Regorafenib Dose Optimization Study (ReDOS): A Phase II Randomized Study of Lower Dose Regorafenib Compared to Standard Dose Regorafenib in Patients With Refractory Metastatic Colorectal Cancer (mCRC)
Phase: PHASE2
Conditions: Colon Adenocarcinoma, Rectal Adenocarcinoma, Stage III Colorectal Cancer AJCC v7, Stage IIIA Colorectal Cancer AJCC v7, Stage IIIB Colorectal Cancer AJCC v7, Stage IIIC Colorectal Cancer AJCC v7, Stage IV Colorectal Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
Sponsor: Academic and Community Cancer Research United

 
  
RU021407I 
 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
Regorafenib Dose Optimization Study (ReDOS): A Phase II Randomized Study of Lower Dose 
Regorafenib Compared to Standard Dose Regorafenib in Patients with Refractory Metastatic Colorectal 
Cancer (mCRC) 
 
For any communications regarding this protocol, please contact 
the protocol resource person on the following page. 
 
 
Study Chairs 
ACCRU: 
Tanios Bekaii-Saab, M.D. 
 
Mayo Clinic Arizona 
507/266-0800 
507/538-0906 (FAX) 
Bekaii-Saab.Tanios@mayo.edu 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
  
 
 
 
 
Drug Availability  
Commercial Agents: Clobetasol Propionate Cream 
Drug Company Supplied: Regorafenib – IND Exempt 
 
√ Study contributor(s) not responsible for patient care. 
 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
 
Document History 
(effective date) 
Activation ACCRU 
March 27, 2015 
Addendum 1 
June 2, 2015 
Addendum 2 
July 3, 2015 
Addendum 3 
June 24, 2016 
Addendum 4 
March 17, 2017 
Addendum 5 
December 1, 2017 
 
 
 
         Addendum 6                 February 16, 2018 

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Addendum 6 
 
 
 
 
 
Index 
 
Schema 
 
 1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors 
 6.0 
Registration/Randomization Procedures 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modification Based on Adverse Events  
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
 
  
 
 
 
 
 
 
 

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Addendum 6 
 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 28 days 
 
 
* Pre-emptive strategy: Clobetasol 0.05% cream for first 12 wks is  prophylactically applied to hands and soles of 
patients. Reactive strategy: Patients will be treated per investigator discretion when they develop Palmar-plantar 
erythrodysesthesia syndrome. 
 
 
Generic name:   Regorafenib 
Brand name(s): Stivarga® 
Availability: Biologics, Inc. 
Generic name:   Clobetasol Propionate Cream 
Brand name(s): Temovate 
Availability: Commercially available  
 
Randomization 
1:1:1:1 
(Progression on previous standard 
therapy, including EGFRi if KRAS WT) 
Arm A 1* 
Regorafenib Start low 
dose (See Section 7.0 
for escalation 
schedule) 
+ pre-emptive 
strategy for Palmar-
plantar 
erythrodysesthesia 
syndrome (PPES) 
Arm A 2* 
Regorafenib Start low 
dose (See Section 7.0 
for escalation 
schedule) 
+ reactive strategy 
for  
Palmar-plantar 
erythrodysesthesia 
syndrome (PPES) 
Arm B 1* 
Regorafenib 160 mg 
PO daily for 21 days 
+ pre-emptive 
strategy for  
Palmar-plantar 
erythrodysesthesia 
syndrome (PPES) 
Arm B 2* 
Regorafenib 160 mg 
PO daily for 21 days 
+ reactive strategy 
for  
Palmar-plantar 
erythrodysesthesia 
syndrome (PPES) 
PD at any time  
Unacceptable adverse  
 
 
 events   
 
 
 EM** 
Patient refusal 
Investigator’s decision 
 
** EM= Event Monitoring 
 

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Addendum 6 
 
 
1.0 
Background 
 
1.1 
Worldwide, nearly 1.3 million patients are diagnosed with and more than 600 000 
patients die from colorectal cancer every year (Ferlay et al, 2013). Regorafenib is a novel 
oral multikinase inhibitor that blocks the activity of several protein kinases, including 
kinases involved in angiogenesis, oncogenesis and tumor microenvironment (Kies et al, 
2010). Regorafenib was recently shown to provide a survival benefit in metastatic 
colorectal cancer patients who have progressed after all standard therapies (Grothey, et 
al). This led to its approval in September 2012 by the FDA for use in the United States. 
Despite the observed benefits in a patient population with no current standard, toxicities 
such as Palmar-planter erythrodysesthesia syndrome (PPES) (which occurs early in the 
first 1-2 weeks) and fatigue have widely limited its use in the US. Multiple practices 
across the US have adopted, and despite the absence of supportive data, various dosing or 
interval scheduling including starting at lower doses and escalate as tolerated, every other 
week dosing intervals and other. 
 
In this study, we propose to design a novel strategy to optimize the dose of regorafenib in 
patients with refractory mCRC to allow maintenance of the observed benefits while 
improving the tolerability profile. The proposed strategy, arm A (combining A1 and A2) 
consists of starting regorafenib at 80 mg/day for 1 week (week1), then if no significant 
drug-related toxicities escalate to 120 mg/ day for another week (week 2), then again if 
no significant related toxicities escalate to a total dose of 160 mg/day (week 3) followed 
by a week break ( week 4 of cycle 1). If at the end of week 1, week 2 or week 3 toxicities 
are unacceptable as defined by the study, the decision will be to deescalate by 40 mg/day 
and there will be no further dose escalations. A comparative arm, arm B (combining B1 
and B2) will include a standard dose/schedule regorafenib of a 160 mg/day starting on 
day 1 of cycle 1. The primary goal of this study is to compare the proportions of patients 
on each arm who complete 2 cycles of protocol treatment and initiate cycle 3. We will 
also assess other outcome and quality of life measures and toxicity profile with a focus on 
regorafenib related toxicities. We will also assess a potential strategy to reduce the 
severity of PPES. Additionally, we will perform limited PK analysis in both arms. 
 
To explore a potential strategy to reduce the severity of PPES, Clobetasol 0.05% cream 
for first 12 weeks will be prophylactically applied to palms and soles of patients in arm 
A1 and (pre-emptive strategy). Patients in arm A2 and B2 will be treated per investigator 
discretion when they develop PPES (reactive strategy). All patients will be required to fill 
HFS14 quality of life questionnaire on C1D14, C2D1, C2D14, and C2D28 intervals. 
 
1.2 
QOL Tools 
 
1.21 
QOL is an important outcome and covariate in this trial because the treatments 
are expected to differ in terms of their symptom profiles and impact on patient 
well-being. Previous data has indicated that the most prevalent QOL issues with 
these patients are fatigue, pain, weight loss, and other symptoms, as well as more 
general aspects of QOL such as ability to enjoy life and contentedness in QOL 
(Odom et. al. 2010). We hypothesize that patients receiving regorafenib will 
experience greater deficits in QOL as reflected by scores on the HSF14, the BFI 
and the LASA. These questionnaires have specific application to this population. 
 
The HSF14 has been specifically designed to capture changes in QOL related to 
PPES. Cronbach’s alpha for this questionnaire is 0.93. It involves 14 questions 

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Addendum 6 
 
 
with three domains: hand, feet, and social. The final score for this questionnaire 
ranges from 2-100, where a higher score indicates greater QOL impairment 
(Sibaud et. al., 2011). For comparison to other QOL questionnaires, the HSF14 
will be converted to a 0-100 scale, where a higher score indicates better QOL. 
 
The Brief Fatigue Inventory (BFI), a 9-item questionnaire, has been validated as 
a short and comprehensive instrument to assess severity of fatigue and fatigue-
related impairment in cancer patients. The reliability estimated with Cronbach’s 
alpha ranges from 0.82 to 0.97. Recently, both the German version and the 
Japanese version of the BFI has been validated with test-reliability (mean scores 
of 0.93) and impairment (mean scores of 0.87) for the German version and 
reliability with Cronbach’s alpha at 0.96 for the Japanese version. Minor 
differences were seen in the validation of the German version compared to the 
original version. 
 
Linear Analogue Self Assessment (LASA) items have been validated as general 
measures of global QOL dimensional constructs in numerous settings (Grunberg 
et al., 1996; Gudex et al, 1996; Hyland et al., 1996; Srivatanakul, 1983; Wewers, 
1990). A series of LASA items have been constructed and validated at Mayo 
Clinic for use in cancer patients (Bretscher et al, 1999). These items have been 
seen to be important prognostic factors for cancer patient survival and should be 
included as covariates in survival analysis (Sloan, JCO, 2012). 
 
1.3 
Correlative Research 
 
1.31 
Regorafenib clinical pharmacokinetics 
 
Regorafenib and its metabolites M2 and M5 have been assessed 
pharmacokinetically in several phase I studies, both with regorafenib dosed 21 
days on/7 days off (Mross K et al. 2012; Strumberg D et al. 2012; Sunakawa Y et 
al. 2014), and with continuous dosing (Kies MS et al. 2010; Finn RS et al. 2013). 
Based on safety, efficacy and PK analysis (higher exposure on dosing days), the 
final dose taken into phase III studies was 160 mg 21 days on/7 days off.  
 
Regorafenib is moderately fast absorbed after oral administration with median 
tmax of 3 to 4 hours, and mean Cmax of 2.5 mg/L. Steady-state is expected to occur 
within 7 days after first administration. The overall mean terminal half-life at 
steady state is 20-30 hours, with a tmax,ss of 5 hrs. Mean Cmax,ss and AUC(0-24)ss 
with 160 mg dosing were 3.9 mg/L and 58.3 mg•h/L. In the dose escalation phase 
I studies, regorafenib PK at doses above 60 mg was less than dose proportional. 
Accumulation of regorafenib from day 1 to day 21 was consistent with linear 
pharmacokinetics (Mross K, et al .2012). 
 
Regorafenib has 2 major active metabolites, M2 and M5. While both regorafenib 
and M2 have elimination half-lifes of 20-30 hrs, the M5 active metabolite has a 
half-life of 60 hrs (range 40-100 hrs). 
 
Regorafenib and its active metabolites have substantial variability in their plasma 
exposure – expressed as either the maximum concentration shortly after 
administration (Cmax) or the area under the concentration-time curve (AUC) – 
after oral regorafenib administration. The coefficient in variation (standard 

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Addendum 6 
 
 
deviation/mean) of Cmax ranges from 61.9% to 173.5%, showing considerable 
interpatient variability in the absorption. This is not unexpected since 
regorafenib’s absorption is influenced by the fat content in the diet (Section 
15.15). Similarly, the AUC has substantial variability with the CVs ranging from 
77.8 to 182.4%. This is also not unexpected since regorafenib undergoes 
enterohepatic recirculation, and is susceptible to a multitude of drug interactions 
since it is a CYP3A4 and UGT1A9 substrate (Section 15.15). Furthermore, 
within-patient variability is present such that an individual patient can have dose-
to-dose variability in their pharmacokinetics.  
 
