero A, et al.  Lancet 2012 2013 Jan 26;381:303-12;  
9)   Regorafenib plus best supportive care versus placebo plus best supportive care in 
Asian patients with previously treated metastatic colorectal cancer (CONCUR): a 
randomised, double-blind, placebo-controlled, phase 3 trial. Li J, Qin S, Xu R, Yau TC, 
et al. Lancet Oncol. 2015 Jun;16(6):619-29.  
10) Demetri G et al.  ASCO 2012. Efficacy and safety of regorafenib for advanced 
gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID: an 
international, muticentre, randomized, placebo-controlled, phase 3 trial.  .  Lancet 2012 
Jan 26;381(9863):295-302. 
11) Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in 
phase II trials in oncology. Biometrics 61: 540-545. 
     
 
 

ICF_000.pdf: 
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INFORMED CONSENT DOCUMENT
GI-094: A Pilot Phase II, single arm, open-label, investigator-initiated clinical trial of 
Regorafenib plus 5- Fluorouracil/Leucovorin (5-FU/LV) beyond progression on 
Regorafenib monotherapy in metastatic colorectal cancer (mCRC)
Principal Investigator: Namrata Vijayvergia, MD
Temple University Hospital/Study Site Investigator: Juhi Mittal, MD 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part.  Please take your time to 
make your decision about taking part.  You should discuss your decision with your friends and 
family.  You will also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
Research studies are voluntary and include only people who choose to take part.  Please read this 
consent form carefully and take your time making your decision.  As your study doctor or study 
staff discusses this consent form with you, please ask him/her to explain any words or information 
that you do not clearly understand.  We encourage you to talk with your family, friends or family 
doctor before you decide to take part in this research study.
You are being asked to take part in this research study because you have metastatic colorectal 
cancer and your cancer progressed when you were treated with Regorafenib monotherapy. 
Metastatic means that your cancer has spread to other parts of your body.
The sponsor of this study is Fox Chase Cancer Center. Namrata Vijayvergia, MD, is the sponsor-
investigator for this study
Why is this research study being done?
The purpose of this research study is to determine whether a combination therapy of Regorafenib 
and 5-fluorouracil (5FU)/ Leucovorin (LV) will result in control of your metastatic colorectal 
cancer. Regorafenib and 5FU combination therapy is not yet approved for treatment of metastatic 
colorectal cancer in humans by FDA. There is some clinical evidence that suggests the 
combination therapy could be beneficial for treating metastatic colorectal cancer.
We do not know if you will benefit from this research study.  It is possible that your condition 
will get better, but it is also possible that there will be no effect on your condition or that your 
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condition will get worse.  We can use what we learn from this research study to help other 
people with the same disease.  
How many people will take part in this research study?
About 15 people will take part in this research study. 
What will happen if you take part in this research study?
Before you begin the research study
You will need to have the following exams, tests or procedures to find out if you can be in the 
research study. These exams, tests or procedures are part of regular cancer care and may be done 
even if you do not join the research study.  If you have had some of them recently, they may not 
need to be repeated.  This will be up to your study doctor.

A review of your medical history and any medications you are currently taking or 
have taken in the past

Physical examination including vital signs, weight and height

You will be asked how cancer effects your daily activities

Blood pregnancy test (2 teaspoons) within 3 days prior to registration, if you are a 
woman and are able to become pregnant.

Routine blood test (1 tablespoon)

Urine test

We will perform EKG to check how your heart is functioning

We will ask you about any side-effects that you may be experiencing from previous 
treatments

A CT scan or MRI scan of your tumor
o
A CT scan is a computerized X-ray that gives your study doctor pictures of the 
inside of your body
o
A MRI scan uses a magnetic field and radio waves to take pictures of the inside of 
your body
During the research study
Study Treatment
The drugs in this study will be administered in cycles. Each cycle is of 28 days and when one 
cycle ends the next cycle begins. During the study you will receive the following drugs to treat 
your cancer.

Regorafenib to be taken orally, once daily for 21 days.

