Clinical trial NCT02795156
Conditions: Non-small Cell Lung Carcinoma Urothelial Carcinoma Gastrointestinal Carcinoma, Non-colon Upper Aerodigestive Tract Carcinoma
Keywords: regorafenib afatinib targeted therapy cabozantinib
Sponsor: SCRI Development Innovations, LLC
Start date: 2016-09-28; Completion date: 2022-08-17
Enrollment: 100 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
With the increased availability of next-generation sequencing, oncologists are starting to incorporate genomic profiling into routine care of cancer patients. If a genomic alteration is identified during profiling, it could help guide the choice of therapy and improve treatment outcomes. This study will examine the anti-tumor activity of selected commercially available molecularly matched targeted therapies in patients who have failed first-line treatment for one of the following tumor types: non-small cell lung cancers; urothelial cancer; non-colon gastrointestinal cancers, and upper aerodigestive tract cancer.

Detailed description:
This four-arm pilot phase II study will evaluate the preliminary antitumor activity of selected commercially available molecularly matched targeted therapies in patients who have failed first line treatment for one of the following tumor types:

1. non-small cell lung cancer,
2. urothelial carcinoma,
3. non-colon gastrointestinal cancers, and
4. upper aerodigestive tract cancers (lip, tongue, salivary glands, gum, mouth, oral cavity, tonsils, oropharynx, nasopharynx, nasal cavity, sinus, and larynx tumors).

Approximately 160 patients (40 per tumour type) are planned for enrollment. Consideration for enrollment will be based on results from profiling with next-generation sequencing technology that was performed outside of the protocol. Eligible patients will receive one of the FDA-approved targeted agents at the recommended dose. The treating physician will decide which targeted agent to prescribe based on the genomic alterations per tumor type and the targets listed in the package insert for each agent.

Arms: arm 1: Patients with non-small cell lung cancer who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations. arm 2: Patients with urothelial carcinoma who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations. arm 3: Patients with non-colon gastrointestinal cancers who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations. arm 4: Patients with upper aerodigestive tract cancers who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations.
Interventions: intervention 1: Afatinib intervention 2: Regorafenib intervention 3: Cabozantinib
Intervention descriptions: intervention 1: 40 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months. intervention 2: 160 mg orally once daily for the first 21 days of each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months. intervention 3: 60 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
Page 1 of 53 
 
PRO 10 
A Phase II Study to Evaluate the Activity of Commercially Available 
Molecularly Matched Targeted Therapies in Selected Tumor Types Based on 
Genomic Alterations  
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
 
PRO 10 
 
STUDY DRUG(S): 
Regorafenib, Afatinib, Cabozantinib 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
(SCDI) 
1100 Charlotte Ave, Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
STUDY CHAIR: 
Howard A. Burris, III, MD. 
Sarah Cannon Research Institute   
1100 Charlotte Avenue , Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
 
DATE FINAL: 
6 May 2016 
AMENDMENT NUMBER 1 
20 May 2016 
AMENDMENT NUMBER 2 
23 January 2018 
 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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Clinical Study Statement of Compliance 
A Phase II Study to Evaluate the Activity of Commercially Available 
Molecularly Matched Targeted Therapies in Selected Tumor Types Based on 
Genomic Alterations  
 
 
This clinical study shall be conducted in compliance with the protocol, as 
referenced herein, and all applicable local, national, and international 
regulatory requirements to include, but not be limited to: 
• 
International Conference on Harmonisation (ICH) Guidelines on Good 
Clinical Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
Food and Drug Administration (FDA) Code of Federal Regulation 
(CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human 
Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical 
Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA)  
As the Study Chair and/or Principal Investigator, I understand that my 
signature on the protocol constitutes my agreement and understanding of my 
responsibilities to conduct the clinical study in accordance to the protocol and 
applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in 
writing from the Sponsor, shall be defined as a deviation from the protocol, and 
shall be formally documented as such. 


 
 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
Page 3 of 53 
 
Clinical Study Signature Approval Page 
A Phase II Study to Evaluate the Activity of Commercially Available 
Molecularly Matched Targeted Therapies in Selected Tumor Types Based on 
Genomic Alterations  
 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS  
STUDY NUMBER: 
 
PRO 10 
STUDY DRUG(S): 
Regorafenib, Afatinib, Cabozantinib 
DATE FINAL: 
6 May 2016 
AMENDMENT NUMBER 1 
20 May 2016 
AMENDMENT NUMBER 2 
23 January 2018 
 
 
__________________________ 
__________________________         ______________  
Study Chair 
Chief Medical Officer 
Sarah Cannon Research Institute 
Study Chair Signature 
 
Date 
 
 
 
 
__________________________ 
__________________________         ______________  
Sarah Cannon Development 
Innovations , LLC 
 
Sarah Cannon Development Innovations 
, LLC 
Representative Signature 
 
Date 
 
 
 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
Page 4 of 53 
 
 
Clinical Study Principal Investigator Signature Form 
A Phase II Study to Evaluate the Activity of Commercially Available 
Molecularly Matched Targeted Therapies in Selected Tumor Types Based on 
Genomic Alterations  
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
 
PRO 10 
DATE FINAL: 
6 May 2016 
AMENDMENT NUMBER 1 
20 May 2016 
AMENDMENT NUMBER 2 
23 January 2018 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
__________________________ _            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Charlotte Avenue, Suite 800 
Atten:  PRO 10 Study Team  
Nashville, TN 37203
 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
Page 5 of 53 
 