No relationship was suggested between AUC or Cmax of regorafenib, M2 or M5 
and adverse events in phase 1 trials, but it was suggested that an exposure of ≥ 60 
mg daily of regorafenib was associated with greater efficacy (regorafenib IB).  
 
1.32 
Rationale for regorafenib pharmacokinetic studies 
 
Regorafenib has clinical activity in CRC, but many patients discontinue 
treatment in the first 2 cycles due to adverse events (Grothey A et al. 2013). In 
the few phase I studies to date, small patient numbers underwent any PK 
evaluation at steady state beyond cycle 1, to understand a possible connection 
between toxicity and PK parameters.  
 
Because this clinical trial seeks to optimize the regorafenib dose and overall 
exposure in patients with refractory mCRC, it is critical that we evaluate the 
pharmacokinetic parameters of regorafenib and its metabolites, and assess 
whether their PK variability is clinically relevant. To our knowledge, no large 
pharmacokinetic correlative studies – or those studies evaluating if plasma 
regorafenib concentrations are associated with its efficacy or toxicity –have been 
conducted to date.  
 
Therefore, as detailed in Section 14.1, we have developed a clinic-friendly 
sampling schedule to collect the PK trough levels (Cmin) for the study drug and its 
metabolites, to maximize patient compliance. In the low dose (dose escalation) 
cohort, as the regorafenib dose is planned to be escalated weekly in cycle 1 from 
80 to 120 to 160mg, trough levels will be collected on days 7, 14 and 21, when 
each regorafenib dose would be expected to reach steady state. These visits 
coincide with regular clinic visits for safety/toxicity evaluation. In cycle 2, PK 
will be collected on days 1 and 21. To be able to compare the low dose, 
escalating cohort with the standard dose cohort, similar time-points for PK 
analysis were chosen. 
 
 
2.0 
Goals  
 
2.1 
Primary 
 
2.11 
Evaluate the proportion of patients who complete 2 cycles of protocol treatment 
and initiate cycle 3 in arm A (pooled arm A1 and A2) and arm B (pooled arm B1 
and B2). 
 
 

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Addendum 6 
 
 
2.2 
Secondary 
 
2.21 
Evaluate outcome measures for efficacy in each arm including progression-free 
survival (PFS), time to progression (TTP), and overall survival (OS). 
 
2.22 
Compare between arms the cumulative dose and dose intensity received within 
the first two cycles. 
 
2.23 
Evaluate the proportion of patients in each arm that exhibit grade 3 Palmar-
plantar erythrodysesthesia syndrome (PPES) and/or fatigue, and make 
comparisons between regorafenib dosing strategies and pre-emptive vs. reactive 
strategies to address PPES. 
 
2.24 
Compare QOL between treatment arms (regorafenib dosing strategies and pre-
emptive vs. reactive PPES strategies) as measured by the HFS14, BFI, and 
LASA questionnaires. 
 
2.3 
Correlative Research 
 
2.31 
Evaluate and compare trough (Cmin) PK during the first 2 treatment cycles for 
regorafenib and active metabolites M2, M5 between the low dose (dose 
escalation) and the standard dose cohorts, and correlate with toxicity profile.  
 
2.32 
Evaluate the correlation between PK parameters and tumor response/stable 
disease after the first two cycles.  
 
2.33 
Evaluate the correlation between PK parameters and PFS and OS. 
 
2.34 
Evaluate if trough (Cmin) concentrations are associated with patient-specific 
factors (such as – but not limited to – age and concomitant medications).  
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histological or cytological documentation of adenocarcinoma of the colon or 
rectum. 
 
3.13 
Advanced or metastatic colorectal cancer with no curative options available and 
progression on previous standard therapy, including an EGFR inhibitor if KRAS 
wild-type. 
 
3.14 
Measurable or non-measurable disease as defined in Section 11.0.  
 
3.15 
ECOG Performance Status (PS) 0 or 1. (Form is available on the ACCRU web 
site https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html). 
 
3.16 
Life expectancy of ≥ 3 months. 

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Addendum 6 
 
 
 
3.17 
The following laboratory values obtained ≤7 days prior to randomization. 
 
• 
Absolute neutrophil count (ANC) >1500/mm3 
• 
Platelet count >100,000/mm3 
• 
Hemoglobin >9.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) and aspartate amino-transferease (AST) ≤ 
2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
• 
Serum creatinine ≤1.5 x ULN 
• 
INR/PTT ≤ 1.5 x ULN 
NOTE: Patients who are therapeutically treated with an agent such as 
warfarin or heparin will be allowed to participate provided that no prior 
evidence of underlying abnormality in coagulation parameters exists. Close 
monitoring of at least weekly evaluations will be performed until INR/PTT is 
stable based on a measurement that is pre-dose as defined by the local 
standard of care. 
• 
Alkaline phosphatase limit ≤2.5 x ULN (≤5 x ULN for patients with liver 
involvement of their cancer) 
 
3.18 
Negative serum pregnancy test done ≤7 days prior to randomization, for women 
of childbearing potential only. NOTE: Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not required to 
undergo a pregnancy test. The definition of adequate contraception will be based 
on the judgment of the investigator. 
 
3.19a 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.19b Provide informed written consent. 
 
3.19c 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19d Willing to provide blood samples for correlative research and banking purposes 
(see Sections 6.0 and 14.0).  
 
3.2 
Exclusion Criteria  
 
3.21 
Prior treatment with regorafenib. 
 
3.22 
Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days 
prior to randomization. 
 
3.23 
Congestive heart failure > New York Heart Association (NYHA) class 2. 
 
3.24 
Unstable angina (angina symptoms at rest), new-onset angina (begun within the 
last 3 months) or myocardial infarction less than 6 months prior to 
randomization. 
 
3.25 
Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: Pace makers, beta 

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Addendum 6 
 
 
blockers or digoxin are permitted. 
 
3.26 
Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic 
pressure > 90 mmHg despite optimal medical management). 
 
3.27 
History of or current pheochromocytoma. 
 
3.28 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism ≤6 months prior to randomization. 
 
3.29a 
Ongoing infection > grade 2 NCI-CTCAE version 4.0. 
 
3.29b Known history of chronic hepatitis B or C. 
 
3.29c 
Patients with seizure disorder requiring medication. 
 
3.29d Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 
months from definitive therapy, has a negative imaging study within 4 weeks of 
randomization and is clinically stable with respect to the tumor at the time of 
randomization. Note: Patient must not be undergoing acute steroid therapy or 
taper (chronic steroid therapy is acceptable provided that the dose is stable for 
one month prior to and following screening radiographic studies). 
 
3.29e 
History of organ allograft (including corneal transplant). 
 
3.29f 
Evidence or history of bleeding diathesis or any hemorrhage or bleeding event 
>CTCAE grade 3 ≤4 weeks prior to randomization. 
 
3.29g Non-healing wound, ulcer, or bone fracture. 
 
3.29h Renal failure requiring hemo-or peritoneal dialysis. 
 
3.29i 
Dehydration CTCAE (version 4.0) grade ≥1. 
 
3.29j 
Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results. 
 
3.29k Known hypersensitivity to any of the study drugs, study drug classes, or 
excipients in the formulation. 
 
3.29l 
Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent. 
 
3.29m Persistent proteinuria of CTC Grade 3 or higher (≥ 3.5 g/24 hrs). 
 
3.29n Patients unable to swallow oral medications. 
 
3.29o Any malabsorption condition. 
 
3.29p Unresolved toxicity greater than CTCAE (version 4.0) Grade 1 attributed to any 

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Addendum 6 
 
 
prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity 
≤Grade 2. 
 
3.29q Albumin levels <2.5 g/dl. 
 
3.29r 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
NOTE: Men and women of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after 
the last dose of study drug. The definition of adequate contraception will be 
based on the judgment of the principal investigator or a designated associate. 
 
3.29s 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.29t 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy. NOTE: Patients known to be HIV 
positive, but without clinical evidence of an immunocompromised state, are 
eligible for this trial. 
 
3.29u Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.29v Previous or concurrent cancer that is distinct in primary site or histology from 
colorectal cancer within 3 years prior to randomization EXCEPT for curatively 
treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder 
tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor 
invades lamina propria)]. Note: All cancer treatments for cancers that were 
distinct in a primary site other than colorectal must be completed at least 3 years 
prior to randomization (i.e., signature date of the informed consent form). 
 
3.29w Pleural effusion or ascites that causes respiratory compromise (≥CTCAE version 
4.0 Grade 2 dyspnea). 
 
3.29x Concurrent anti-cancer therapy ≤4 weeks from registration (chemotherapy, 
radiation therapy, surgery, immunotherapy, biologic therapy, or tumor 
embolization). 
 
3.29y Current use of clobetasol propionate. 
 
3.29z 
Use of any herbal remedy (e.g. St. John’s Wort [Hypericum perforatum]). 
 

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Addendum 6 
 
 
3.29aa Patients unable to ambulate or who have amputations or paralysis of any 
extremity. 
 
3.29bb History of contact dermatitis to clobetasol propionate or similarly fluorinated 
steroids or other steroids with the propionate ester. 
 