5FU will be administered at the clinic intravenously on day 1 and day 15 of each cycle.
The treatment will go on as long as you continue to derive benefit from it, that is, your cancer is 
getting better or does not progress. The treatment will stop if your cancer gets worse or you have 
severe side-effects or if in your Physician’s opinion it is best for you to discontinue from the 
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study.  We will evaluate how you are responding to the treatment by performing MRI or CT scan 
of your tumor every 2 cycles (8 weeks).  
Tests and Procedures
If the exams, tests and procedures show that you can be in the research study, and you choose to 
take part, then you will need the following tests and procedures. They are part of regular cancer 
care. They are being done more frequently because you are in this research study.
 

We will ask you about all the medicines that you are taking

We will perform physical examination including vital signs and weight

We will ask you how cancer effects your daily activities

Routine blood test (1 tablespoon)

Urine test

We will ask you if you are experiencing any side-effects due to the treatment

An MRI or CT scan of your tumor
Possible use of a port  
If the doctors or nurses cannot draw blood or give you medicine through your veins, you may be 
asked to have minor surgery to place an “indwelling catheter port” into a large vein in your 
chest. Medical staff will use the “port” to give you medicines and to draw blood.  You will be 
asked to sign a separate consent form for this procedure, and the “port” will not be used unless 
you agree.  If a port is necessary and you do not agree to its use, you may be unable to continue 
as part of the research study.
After you have finished study treatment
We will perform a safety follow-up after 30 days of the discontinuation of the treatment. In this 
follow-up visit we will:

Ask you about the medication that you are taking

Perform a physical examination including vital signs, and weight

We will ask you how cancer affects your daily activities

Routine blood test (1 tablespoon)

Urine test

We will ask you about any side-effects that you may be experiencing due to the study 
treatment
We will continue to follow-up with you after the safety follow-up every 3 months for the next 2 
years, every 6 months during 3rd and 4th year and then annually until death. During this follow-up 
your tumor may be monitored by MRI or a CT scan.
Another way to find out what will happen to you during the research study is to read the chart 
below. Start reading at the top and read down the list, following the lines and arrows. 
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Start Here
You sign the informed consent document and test show that you can take part in the study
Study treatment

You begin the study treatment in clinic on Day 1 of cycle1. You will undergo study 
related tests and procedures

You start taking Regorafenib, orally, daily, for the first 21 days of the 28 days cycle

5FU will be administered intravenously on Day 1 and Day 15 of each cycle

After the end of cycle 1 (28 days), the next cycle begins. During the first 2 cycles you 
will visit clinic on day1, 8, 15 and 22. After 2 cycles you will visit clinic only on day 
1 and 15.

Your tumor will be measured every 2 cycles (8 weeks) to assess the treatment 
response
You continue to receive the treatment until

Your disease gets worse 

You decide to withdraw from the study

You experience severe side-effects

In your Physician’s opinion it is best for you to discontinue from the 
study
After you stop the study treatment

Safety follow-up after 30 days of discontinuation

Long-term follow-up every 3 months for the next 2 years

Lon-term follow-up every 6 months during 3rd and 4th year

Long-term follow-up annually until death
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How long will you be in the research study?
You will be asked to take Regorafenib and 5FU until your cancer gets worse or you have 
unacceptable toxicity or your doctor thinks it is best for you to stop being in the study.  After you 
are finished taking the study treatment, the study doctor will ask you to visit the office for 
follow-up exams after 30 days of discontinuation and then every 3 months for the next 2 years 
and every 6 months for the 3rd and 4th year and then annually until death.
 
Can you stop being in the research study?
Yes.  You can decide to stop at any time.  Your participation in this research is completely 
voluntary. If you agree to participate now and change your mind later, you may withdraw at any 
time.   Tell the study doctor if you are thinking about stopping or decide to stop.  He or she will 
tell you how to stop safely and will discuss with you options for withdrawal such as continuing to 
provide further data collection from routine medical care.  
Can you be removed from this research study?
The study doctor may stop you from taking part in this research study at any time if he/she 
believes it is in your best interest; if you do not follow the research study rules; or if the research 
study is stopped.
What side effects or risks can you expect from being in the research study?
You may have side effects while on the research study.  Everyone taking part in the research 
study will be watched carefully for any side effects.  However, doctors don't know all the side 
effects that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you stop 
taking regorafenib and 5FU. In some cases, side effects can be serious, long lasting, or may 
never go away. In rare but serious circumstances there is also a risk of death.
You should talk to your study doctor about any side effects that you have while taking part in the 
research study. 
Risks and side effects related to the regorafenib include those which are:
Likely (>20%)