PRO 10 Protocol Summary of Changes 
AMENDMENT NUMBER 2 
AMENDMENT DATE 23 January 2018 
Global changes  
Cabozantinib has been added as a possible IP 
Minor editorial and formatting changes are not detailed in this Summary of Changes 
 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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PRO 10 PROTOCOL SYNOPSIS 
Title of Study: 
A phase II study to evaluate the activity of commercially available molecularly matched 
targeted therapies in selected tumor types based on genomic alterations  
Sarah Cannon 
Development 
Innovations Study 
Number: 
PRO 10; ONC-2014-138 (Bayer); PRO10/1200.262 (Boehringer Ingelheim)/Pro 10 Exelixis 
Sponsor: 
Sarah Cannon Development Innovations, LLC – Nashville – TN 
Study Duration: 
Enrollment will occur over approximately 18 months.  The 
total duration of the study is planned to be approximately 
27 months. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at approximately 20 sites. 
Number of 
Patients: 
Up to 160 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is to: 
• 
Determine the overall response rate (Complete Response [CR] + Partial Response 
[PR]) in each patient population receiving targeted therapy based on relevant 
genomic alterations. 
Secondary Objectives 
The secondary objectives of this study are to: 
• 
Evaluate the clinical benefit rate (CR + PR + stable disease [SD] ≥ 6 months) in 
each patient population receiving targeted therapy based on relevant genomic 
alterations. 
• 
Determine the time to treatment failure (measured from the first day of treatment 
until the patient is removed from study for toxicity, disease progression, patient 
choice, or death) in each patient population receiving targeted therapy based on 
relevant genomic alterations. 
• 
To determine the progression free survival (PFS) in each patient population 
receiving targeted therapy based on relevant genomic alterations. 
Study Design: 
This four-arm pilot phase II study will evaluate the preliminary antitumor activity of selected 
commercially available molecularly matched targeted therapies in patients who have failed 
first line treatment for one of the following tumor types:   (1) non-small cell lung cancer, (2) 
urothelial carcinoma, (3) non-colon gastrointestinal cancers, and (4) upper aerodigestive 
tract cancers.  Patients will be profiled with next-generation sequencing technology results 
known prior to consideration for enrollment on this protocol.  Patients with the specified 
tumor types demonstrating one of the genomic alterations described in Table 1 may be 
assessed for protocol eligibility and treatment.  All eligible patients will receive one of the 
FDA-approved targeted agents at the recommended dose outlined in Table 2.  Patients with a 
genomic alteration that is not described in Table 1 but is covered by a targeted agent in 
Table 2 will also be eligible. Dose modifications will be implemented based on criteria 
outlined in the product package insert for each individual agent.  Patients will be 
re-evaluated for treatment response after receiving 8 weeks of oral therapy (with the 
exception of regorafenib which is dosed intermittently for 21 out of every 28 days).  
Response to therapy will be assigned using RECIST v1.1 (see Section E).  Patients who have 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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objective response (OR) or stable disease (SD) will continue treatment with re-evaluations 
every 8 weeks, until the time of tumor progression or intolerable treatment-related side 
effects.  If a patient was not profiled with Foundation One® prior to study enrolment, Sarah 
Cannon Development Innovations shall use reasonable efforts to collect and send to 
Foundation Medicine adequate tumor tissue meeting the tissue specimen requirements for 
Foundation One® for retrospective profiling that will be completed and compared to the 
profiling report provided at study entry. 
A total of 160 patients are planned to be enrolled on the trial (40 patients per study arm).   
Study Drugs, 
Doses, and Modes 
of Administration: 
The study drugs are outlined in Table 2 and will be provided to the sites.  The initial dosing 
regimen for each agent is outlined in Section 8.1.  All drugs are to be administered orally 
according to the dosing guidelines in the product package insert.  Copies of the product 
package inserts are included in Appendices G and H. 
Inclusion Criteria: 
1. Patients with a histologically or cytologically confirmed diagnosis of one of the 
following tumor types whose disease has progressed following one line of standard 
therapy and/or for which no standard treatment is available that has been shown to 
prolong survival: 
a. 
Non-small cell lung cancer 
b. Urothelial carcinoma 
c. 
Non-colon gastrointestinal cancers (including hepatobiliary, pancreatic, 
and gastroesophageal tumors) 
d. upper aerodigestive tract cancers (including lip, tongue, salivary gland, 
gum, oral cavity, mouth, tonsils, oropharynx, nasopharynx, nasal cavity, 
sinus, and larynx tumors) 
2. Patients must have a predefined genomic alteration included in Table 1 that can be 
targeted with one of the FDA-approved targeted agents listed in Table 2.  Patients 
with a genomic alteration that is not described in Table 1 but is covered by a 
targeted agent in Table 2 will also be eligible. 
3. Patients must have measurable disease as measured by Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria version 1.1 (Appendix E). 
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status score of 0 or 1 (Appendix A). 
5. Age greater than or equal to 18 years. 
6. Adequate hematologic function defined as: 
- 
Absolute neutrophil count (ANC) ≥1500/μL 
- 
Platelets ≥75,000/µL 
7. Adequate liver function defined as: 
- 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
the upper limit of normal (ULN) or ≤ 5.0 X ULN if liver metastases present 
- 
Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation 
due to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin) 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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8. Adequate renal function defined as serum creatinine ≤1.5 x the upper limit of 
normal OR measured or calculated creatinine clearance ≥50 mL/min for patients 
with creatinine levels greater than or equal to 1.5 x the upper limit of normal. 
9. Patients who are therapeutically treated with an agent such as warfarin or heparin 
will be allowed to receive either regorafenib or afatinib, provided that their 
medication dose and INR/PTT are stable.  Close monitoring is mandatory if the 
patient is receiving anticoagulants.  If values are above the therapeutic range the 
anticoagulant doses should be modified and assessments should be repeated until 
stable.  (See Exclusion Criteria 15 for anticoagulant therapy information for 
patients receiving cabozantinib).  
10. Male patients with female partners of childbearing potential and women patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 90 days 
following last dose of study drug(s).  Male patients must also refrain from donating 
sperm during their participation in the study and for 90 days after the last dose of 
study drug (Appendix C). 
11. Willingness and ability to comply with study and follow-up procedures. 
12. Ability to understand the nature of this study and give written informed consent.  
Exclusion Criteria: 
1. Two or more prior chemotherapy regimens in the metastatic setting. 
2. Most recent chemotherapy ≤ 3 weeks and > Grade 1 chemotherapy-related side 
effects, with the exception of neuropathy (> grade 2 excluded) and alopecia.   
3. Use of a study drug or targeted therapy ≤21 days or 5 half-lives (whichever is 
shorter) prior to the first dose of study treatment.  For study drugs for which 5 half-
lives is ≤21 days, a minimum of 10 days between termination of the study drug and 
administration of study treatment is required. 
4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to 
starting study drug or has not recovered from side effects of such therapy. 
5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
6. Previously untreated brain metastases.  Patients who have received radiation or 
surgery for brain metastases are eligible if therapy was completed at least 2 weeks 
prior to study entry and there is no evidence of central nervous system disease 
progression, mild neurologic symptoms, and no requirement for chronic 
corticosteroid therapy. Enzyme- inducing anticonvulsants are contraindicated.    
7. Pregnant or lactating 
8. Acute or chronic liver, renal, or pancreas disease. 
9. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral 
therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, 
and malabsorption syndrome).  
10. Any of the following cardiac diseases currently or within the last 6 months: 
• 
Unstable angina pectoris 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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• 
Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2 
[Appendix B]) 
• 
Acute myocardial infarction 
• 
Conduction abnormality not controlled with pacemaker or medication 
• 
Significant ventricular or supraventricular arrhythmias (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities 
are eligible) 
• 
Valvular disease with significant compromise in cardiac function 
11. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 
mmHg or diastolic blood pressure (DBP) >100 mmHg) (patients with values above 
these levels must have their blood pressure (BP) controlled with medication prior to 
starting treatment). 
12. Thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident 
(including transient ischemic attacks) deep vein thrombosis or pulmonary embolism 
within 6 months of start of treatment. 
13. Evidence or history of bleeding diathesis or coagulopathy; any haemorrhage or 
bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of treatment. 
14. For patients receiving cabozantinib only: Do not administer cabozantinib to 
patients that have high risk or at high risk for severe haemorrhage.  Examples 
include:  
a. 
The patient has radiographic evidence of cavitating pulmonary lesion(s).  
b. The patient has tumor invading or encasing any major blood vessels.   
c. 
The patient has had hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood 
within 3 months before the first dose of study treatment. 
d. The patient has experienced clinically significant GI bleeding within 6 
months of the first dose of study treatment. 
e. 
The patient has experienced any other signs indicative of pulmonary 
hemorrhage within 3 months of the first dose of study treatment.  
15. For patients receiving cabozantinib only: Do not administer cabozantinib to 
patients that have high risk or at high risk of perforation or fistula:  
a. 
The patient has evidence of tumor invading the GI tract, active peptic ulcer 
disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, 
acute obstruction of the pancreatic duct or common bile duct, or gastric 
outlet obstruction. 
b. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed 
before first dose. 
c. 
The patient has pre-existing fistula of head and neck area.  
Note: Treatment areas should be healed with no sequelae from prior 
radiation therapy that would predispose to fistula formation.  


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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d. The patient has pre-existing osteonecrosis of the jaw. 
16. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, 
warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors 
(eg, clopidogrel).  [Patients receiving cabozantinib only] 
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-
dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) 
are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in 
subjects without radiographic evidence of brain metastasis, who are on a stable 
dose of LMWH for at least 12 weeks before randomization, and who have had no 
complications from a thromboembolic event or the anticoagulation regimen. 
17. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
18. Patients with phaeochromocytoma. 
19. Serious active infection at the time of treatment, or another serious underlying 
medical condition that would impair the ability of the patient to receive protocol 
treatment. 
20. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 
21. Presence of other active cancers unless indolent and not requiring therapy.  Patients 
with Stage I cancer who have received definitive local treatment and are considered 
unlikely to recur are eligible.  All patients with previously treated in situ carcinoma 
(i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin 
cancer. 
22. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
Correlative 
Testing: 
Patients will be profiled with next-generation sequencing technology outside of this protocol 
and will be enrolled based on the results of this profiling.  If a patient was not profiled with 
Foundation One® prior to study enrolment, Sarah Cannon Development Innovations shall 
use reasonable efforts to collect and send to Foundation Medicine adequate tumor tissue 
meeting the tissue specimen requirements for Foundation One® for retrospective profiling 
that will be completed and compared to the profiling report provided at study entry.   
Statistical 
Methodology 
The design of this trial uses an exact single-stage design for each of the four arms. (A’Hern 
2001)  For this investigation, it has been determined that an ORR (CR + PR) of 10% or 
worse has low activity in line with standard of care.  An ORR of 25% (or better) is 
considered to indicate interesting activity.  Using a one-sided alpha of 5% and power of 
80%, 40 evaluable patients will be required in each arm.  A minimum of 8 responders in a 
particular arm would indicate that the corresponding tumor type would be worthy of further 
investigations.   
 
 


 
 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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ASSESSMENTS 
PRE-
TREATMENT 
 
STUDY TREATMENT  (Cycles repeated every 28 days 
)
FOLLOW-UP 
Cycle 1 
Day 1a 
 
Cycle 1 
Day 15 
Cycles 2+h 
End of Study 
Evaluationi 
Baselinea 
Tests and Observations 
Informed consent 
X 
 
 
 
 
Medical history 
  X 
  X 
 
 
 X 
Physical exam (including vital signs)b 
X 
X 
Xj 
X 
X 
ECOG PS  
X 
X 
 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
Adverse event evaluation 
 
 
X 
X 
X 
Study Drug Compliance Reviewc 
 
 
X 
X 
X 
Laboratory Observations 
CBC, 3-part differential, and plateletsd 
X 
X 
X 
X 
X 
CMP plus magnesiumd 
X 
X 
X 
X 
X 
PT/INR/PTT 
X 
 
 
 
 
Serum or urine pregnancy teste 
X 
X 
 
X 
 
Disease Assessment 
Tumor marker (if applicable) 
X 
 
 
X 
 
CT Scan chest/abdomen/pelvisf 
X 
 
 
X 
 
MRI or CT Scan of Braing 
X 
 
 
 