 

 
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12 
 
 
 
Addendum 6 
4.0 
Test Schedule 
 
 
Active Monitoring Phase 
Tests and procedures 
≤7 days prior 
to 
randomization 
Cycle 113 
Cycle 213 
After week 8: Every 
4 weeks until 
progression (+/- 3 
days) 
At PD, 
withdrawal or 
removal 
Week1  
(Day 1) 
Week 2 
(Day 8) 
Week 3 
(Day 15) 
Week 4 
(Day 22) 
Week 1 
(Day 1) 
Week 2 
(Day 8) 
Week 3 
(Day 15) 
Week 4 
(Day 22) 
History and exam, weight, 
ECOG PS12, blood pressure 
X 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 8, 11: 
CBC/ differential, ANC, 
INR/PTT 8, 10 
X 
X 
 
 
 
X 
 
 
 
X 
 
Chemistry 8, 11: SGOT (AST), 
alk phos, T. bili, serum 
creatinine, calcium, glucose, 
Na, K, SGPT (ALT) 
X 
X 
 
X7 
 
X7 
 
X7 
 
X 
 
Albumin 
X 
 
 
 
 
 
 
 
 
 
 
Urine proteinuria or urine 
protein creatinine ratio 
X 
 
 
 
 
 
 
 
 
 
 
Tumor measurement8 (CT 
scan of chest, abdomen and 
pelvis ) (MRI if CT is not 
feasible) 
X1 
 
 
 
 
 
 
 
X1 
X1 
X1,9 
ECG6 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X2 
 
 
 
 
 
 
 
 
 
 
Mandatory blood sample (see 
Section 14.0) 
X4,R 
(Day 7) 
X4,R 
(Day 14) 
X4,R 
(Day 21) 
X4,R 
 
(Day 1) 
X4,R 
 
(Day 21) 
X4,R 
 
 
 
Patient Medication Diary 
(Appendix II)3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Questionnaire 
Booklets (Appendices IV, V, 
VI) 
X5 
 
X5, 8 
 
 
X5, 8 
X5, 8 
 
X5, 8 
 
 
1. CT scans preferred (MRI if CT is not feasible) of the chest, abdomen and pelvis. Use same imaging throughout the study. Tumor measurements at 
baseline (≤28 days prior to randomization) and every 8 weeks until progression.  
2. For women of childbearing potential only.  

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Addendum 6 
 
3. The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution weekly 
during Cycles 1 and 2 and every 4 weeks thereafter. 
4. Kits are required for this collection. Samples will be collected for PK analysis of Cmin of regorafenib, M2 and M5 at the following time points: Cycle 1, 
days 7, 14 and 21 prior to treatment; Cycle 2, days 1 and 21 prior to treatment. Samples will be collected for research banking at the following time 
points: Baseline, prior to treatment; Cycle 2, days 1 and 21, prior to treatment. See Section 14.0 for specific instructions.  
5. Patient questionnaires will be completed at baseline (appendices IV and V only), Cycle 1 Day 14, Cycle 2 Day 1, Cycle 2 Day 14 and Cycle 2 Day 28. 
Cycle 2 Day 14 and Cycle 2 Day 28 patient questionnaire can be sent home with the patient to complete and return at their next clinic visit if needed. 
Patient questionnaire booklets must be used; copies are not acceptable for this submission. 
6. Performed at screening and then as needed. 
7. AST, ALT and total bilirubin will be checked at baseline and every other week during Cycles 1 and 2.  
8.  +/- 1 day. Applies to days 1, 8, 15, and 22; includes baseline tests and procedures for Day 1 Cycle 1. 
9. If patient goes off study during Cycle 1 and last CT scan was done >28 days prior, the CT scan must be done. 
10. If a subject is on warfarin with stable PT/INR at baseline, the PT/INR should be assessed on Day 5 (+/- 3 days). If value is above the therapeutic range, 
the dose should be modified and the assessment should be repeated weekly until it is stable. 
11. Hematology and chemistry tests to be done prior to each cycle. 
12. If baseline history, exam, weight, ECOG PS, and blood pressure were performed ≤3 days of Cycle 1 Day 1, they do not need to be repeated for Cycle 
1 Day 1. 
13. It is suggested that patients start treatment Tuesday-Friday to avoid PK collection on Sundays. 
R Research funded (see Section 19.0) 
 

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     14  
 
Addendum 6 
 
 
5.0 
Stratification Factors: None 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Randomization Procedures 
 
6.11 
To randomize a patient, access the ACCRU web page at 
 click on “Training Page” and enter the 
registration/randomization application. The registration/randomization application is available 
24 hours a day, 7 days a week. Back up and/or system support contact information is available 
on the Web site. If unable to access the Web site, call the Academic and Community Cancer 
Research United (ACCRU) Registration Office at 
 between the hours of 8 a.m. 
and 4:30 p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available by using the Help 
button. Prior to initiation of protocol study intervention, this process must be completed in its 
entirety and an ACCRU subject ID number must be available as noted in the instructions. It is 
the responsibility of the individual and institution registering the patient to confirm the process 
has been successfully completed prior to release of the study agent. Patient registration via the 
registration/randomization application can be confirmed in any of the following ways: 
 
• 
Contact the ACCRU Registration Office 
. If the patient was fully 
registered, the ACCRU Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.12 
Correlative Research 
 
• 
A mandatory correlative research component is part of this study. The patient will be 
automatically registered onto this component (see Sections 3.0 and 14.0). 
• 
A mandatory banking component is part of this study. The patient will be 
automatically registered onto this component (see Sections 3.0 and 14.0). 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (
. If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
 
 

RU021407I 
     15  
 
Addendum 6 
 
 
6.14 
Prior to accepting the registration/randomization, the registration/randomization application 
will verify the following: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.15 
At the time of randomization, the following will be recorded: 
 
• 
Patient has given permission for ACCRU to give his/her sample(s) to outside 
researchers. 
 
6.16 
Treatment cannot begin prior to randomization and must begin ≤7 days after 
randomization. 
 
6.17 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.19a 
Treatment on this protocol must commence at an ACCRU institution under the supervision 
of a medical oncologist. 
 
 
6.19b Blood draw kit is available on site. 
 
6.19c 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission. 
 
6.2 
Randomization Procedures 
 
6.21 
The registering membership will be used as the only stratification factor for this study. 
 
6.22 
After the patient has been registered into the study, the patient will be assigned to one of 
the following treatment groups, in 1:1:1:1 fashion, using the Pocock and Simon dynamic 
allocation procedure which balances the marginal distributions of the stratification factors 
between the treatment groups (Pocock-Simon, 1975).  
 
• 
Arm A 1: Regorafenib Cycle 1: 80 mg daily Week 1/120 mg daily Week 2/160 mg 
daily week 3 then 1 week off followed by Cycle 2+ (160 mg for 21 days/1 week off) + 
pre-emptive strategy for PPES starting Cycle 1 Day 1  
• 
Arm A 2: Regorafenib Cycle 1: 80 mg daily week 1/120 mg daily week 2/160 mg daily 
week 3 then 1 week off followed by Cycle 2+ (160 mg for 21 days/then 1 week off) + 
reactive strategy for PPES 
• 
Arm B 1: Regorafenib 160 mg daily for 21 days/then 1 week off + pre-emptive 
strategy for PPES starting Cycle 1 Day 1  
• 
Arm B 2: Regorafenib 160 mg daily for 21 days/then 1 week off + reactive strategy for 
PPES  
 
 
 
 

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     16  
 
Addendum 6 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule  
 
Arm 
Agent 
Dose  
Route 
Frequency 
ReRx 
A 1  
Regorafenib 
80 mg daily (Starting 
dose) 
See Section 7.11 
PO  
Daily for 21 days 
of 28 day cycle 
Every 28 days 
Clobetasol 
(pre-emptive) 
0.05% cream thin 
layer to palms and 
soles, avoid washing 
hands or feet for 1 
hour after application 
Topical 
BID for first 12 
weeks 
BID for first 12 
weeks starting 
Day 1 of 
regorafenib dose 
A 2 
Regorafenib 
80 mg daily (Starting 
dose) 
See Section 7.11 
PO  
Daily for 21 days 
of 28 day cycle 
Every 28 days 
Clobetasol 
(reactive) 
0.05% cream thin 
layer to palms and 
soles, avoid washing 
hands or feet for 1 
hour after application 
Topical 
BID (per 
physician 
discretion; 
recommend no 
longer than 12 
weeks from 
initiation) 
BID (per 
physician 
discretion upon 
occurrence of 
PPES Grade ≥1; 
recommend no 
longer than 12 
weeks from 
initiation) 
B 1  
Regorafenib 
160 mg 
(Starting dose) 
PO  
Daily for 21 days 
of 28 day cycle 
Every 28 days 
Clobetasol 
(pre-emptive) 
0.05% cream thin 
layer to palms and 
soles, avoid washing 
hands or feet for 1 
hour after application 
Topical 
BID for first 12 
weeks 
BID for first 12 
weeks starting 
Day 1 of 
regorafenib dose 
B 2 
Regorafenib 
160 mg 
(Starting dose) 
PO  
Daily for 21 days 
of 28 day cycle 
Every28 days 
Clobetasol 
(reactive) 
0.05% cream thin 
layer to palms and 
soles, avoid washing 
hands or feet for 1 
hour after application 
Topical 
BID (per 
physician 
discretion; 
recommend no 
longer than 12 
weeks from 
initiation) 
BID (per 
physician 
discretion upon 
occurrence of 
PPES Grade ≥1; 
recommend no 
longer than 12 
weeks from 
initiation) 
 
 
Regorafenib tablets should be taken once a day with approximately 8 fluid ounces (240 mL) of water after 
a low-fat (<30% fat) meal. Regorafenib should be taken with a meal at the same time every day. 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). 

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     17  
 
Addendum 6 
 
 
• 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. 
 
7.11 
Arm A Regorafenib Dose Escalation 
 
Cycle 1: 
 
Week 
Dose 
1 
Starting Dose 
80 mg*  
2 
120 mg  
3 
160 mg  
4 
Off  
*starting dose level  
 
Cycle 2 and beyond: 
 
Week 
Dose 
1 
Remain at 
highest 
tolerated dose 
from Cycle 1 
(up to 160 mg) 
 
2 
3 
4 
Off  
 
 
7.12 
Arm B Regorafenib Dose (all cycles) 
 
Week 
Dose 
1 
Starting Dose 
 
160 mg 
2 
3 
4 
Off  
 
7.2 
Patients can be instructed in administration techniques and granted treatment independence with 
nursing staff approval. 
 
7.3 
For this protocol, the patient must return to the consenting ACCRU institution for evaluation at 
least every 7 days during treatment and every 28 days during active monitoring. 
 
7.4 
Treatment by a local medical doctor (LMD) is not allowed. 
 
 
 
 

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     18  
 
Addendum 6 
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in the following tables for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to produce 
mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, administer dose 
based on greatest reduction required for any single adverse event observed. Reductions or increases apply 
to treatment given in the preceding cycle and are based on adverse events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Arm A Regorafenib Dose Escalation/Reduction  
 
Dose level 
If No SDRT 
If + SDRT** 
80 mg*  
Proceed to 
next dose 
level 
- 
120 mg  
Proceed to 
next dose 
level  
Decrease to  
80 mg 
160 mg  
- 
Decrease to 
120 mg  
*starting dose level  
**SDRT = Significant Drug Related Toxicities 
 
8.11 
After week 8, if toxicities have resolved to ≤ Grade 0-1, re-escalation is allowed 40 mg at a 
time every 4 weeks to a maximum of 160 mg and at the discretion of the treating 
investigator. 
 