Fatigue (feeling of being overly tired and lacking energy)

Weakness

Palmar-Plantar Erythrodyesthesia (Hand-Foot-Syndrome) Redness, tenderness, pain and 
possible peeling of the palms of the hands and soles of the feet. The redness looks like a 
sunburn. The affected area can become dry and peel with numbness or tingling 
developing

Rash

Diarrhea (increased frequency of bowel movements with loose, watery stools)
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
Mucositis/stomatitis- sores in the lining of your mouth and/or throat that can be painful 
and make it hard to swallow

Loss of appetite

Weight loss

Hypertension (high blood pressure) Symptoms may include headache, dizziness, 
palpitations, blurred vision, ringing in the ears and nose bleeds

Voice changes/hoarseness/difficulty forming sound

Thrombocytopenia (low platelet count) – platelets are important in stopping bleeding. A 
low platelet count can increase the time to form a blood clot

Leukopenia/Neutropenia (low white blood cell count) – a low white blood cell count 
makes it hard for you to fight infections

Hypocalcemia (low calcium levels in the blood) Symptoms of a low calcium level may 
include numbness and tingling in the hands and feet, muscle cramps, twitches and 
spasms, fatigue, confusion, disorientation and seizures.

Hyponatremia (low sodium levels in the blood) Symptoms may include nausea and 
vomiting, loss of appetite, headache, confusion, fatigue, restlessness and irritability, 
muscle weakness, spasms or cramps, decreased consciousness, seizures or coma.

Low blood levels of phosphorous (can affect your bones, muscles, heart, and central 
nervous system)

Increased blood levels of the pancreas enzyme called lipase

Increased levels of protein in the urine- this may a sign of kidney damage
Less Likely (5-19%)

Headache

Fever

Infection

Bleeding

Hair loss

Altered taste

Dry mouth

Pain

Muscle stiffness

Anemia (low hemoglobin, low hematocrit or low red blood cell count) – red blood cells 
carry oxygen and nutrients throughout the body. Symptoms that may be experienced as a 
result of low red blood cell counts may include feeling tired and weak, shortness of 
breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and pale 
skin.

Hypokalemia (low levels of potassium) Symptoms may include muscle weakness, 
cramping, leg discomfort, an irregular heart beat and confusion

Elevated liver enzymes: Liver enzymes, proteins made by the liver, indicate how well 
your liver is functioning. High liver enzyme levels may cause you to feel overly tired or 
weak, you may bruise or bleed more easily, and you may experience abdominal pain or 
have a yellowing of the skin or eyes

Hyperbilirubinemia (elevated bilirubin levels in the blood) Bilirubin is a chemical that is 
released when red blood cells are broken down. Bilirubin is used by the liver to make 
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bile. Symptoms of elevated bilirubin levels include a yellowing of the skin, eyes and 
mucous membranes.

Low thyroid hormone production, which may cause symptoms including tiredness, 
depression, weight gain, cold intolerance, dry coarse hair, difficulty having bowel 
movements, dry skin, muscle cramps, high cholesterol, trouble with concentration and 
swelling of the legs.
Rare but serious (< 5%)

Delay in wound healing or breakdown of a wound that has healed

Gastrointestinal (GI) perforation which is the development of an opening or hole in the 
wall of the bowel or stomach (gastrointestinal tract) that may require surgery to repair 
and can be life threatening

Fistula- breakdown in the surgical connection between two pieces of bowel

Reversible Posterior Leukoencephlopathy Syndrome (RPLS): a neurological disorder 
which can present with a headache, confusion, seizures, or vision changes

Heart attack
Risks and side effects related to the 5-fluorouracil (5-FU) includes those which are:
Likely (>20%)

Diarrhea – increased frequency of bowel movements with loose watery stools

Abdominal pain

Anemia (low hemoglobin, low hematocrit or low red blood cell count) – red blood cells 
carry oxygen and nutrients throughout the body. Symptoms that may be experienced as a 
result of low red blood cell counts may include feeling tired and weak, shortness of 
breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and pale 
skin