 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT INNOVATIONS STUDY NUMBER:  PRO 10 
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a 
Baseline procedures including medical history, physical examination, 12-lead ECG, ECOG PS, and laboratory tests should be done ≤7 days prior to 
initiation of treatment.  However, if these initial examinations are obtained within 72 hours of Cycle 1 Day 1 they do not have to be repeated. 
b 
Physical examination will include measurements of height (pretreatment visit only), weight, and vital signs. 
c 
On day 15 of cycle 1 and at the beginning of each subsequent treatment cycle, study drug compliance should be reviewed with the patient and a 
sufficient supply of drug should be dispensed to the patient to take at home.  A final drug compliance assessment should be done at the End of 
Treatment visit (if applicable) and any remaining drug should be retrieved from the patient.   
d 
May be done up to 72 hours prior to day 1 of each treatment cycle. 
e 
Serum or urine pregnancy test required on day 1 of each treatment cycle in women of child-bearing potential only. 
f 
CT scan s of the chest/abdomen/pelvis required at baseline.  Scans will be repeated every 2 cycles.  Only abnormal scans need to be repeated after 
baseline. 
g 
Head CT or MRI scan required at baseline for patients with a history of treated brain metastases only. 
h 
There is a +/- 7 day window on day 1 of all subsequent cycles to accommodate scheduling issues. 
i 
Patients must be followed for AEs for 30 calendar days after the last dose of study drug.  Patients who have not progressed at the time of study 
discontinuation will be followed for disease assessment only every 3 months (± 1 month) until disease progression. 
j. 
On CD15, vital signs only.  No physical exam is required on this visit. 
 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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PRO 10 CONTACT INFORMATION 
Sarah Cannon Development Innovations 
Contact Information: 
Sarah Cannon Development Innovations 
 1100 Charlotte Avenue, Suite 600 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
Study Chair: 
Howard A. Burris, III, MD 
Sarah Cannon Development Innovations  1100 
Charlotte Avenue, Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
Safety Dept. Fax #: 
Safety Dept. Email: 
1-866-807-4325 
CANN.SAE@SCRI-Innovations.com 
Regulatory Phone #   
Regulatory Email: 
1-877-MY-1-SCRI  
SCRIRegulatory@SCRI-Innovations.com 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Adverse reaction 
AST (SGOT) 
Aspartate aminotransferase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMP 
Comprehensive metabolic profile 
CR 
Complete response/remission 
CRF 
Case Report Form 
CT 
Computerized tomography 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OR 
Objective response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PHI 
Protected health information 
PIS 
Patient Information Sheet 
PFS 
Progression-free survival 
PR 
Partial response/remission 
QA 
Quality assurance 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SD 
Stable disease 
UAE 
Unexpected Adverse Event 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 18 
1.1 
Background and Rationale .................................................................................... 18 
1.2 
Targeted Treatment for Known Genomic Alterations .......................................... 21 
1.3 
Rationale for the Study .......................................................................................... 21 
2. 
STUDY OBJECTIVES ......................................................................................... 22 
2.1 
Primary Objective.................................................................................................. 22 
2.2 
Secondary Objectives ............................................................................................ 22 
3. 
STUDY PATIENT POPULATION ...................................................................... 22 
3.1 
Inclusion Criteria ................................................................................................... 22 
3.2 
Exclusion Criteria .................................................................................................. 24 
3.3 
Discontinuation from Study Treatment ................................................................. 26 
4. 
STUDY REGISTRATION.................................................................................... 27 
5. 
STUDY DESIGN .................................................................................................. 27 
5.1 
Treatment Plan ...................................................................................................... 28 
5.1.1 
FDA-Approved Targeted Agents .......................................................................... 28 
5.2 
Treatment Duration ............................................................................................... 29 
5.3 
Concomitant Medications...................................................................................... 29 
5.3.1 
Permitted Concomitant Medications ..................................................................... 29 
5.3.2 
Prohibited Concomitant Medications .................................................................... 29 
6. 
DOSE MODIFICATIONS .................................................................................... 30 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 30 
7.1 
Overview ............................................................................................................... 30 
7.2 
Baseline Study Assessments ................................................................................. 31 
7.3 
Study Treatment Assessments ............................................................................... 31 
7.3.1 
Day 1 of each cycle ............................................................................................... 31 
7.3.2 
Day 15 of Cycle 1 Only ......................................................................................... 32 
7.4 
End of Study Treatment ........................................................................................ 32 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 33 
8.1 
FDA-Approved Targeted Agents .......................................................................... 33 
8.1.1 
Labeling, Packaging, and Supply .......................................................................... 33 


 
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8.1.2 
Precautions and Risks Associated with FDA-Approved Targeted Agents ........... 33 
8.2 
Accountability for All Study drugs ....................................................................... 33 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 34 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 34 
10.1 
Statistical Design ................................................................................................... 34 
Sample Size Considerations ................................................................................................... 34 
10.2 
Data Analysis ........................................................................................................ 34 
10.2.1 
Demographics and Baseline Characteristics ......................................................... 35 
10.2.2 
Efficacy Analysis .................................................................................................. 35 
10.3 
Analysis Time Points............................................................................................. 36 
10.3.1 
Final Analysis ........................................................................................................ 36 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 36 
11.1 
Definitions ............................................................................................................. 36 
11.1.1 
Adverse Events ...................................................................................................... 36 
11.1.2 
Serious Adverse Event .......................................................................................... 37 
11.1.3 
Adverse Reaction .................................................................................................. 37 
11.1.4 
Suspected Adverse Reaction ................................................................................. 37 
11.1.5 
Recording and Reporting of Adverse Events ........................................................ 38 
11.1.6 
Assessment of Adverse Events.............................................................................. 39 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 39 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 41 
11.3.1 
Diagnosis versus Signs and Symptoms ................................................................. 41 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 41 
11.3.3 
Abnormal Laboratory Values ................................................................................ 41 
11.3.4 
Deaths .................................................................................................................... 42 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 42 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 42 
11.3.7 
New Cancers.......................................................................................................... 43 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 43 
11.3.9 
FDA-Approved Targeted Agent Overdose ........................................................... 43 
11.4 
Sarah Cannon Development Innovations Safety Department Serious Adverse 
Event Reporting ..................................................................................................... 43 
11.4.1 
Sarah Cannon Development Innovations Safety Department Assessment of 
Unexpected ............................................................................................................ 44 
11.4.2 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application ............................................................................................................ 44 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 45 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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INNOVATIONS STUDY NUMBER:  PRO 10 
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12.1 
Study Monitoring, Auditing, and Inspecting ......................................................... 45 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 45 
13.1 
Institutional Review Board Approval.................................................................... 45 
13.2 
Regulatory Approval ............................................................................................. 46 
13.3 
Informed Consent .................................................................................................. 46 
13.3.1 
Confidentiality ....................................................................................................... 46 
13.4 
Financial Information ............................................................................................ 48 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 48 
14.1 
Amendments to the Protocol ................................................................................. 48 
14.2 
Documentation Required to Initiate the Study ...................................................... 49 
14.3 
Study Documentation and Storage ........................................................................ 49 
14.4 
Data Collection ...................................................................................................... 51 
14.5 
Disclosure and Publication Policy ......................................................................... 51 
15. 
REFERENCES ...................................................................................................... 53 
 
LIST OF TABLES 
Table 1:  Common Genomic Alterations by Tumor Type ..................................................... 19 
Table 2:  FDA-Approved Targeted Agents ........................................................................... 21 
 
 
Post Text Supplement 
 
Appendix A: ECOG Performance Status Criteria 
Appendix B: New York Heart Association Classification of Cardiac Disease 
Appendix C:  Guidelines for Female Patients of Childbearing Potential and Fertile Male 
Patients  
Appendix D: Schedule of Assessments 
Appendix E:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Appendix F:  Common CYP Inhibitors, Inducers, and Substrates 
Appendix G: Stivarga (regorafenib) Package Insert 
Appendix H: Gilotrif (afatinib) Package Insert 
Appendix I  
Cabozantinib 
 


 
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INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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1. 
INTRODUCTION 
1.1 
Background and Rationale 
Advances in next generation sequencing technologies in combination with decreasing costs of 
testing has allowed broader implementation of genomic profiling in the clinical practice of 
medical oncology and clinical research. (Thomas et al. 2014; Johnson et al. 2014; Gray et al. 
2014; Schwaederle et al. 2014)  The identification of genomic alterations that drive the 
development and progression of specific tumors has resulted in the discovery of targeted agents 
that may produce tumor regressions in tumors that possess the alteration.  More than 30 targeted 
small molecules and monoclonal antibodies have been approved by the FDA for the treatment of 
a variety of cancers.  
Johnson et al. recently published a retrospective evaluation of the use of a targeted next-
generation sequencing platform (FoundationOne) in advanced cancer patients.  (Johnson et al. 
2014) The assay identified potentially actionable genomic alterations in 83% of tumors with a 
median of two actionable mutations per patient.  Fifty-seven percent of patients were identified 
by NGS testing as potential candidates for clinical trials in which the tumor-targeted treatment 
had demonstrated early clinical activity or preclinical rationale for use.  Twenty-six percent of 
patients had alterations that predicted sensitivity to targeted agents that were already approved 
for the cancer type assessed and an additional 17% demonstrated alterations that could be 
targeted by an FDA-approved agent for another tumor type. 
Researchers at MD Anderson Cancer Center have also reported on the ability to select therapy in 
a phase I clinical trials program based on tumor alterations detected with an institutionally 
developed CLIA-certified sequencing panel.  (Tsimberidou et al, 2012)  Approximately 40% of 
the patients tested had 1 or more alteration.  Patients whose tumors had an alteration were treated 
with matched targeted therapy when available and compared to a group without matched 
targeted therapy.  Patients receiving matched therapy had a higher overall response rate (27% vs 
5%), longer time to treatment failure (5.2 vs 2.2 months) and longer survival (13.4 vs 9 months) 
compared to the non-matched group. In a separate manuscript, patients with PIK3CA mutations 
were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway and 
compared to patients with wild-type PIK3CA treated on the same protocols.  (Janku et al. 2012)  
Patients with PIK3CA mutations who were treated with targeted therapies demonstrated a higher 
response rate than patients without mutations (30% vs 10%). 
Similar data have been reported by Von Hoff et al.  In this pilot study, patients from nine 
different centers were molecularly profiled in a CLIA-certified lab. (Von Hoff et al 2010)  A 
molecular target was detected in 98% of patients and 66 patients were treated with the regimen 
recommended by the profiling.  Patients in the study served as their own control as progression-
free survival following the treatment regimen selected by molecular profiling was compared with 
the progression-fee survival for the most recent regimen on which the patient experienced 
progression. The molecular-profiling approach to treatment selection resulted in a longer 