8.12 
Patients with dose reductions below 80 mg should go off treatment and go to event 
monitoring. 
 
8.13 
Any patients with toxicities requiring >4 week delay should go off treatment and then to 
event monitoring. 
 
Regorafenib may be dose reduced per the table in Section 8.2 in case of intolerable toxicity such as weight 
loss, fatigue, rash or anorexia. 
 
8.2 
Arm B Regorafenib Dose Levels (Based on Adverse Events in Tables 8.3.) 
 
Dose 
Level 
Drug  
Dose 
 0* 
 
Regorafenib 
160 mg daily, Four 40-mg tablets  
-1 
 
Regorafenib 
120 mg daily, Three 40-mg tablets  
-2 
 
Regorafenib 
80 mg daily, Two 40-mg tablets  
* Dose level 0 refers to the starting dose. 
 
8.21 
After week 8, if toxicities have resolved to ≤ Grade 0-1, re-escalation is allowed 40 mg at a 
time every 4 weeks to a maximum of 160 mg and at the discretion of the treating 
investigator. 
 

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     19  
 
Addendum 6 
 
 
8.22 
Patients with dose reductions below 80 mg should go off treatment and go to event 
monitoring. 
 
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. 
 
8.3 
Regorafenib Dose Modifications 
 
Table 8.31 Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/AST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose Modification b 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
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, version 
4.0 
b. Excludes alopecia, non-refractory nausea/vomiting, lymphocyte count decreased, non-refractory 
hypersensitivity and nonclinical and asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless subject is 
deriving clinical benefit. 
* 
Modify according to study specific cycle length 
If greater than 2 dose level reductions are required, regorafenib will be discontinued and the rest of 
the study follow up may be continued. The following tables outline dose adjustments for toxicities 
related to regorafenib except hand-foot skin reaction, hypertension and liver function test 
abnormalities. 
 
The table above outlines dose adjustments for hematologic and non-hematologic toxicities related 
to regorafenib except PPES and hypertension. In addition to these recommended dose 
modifications, subjects who develop diarrhea, mucositis, anorexia or other events predisposing to 
fluid loss or inadequate fluid intake should be carefully monitored and rehydrated as clinically 
necessary. This is in order to minimize the risk of postural hypotension and renal failure. 
 
 

RU021407I 
     20  
 
Addendum 6 
 
 
 
Table 8.32: Grading for Palmar-plantar erythrodysesthesia syndrome 
 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
changes 
Numbness, dysesthesia / 
paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting instrumental 
activities of daily life 
(e.g., preparing meals, 
shopping for groceries 
or clothes, using the 
telephone, managing 
money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, dressing 
and undressing, feeding 
self, using the toilet, 
taking medications) 
and not bedridden 
a. 
Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked discomfort, 
swelling, and tingling in the palms of hands or the soles of the feet. 
 
 
Table 8.33 Recommended dose modification for Palmar-plantar erythrodysesthesia syndrome 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 0-1b,d 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. 
When resuming treatment, treat at reduced dose level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. 
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 levelb,d  
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is not permitted. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
f. Refer to Section 9.0 for management strategies for Palmer-plantar erythrodysesthesia syndrome reactions. 
 
 
 

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     21  
 
Addendum 6 
 
 
8.34 
Hypertension 
 
Hypertension is a known AE associated with regorafenib treatment. Subject will have their 
blood pressure measured at least weekly during the first 5 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, Tables Section 8.1 
and 8.2 outline suggested dose reductions. 
 
Table 8.34: Management of Treatment-Emergent Hypertension 
Grade 
(CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
 
Prehypertension 
(systolic BP120 - 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. 
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 resolvea 
 
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. 
 
If Grade 3 hypertension recurs despite 
dose reduction and antihypertensive 
therapy, reduce another dose level. 
4 
 
Life-threatening 
consequences 
(e.g., malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 

RU021407I 
     22  
 
Addendum 6 
 
 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
If BP remains controlled for at least one cycle. Patients requiring >2 dose reductions 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. 
 
8.35 
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 below should be 
followed. 
 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may 
occur in patients with Gilbert’s syndrome. 
 
Table 8.35: Dose modifications/interruption for ALT and/or AST and/or bilirubin increases 
related to study drug 
Increases in ASL/ALT 
(per NCI-CTCAE v 4.0) 
1st Occurrence 
Restart 
Re-occurrence 
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 >5 X 
ULN (≥ Grade 3) 
Interrupt dosing, with 
weekly monitoring 
until transaminases 
return to <3 X ULN or 
baseline. 
If the potential benefit 
for reinitiating 
regorafenib/ placebo is 
considered to outweigh 
the risk of 
hepatotoxicity: Reduce 
one dose level and 
measure serum liver tests 
weekly for at least 4 
weeks. 
Discontinue 
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 
liver tests weekly until 
resolution. Exception: 
patients with Gilbert’s 
syndrome who 
develop elevated 
transaminases should 
be managed as per the 
recommendations 
outlined above for 
ALT/AST elevations. 
 
 
During the first 2 cycles of treatment, ALT, AST and bilirubin must be monitored every 2 weeks. 
 
8.4 
No dose modifications expected for clobetasol propionate. 
 
 
 

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     23  
 
Addendum 6 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the ASCO 2006 Update of Recommendations for the Use of White Blood Cell 
Growth Factors: An Evidence Based Clinical Practice Guideline. Journal of Clinical Oncology, Vol 
24, No 19 (July 1), 2006: pp. 3187-3205. 
 
9.3 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days 
after the final dose will be recorded in the medical records. 
 
9.4 
At first occurrence of PPES, independent of grade, prompt institution of supportive measures 
such as topical emollients, low potency steroids, or urea-containing creams should be 
administered. 
 
9.41 
Recommended prevention/management strategies for skin toxicities consistent with PPES 
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 
 
• Over the counter moisturizing creams or ointments are allowed, but patients cannot 
apply these within 1 hour before and after clobetasol applications. 
• For grades 2 or 3, topical analgesics (e.g. lidocaine 5% patches, lidocaine/prilocaine 
cream TID, lidocaine 2-5% creams) are to be considered for pain control. 
• Topical corticosteroids like clobetasol 0.05% should be instituted for subjects with 
Grade 2 or 3 PPES (in reactive arm). Avoid systemic steroids. 
• For grade 2/3 Oral NSAIDs (celecoxib, ibuprofen) may be used for pain control 
• Continue clobetasol during dose interruptions or decreased dosing/rechallenge 
• Continue analgesia with topical analgesics or oral NSAIDs during dose interruptions or 
decreased dosing/rechallenge 
 
 
 

RU021407I 
     24  
 
Addendum 6 
 
 
Tender areas should be protected as follows: 
 
• Use of thick socks/gloves to cover moisturizing creams 
• Wear well-padded footwear 
• Use insole cushions or inserts (e.g. silicon, gel) 
• Foot soaks with tepid or cool water  
• Use soft shoes or slippers (Crocs, TempurPedic slippers), avoid high heels and wood 
soles/heels 
 
Suggested PPES Reaction Treatment 
 
• 
CTCAE v4 Grade 1 ((Minimal skin changes or dermatitis (e.g., erythema, edema or 
hyperkeratosis) without pain)) - Continue regorafenib at current dose.  
• 
CTCAE v4 Grade 2 ((Skin changes (e.g., peeling, blisters, bleeding, edema, or 
hyperkeratosis) with pain, limiting instrumental ADL (or intolerable grade 2, defined 
as grade 2 AE that does not decrease to grade ≤1 after 2 weeks of therapy OR that is 
considered intolerable per patient)) – See Section 8.33.  
 
Oral (NSAIDs or narcotics) OR topical analgesia (lidocaine cream or patches 
PRN. 
• 
CTCAE v4 Grade ≥3 ((Ulcerative dermatitis or skin changes with pain interfering with 
function. Severe skin changes (eg, peeling, blisters, bleeding, edema, or hyperkertosis) 
with pain; limiting self-care ADL)) – Interrupt regorafenib dose and monitor 
 Topical steroid cream BID AND topical anesthetics 
 
Oral (NSAIDs or narcotics) OR topical analgesia (lidocaine cream or patches 
PRN. 
 
9.5 
Prevention/management strategies for diarrhea: Diarrhea can be a common side effect of 
regorafenib. The same dose-modification algorithm used for skin toxicities can be used to address 
these toxicities. However, the preventive/management strategies for diarrhea should be consistent 
with local standards (e.g., anti-diarrheals and optimized hydration status). Anti-diarrhea 
medications may be introduced if symptoms occur. Previous trials have shown that the diarrhea 
could be managed with loperamide. The recommended dose of loperamide is 4 mg at first onset, 
followed by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. In the event of grade 3 or 4 
diarrhea, the following supportive measures are allowed: hydration, octreotide, and antidiarrheals. 
 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. First, 
identify and grade the severity of the event using the CTCAE version 4.0. Next, determine 
whether the event is expected or unexpected (see Section 10.2) and if the adverse event is 
related to the medical treatment or procedure (see Section 10.3). With this information, 
determine whether the event must be reported as an expedited report (see Section 10.4). 

RU021407I 
     25  
 
Addendum 6 
 
 
Important: Expedited adverse event reporting requires submission of a MedWatch 3500A 
report(s). Expedited reports are to be completed within the timeframes and via the 
mechanisms specified in Sections 10.2 and 10.3. All AEs reported via expedited 
mechanisms must also be reported via the routine data reporting mechanisms defined by 
the protocol (see Sections 10.5 and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event used 
for medical documentation and scientific analysis and is a single MedDRA Lowest Level 
Term (LLT). 
 
• 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific information 
provided in Section 15.0 of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in Section 15.0 
of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither identified 
in nature, severity, or frequency of risk in the information provided for IRB review nor mentioned 
in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the drug 
and the adverse event.  
 
10.31 Special Situations for Expedited Reporting  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse 
Events where the AE is EXPECTED. Any protocol specific reporting procedures MUST 
BE SPECIFIED BELOW and will supersede the standard Expedited Adverse Event 
Reporting Requirements: 
 
Note: These exceptions only apply if the adverse event does not result in hospitalization.  
 