Leukopenia/Neutropenia (low white blood cell count) – a low white blood cell count 
makes it hard for you to fight infections

Thrombocytopenia (low platelet count) Platelets are important in stopping bleeding. A 
low platelet count can increase the time to form a blood clot, causing you to bruise or 
bleed more easily

Nausea – feeling sick to your stomach

Vomiting – throwing up

Mucositis/stomatitis – sores in the lining of the mouth and/or throat that can be painful 
and make it painful or hard to swallow

Photosensitivity – skin sensitivity to the sun causing a painful rash and burn

Loss of appetite
Less Likely (5-19%)

Hair loss

Dry itchy and cracked skin

Darkening of nail beds and the vein where the drug was infused.
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
Nail loss

Palmar-Plantar Erythrodyesthesia (Hand-Foot-Syndrome) – redness, tenderness, pain and 
possible peeling of the palms of the hands and soles of the feet. The redness looks like a 
sunburn. The affected area can become dry and peel with numbness or tingling 
developing.

Headache

Confusion

Changes in vision

Nose bleeds

Chest pain

Shortness of breath

Irritation and/or tearing of the eyes

Irritation of the veins
Rare but serious (< 5%)

Heart attack – symptoms may include chest pain/tightness, shortness of breath, nausea, 
sweating and dizziness

Hypersensitivity Reaction (allergic Reaction) – an overactive immune response that 
results in local tissue injury or other changes throughout the body in response to a foreign 
substance or drug. Symptoms of an allergic reaction may include fever, fast heart rate, 
rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and 
shortness of breath.

Anaphylaxis – a severe allergic reactions which can cause shock, low blood pressure and 
death

Stomach ulcer/bleeding
Risks and side effects related to the Leucovorin (LV) include those which are:
 
Likely (>20%)

Fatigue – feeling of being overly tired and lacking energy

Nausea – feeling sick to your stomach

Vomiting – throwing up

Diarrhea – increased frequency of bowel movements with loose, watery stools

Rash 

Itching
Rare but serious (< 5%)
  

Hypersensitivity Reaction (Allergic Reaction) – an overactive immune response that 
results in local tissue injury or other changes throughout the body in response to a foreign 
substance or drug. Symptoms of an allergic reaction may include rash, hives, swelling, 
itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breadth
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Radiation Risk for Diagnostic Imaging

It is unlikely that there will be any harmful effects from the radiation exposure you will 
receive from participating in this study.

At high levels of exposure, scientists agree that radiation can cause cancer.

At low exposure levels most scientists agree that the risk, if any, is very low.  You will 
have low levels of radiation exposure with diagnostic imaging procedures.

Risks from exposure to radiation may accumulate over a lifetime.
Blood Draw Risks

Fainting

Bleeding

Bruising at the place on your arm where the blood was drawn or needle inserted

Pain at the needle insertion site

Swelling

Infection (rare)
Reproductive Risks

Study treatments may make you sterile (unable to have children).

The drugs in this study may affect a baby, before or after the baby is born.

You should not become pregnant or father a baby while on this research study because 
the drugs you take could possibly hurt an unborn baby.

If you are pregnant now or if you are breast-feeding now, you may not take part in this 
research study.

If you become pregnant while you are on the research study, you may not continue to 
take part in the research study.
For women who can become pregnant:

You should not become pregnant while you are in this study.

You should not breast-feed your baby while taking drugs for this research study.
For men:

You should not make a woman pregnant while you are in this study.
For women and men:

If you are having sex that could lead to pregnancy, you should use birth control while you 
are in this study.

Check with the study doctor about birth control methods and how long to use them.  
Some methods might not be approved for use in this study.  
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope that the 
regorafenib and 5FU combination therapy will be more useful against cancer compared to the 
usual treatment, there is no proof of this yet.  We do know that the information from this study 
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will help doctors learn more about the regorafenib and 5FU combination therapy as a treatment 
for cancer.  This information could help future cancer patients.
What other choices do you have if you do not take part in this research study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study 

Taking part in another study 

Getting no treatment 

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Talk to your doctor about your choices before you decide if you will take part in this study.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards of 
The Fox Chase Cancer Center and Temple University, Temple University, Temple 
University Health system, Inc., and its affiliates or subsidiaries and other authorized 
representatives of these organizations.