 
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progression-free survival in 27% of patients compared to the progression-free survival obtained 
with their most recent therapy. 
The University of California San Diego Moores Cancer Center recently reported their initial 
experience with a molecular tumor board created to review molecular test results.  (Schwaederle 
et al. 2014)  There was a median of 4 molecular alterations per patient found by next-generation 
sequencing.  Among the 11 evaluable patients whose treatment was determined by molecular 
diagnostics, 3 achieved partial responses.  The most common reasons for not acting on the 
molecular diagnostics results were that patients were ineligible for or could not travel to an 
appropriately targeted clinical trial and/or that insurance would not cover the recommended 
agent. 
Targeting specific molecular alterations with next-generation sequencing and other genomic 
technologies could transform oncology.  In order to facilitate the incorporation of molecular 
profiling into routine clinical practice, the French National Cancer Institute and French Ministry 
of Health have established a process to profile patients free of charge nationwide across the 
health-care system.  (Nowak et al. 2012) Decreasing technology costs and increased insurance 
coverage of sequencing tests will allow for increased availability in other regions.  Additional 
challenges that may limit widespread use of molecular profiling include information processing, 
genomic medical education and interpretation, cost, and reimbursement. (Thomas et al. 2014)  
Perhaps the biggest challenge for physicians utilizing molecular profiling is being unable to act 
on a known alteration because a targeted drug is not available commercially for that indication or 
in the clinical trial setting.  (Munoz et al. 2013)  Both the clinical trial system and the system of 
financial coverage for approved drugs are inadequate, as they were designed for individual drugs 
being utilized in unselected patient populations. Preliminary profiling results suggest that an 
individual patient’s tumor possesses a unique set of molecular alterations that may require a 
customized treatment regimen based on the targeted alterations rather than the histologic tumor 
type. Initial trials have demonstrated improved clinical outcomes in patients receiving treatment 
regimens matched to known molecular alterations.  However, additional trials in this setting are 
warranted to further identify patient subgroups that may benefit from targeted therapies. 
This phase II study will evaluate the preliminary antitumor activity of selected commercially 
available molecularly matched targeted therapies in patients whose tumors have progressed 
while receiving or following first line treatment for one of the following four tumor types:   (1) 
non-small cell lung cancer, (2) urothelial carcinoma, (3) non-colon gastrointestinal cancers 
(including hepatobiliary, pancreatic, and gastroesophageal tumors), and (4) upper aerodigestive 
tract cancers (including lip, tongue, salivary glands, gum, oral cavity, mouth, tonsils, oropharynx, 
nasopharynx, nasal cavity, sinus, and larynx tumors).  The most common genomic alterations 
associated with these tumors are summarized in Table 1. 
 
Table 1:  Common Genomic Alterations by Tumor Type 
NSCLC 
Urothelial 
Non-Colon GI 
Upper 
Aerodigestive 


 
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Carcinoma 
Cancers 
Tract 
AKT1 
EGFR 
ALK 
EGFR 
ALK 
FGFR1,3 
BRAF 
FGFR3 
BRAF 
HER2 
EGFR 
HER2 
DDR2 
mTOR 
FGFR fusions 
HRAS 
EGFR 
PIK3CA 
HER2 
KIT 
FGFR1 
RAS 
KRAS 
KRAS 
HER2 
TSC1,2 
NRAS 
MET 
KRAS 
VEGF 
PDGFRα 
PDGFRα 
MEK1 
 
PDGFRβ 
PI3K 
MET 
 
PIK3CA 
PTEN 
NRAS 
 
PTEN 
 
PIK3CA 
 
TSC1,2 
 
PTEN 
 
 
 
RET 
 
 
 
ROS1 
 
 
 
Sourced from My Cancer Genome Website and COSMIC database 
  
Patients will be profiled with next-generation sequencing technology outside of this protocol and 
will be enrolled based on the results of this profiling. This testing can be tissue or blood.  If a 
patient was not profiled with Foundation One® prior to study enrolment, Sarah Cannon 
Development Innovations shall use reasonable efforts to collect and send to Foundation 
Medicine adequate tumor tissue meeting the tissue specimen requirements for Foundation One® 
for retrospective profiling that will be completed and compared to the profiling report provided 
at study entry.  Patients with the specified tumor types that demonstrate one of the above 
genomic alterations may be assessed for protocol eligibility and treatment.  Patients with a 
genomic alteration that is not described in Table 1 but is covered by a targeted agent in Table 2 


 
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will also be eligible.  Non-small cell lung cancer patients with ALK or EGFR mutations should 
receive targeted treatment as part of standard of care and will not be eligible for this protocol.  
RAS and BRAF mutations are in the MAPK/ERK pathway and may be targeted with BRAF 
inhibitors as appropriate. 
 
1.2 
Targeted Treatment for Known Genomic Alterations 
Table 2 lists the FDA-approved targeted agents that will be utilized in this study as matched 
therapies for the genomic alterations.   
Table 2:  FDA-Approved Targeted Agents 
Approved 
Drug 
Targets Listed in 
Package Insert  
Manufactu
rer 
Recommended Dose 
Regorafenib 
(Stivarga) 
RET, VEGF1-3, KIT, 
PDGFR-α and β, FGFR1-
2, TIE2, DDR2, Trk2A, 
Eph2A, RAF-1, BRAF, 
SAPK2, PTK5, Abl 
Bayer 
160 mg once daily for 
the first 21 days of each 
28 day cycle 
Afatinib 
(Gilotrif™) 
EGFR, HER2, HER4 
Boehringer 
Ingelheim 
40 mg once daily 
Cabozantinib 
(CabometyxTM) 
MET, VEGFR1-3, AXL, 
RET, ROS1, TYRO3, 
MER, KIT, TRKB, FLT-
3, TIE2 
Exelixis, Inc 60 mg once daily 
All drugs will be administered according to the recommended package insert dose.  Dosing will 
be continuous daily for all drugs except regorafenib, which is dosed for 21 days out of every 28 
days.  For the purposes of the study, a treatment cycle will be defined as 28 days.  Recommended 
dose modifications for treatment-related toxicities are outlined in the package insert prescribing 
information.  Patients will return to clinic on day 1 of every treatment cycle for evaluation and 
scans will be performed every 2 cycles for disease assessment.  The product package inserts for 
the individual drugs are included in Appendices G and H. 
 
1.3 
Rationale for the Study 
With the increased availability of next-generation sequencing, oncologists are beginning to 
incorporate genomic profiling into the routine care of cancer patients.  More than half of all 
patients will have an actionable genomic alteration in their tumor when profiled, which could 
help guide the choice of targeted therapy treatment.  Multiple targeted agents are now available 


 
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for clinical use and numerous additional agents are currently in clinical trials.  Several agents that 
target specific genomic mutations have been approved based on improved treatment outcomes in 
a population of patients enriched for the specific genomic alteration (eg. crizotinib, vemurafenib, 
dabrafenib, ceritinib).  Preliminary studies also suggest that targeting treatment toward known 
tumor genomic characteristics improves the chances of disease response with targeted agents.  
This pilot study will evaluate the preliminary antitumor activity of selected commercially 
available molecularly matched targeted therapies in patients who have failed first line treatment 
for one of the following four tumor types:   (1) non-small cell lung cancer, (2) urothelial 
carcinoma, (3) non-colon gastrointestinal cancers, and (4) upper aerodigestive tract cancers.   
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to: 
• Determine the overall response rate (Complete Response [CR] + Partial Response 
[PR]) in each patient population receiving targeted therapy based on relevant 
genomic alterations.   
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate the clinical benefit rate (CR + PR + stable disease [SD] ≥ 6 months) in 
each patient population receiving targeted therapy based on relevant genomic 
alterations. 
• Determine the time to treatment failure (measured from the first day of treatment 
until the patient is removed from study for toxicity, disease progression, patient 
choice, or death) in each patient population receiving targeted therapy based on 
relevant genomic alterations. 
• To determine the progression free survival (PFS) in each patient population 
receiving targeted therapy based on relevant genomic alterations. 
3. 
STUDY PATIENT POPULATION  
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Patients with a histologically or cytologically confirmed diagnosis of one of the following 
tumor types whose disease has progressed following one line of standard therapy and/or 
for which no standard treatment is available that has been shown to prolong survival: 
a. Non-small cell lung cancer 