If the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
 

RU021407I 
     26  
 
Addendum 6 
 
 
 
System Organ Class (SOC) 
Adverse event/Symptoms 
CTCAE Grade at which the 
event will not be 
expeditiously reported. 
Gastrointestinal Disorders 
Diarrhea 
Any Grade 
Dyspepsia 
Nausea 
Vomiting 
Colitis 
Grades 1-3 
Pancreatitis 
General disorders and 
administrations site conditions 
Anorexia 
Any Grade 
Asthenia 
Dehydration 
Fatigue 
Malaise 
Weight loss 
Hepatobiliary disorders 
Cholecystitis 
Grades 1-3 
Infections and infestations 
Lung Infection 
Grades 1-3 
Sinusitis 
Skin infection 
Urinary tract infection 
Investigations 
Alkaline phosphatase increased 
Any Grade 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Lymphocyte count decreased 
Metabolism and nutrition 
disorders 
Hyperkalemia 
Any Grade 
Hypocalcemia 
Hypomagnesemia 
Hyponatremia 
Musculoskeletal and connective 
tissue disorders 
Arthralgia 
Any Grade 
Back pain 
Musculoskeletal and connective tissue 
disorder – Other (muscle spasms) 
Skin and subcutaneous tissue 
disorders 
Alopecia 
Any Grade 
Rash acneiform 
Rash maculo-papular 
Palmar-plantar erythrodysesthesia syndrome 
 
 
10.311 
Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
 
 

RU021407I 
     27  
 
Addendum 6 
 
 
10.312 
Death 
 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term associated with Grade 
5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benigh, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
  
10.313 
Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE to be reported. Three options are available to describe the 
event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.314 
Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy). Second malignancies 
require ONLY routine reporting. 
 
 
 

RU021407I 
     28  
 
Addendum 6 
 
 
10.4 
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial 
within 30 Days of the Last Administration of a Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.31 of the protocol. 
 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period.3 
 
Effective Date: May 5, 2011 
 
 
 

RU021407I 
     29  
 
Addendum 6 
 
 
Additional Instructions: 
 
1. An increased incidence of an expected adverse event (AE) is based on the patients treated for 
this study at their site. A list of known/expected AEs is reported in the package insert or the 
literature, including AEs resulting from a drug overdose. 
 
2. Submit form 3500A to the FDA, MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, 
by fax at 1-800-332-0178 or online at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm.  
 
3. 
ACCRU Sites: Follow site-specific reporting guidelines. Provide copies by fax 
to the ACCRU SAE Coordinator. The ACCRU SAE Coordinator will then 
electronically send the report to Bayer:  
 
Electronic Mailbox: 
Facsimile: 
  
Address: 
  
Mail only 
  
  
Address: 
 
FDX or UPS only: 
 
Reports for all Bayer products can also be phoned in via our Medical Communications 
Department  
 
Phone: 
 
 
The Site Investigator shall report to ACCRU within 24 hours of the investigator’s awareness 
of other events such as: 
 
• 
An adverse event related to study specific procedures  
• 
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. 
 
Pregnancy: If a pregnancy occurs, follow the patient throughout the pregnancy until the outcome of 
the pregnancy is available. Subsequent follow-up will depend on the outcome of the pregnancy. If 
there is an abnormal outcome or pregnancy complications, additional follow-up may be requested 
to obtain further information. 
 
Any communication concerning safety related information to regulatory authorities or ethics 
committees including but not limited to: 
 
• 
Development Safety Update Reports (DSUR) / relevant parts of IND reports for the STUDY; 
• 
Any other safety related reports, issues and queries that are either raised by or communicated to 
regulatory authorities or ethics committees; 
 
 

RU021407I 
     30  
 
Addendum 6 
 
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Gastrointestinal 
disorders 
Diarrhea 
# stools per 
day 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
General 
Disorders 
Fatigue 
X 
X 
Palmar-plantar 
erythrodysesthesia syndrome 
X 
X 
Skin and 
Subcutaneous 
Tissue Disorders 
Rash maculo-papular 
X 
X 
Vascular 
disorders 
Hypertension 
X 
X 
 
 
10.52 Submit via appropriate Academic and Community Cancer Research United (ACCRU) 
Case Report Forms (i.e., paper or electronic, as applicable) the following AEs experienced 
by a patient and not specified in Section 10.5: 
 
10.521 
Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 
Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.523 
Grade 5 AEs (Deaths) 
 
10.5231 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly treatment 
related must also be submitted as a Grade 5 AE, with a CTCAE 
type and attribution assigned. 
 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the table 
regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
 
Response and progression will be evaluated in this study using the new international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) (Eisenhauer et 
al., 2009). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
short axis measurements in the case of lymph nodes are used in the RECIST guideline. 
 

RU021407I 
     31  
 
Addendum 6 
 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated every 8 
weeks. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21 Measurable Disease 
 
11.211 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI. 
 
11.212 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging. In the case of 
skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
 
11.213 
A malignant lymph node is considered measurable if its short axis is >1.5 cm 
when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  
 
11.22 Non-Measurable Disease 
 
11.221 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis <1.0 
cm are considered non pathological (i.e., normal) and should not be recorded or 
followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:  
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients having 
only lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both 
pre- and post-treatment tumor assessments.  
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a 
treatment.  
 
11.32 Acceptable Modalities for Measurable Disease: 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  

RU021407I 
     32  
 
Addendum 6 
 
 
• 
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
The lesions should be measured on the same pulse sequence. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
• 
Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
 
11.33 Measurement at Follow-up Evaluation: 
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 8 weeks (see Section 
11.44). 
• 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as defined 
in 11.21), where no more than 2 lesions are from the same organ and no more than 2 
malignant nodal lesions are selected. 
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions. 
 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected. 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target lesions 
plus the sum of the short axis of all the target lymph nodes will be calculated and 
reported as the baseline sum of dimensions (BSD). The BSD will be used as reference 
to further characterize any objective tumor response in the measurable dimension of the 
disease. 
 
 

RU021407I 
     33  
 
Addendum 6 
 
 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned. If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions or non-
target lymph nodes and should also be recorded at baseline. These lesions and lymph nodes 
should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest 
X-ray/physical examination must be measured on re-evaluation at evaluation 
times specified in Section 11.1. Specifically, a change in objective status to 
either a PR or CR cannot be done without re-measuring target lesions and target 
lymph nodes. 
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at 
each assessment, especially in the case of first response or confirmation of 
response. In selected circumstances, certain non-target organs may be evaluated 
less frequently. For example, bone scans may need to be repeated only when 
complete response is identified in target disease or when progression in bone is 
suspected. 
 
11.432 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to <1.0 cm. 
 
• 
Partial Response (PR): 
At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference the BSD (see 
Section 11.41). 
 
• 
Progression (PD): At least one of the following must be true: 
 
a. At least one new malignant lesion, which also includes any lymph node 
that was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 
cm short axis during follow-up. 
 
 

RU021407I 
     34  
 
Addendum 6 
 
 
b. At least a 20% increase in PBSD (sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes 
at current evaluation) taking as reference the MSD (Section 11.41). In 
addition, the PBSD must also demonstrate an absolute increase of at least 
0.5 cm from the MSD. 
 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
 
11.433 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions. 
b. Each non-target lymph node must have a reduction in short axis to <1.0 
cm. 
 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-target 
lymph nodes. 
 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node 
that was normal at baseline (< 1.0 cm short axis) and increased to ≥1.0 
cm short axis during follow-up. 
b. Unequivocal progression of existing non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal progression should not normally 
trump target lesion and target lymph node status. It must be representative 
of overall disease status change.) 
 
11.44 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, and 
new disease as defined in the following tables: 
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 

RU021407I 
     35  
 
Addendum 6 
 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New 
Sites of Disease 
Overall Objective 
Status 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection 
and analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
For Patients with Non-Measurable Disease Only: 
 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New 
Sites of Disease 
Overall 
Objective Status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD  
Not All Evaluated* 
No 
Not Evaluated (NE) 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*See Section 11.431 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic 
deterioration. A patient is classified as having PD due to “symptomatic deterioration” if 
any of the following occur that are not either related to study treatment or other medical 
conditions: 
 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
 
12.1 
BRAF analysis done: Yes vs. no. 
 
12.11 If yes, wild-type vs. mutated. 
 
12.2 
KRAS analysis done: Yes vs. no. 
 
12.21 If yes, wild-type vs. mutated. 
 
12.3 
ECOG Performance Status: 0 vs. 1. 
 
12.4 
Age:  <70 vs.  ≥70. 
 
 
 

RU021407I 
     36  
 
Addendum 6 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of registration, 
the patient did not satisfy each and every eligibility criteria for study entry. The patient may 
continue treatment off-protocol at the discretion of the physician as long as there are no safety 
concerns, and the patient was properly registered. The patient will go directly to the event-
monitoring phase of the study (or off study, if applicable). 
 
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility must 
be submitted. Event monitoring will be required per Section 18.0 of the protocol. 
• 
If the patient never received treatment, on-study material must be submitted. Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.2 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are so severely violated that evaluability for the primary endpoint is 
questionable. All data up until the point of confirmation of a major violation must be submitted. 
The patient will go directly to the event-monitoring phase of the study. The patient may continue 
treatment off-protocol at the discretion of the physician as long as there are no safety concerns, and 
the patient was properly registered. Event monitoring will be required per Section 18.0 of the 
protocol. 
 
13.3 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given. On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted. No further data submission is necessary. 
 
13.4 
Patients will continue treatment until progression, unacceptable adverse events, or patient refusal. 
Treatment will then be discontinued and the patient will go to event monitoring and be followed 
per Section 18.0. 
 
13.5 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.6 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.7 
Patients who go off protocol treatment for reasons other than PD will go to the event-monitoring 
phase per Section 18.0. 
 
 
14.0 
Body Fluid Biospecimens  
 
14.1 
Body Fluid Biospecimen Submission  
 
14.11 Summary Table of Body Fluid Specimens for This Protocol  
 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products (EDTA 
whole blood) 
Mandatory 
Multiple draws (see 
Section 14.21for 
schedule) 
Defined translational 
studies (Section 14.211) 
Section 14.2 
Blood/blood 
products (EDTA 
whole blood) 
Mandatory 
Baseline Prior to 
Treatment and 
Multiple Draws 
Banking (Section 14.212) 
Section 14.2 

RU021407I 
     37  
 
Addendum 6 
 
 
 
14.12 Kits are required for this study. 
 
14.121 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
14.122 
Participating institutions may obtain kits by completing and faxing the Supply 
Order Form (found in the Forms Packet) to the number listed on the form. Fill 
out the site address to where the kits will be shipped on the Fax Supply form. 
Because we are now being charged for all outgoing kits, a small, but sufficient, 
supply of the specimen collection kits should be ordered prior to patient entry. 
Do not send the unused kits back to Biospecimen Accessioning and 
Processing (BAP) Receiving or the BAP Shared Resource. 
 