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 

Bayer Pharmaceuticals-supplier of the study drug Regorafenib
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required    
       by U.S. Law. This Web site will not include information that can identify you. At most, the 
       Web site will include a summary of the results. You can search this Web site at any time.
You will be given a separate form to review regarding the steps we will take to guard your 
privacy as part of your participation in the research study.  By signing that additional 
authorization, you will be providing your consent to use and disclose information described in 
that form connected with your participation in this research study.
What are the costs?
 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
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for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.
Bayer will supply regorafenib at no charge while you take part in this study.  Bayer does not 
cover the cost of getting regorafenib ready and giving it to you, so you or your insurance 
company may have to pay for this.
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide regorafenib to Bayer.  If this would occur, other possible options are:

You might be able to get regorafenib from the manufacturer or your pharmacy but you or 
your insurance company may have to pay for it.

If there is no regorafenib available at all, no one will be able to get more and the study 
would close.
If a problem with getting regorafenib occurs, your study doctor will talk to you about these 
options. 
5FU is commercially available and will be billed to you in the same way you are usually billed 
for medicines.  
If your insurance will not pay for medicines you may need to help with side effects, you may 
have to pay for them.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
Will you be compensated?
You will not be paid for taking part in this study.
What if you are injured while taking part in this research study?
If you are injured as a result of your participation in this research study, seek immediate medical 
care.  Temple University Health System or its subsidiaries will treat the injury, though there is no 
commitment to provide monetary compensation or free medical care. Other financial 
compensation (such as lost wages or pain and suffering) for such injuries is not available.  
What are your rights if you take part in this research study?
Taking part in this research study is your choice.  You may choose either to take part or not to 
take part in the research study.  If you decide to take part in this study, you may leave the study 
at any time.  No matter what decision you make, there will be no penalty to you and you will not 
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lose any of your regular benefits.  Leaving the study will not affect your medical care. You can 
still get your medical care from our institution. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
New findings
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
Who can answer your questions about the research study?
Important Contact Numbers
If you are enrolled at the Fox Chase location (333 Cottman Ave)
If you have questions about:
Please Call:
This study, including if you get sick or hurt
Dr. Namrata Vijayvergia at 215-728-4300
If you have a concern or complaint
Risk Management Department at 215-728-2591
Your rights as a research participant on this study 
FCCC Institutional Review Board at 215-214-3754
Your bills or health insurance coverage
Clinical Trial Financial Counselor at 215-214-3768
If you are enrolled at the Temple University Location (3401 N Broad Street)
If you have questions about:
Please Call:
This study, including if you get sick or hurt
Dr. Juhi Mittal at 215-707-2777
If you have a concern or complaint
Risk Management Department at 215-728-2591
Your rights as a research participant on this study
FCCC Institutional Review Board at 215-214-3754
Your bills or health insurance coverage
Social Work Department at 215-707-7569
Where can you get more information?
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI website at http://cancer.gov

For NCI's clinical trials information, go to: http://cancer.govclinicaltrials/ 

For NCI's general information about cancer, go to: http://cancer.gov/cancerinfo/ 
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By signing below, you tell us that you have gotten all of the information you need; that you have 
received clear answers to your questions, and that you agree to take part in the research study.  
You will receive a copy of this form.  You may also request a copy of the research plan. 
___________________________   ________________________           _____________
Signature of Participant
Print Name of Participant              Date
By signing this form the Physician obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study.
____________________________   _______________________           ____________
Signature of Physician
Print Name of Physician 
          Date
Obtaining Consent
Obtaining Consent
By signing this form the person obtaining consent indicates that the research participant has been 
fully informed of all aspects of the research study.
____________________________   _______________________           ____________
Signature of Person
Print Name of Person 
          Date
Obtaining Consent
Obtaining Consent
____________________________________________________               _________________
Signature of Legally Authorized Representative (LAR)                   Date
________________________________                         ________________________________
Print Name of LAR                                                       Relationship of LAR to Participant                                
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania)
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