 
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b. Urothelial carcinoma 
c. Non-colon gastrointestinal cancers (including hepatobiliary, pancreatic, and 
 
gastroesophageal tumors) 
d. Upper aerodigestive tract cancers (including lip, tongue, salivary gland, gum, oral 
cavity, mouth, tonsils, oropharynx, nasopharynx, nasal cavity, sinus, and larynx tumors) 
2. Patients must have a predefined genomic alteration included in Table 1 that can be 
targeted with one of the FDA-approved targeted agents listed in Table 2.  Patients with a 
genomic alteration that is not described in Table 1 but is covered by a targeted agent in 
Table 2 will also be eligible. 
3. Patients must have measurable disease as measured by Response Evaluation Criteria in 
Solid Tumors (RECIST) criteria version 1.1 (Appendix E). 
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
score of 0 or 1 (Appendix A). 
5. Age greater than or equal to 18 years. 
6. Adequate hematologic function defined as: 
- Absolute neutrophil count (ANC) ≥1500/μL 
- Platelets ≥75,000/µL 
7. Adequate liver function defined as: 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
the upper limit of normal (ULN) or ≤ 5.0 X ULN if liver metastases present 
- Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin) 
8. Adequate renal function defined as serum creatinine ≤1.5 x the upper limit of normal OR 
measured or calculated creatinine clearance ≥50 mL/min for patients with creatinine 
levels greater than or equal to 1.5 x the upper limit of normal. 
9. Patients who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to receive either regorafenib or afatinib provided that their medication dose and 
INR/PTT are stable.  Close monitoring is mandatory if the patient is receiving 
anticoagulants.  If values are above the therapeutic range the anticoagulant doses should 
be modified and assessments should be repeated until stable.  (See Exclusion Criteria 15 
for anticoagulant therapy information for patients receiving cabozantinib).  
10. Male patients with female partners of childbearing potential and women patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 90 days 
following last dose of study drug(s).  Male patients must also refrain from donating 


 
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sperm during their participation in the study and for 90 days after the last dose of study 
drug (Appendix C). 
11. Willingness and ability to comply with study and follow-up procedures. 
12. Ability to understand the nature of this study and give written informed consent. 
 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Two or more prior chemotherapy regimens in the metastatic setting. 
2. Most recent chemotherapy ≤ 3 weeks and > Grade 1 chemotherapy-related side effects, 
with the exception of neuropathy (> grade 2 excluded) and alopecia.   
3. Use of a study drug or targeted therapy ≤21 days or 5 half-lives (whichever is shorter) 
prior to the first dose of study treatment.  For study drugs for which 5 half-lives is ≤21 
days, a minimum of 10 days between termination of the study drug and administration of 
study treatment is required. 
4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy. 
5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
6. Previously untreated brain metastases.  Patients who have received radiation or surgery 
for brain metastases are eligible if therapy was completed at least 2 weeks prior to study 
entry and there is no evidence of central nervous system disease progression, mild 
neurologic symptoms, and no requirement for chronic corticosteroid therapy.  Enzyme- 
inducing anticonvulsants are contraindicated.    
7. Pregnant or lactating 
8. Acute or chronic liver, renal, or pancreas disease. 
9. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and 
malabsorption syndrome).  
10. Any of the following cardiac diseases currently or within the last 6 months: 
- Unstable angina pectoris 
- Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2 
[Appendix B]) 
- Acute myocardial infarction 


 
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- Conduction abnormality not controlled with pacemaker or medication 
- Significant ventricular or supraventricular arrhythmias (patients with chronic rate-
controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 
- Valvular disease with significant compromise in cardiac function 
11. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 mmHg or 
diastolic blood pressure (DBP) >100 mmHg) (patients with values above these levels 
must have their blood pressure (BP) controlled with medication prior to starting 
treatment). 
12. Thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident 
(including transient ischemic attacks) deep vein thrombosis or pulmonary embolism 
within 6 months of start of treatment. 
13. Evidence or history of bleeding diathesis or coagulopathy; any haemorrhage or bleeding 
event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of treatment. 
14. For patients receiving cabozantinib only: Do not administer cabozantinib to patients 
that have high risk or at high risk for severe haemorrhage.  Examples include:  
a. The patient has radiographic evidence of cavitating pulmonary lesion(s).  
b. The patient has tumor invading or encasing any major blood vessels.   
c. The patient has had hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 
months before the first dose of study treatment. 
d. The patient has experienced clinically significant GI bleeding within 6 months of 
the first dose of study treatment. 
e. The patient has experienced any other signs indicative of pulmonary hemorrhage 
within 3 months of the first dose of study treatment. 
15. For patients receiving cabozantinib only: Do not administer cabozantinib to patients 
that have high risk or at high risk of perforation or fistula:  
a. The patient has evidence of tumor invading the GI tract, active peptic ulcer 
disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute 
obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction. 
b. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed before 
first dose. 
c. The patient has pre-existing fistula of head and neck area.  


 
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Note: Treatment areas should be healed with no sequelae from prior radiation 
therapy that would predispose to fistula formation.  
d. The patient has pre-existing osteonecrosis of the jaw. 
16. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, 
direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).  
[Patients receiving cabozantinib only] 
17. Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose 
warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are 
permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects 
without radiographic evidence of brain metastasis, who are on a stable dose of LMWH 
for at least 12 weeks before randomization, and who have had no complications from a 
thromboembolic event or the anticoagulation regimen.Presence of a non-healing wound, 
non-healing ulcer, or bone fracture. 
18. Patients with phaeochromocytoma. 
19. Serious active infection at the time of treatment, or another serious underlying medical 
condition that would impair the ability of the patient to receive protocol treatment. 
20. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 
21. Presence of other active cancers unless indolent and not requiring therapy.  Patients with 
Stage I cancer who have received definitive local treatment and are considered unlikely 
to recur are eligible.  All patients with previously treated in situ carcinoma (i.e., non-
invasive) are eligible, as are patients with history of non-melanoma skin cancer. 
22. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
3.3 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the investigator’s discretion) 
• 
Inability of the patient to comply with study requirements 
• 
Patient requests to discontinue treatment 
• 
Patient withdraws consent from the study  
• 
Non-compliance/lost to follow-up 
• 
Pregnancy 


 
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INNOVATIONS STUDY NUMBER:  PRO 10 
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After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 days after their last dose of study drug.  All new AEs occurring during this period 
must be reported and followed until resolution, unless, in the opinion of the investigator, these 
values are not likely to improve, because of the underlying disease.  In this case, the investigators 
must record his or her reasoning for this decision in the patients’ medical records and as a 
comment in the electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v 4.03 at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the investigator, not likely that these values are to improve.  In this 
case, the investigator must record his or her reasoning for making this decision in the patients’ 
medical records and as a comment in the eCRF. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, treatment alternatives, side-effects, risks, 
and discomforts.  Human protection committee (Institutional Review Board/Independent Ethics 
Committee [IRB/EC]) approval of this protocol and consent form is required.  Eligible patients 
who wish to participate in the study will be enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled through the Sarah Cannon Development Innovations Central 
Enrollment Desk.  The enrollment desk may be reached by calling (877) MY-1-SCRI.  
Registration may be done via fax (866) 699 0258 Monday through Friday, 8:30 a.m. to 4:30 
p.m., Central Standard Time.  Patient registration will be confirmed via email within 24 hours, or 
by the next business day. 
5. 
STUDY DESIGN 
This four-arm pilot phase II study will evaluate the preliminary antitumor activity of selected 
commercially available molecularly matched targeted therapies in patients who have failed first 
line treatment for one of the following tumor types:  (1) non-small cell lung cancer, (2) urothelial 
carcinoma, (3) non-colon gastrointestinal cancers, and (4) upper aerodigestive tract cancers.  
Patients will be profiled with next-generation sequencing technology results known prior to 
consideration for enrollment on this protocol.  Patients with the specified tumor types 
demonstrating one of the genomic alterations described in Table 1 may be assessed for protocol 
eligibility and treatment.  Patients with a genomic alteration that is not described in Table 1 but is 
covered by a targeted agent in Table 2 will also be eligible.  All eligible patients will receive one 
of the FDA-approved targeted agents at the recommended dose outlined in Table 2.  Dose 
modifications will be implemented based on criteria outlined in the product package insert for 
each individual agent.  Patients will be re-evaluated for treatment response after receiving 8 


 
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weeks of oral therapy (with the exception of regorafenib which is dosed intermittently for 21 out 
of every 28 days).  Response to therapy will be assigned using RECIST v1.1 (see Appendix E).  
Patients who have objective response (OR) or stable disease (SD) will continue treatment with 
re-evaluations every 8 weeks, until the time of tumor progression or intolerable treatment-related 
side effects.  If a patient was not profiled with Foundation One® prior to study enrolment, Sarah 
Cannon Development  Innovations shall use reasonable efforts to collect and send to Foundation 
Medicine adequate tumor tissue meeting the tissue specimen requirements for Foundation One® 
for retrospective profiling that will be completed and compared to the profiling report provided 
at study entry. 
A total of 160 patients are planned to be enrolled on the trial (40 patients per study arm).  
5.1 
Treatment Plan 
5.1.1 
FDA-Approved Targeted Agents 
The FDA-approved targeted agents that will be administered during the study are outlined in 
Table 2.  Study drugs will be provided by the manufacturer and will not be billed to the patient’s 
insurance as the proposed usage is considered off-label for the agent.  The treating physician will 
decide which targeted agent will be prescribed based on the  genomic alterations per tumor type 
and the targets listed in the package insert for each agent that are outlined in Tables 1 and 2.  
Patients with a genomic alteration that is not described in Table 1 but is covered by a targeted 
agent in Table 2 will also be eligible.  The Medical Monitor will verify the genomic alteration 
and prescribed targeted agent when the patient is registered for the trial. 
All patients entering this study will receive one of the targeted agents orally either daily 
continuously at the prescribed dose listed in Table 2 (except for regorafenib which is dosed daily 
for 21 out of every 28 days).  Patients will be instructed to take the medication with or without 
food as directed in the product package insert.  The time of day for administration of study drug 
should be consistent. 
If the patient misses a dose of study drug, the patient should skip the missed dose and take the 
next dose as scheduled. 
If vomiting occurs after taking the study medication, the patient should be instructed not to 
retake the dose.  Patients should take the next scheduled dose of study drug.  If vomiting persists 
the patient should contact the investigator. 
No routine prophylactic antiemetics will be given.  However, antiemetics may be administered 
for the treatment of nausea and vomiting when they occur, and may be given prophylactically 
afterwards. 
Study drug compliance will be assessed by pill counts on Day 1 of each cycle.  The research staff 
will count and document the amount of study drug taken and returned by the patient. 