14.123 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions. Allow at least two weeks to receive the kits.  
 
14.124 
Kits will not be sent via rush delivery service unless the participating institution 
provides their own FedEx® account number or alternate billing number for 
express service. ACCRU will not cover the cost for rush delivery of kits. 
 
14.13 All samples must be collected Monday –Friday.  
 
14.14 Label specimen tube(s) with protocol number, ACCRU patient ID number, and time and 
date blood is drawn and sample type. 
 
14.15 Collect and process all blood/blood products according to the directions below and the kit 
instructions for the table below. 
 
14.151 
Baseline and Cycle 2 EDTA Tube: Centrifuge the EDTA tubes in a refrigerated 
centrifuge within 2 hours or less after collection all time points. Centrifuge 
sample 3000 rpm x 10 minutes. Carefully pipette 1.0 mL of plasma into each of 
the 3 cryovials. Next pipette the white blood cells being careful to not disturb the 
underlying cell layer into the 4th cryovial. Carefully tighten the caps. Discard the 
EDTA collection tube. 
 
14.152 
Serial Draws: Centrifuge the EDTA tubes in a refrigerated centrifuge within 2 
hours or less after collection all time points. Centrifuge sample 3000 rpm x 10 
minutes. Carefully pipette 1.0 mL of plasma into each of the 3 cryovials. 
Carefully tighten the caps. Discard the EDTA collection tube. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

RU021407I 
     38  
 
Addendum 6 
 
 
14.153 
Freeze all cryovials at -70°C or colder until shipped. 
 
Indicate if 
specimen is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number 
of tubes to 
be 
collected) 
Blood 
product being 
processed and 
submitted by 
participating 
site 
Baseline, 
Prior to 
Tx 
Cycle 1, Day 7 
Prior to Tx, 
Cycle 1 Day 14 
Prior to Tx, 
Cycle 1 Day 21 
prior to Tx 
Cycle 2 Day 1 
Prior to Tx and 
Cycle 2 Day 21 
Prior to Tx 
Additional 
processing 
required at 
site after 
blood draw? 
Storage 
/shipping 
conditions 
Mandatory 
EDTA 
10 ml (1) 
Plasma 
(PK) 
 
X 
X 
Yes 
Freeze/dry 
ice 
Mandatory 
EDTA 
10 ml (1) 
Plasma, 
White Blood 
Cells 
(banking) 
X 
 
X 
Yes 
Freeze/dry 
ice 
 
14.16 Shipping 
 
14.161 
Verify ALL sections of the Blood Specimen Submission Form (see Forms 
Packet), BAP Requisition Form (provided in kit), and specimen collection labels 
are completed and filled in correctly. Enter information from the Blood 
Specimen Submission Form. 
 
14.162 
Ship all plasma and white blood cells via Priority Overnight service on dry ice. 
 
14.163 
Ship specimens via Priority Overnight service, Monday – Friday, to BAP 
Freezer according to kit instructions. Do not send samples on weekends or just 
prior to federal holidays.  
 
14.164 
The BAP kits will include a smart shipper label (3x5 white barcoded label) 
affixed to the shipping boxes. The smart shipper label is a pre-addressed return 
label, which replaces the need for an airbill. Shipping costs will be covered by 
ACCRU if the shipping box provided with the BAP kit is used for shipping 
specimens to BAP Freezer. 
 
14.165 
BAP Freezer will receive the samples and immediately forward specimens to the 
ACCRU Research Base BAP Shared Resource, Stabile SL-16, Attention: BAP 
Supervisor. 
 
14.2 
Study Methodology and Storage Information 
 
14.21 Blood/blood product samples will be collected for pharmacokinetic analysis. 
 
PK analysis for regorafenib and M2 and M5 will be performed as follows: 
 
- Cycle 1 day 7: 0, prior to dosing (Cmin, trough levels) 
- Cycle 1 day 14: 0, prior to dosing (Cmin, trough levels) 
- Cycle 1 day 21: 0, prior to dosing (Cmin, trough levels) 
- Cycle 2 day 1: 0, prior to dosing (Cmin, trough levels) 
- Cycle 2 day 21; 0, prior to dosing (Cmin, trough levels)  
- Window sampling times are predose ≤12 hours. 
 
14.211 
A portion of the plasma, 0.5 ml (500 mcl), for each sample will initially be 
analyzed for the amount of regorafenib in Dr. Jeannine McCune’s laboratory 
using standard laboratory protocols. The samples will be shipped upon request to 

RU021407I 
     39  
 
Addendum 6 
 
 
 
 
 
 
 
According to patient consent information, remaining white blood cells/plasma 
will be stored frozen at -70/-80ºC by BAP until specific analyses are identified. 
As protocols are developed, they will be presented for ACCRU and IRB review 
and approval. (This collection is part of a general strategy of investigation for the 
majority of ACCRU studies.) 
 
14.212 
Ongoing research is likely to identify putative biomarkers for regorafenib 
efficacy and/or toxicity in the near future. Given the key importance of such 
biomarker identification, our study offers a unique opportunity to validate such 
discoveries given its size and prospective nature. As such, and as part of ongoing 
ACCRU research, we will collect plasma and white blood cells for future 
research studies, according to patient consent information, on molecular 
determinants of efficacy and tolerability. Samples will be stored frozen at -70ºC 
by BAP until specific analyses are identified. As protocols are developed, they 
will be presented for ACCRU (scientific) and IRB review and approval prior to 
any samples being used.  
 
14.3 
Return of Genetic Testing Research Results 
 
For this study, DNA (White Blood Cells) is only being banked, and no specific genetic testing is 
being performed. If, at any time, genetic results are obtained that may have clinical relevance, IRB 
review and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required. Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies and testing 
has been done in CLIA-approved laboratories. 
 
 
 
 

RU021407I 
     40  
 
Addendum 6 
 
 
15.0 
Drug Information 
 
IND exempt 
• 
Investigator brochure - Available on the ACCRU website. 
 
15.1 
Regorafenib (BAY 73-4506, Stivarga®)  
 
15.11 Background: Regorafenib is a novel oral multi-kinase inhibitor that targets tumor cells 
and the tumor microenvironment. It inhibits tumor growth, progression and metastasis by 
inhibiting the proliferation of tumor cells, the formation of new tumor vasculature and 
stromal signaling in the microenvironment of the tumor. 
 
15.12 Formulation: Regorafenib 40-mg tablets contains regorafenib and the inactive excipients 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone, colloidal 
anhydrous silica, polyvinyl alcohol-part hydrolyzed, talk, titanium dioxide E171 (color 
index 77891), Macrogol/PEG 33350, lecithin (soy), iron oxide yellow – E172 (color index 
77491), iron oxide red – E172. 
 
Regorafenib will be provided by Bayer as coated, not divisible, gray-orange-red, oval 
tablets (length 16 mm, width 7 mm, thickness 4.9-5.6 mm). Tablets are in an immediate-
release dosage form with rapid dissolution characteristics under the in vitro test conditions. 
 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white 
child resistant closure and induction seal. Each bottle includes 28 tablets and a 3-gram 
desiccant. The bottles will have a label affixed containing study identification, product 
identification, and quantity of tablets. 
 
15.13 Preparation and storage: Once the drug has been received it must be kept in a 
secure, dry location. Study drug must be stored in its original bottle at a temperature 
not above 25°C (77°F). The study drug must be exclusively used for the 
investigation specified in this protocol and it will only be accessible to authorized 
staff. 
 
15.14 Administration: Regorafenib tablets should be taken at the same time every day with 
approximately 8 fluid ounces (240 mL) of water after a low-fat (<30% fat) meal. 
Regorafenib should not be taken with grapefruit juice. 
 
15.15 Pharmacokinetic information: 
a) Absorption – A high-fat meal increased the mean AUC of the parent drug by 
48% compared to the fasted state and decreased the mean AUC of the M-2 (N-
oxide) and M-5 (N-oxide and N-desmethyl) active metabolites by 20% and 51%, 
respectively. A low-fat meal increased the mean AUC of regorafenib, M-2 and 
M-5 by 36%, 40% and 23%, respectively (as compared to the fasted state). 
b) Distribution – Regorafenib undergoes enterohepatic circulation with multiple 
plasma concentration peaks observed across the 24-hour dosing interval. 
Regorafenib is highly bound (99.5%) to human plasma proteins. 
c) Metabolism – Regorafenib is metabolized by CYP3A4 and UGT1A9. The main 
circulating metabolites measured at steady state are M-2 (N-oxide) and M-5 (N-
oxide and N-desmethyl), both of them having similar in vitro pharmacological 
activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly 
protein bound (99.8% and 99.95%, respectively). 
 
 

RU021407I 
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Addendum 6 
 
 
d) Excretion – Elimination half-lives for regorafenib and the M-2 metabolite in 
plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. 
M-5 has a longer mean (range) elimination half-life of 51 hours (32 to 70 hours). 
Elimination occurs through: Feces (71%; 47% as parent compound; 24% as 
parent compound; 24% as metabolites); Urine (19%). 
 
15.16 Potential Drug Interactions: Avoid concomitant use of strong CYP3A4 inducers 
(i.e. rifampin, phenytoin, carbamazepine, phenobarbital and St. John’s Wort) and 
strong CYP3A4 inhibitors (i.e. clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, posaconazole, telithromycin and voriconazole). 
 
15.17 Known potential toxicities:  
Serious Adverse Effects: 
Hepatotoxicity: [U.S. Boxed Warning]: Severe liver toxicity and hepatic failure 
(sometimes resulting in death) have been observed in clinical trials; hepatocyte 
necrosis with lymphocyte infiltration has been demonstrated with liver biopsy. 
Monitor hepatic function at baseline and during treatment. Interrupt therapy for 
hepatotoxicity; dose reductions or discontinuation are necessary depending on the 
severity and persistence. 
 
Most Common Adverse Events, >10% 
Cardiovascular: Hypertension 
Central nervous system: Fatigue, dysphonia, pain, fever, headache. 
Dermatologic: Palmar-plantar erythrodysesthesia, rash, alopecia 
Endocrine & metabolic: Hypocalcemia, hypophosphatemia, hyponatremia, 
hypokalemia, hypothyroidism 
Gastrointestinal: Appetite decreased, lipase increased, diarrhea, mucositis, weight 
loss, amylase increased, nausea, vomiting 
Hematologic: Anemia, lymphopenia, thrombocytopenia, INR increased, 
hemorrhage, neutropenia 
Hepatic: AST increased, ALT increased, hyperbilirubinemia 
Neuromuscular & skeletal: Stiffness 
Renal: Proteinuria 
Miscellaneous: Infection 
 
Less Common Adverse Events, 1% - 10% 
Cardiovascular: Myocardial ischemia and infarction 
Gastrointestinal: Taste disturbance, xerostomia, gastroesophageal reflux 
Neuromuscular & skeletal: Tremor 
Respiratory: Dyspnea 
 
Rare Adverse Events (Important or life-threatening), <1% 
Bradycardia, erythema multiforme, gastrointestinal fistula, hypertensive crisis, liver 
injury (severe), liver failure, reversible posterior encephalopathy syndrome (RPLS), 
skin cancer (keratoacanthoma, squamous cell carcinoma), Stevens-Johnson 
syndrome, toxic epidermal necrolysis 
 
 
 

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Addendum 6 
 
 
15.18 Study agent procurement:  
Bayer HealthCare Pharmaceuticals will supply regorafenib tablets to Biologics, Inc. Each 
participating ACCRU treating location will order the drug from Biologics, Inc. Fax the 
Drug Order Request Form (found in the forms packet) to: 
 
  
 
 
Each participating ACCRU treating location will be responsible for monitoring the supply 
of regorafenib and will use the Drug Order Request Form to order additional supplies as 
needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place at each 
institution.  
 
15.19 Nursing Guidelines 
 
15.191 
Liver toxicity and liver failure have resulted from this agent. Monitor LFT’s 
closely and instruct patients to report any abdominal pain, jaundice or significant 
fatigue to the study team. Dose reduce or interrupt treatment as per protocol. 
 
15.192 
Hypertension has been seen. Monitor blood pressure as outlined in protocol. 
 
15.193 
Instruct patient to report and rash, or signs symptoms of palmar-plantar 
erythrodysesthesia to study team. Rarely SJS and TENS have been seen with this 
agent. Instruct patients to seek immediate medical attention if they experience 
rash with fever, blisters, sloughing of tissue (especially in the mouth and vaginal, 
anal regions). Treat symptomatically and monitor for effectiveness. 
 
15.194 
Warn patients of possibility of alopecia. 
 
15.195 
Gastrointestinal side effects can include, diarrhea, nausea, vomiting, decreased 
appetite, weight loss, mucositis and less commonly taste changes, dry mouth, 
and reflux. Treat symptomatically and monitor for effectiveness.  
 
15.196 
Cytopenias are seen with agent. Monitor CBC w/diff and instruct patient to 
report signs, symptoms of infection or any unusual bruising or bleeding to the 
study team.  
 
15.197 
Secondary skin cancers have been reported. Instruct patients to report new or 
changing lesions to study team. 
 
15.198 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a rare (<1%) 
but serious condition. Presenting symptoms may include changes in mental 
status, visual disturbance, seizure, or other CNS changes. Patients with this 
syndrome generally had HTN as well, therefore BP monitoring is important. 
Instruct patient to report any mental status changes, visual changes, seizures, or 
other CNS changes to the MD immediately. These may be a sign of RPLS or 
more serious condition, such as hemorrhagic event in the CNS. 
 
 
 

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Addendum 6 
 
 
15.2 
Clobetasol Propionate Cream (Temovate®) 
 
15.21 Background: Clobetasol propionate cream has anti-inflammatory, antipruritic and 
vasoconstrictive properties. Topical corticosteroids may depress the formation, release, and 
activity of endogenous chemical mediators of inflammation (kinins, histamine, liposomal 
enzymes, prostaglandins) through the induction of phospholipase A2 inhibitor proteins 
(lipocortins) and sequential inhibition of the release of arachidonic acid. Clobetasol has 
very high range potency. 
 
15.22 Formulation: Clobetasol propionate 0.05% cream contains clobetasol propionate 0.5 mg/g 
in a cream base of propylene glycol, glyceryl monostearate, cetostearyl alcohol, glyceryl 
stearate, PEG 100 stearate, white wax, chlorocresol, sodium citrate, citric acid 
monohydrate, and purified water.  
 
15.23 Preparation and storage: Once the drug has been received it must be kept in a secure, dry 
location. Clobetasol propionate must be stored in its original packaging at a temperature 
between 15°C and 30°C (59°F and 77°F). Cream should not be refrigerated. 
 
15.24 Administration: Apply a thin layer of clobetasol propionate cream to the palms of the 
hands and soles of the feet. Avoid washing hands and feet for one hour after application of 
clobetasol propionate cream. The use of clobetasol propionate is for external use only. 
Avoid contact with the eyes and mucous membranes. Do not apply to face or intertriginous 
areas. Do not use if there is atrophy at the treatment site. Minimize contact to nonaffected 
areas of the body. The treated skin should not be bandaged, otherwise covered, or wrapped 
so as to be occlusive unless directed by the physician.  
 
15.25 Pharmacokinetic information: 
Absorption: Percutaneous absorption is variable and dependent upon many factors 
including vehicle used, integrity of epidermis, dose, and use of occlusive dressings (not 
recommended)  
 
Metabolism: Hepatic  
 
Excretion: Urine and feces 
 
15.26 Potential Drug Interactions: Due to the topical use of clobetasol propionate, drug-drug 
interactions are thought to be minimal. 
 
15.27 Known potential toxicities:  
Precautions: 
Systemic absorption of topical corticosteroids can produce reversible HPA axis 
suppression with the potential for glucocorticosteroid insufficiency after withdrawal from 
treatment. Manifestations of Cushing syndrome, hyperglycemia, and glucosuria can also be 
produced in some patients by systemic absorption of topical corticosteroids while on 
therapy. Patients applying a topical steroid to a large surface area or to areas under 
occlusion should be evaluated periodically for evidence of HPA axis suppression. This 
may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free 
cortisol tests. Patients receiving super-potent corticosteroids should not be treated for more 
than 2 weeks at a time, and only small areas should be treated at any one time due to the 
increased risk of HPA suppression. 
 
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to 
reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery 
of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. 

RU021407I 
     44  
 
Addendum 6 
 
 
Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur that 
require supplemental systemic corticosteroids. For information on systemic 
supplementation, see prescribing information for those products. If irritation develops, 
clobetasol propionate cream should be discontinued and appropriate therapy instituted. 
Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure 
to heal rather than noting a clinical exacerbation as with most topical products not 
containing corticosteroids. Such an observation should be corroborated with appropriate 
diagnostic patch testing. If concomitant skin infections are present or develop, an 
appropriate antifungal or antibacterial agent should be used. If a favorable response does 
not occur promptly, use of clobetasol propionate cream should be discontinued until the 
infection has been adequately controlled. 
 
Adverse reactions, significant 
Frequency not always defined; may depend upon formulation used, length of application, 
surface area covered, and the use of occlusive dressings. 
 
Central nervous system: Localized burning (5% to 40%), stinging sensation (<2% to 5%), 
numbness of fingers (<2%), local pain (1%), intracranial hypertension (systemic effect 
reported in children treated with topical corticosteroids) 
Dermatologic: Pruritus (<2% to 3%), eczema asteatotic (2%), erythema (<2%), folliculitis 
(<2%), skin atrophy (<2%), telangiectasia (<2%), xeroderma (<1% to 2%), atrophic 
striae (children) 
Endocrine & metabolic: Adrenal suppression, Cushing's syndrome, glucosuria, growth 
suppression, HPA-axis suppression, hyperglycemia 
Local: Skin fissure (<2%), local irritation (1%) 
Respiratory: Upper respiratory tract infection (8%), nasopharyngitis (5%), streptococcal 
pharyngitis (1%) 
<1% (Limited to important or life-threatening): Alopecia, exfoliation of skin, skin rash, 
urticaria 
 
15.28 Study agent procurement:  
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
 
15.29 Nursing Guidelines 
 
15.291 
As therapy is a topical preparation, side effects are expected to be minimal. 
 
15.292 
Instruct patients to apply a thin layer to palms of hands and soles of feet.Patients 
should be instructed not to wash these areas for a minimum of 1 hour after 
application. 
 
15.293 
Instruct patients to avoid contact with the eyes and mucous membranes. 
 
15.294 
Patients may experience a local burning/stinging sensation depending on the 
strength. 
 
15.295 
Rarely after prolonged use and discontinuation, patients may display 
symptomatic signs of glucocorticoid insufficiency. Instruct patients to report any 
excessive fatigue, facial puffiness (moon face) to the study team. 
 
15.296 
Rarely after prolonged use, patients may experience elevated glucose levels, 
instruct diabetics to monitor sugar levels and report any fluctuations to the study 
team. 

RU021407I 
     45  
 
Addendum 6 
 
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Study Design  
 
This is a randomized phase II study of regorafenib starting at low dose (Arm A, combining A1 and 
A2) compared to standard dose of regorafenib (Arm B, combining B1 and B2) in patients with 
refractory metastatic colorectal cancer (mCRC). Patients will be randomized 1:1:1:1 to one of the 
following 4 arms: 
A1: Regorafenib start low dose and pre-emptive Clobetasol for PPES 
A2: Regorafenib start low dose and reactive Clobetasol for PPES  
B1: Standard dose of regorafenib and pre-emptive Clobetasol for PPES 
B2: Standard dose of regorafenib and reactive Clobetasol for PPES  
(see Schema)  
 
16.2 
Sample Size, Accrual Time and Study Duration  
 
Accrual time is anticipated to be 18 months, with approximately 2 months of follow-up per patient 
until occurrence of the primary endpoint and approximately 6 months of planned follow-up overall 
per patient. The sample size will be 110 patients, with approximately 28 patients randomized per 
regorafenib and strategy treatment sub-arm (A1, A2, B1, B2). An additional 13 patients overall will 
be enrolled to account for drop-out, cancels, ineligibles, etc., to give a total sample size of 123 
patients. The total study duration (accrual and follow-up) is expected to be approximately 2 years. 
 