 
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5.2 
Treatment Duration 
Patients will continue to receive treatment until disease progression, the patient requests to 
discontinue treatment, or the treating physician feels it is in the best interest of the patient to 
discontinue.  
For the purposes of the study, a treatment cycle is defined as 28 days.  Patients will be evaluated 
for toxicity at the start of each cycle.  Every 2 cycles restaging will occur with imaging, 
laboratory tests will be assessed as defined in Appendix E. 
5.3 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he is taking or has taken after the start of the study drug. 
5.3.1 
Permitted Concomitant Medications 
No routine prophylactic antiemetics will be given.  However, antiemetics may be administered 
for the treatment of nausea and vomiting when they occur, and may be given prophylactically 
afterwards.  Anti-emetics may be administered according to standard practice guidelines. 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
• Bisphosphonate use, as recommended according to practice guidelines 
• Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor use, as 
recommended according to practice guidelines 
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the investigator. 
5.3.2 
Prohibited Concomitant Medications 
The following treatments are prohibited or should be used with caution while in this study: 
• No other investigational therapy should be given to patients.  No anticancer agents other 
than the study medications should be given to patients.  If such agents are required for a 
patient, then the patient must first be withdrawn from the study. 
• Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  
Patients should stop using these herbal medications 7 days prior to first dose of study drug. 
• Regorafenib and cabozantinib are metabolized by the cytochrome P450 (CYP) system.  
Therefore, drugs that are strong inducers or inhibitors of CYP3A4 should be avoided.  
These drugs are listed in Appendix F.  Other potential drug interactions are described in the 


 
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product package inserts for the individual agents and should be reviewed prior to the start 
of study treatment. 
• Afatinib is a substrate of the P-glycoprotein transporter (MDR1).  Caution should be 
exercised when combining afatinib with P-gp modulators.  Below are the lists of potent P-
gp inhibitors and inducers.  Additional information can be found in the afatinib product 
package insert in Appendix H. 
 
Potent P-glycoprotein Inhibitors:  amiodarone, azithromycin, captopril, carvedilol, 
clarithromycin, 
conivaptan, 
cyclosporine, 
diltiazem, 
dronedarone, 
erythromycin, 
felodipine, itraconazole, ketoconazole, lopinavir, nelfinavir, ritonavir, quinidine, 
ranolazine, saquinavir, tacrolimus, ticagrelor, verapamil. 
Potent P-glycoprotein Inducers:  carbamazepine, phenytoin, rifampicin, St John’s Wort, 
phenobarbital salt, tipranavir, ritonavir. 
6. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), and appropriate supportive care treatment will be 
administered to decrease the signs and symptoms thereof.  Dose adjustments will be based on the 
organ system exhibiting the greatest degree of toxicity. 
Doses of study drug will be modified based on hematologic and non-hematologic toxicity as 
outlined in the product package insert for each FDA-approved targeted agent.  If dose reductions 
are necessary, they will be permanent for the remainder of the treatment.  Any patient requiring a 
toxicity-related dose delay of more than 28 days from the intended day of the next scheduled 
dose must be discontinued from the study. 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is shown in Appendix D.  The baseline physical 
examination, medical history, ECOG PS, and laboratory assessments should be done ≤7 days 
prior to initiation of treatment.  However, if these initial examinations are obtained within 72 
hours of Cycle 1 Day 1 they do not have to be repeated.  A pregnancy test must be performed 
within 72 hours of Cycle 1 Day 1.  CT scans should be performed ≤28 days prior to initiation of 
treatment, as should tumor markers, if appropriate.   


 
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7.2 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
screening: 
• Written informed consent  
• Medical history 
• Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, blood pressure [BP], respiratory rate, and oral temperature) 
• ECOG performance status (see Appendix A) 
• Concomitant medication review 
• CBC (complete blood count) including hemoglobin, hematocrit, WBC with 3-part 
differential and platelets 
• CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALT), AST, ALT, total 
bilirubin, total protein, and albumin plus magnesium. 
• Coagulation analysis: prothrombin time (PT)/International Normalization Ratio (INR) 
and partial thromboplastin time (PTT) 
• Serum or urine pregnancy test in women of child-bearing potential only (must be 
performed within 72 hours of Cycle 1 Day 1) 
• CT scans of chest, abdomen and pelvis. 
• Tumor markers (if applicable) 
• Head CT or MRI scan [Required for patients with a history of treated brain 
metastases] 
7.3 
Study Treatment Assessments  
7.3.1 
Day 1 of each cycle 
• Update of medical history 
• Physical examination, including measurement of weight and vital signs 
• ECOG performance status 
• Adverse event (AE) assessment 
• Concomitant medication review 
• Study drug compliance review (Cycle 2 and beyond) 
• CBC, including 3-part differential and platelets (may be done up to 72 hours prior to 
treatment) 


 
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• CMP plus magnesium (may be done up to 72 hours prior to treatment) 
• Serum or urine pregnancy test in women of child-bearing potential only 
• Tumor markers (if applicable) 
• CT scans of chest, abdomen, and pelvis (if abnormal at baseline) [Every 2 cycles] 
7.3.2 
Day 15 of Cycle 1 Only 
• AE assessment 
• Concomitant medication review 
• Vital signs 
• Study drug compliance review 
• CBC, including 3-part differential and platelets 
• CMP plus magnesium 
7.4 
End of Study Treatment 
The follow-up evaluations required after treatment ends due to completion of the planned study 
treatment period, disease progression, or once the patient is discontinued due to unacceptable 
toxicity or decision to discontinue treatment by the patient or the study physician are specified in 
Appendix D. 
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfil the End-of-Treatment Visit. 
After withdrawal from or completion of protocol treatment, patients must be followed for AEs 
for 30 calendar days after the last dose of study drug.  The following assessments will be 
performed: 
• Update of medical history 
• Physical examination, including measurement of weight and vital signs 
• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• Review study drug compliance with the patient, and collect unused study drug 
• CBC, including 3-part differential and platelets 
• CMP plus magnesium 
 


 
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Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed for disease assessment only every 3 months (±1 month) from the date of last dose of 
study drug until disease progression. 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
FDA-Approved Targeted Agents 
 
Study Drug 
Dosage Form and Strength 
Manufacturer 
Regorafenib 
40 mg tablet 
Bayer 
Afatinib 
40 mg, 30 mg, and 20 mg tablets 
Boehringer Ingelheim 
Cabozantinib 
20 mg, 40 mg and 60 mg tablets 
Exelixis 
 
8.1.1 
Labeling, Packaging, and Supply 
The study drugs described in Section 8.1 will be supplied to Sarah Cannon Research Institute by 
the manufacturers. 
At each visit, patients will be dispensed sufficient supplies until the next visit.  Study drug 
compliance will be assessed at each patient visit.  The research staff will count and document the 
amount of study drug taken and returned by the patient. 
The immediate packaging will contain a statement to conform with U.S. Food and Drug 
Administration (FDA) Investigational New Drug (IND) requirements as follows: Caution: New 
Drug - Limited by Federal (or United States) law to investigational use. 
All study drugs must be kept in a secure place at controlled room temperature.  Storage 
conditions for each study drug are included on the product label and in the product package 
inserts included in Appendices G and H. 
8.1.2 
Precautions and Risks Associated with FDA-Approved Targeted Agents 
Precautions and risks are described in the product package inserts for each drug included in 
Appendices G and H. 
8.2 
Accountability for All Study drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 


 
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At the end of the study, all Sarah Cannon Development Innovations Drug Accountability Record 
Form(s) will be completed by the site and sent to the Sarah Cannon Development Innovations 
Regulatory Department.  Study drug supplies must not be destroyed unless prior approval has 
been granted by the Sponsor or its representative.  Please contact Sarah Cannon Development 
Innovations regarding disposal of any study drug. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using the Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 (see Appendix E).  Lesions are either measurable or non-
measurable according to the criteria.  The term “evaluable” in reference to measurability will not 
be used, as it does not provide additional meaning or accuracy. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This four-arm pilot phase II study will evaluate the preliminary antitumor activity of selected 
commercially available molecularly matched targeted therapies in patients who have failed first 
line treatment for one of the following tumor types:   (1) non-small cell lung cancer, (2) 
urothelial carcinoma, (3) non-colon gastrointestinal cancers, and (4) upper aerodigestive tract 
cancers.  Patients will be profiled with next-generation sequencing technology results known 
prior to consideration for enrolment on this protocol.  Patients with the specified tumor types 
demonstrating one of the genomic alterations described in Table 1 may be assessed for protocol 
eligibility and treatment.  Patients with a genomic alteration that is not described in Table 1 but is 
covered by a targeted agent in Table 2 will also be eligible. All eligible patients will receive one 
of the FDA-approved targeted agents at the recommended dose outlined in Table 2. 
Sample Size Considerations 
The design of this trial uses an exact single-stage design for each of the four arms. (A’Hern 
2001)  For this investigation, it has been determined that an ORR (CR + PR) of 10% or worse 
has low activity in line with standard of care.  An ORR of 25% (or better) is considered to 
indicate interesting activity.  Using a one-sided alpha of 5% and power of 80%, 40 evaluable 
patients will be required in each arm.  A minimum of 8 responders in a particular arm would 
indicate that the corresponding tumor type would be worthy of further investigations.   
10.2 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented. Time to events endpoints will be reported using Kaplan-Meier 
estimates, with 95% confidence intervals (CI) for median time to event. 