16.3 
Statement for Primary Endpoint  
 
The primary endpoint is the proportion of patients in each arm who complete 2 cycles of protocol 
treatment and initiate cycle 3.  The proportion will be calculated among evaluable patients 
separately by arm (Arm A vs. Arm B).  Evaluable patients are defined as patients who are eligible, 
consented, received any protocol treatment.   In the CORRECT trial, among patients who were 
randomized to regorafenib, 45% continued treatment beyond cycle 2.  Other than disease 
progression, majority of patients discontinued regorafenib due to adverse events not associated 
with progression. It was noted that most adverse events occurred during Cycles 1-2 of the treatment 
(Grothey A et. al., 2013, Lancet). Assuming 45% of patients would complete 2 cycles of protocol 
treatment and initiate cycle 3  in the control (standard dose; pooled arms B1 andB2) group, and 
desiring an improvement to 63% in the experimental (starting low dose) group (pooled arms A1 
and A2), a one-sided test with alpha = 0.20 and power of 80% will require a sample size of 110 
patients enrolled to both regorafenib arms (A and B). We will enroll 13 additional patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons.  Maximum 
projected accrual is therefore 123 patients.  A Fisher exact test will be used to detect a difference in 
proportion of patients who complete 2 cycles of protocol treatment and initiate cycle 3 between 
arms (starting low dose [pooled arm A1 and A2] vs. standard dose [poled arm B1 and B2]).  The 
proportion of patients who complete 2 cycles of protocol treatment and initiate cycle 3 will be 
computed by arm with its 95% confidence interval using exact method. 
 
 
 

RU021407I 
     46  
 
Addendum 6 
 
 
16.4 
Supplementary Analysis Plans (includes all secondary and translational goals) 
 
16.41 Overall survival (OS) is defined as time from randomization to death due to any cause. OS 
will be estimated with Kaplan-Meier survival curves and differences between regorafenib 
arms (A vs. B) tested using log-rank tests, though we note these analyses are not powered 
for formal non-inferiority assessments. See Section 2.21. 
 
16.42 Progression-free survival (PFS) is defined as the time from randomization to the earlier of 
disease progression or death due to any cause, where progressed disease (PD) is as defined 
by RECIST 1.1 (see Section 11.0). PFS will be estimated with Kaplan-Meier survival 
curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, 
though we note these analyses are not powered for formal non-inferiority assessments. See 
Section 2.21. 
 
16.43 Time to progression (TTP) is defined as the time from randomization to disease 
progression, where progressed disease (PD) is defined by RECIST 1.1 (see Section 11.0. 
TTP will be estimated with Kaplan-Meier survival curves and differences between 
regorafenib arms (A vs. B) tested using log-rank tests, though we note these analyses are 
not powered for formal non-inferiority assessments. See Section 2.21. 
 
16.44 The cumulative (total) dose of regorafenib received by patients and dose intensity in the 
first two cycles will be summarized with descriptive statistics and compared between 
regorafenib arms (A vs. B) using the t-test (if approximately normally distributed) or the 
Wilcoxon rank sum test (if not approximately normally distributed). Dose intensity is 
defined as the cumulative (total) dose of regorafenib divided by the expected total dose.  
See Section 2.22. 
 
16.45 The proportion of patients overall and within each arm experiencing grade 3 or 4 HFS or 
fatigue will be computed with 95% confidence intervals, and differences between 
regorafenib dosing strategies (pooled across HFS strategies) tested using a Fisher Exact 
test. The incidence of grade 3 or 4 HFS will also be descriptively compared between those 
receiving a pre-specified preemptive vs. reactive approach for hand and foot syndrome 
(pooled across dosing strategies), and tested using a Fisher Exact test. See Section 2.24. 
Adverse event reports will be shared with Dr. Lacouture of Memorial Sloan Kettering 
Cancer Center 1-2 times per month for review. 
 
16.46 Furthermore, patients will be descriptively compared between treatment arms and between 
HFS treatment strategies (pre-emptive vs. reactive) according to self-reported outcomes 
given on the HFS14 questionnaire. See Section 2.24. Results from the cycle 1 and 2 HSF14 
questionnaires will also be summarized descriptively as they relate to the pre-emptive 
versus reactive PPES strategies, with comparisons made within and between arms using 
the t-test or Wilcoxon rank sum test as appropriate, as well as taking time-dependence into 
account. Changes in QOL (according to the LASA questionnaire as measured by the 
overall QOL question) from baseline will also be compared between the treatment arms 
using the t-test or Wilcoxon rank sum test. We hypothesize that patients receiving 
regorafenib will experience greater deficits in QOL as reflected by scores on the HSF14, 
the BFI and the LASA. These questionnaires have specific application to this population. 
See Section 2.24. 
 
16.47 Pharmacokinetic Analysis 
 
The samples will be analyzed for the regorafenib concentrations using liquid 
chromatography mass spectrometry, with the anticipated method being a modified version 

RU021407I 
     47  
 
Addendum 6 
 
 
of that published by Van Erp et al. The samples will be analyzed for M2 and M5, if cost-
free standards can be obtained from Bayer.  
 
After quantitation, the average regorafenib concentration will be calculated by arms (Arm 
A vs. B) at each time point.  
 
As exploratory analysis, this average concentration will be correlated with toxicity and 
efficacy endpoints. Further descriptive characteristics of the pharmacokinetics will also be 
calculated, An example includes (but is not limited to) within-patient variability in the 
trough concentrations pharmacokinetic parameters will also be calculated, both overall and 
within cycles, as a ratio of the maximum:minimum value.  
 
16.5 
Adverse Event Stopping Rule  
 
Because this study randomizes patients to either a standard of care treatment or a lower dose of the 
same treatment, stopping rules for toxicity will not apply. However, as noted below in Section 
16.7, regular meetings of the DSMB will review all toxicity and adverse event data while patients 
are being treated. 
 
16.6 
Accrual Monitoring Stopping Rule  
 
There is no stopping rule related to accrual. 
 
16.7 
Study Monitoring  
 
This study will be monitored by the Mayo Clinic Data Safety Monitoring Board (DSMB). Reports 
containing patient characteristics, toxicity and administrative information will be provided to the 
DSMB every six months, with the first report due at the first reporting period after study initiation.  
 
16.8 
Missing Data  
 
Patients with missing data will be excluded from relevant analyses; no imputation of missing data 
will be performed.  
 
16.9 
Primary Endpoint Completion Time Estimation  
 
Given 18 months of accrual and 2 months of follow-up per patient to observe the primary endpoint, 
a total of 20 months will be required to observe all primary endpoint events, with subsequent time 
required for data cleaning and analysis (approximately 2 months). 
 
 
17.0 
Pathology Considerations/Tissue Biospecimens: 
None 
 
 
 
 

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     48  
 
Addendum 6 
 
 
18.0 
Records and Data Collection Procedures 
 
Access the RAVE system through the iMedidata portal at https://login.imedidata.com. All data must be 
entered by Remote Date Entry (RDE) and completed by qualified and authorized personnel. All data on the 
CRF must reflect the corresponding source document.  
 
18.1 
Submission Timetable 
 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
≤2 weeks after registration 
On-Study  
On-Study: Prior Radiation2 
On-Study: Prior Systemic Therapy2 
Adverse Events: Baseline 
RECIST Measurements: Baseline 
Measurements (Non-Measurable Disease 
Only): Baseline 
Op and Pathology Reports1 
Supporting Documentation: Baseline 
Patient Status: Baseline 
Specimen Submission: Blood -Baseline (see 
Section 14.0) 
Off Treatment 
Submit ≤2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
Patient Questionnaire Booklet: Baseline 
≤ 2 weeks after registration - Patient questionnaire 
booklet must be used; copies are not acceptable for 
this submission. 
Booklet Compliance 
≤ 2 weeks after registration - This form must be 
completed only if the Patient Questionnaire 
Booklet contains absolutely NO patient provided 
assessment information. 
1. Submit Op and Path Reports via the Supporting Documentation: Baseline form. 
2. Submit only if applicable. 
 
 
 

RU021407I 
     49  
 
Addendum 6 
 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Treatment (Intervention) 
X4 
X 
Treatment (Intervention): Dose 
Modifications, Omissions and Delays 
X5 
 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other 
 
 
RECIST Measurements 
X1 
X1 
Measurements (Non-Measurable Disease 
Only) 
X1 
X1 
Supporting Documentation  
X1 
 
Specimen Submission: Blood- Cycle 1 
X (see Section 14.0) 
 
Specimen Submission: Blood – Cycle 2 
X (see Section 14.0) 
 
Patient Questionnaire Booklet: Treatment 
X2 
 
Booklet Compliance 
X3 
 
Patient Status : Treatment (Intervention) 
X 
 
Off Treatment 
 
X 
Notice of New Primary5 
X 
 
Consent Withdrawal (choose appropriate 
form)5 
• 
Consent Withdrawal: QOL Only 
• 
Consent Withdrawal: Specimen Only 
• 
Consent Withdrawal: All Follow-Up 
X 
 
Lost to Follow-Up5 
X 
 
Deviation Form5 
X 
 
1. Attach a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 
2. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
3. This form must be completed only if the Patient Questionnaire Booklet contains absolutely NO 
patient provided assessment information. 
4. Complete at each evaluation during Active Treatment (see Section 4.0). 
5. Submit only if applicable. 
 
 
 

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     50  
 
Addendum 6 
 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
q. 6 
months 
until PD 
At PD 
After 
PD q. 6 
mos. 
Death 
At Each Event 
Occurrence 
Patient Status: Survival and 
Disease Status Follow-Up/Event 
Monitoring 
X2 
X2 
X 
X 
At each 
occurrence 
Adverse Events: Late3 
 
 
 
 
At each 
occurrence 
Lost to Follow-Up3 
 
 
 
 
At each 
occurrence 
Notice of New Primary3 
 
 
 
 
At each 
occurrence 
First Non-Protocol Treatment4 
 
 
 
 
At each 
occurrence 
Consent Withdrawal (choose 
appropriate form)3 
• 
Consent Withdrawal: QOL 
Only 
• 
Consent Withdrawal: 
Specimen Only 
• 
Consent Withdrawal: All 
Follow-Up 
 
 
 
 
At each 
occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
2. Attach a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 
3. Submit only if applicable. 
4. Please use the “Add Event” function to record the first instance of non-protocol treatment 
received.  If the patient has never had any non-protocol treatment, record as “no” at the end of 
the Event Monitoring Phase. 
 
 
19.0 
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and regional 
coverage policies, to determine which items are standard of care and which are research at their 
site. Refer to the payment synopsis for funding provided per accrual for covering study costs, as 
well as any additional invoiceables that may be allowed. 
 
19.2 
Tests to be research funded: Mandatory blood samples for correlative research. 
 
19.3 
Other budget concerns:  
 
19.31 Regorafenib will be supplied by Bayer Pharmaceuticals. Clobetasol propionate will not be 
supplied, but is commercially available. 
 
19.32 Remuneration will be provided to patients for the first 2 cycles of treatment. 
 
 

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Addendum 6 
 
 
20.0 
References 
 
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