 
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10.2.1 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized.  Data to be tabulated will 
include demographic features such as age, sex and race, as well as disease-specific 
characteristics. 
The number and percentages of patients screened, treated, and withdrawn from treatment/study 
for any reason will be presented overall and also by study arm. 
10.2.2 
Efficacy Analysis 
All efficacy analyses will be performed using the Intent-To-Treat Population. 
• Overall Response Rate (ORR) is defined as the proportion of patients with confirmed 
complete response (CR) or partial response (PR (i.e. 2 CRs or PRs at least 4 weeks apart) 
according to the RECIST v1.1.  
 
• Clinical Benefit Rate (CBR) is defined as the proportion of patients with CR, PR or SD ≥ 
6 months according to the RECIST v1.1. 
 
o For ORR and CBR, patients without a post-baseline tumor assessment will be 
classed as not evaluable (NE) and considered as non-responder. 
 
• Time to treatment failure (TTF) is measured from the first day of treatment until the 
patient is removed from study for toxicity, disease progression, patient choice, or death. 
 
• Progression Free Survival (PFS) is defined as the time from the first day of study drug 
administration (Day 1) to disease progression as defined by the RECIST v1.1, or death on 
study.  Patients who are alive and free from disease progression will be censored at the 
date of last tumor assessment. 
For ORR and CBR, the estimates and the associated 95% CI (based on the Clopper-Pearson 
method) in each treatment group will be calculated. 
For PFS, Kaplan-Meier curves will be generated and the median time to event and the associated 
95% CI will be provided. 
10.2.3 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE v. 4.03.  A copy of CTCAE scoring system may be 
downloaded from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized using system organ class and preferred term by treatment arm for all patients in the 


 
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Safety Population.  In addition, summaries of SAEs, AEs leading to treatment discontinuation, 
AEs by maximum NCI CTCAE grade, and AEs related to study treatment will also be presented 
by treatment arm. 
Other safety endpoints including laboratory results, vital signs and ECG findings will be 
summarized for all patients in the Safety Population  
10.3 
Analysis Time Points 
10.3.1 
Final Analysis 
The final analysis of the study will occur when the required number of response evaluable 
patients has been reached in each treatment arm. 
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and Serious 
Adverse Events (SAEs), measurement of protocol-specified laboratory tests and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing and reporting AEs to the Sarah Cannon 
Development Innovations Safety Department.  It is the Sponsor’s responsibility to report relevant 
SAEs to the applicable local, national, or international regulatory bodies.  In addition, 
Investigators must report SAEs and follow-up information to their responsible IRB/EC according 
to the policies of that IRB/EC.  
 The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
11.1 
Definitions   
11.1.1 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An adverse event (also known as adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporarily associated with the use of a drug, without any judgement about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, dose or 
including overdose. 


 
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11.1.2 
Serious Adverse Event 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of 
the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization of at least 24-hours or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 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.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.   
It is important to distinguish between “serious” and “severe” AE, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
11.1.3 
Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions where there is a reason to conclude that the drug caused the 
event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  Reasonable possibility means that there is evidence to 
suggest a causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 


 
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11.1.5 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes a serious adverse event (SAE) or not, any action taken (e.g., 
changes to study treatment), and outcome, should be provided, along with the investigator’s 
assessment of causality (i.e., the relationship to the study treatment[s]).  For an AE to be a 
suspected treatment-related event there should be at least a reasonable possibility of a causal 
relationship between the protocol treatment and the AE.  Adverse events will be graded 
according to the NCI CTCAE v4.03, and changes will be documented. 
If the AE is serious, it should be reported immediately to Sarah Cannon Development 
Innovations Safety Department.  Other untoward events occurring in the framework of a clinical 
study are to be recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that 
are related to a protocol-mandated intervention, including invasive procedures such as biopsies, 
medication washout, or no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment, and/ or test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the investigator. 
Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to the FDA-approved targeted agents (called 
study treatment), spanning from the start of study treatment, until 30 calendar days after 
discontinuation or completion of study treatment as defined by the clinical study for that patient, 
are to be recorded on the corresponding screen(s) included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the investigator, the AE or laboratory abnormality/ies are not 
likely to improve because of the underlying disease.  In this case, the investigators must record 
his or her reasoning for this decision in the patient’s medical record and as a comment on the 
eCRF screen. 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the investigator as treatment related are to be reported. 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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11.1.6 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study medication, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to Sarah Cannon Development Innovations Safety Department in order to comply with 
regulatory requirements.  Determination of life-threatening or serious is based on the opinion of 
either the Sponsor or the Investigator.   
Serious AEs may occur at any time from the start of study treatment through the 30 day follow-
up period after the last study treatment.  The Sarah Cannon Development Innovations Safety 
Department must be notified of all SAEs, regardless of causality, within 24 hours of the 
first knowledge of the event by the treating physician or research personnel.   
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to Sarah Cannon Development Innovations Safety Department 
via fax or e-mail using the using the following contact information (during both business and 
non-business hours): 
Sarah Cannon Development Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report, 
and a copy of the confirmation should be retained with the patient’s records. 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product (s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the AE or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to Sarah Cannon Development Innovations Safety Department as soon as it is 
available; these reports should be submitted using the Sarah Cannon Development Innovations 
SAE Report Form.  The detailed SAE reporting process will be provided to the sites in the SAE 
reporting guidelines contained in the study reference manual. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
The Sponsor Safety department (SCRI Innovations) shall report all SAEs and non-serious AEs 
which are relevant to a reported SAE by FAX using MEDWATCH form with accompanying BI 
cover letter form to the BI Unique Entry Point as detailed below in accordance with the 
following timelines as specified in the pharmacovigilance agreement: 
• Within five (5) calendar days upon receipt of initial and follw-up SAEs containing at 
least one fatal or immediately life-threatening event; 
• Within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
 
Boehringer Ingelheim Pharmaceuticals, Inc. 
900 Ridgebury Road 
Ridgefield, CT 06877 
FAX:  1-203-837-4329 
Expedited Reporting by Investigator to Pharmaceutical Companies Providing Drug Supply 
(Bayer, Boehringer Ingelheim, or Exelixis) 
Expedited reporting will be completed by the Sponsor Safety Department of Sarah Cannon 
Development Innovations Safety Department.  Expedited reports will not be sent to Bayer, 
Boehringer Ingelheim, or Exelixis by the Site investigator.  SAE reports are submitted by the 
participating site investigator within 24 hours of awareness to the Sarah Cannon Development 
Innovations Safety Department.  The Expedited Reporting responsibilities belong to Sarah 
Cannon Development Innovations Safety Department.  Upon fax confirmation receipt from the 
submission of the expedited report, a copy will be forwarded to Bayer, Boehringer Ingelheim, or 
Exelixis.   
Drug Safety and Pharmacovigilance Contact Information: 
Bayer Healthcare Pharmaceuticals Email at DrugSafety.GPV.US@Bayer.com or 973-709-2185 
(FAX). 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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Boehringer Ingelheim Pharmaceuticals 1-203-837-4329 (FAX). 
Exelixis at drugsafety@exelixis.com (e-mail) or (650) 837-7392. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as an 
SAE. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if: the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment, and/ or laboratory findings 
require additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the investigator. 


 
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11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Study Discontinuation” 
eCRF screen.  All other on study deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the Sarah Cannon Development Innovations Safety 
Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event screen of the eCRF.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event 
screen.  During post-study survival follow-up, deaths attributed to progression of disease will be 
recorded only on the “After Progressive Disease Follow-Up” eCRF screen. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, Custodial care or Respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as an SAE to the Sarah Cannon 
Development Innovations Safety Department. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria.  New primary cancers are those that are not the primary 
reason for the administration of the study treatment and have developed after the inclusion of the 
patient into the study.  They do not include metastases of the original cancer.  Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE, as they are considered to 
be disease progression. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form should be 
completed and faxed to the Sarah Cannon Innovations Safety Department.  Sarah Cannon 
Development Innovations Safety Department should be notified expeditiously, irrespective of 
whether or not it meets the criteria for expedited reporting.  Abortions (spontaneous, accidental, 
or therapeutic) must also be reported to Sarah Cannon Development Innovations Safety 
Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Sarah Cannon Development Innovations Safety 
Department immediately.  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
FDA-Approved Targeted Agent Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the Sarah Cannon Development Innovations Safety 
Department no greater than 24 hours from first knowledge of the event using the corresponding 
screens in the eCRF and following the same process described for SAE reporting if the overdose 
is symptomatic. 
For information on how to manage an overdose of the FDA-approved targeted agents, see the 
product package insert for each individual agent included in Appendices G and H. 
 
11.4 
Sarah Cannon Development Innovations Safety Department Serious Adverse 
Event Reporting 
Sarah Cannon Development Innovations Safety Department will forward SAE information to the 
appropriate pharmaceutical company within 1 business day of Sarah Cannon Development 
Innovations Safety Department becoming aware of the SAE. 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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Sarah Cannon Development Innovations Safety Department is responsible for reporting relevant 
SAEs to the competent authority, other applicable regulatory authorities, and participating 
investigators, in accordance with International Conference on Harmonization (ICH) guidelines, 
FDA regulations, and/or local regulatory requirements. 
11.4.1 
Sarah Cannon Development Innovations Safety Department Assessment of 
Unexpected 
Sarah Cannon Development Innovations is responsible for assessing an AE or SAR as 
“unexpected”. 
An AE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB (or current USPI) 
• Event(s) is not listed at the specificity or severity that has been observed 
• An event(s) is not consistent with the General Investigative Plan or in the current 
application 
• Includes AEs or SAR that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation. 
When applicable, an unexpected AE may also apply to an event that is not listed in the current 
USPI or an event that may be mentioned in the USPI, but differs from the event because of 
greater severity or specificity. 
Known as Suspected Unexpected Serious Adverse Reactions (SUSAR), these events suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
Investigator’s Brochure [IB] or USPI), and are serious (as defined by the protocol) and require 
expedient submission to relevant health authorities within 7 days (fatal or life-threatening event) 
or 15 days (all serious events), or as defined by law.  The term SUSAR is used primarily in the 
reporting of events to regulatory authorities. 
Expected AEs are those events that are listed or characterized in the USPI or current IB. 
11.4.2 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application 
All written IND Safety Reports submitted to the FDA by the Sarah Cannon Development 
Innovations Safety Department must also be faxed to pharmaceutical company (ies) that are 
supporting the study with either funding or drug supply: 
• 
Reports for regorafenib should be sent to Bayer Healthcare Pharmaceuticals at: 
DrugSafety.GPV.US@bayer.com (electronic mailbox) or (973) 709-2185 (FAX) 
• 
Reports for afatinib should be sent to Boehringer Ingelheim at:  (203) 837-4329 
(FAX) 


 
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STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
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• 
Reports for cabozantinib should be sent to Exelixis at : drugsafety@exelixis.com 
(e-mail) or (650) 837-7392. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Study Monitoring, Auditing, and Inspecting 
The investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor or its representative(s), government regulatory authorities, and the IRB/EC of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The investigator will ensure the capability for inspections of applicable 
study-related facilities.  The investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all data 
items or a percentage thereof. 
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor or its representative(s), or the pharmaceutical 
companies providing drug supply for the study. 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
outlined in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government 
regulations, institutional research policies and procedures and any other local applicable 
regulatory requirement(s). 
13.1 
Institutional Review Board Approval 
The clinical study protocol, informed consent form (ICF), Patient Information Sheet (PIS), 
product package insert, available safety information, patient documents (e.g., study diary), 
patient recruitment procedures (e.g., advertisements), information about payments (i.e., Principal 
Investigator payments) and compensation available to the patients and documentation evidencing 
the Principal Investigator’s qualifications should be submitted to the IRB for ethical review and 
approval if required by local regulations, prior to the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  Investigators 
will be advised by the Sponsor or designee whether an amendment is considered substantial or 
non-substantial and whether it requires submission for approval or notification only to an IRB. 


 
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Safety updates for the individual FDA-approved targeted agents will be prepared by the Sponsor 
or its representative as required, for distribution to the Investigator(s) and submission to the 
relevant IRB. 
13.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
13.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form (ICF). 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
FDA, as well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
13.3.1 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 


 
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• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
• The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 
• The rights of a research patient to revoke his or her authorization 
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB/EC direct access to review the patient’s original medical records at the 
site for verification of study-related procedures and data.  
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF.  No material bearing a patient’s name will 
be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the Sarah Cannon 
Development Innovations database, and shall be treated in compliance with all applicable laws 
and regulations.  When archiving or processing personal data pertaining to the investigator or sub 
investigator, Sarah Cannon Development Innovations shall take all appropriate measures to 
safeguard and prevent access to this data by any unauthorized party. 


 
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13.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
Sarah Cannon Development Innovations, LLC and applicable parties.  Any Investigator financial 
disclosures as applicable to 21CFR Part 54 shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor.  All amendments require review and approval of all pharmaceutical companies 
and the Principal Investigator supporting the study.  The written amendment must be reviewed 
and approved by the Sponsor, and submitted to the IRB at the investigator’s facility for the 
board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable, and IRB approval obtained, and specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed; or, when the addition or removal of 
an Investigator is necessitated. 
Items requiring a protocol amendment approval from IRB and/or FDA or other regulatory 
authorities includes, but are not limited to, the following: 
• Change to study design 
• Risk to patient 
• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and / or procedures 
• Addition/removal of a new Investigator 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 


 
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14.2 
Documentation Required to Initiate the Study 
Before the study may begin certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations 
Regulatory Department 
1100 Charlotte Avenue, Suite 600 
Nashville, TN  37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current Curricula Vitae for the principal investigator and any associate investigator(s) 
who will be involved in the study 
• Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB-approved consent form (and patient information sheet, if applicable) 
containing permission for audit by representatives of  Sarah Cannon Development 
Innovations, the IRB, and the FDA and other regulatory agencies (as applicable) 
• Financial disclosure forms for all investigators listed on Form FDA 1572 (if applicable) 
• Site qualification reports, where applicable 
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s)  
 
14.3 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 


 
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traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
copies of completed eCRFs, IRB approval documents, Financial Disclosure forms, patient 
identification lists, enrollment logs, delegation of authority log, staff qualification documents, 
laboratory normal ranges, records relating to the study drug including accountability records.  
Drug accountability records should, at a minimum, contain information regarding receipt, 
shipment, and disposition.  Each form of drug accountability record, at a minimum, should 
contain Principal Investigator name, date drug shipped/received, date, quantity and batch/code, 
or lot number for identity of each shipment.  In addition, all original source documents 
supporting entries in the eCRF must be maintained and be readily available. 
The Sponsor shall maintain adequate product records and financial interest records as per 21CFR 
Part 54.6 and Part 312.57 for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and the FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
shipment / delivery of the drug for investigational use is discontinued and the FDA has been 
notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs, medical records), all 
original, signed ICFs, and copies of all eCRFs, SAE Reporting forms, source documents, 
detailed records of treatment disposition, and related essential regulatory documents.  The 
documents listed above must be retained by the investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  Sponsor will notify the investigator(s)/institutions(s) when 
the study-related records are no longer required. 
If the investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor 
and its representative should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
investigator must obtain the Sponsor’s written permission before disposing of any records, even 
if retention requirements have been met.  All study files will be maintained by the Sponsor 
(Sarah Cannon Development Innovations) throughout the study, and will be held by the Sponsor 
at the conclusion of the study. 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
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14.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, initials and date of birth 
will identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to Sarah 
Cannon Development Innovations and replaced instead with the patient number and patient’s 
initials.  The investigator will maintain a personal patient identification list (patient numbers with 
corresponding patient identifiers) to enable records to be identified and verified as authentic.  
Patient data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations. 
All data requested in the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The investigator will sign and date the patient eCRF casebook indicating that the data in the 
eCRF has been assessed.  Each completed eCRF will be signed and dated by the Principal 
Investigator, once all data for that patient is final. 
14.5 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
Inclusion of the investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The investigator acknowledges that the study 
is part of a multicenter study and agrees that any publication by the investigator of the results of 
the study conducted at research site shall not be made before the first multicenter publication.  In 
the event there is no multicenter publication within fifteen (15) months after the study has been 
completed or terminated at all study sites, and all data has been received, the investigator shall 
have the right to publish its results from the study, subject to the notice requirements described 
herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide 
the Sponsor thirty (30) days to review a manuscript or any poster presentation, abstract or other 
written or oral material which describes the results of the study for the purpose only of 
determining if any confidential or patentable information is disclosed thereby.  If the Sponsor 
requests in writing, the investigator shall withhold any publication or presentation an additional 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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sixty (60) days solely to permit the Sponsor to seek patent protection and to remove any Sarah 
Cannon Development Innovations Confidential Information from all publications. 


 
CONFIDENTIAL 
STUDY DRUG(S):  REGORAFENIB/AFATINIB/CABOZANTINIB 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER:  PRO 10 
FINAL PROTOCOL DATE:  6 MAY 2016  
 
 
VERSION 3 
AMENDMENT NUMBER 2:23 JANUARY 2018 
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15. 
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