Clinical trial NCT02859064
Conditions: Neuroendocrine Tumors Gastrointestinal Neoplasms Carcinoid Tumors
Keywords: radioembolization somatostatin analogs carcinoid neuroendocrine liver-directed therapy
Sponsor: SCRI Development Innovations, LLC
Start date: 2017-07-28; Completion date: 2022-06-10
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Neuroendocrine tumors (NETs) and cancers that originate from the gastrointestinal tract can be resistant to standard chemotherapy and often metastasize to the liver. Lanreotide (Somatuline® Depot) Injection and Yttrium-90 microspheres (SIR-Spheres®) each have FDA approval to treat patients with metastatic NETs. The purpose of this study is to determine if treatment for patients with NETs can be optimized by combining these therapies.

Detailed description:
This is an open-label, prospective, multi-center Phase II study for patients with metastatic well-to-moderately differentiated neuroendocrine tumors, including typical carcinoid and pancreatic neuroendocrine tumors, who are candidates for liver-directed radioembolization.

Lanreotide (Somatuline® Depot) Injection, is FDA-approved for treating unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroentero-pancreatic neuro-endocrine tumors (GEP-NETs) to improve progression-free survival. Radioembolization with yttrium-90 microspheres (SIR-Spheres® therapy) is FDA-approved for treating liver metastases from colorectal cancer. While each of these individual treatments has had promising results, investigators hypothesize that treatment for patients with NETs can be optimized by co-administration of both therapies. Patients will receive treatment with lanreotide (120 mg subcutaneously every 28 days) in combination with SIR-Spheres therapy. The dose and treatment day of SIR-Spheres will be determined by the treating radiation oncologist. Patients who are currently receiving or have previously received lanreotide are eligible, and treatment with lanreotide can continue monthly until disease progression or unacceptable toxicity. Up to 25 patients are planned for enrollment to be conducted at approximately 5 investigational sites in the U.S.

Arms: arm 1: Lanreotide: 120 mg by subcutaneous injection (SQ) on Day 1 of every cycle (every 28 days) in combination with SIR-Spheres therapy.

Y-90 (Yttrium-90) microspheres \[SIR-Spheres therapy\]: dose and treatment day to be determined by treating radiation oncologist.
Interventions: intervention 1: Lanreotide intervention 2: Y-90 microspheres
Intervention descriptions: intervention 1: Administered every 28 days irrespective of when SIR-Spheres is administered. No waiting or adjusting of schedule is required. Lanreotide treatment may continue monthly until disease progression or unacceptable toxicity occurs. intervention 2: To be administered by injection through a trans-femoral catheter into the hepatic artery.

Protocol documents:
Prot_SAP_000.pdf: 
  
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STUDY DRUG: LANREOTIDE 
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GI 221 
A Phase II Study of Lanreotide in Patients with Metastatic Gastrointestinal 
Neuroendocrine Tumors Undergoing Liver-directed Radioembolization with 
Yttrium-90 Microspheres (SIR-Spheres®) 
SARAH CANNON DEVELOPMENT  
INNOVATIONS STUDY NUMBER: 
 
GI 221 
STUDY DRUG: 
Lanreotide 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
(Sarah Cannon Innovations) 
1100 Charlotte Avenue, Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
STUDY CHAIR: 
Johanna Bendell, MD 
Sarah Cannon   
1100 Charlotte Avenue, Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
DATE FINAL: 
28 April 2016 
AMENDMENT 1: 
24 February 2017 


  
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Clinical Study Statement of Compliance 
A Phase II Study of Lanreotide in Patients with Metastatic Gastrointestinal 
Neuroendocrine Tumors Undergoing Liver-directed Radioembolization with 
Yttrium-90 Microspheres (SIR-Spheres®) 
 
 
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 
o 
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. 
 


 
 
 
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Clinical Study Signature Approval Page 
A Phase II Study of Lanreotide in Patients with Metastatic Gastrointestinal 
Neuroendocrine Tumors Undergoing Liver-directed Radioembolization with 
Yttrium-90 Microspheres (SIR-Spheres®) 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
 
GI 221 
STUDY DRUG: 
Lanreotide 
DATE FINAL: 
28 April 2016 
AMENDMENT 1: 
24 February 2017 
 
__________________________ 
__________________________         ______________  
Study Chair 
Sarah Cannon  
Study Chair Signature 
 
Date 
 
 
 
 
 
 
__________________________ 
__________________________         ______________  
Sponsor Representative  
Sarah Cannon Development 
Innovations, LLC 
 
Sarah Cannon Development Innovations, 
LLC  Representative Signature 
 
Date 
 
 
 


 
 
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Clinical Study Principal Investigator Signature Form 
A Phase II Study of Lanreotide in Patients with Metastatic Gastrointestinal 
Neuroendocrine Tumors Undergoing Liver-directed Radioembolization with 
Yttrium-90 Microspheres (SIR-Spheres®) 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
 
GI 221 
DATE FINAL: 
28 April 2016 
AMENDMENT 1: 
24 February 2017 
 
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 
ATTN: Regulatory Department 
1100 Charlotte Avenue, Suite 800 
Nashville, TN 37203 


 
 
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GI 221 Summary of Change 
AMENDMENT NUMBER: 
 1 
AMENDMENT DATE:        24 February 2017 
Global Changes 
The name Sarah Cannon Research Institute (SCRI) Development Innovations, LLC, has been 
changed throughout to Sarah Cannon Development Innovations, LLC, and the former logo has 
been replaced with the new company logo.  A few minor typographical errors have been 
corrected. 
Protocol Synopsis and Section 3.1 – Inclusion Criteria 
8. 
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 30 days 3 months (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 3 months (90 days) after the last dose of study drug 
(Appendix C). 
Protocol Synopsis and Section 3.2 – Exclusion Criteria 
12. 
Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.  
Laboratory test results ≤ 1 year will be confirmed by the treating physician prior to study 
enrollment.  If results are ≥ 1 year old, a fresh blood sample will be required for a new test.   
Section 7.1 – Study Assessments and Evaluations - Overview 
The baseline physical examination, medical history, ECOG PS, electrocardiogram (ECG), 
complete blood counts (CBC), 3-part differential and platelets, comprehensive metabolic profile 
(CMP), urinalysis, and prothrombin time (PT)/partial thromboplastin time (PTT)/International 
Normalization Ratio (INR) 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.   
Section 7.2 – Baseline Study Assessments and Appendix D 
• Results of HIV, hepatitis B, and hepatitis C tests will be confirmed if taken within the 
past 1 year. If test results are >1 year old, patient will be required to provide a fresh 
blood sample for a new test. 
 
The ICF associated with this protocol is being updated accordingly. 
 


 
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GI 221 PROTOCOL SYNOPSIS 
Title of Study: 
A Phase II Study of Lanreotide in Patients with Metastatic Gastrointestinal Neuroendocrine 
Tumors Undergoing Liver-directed Radioembolization with Yttrium-90 Microspheres (SIR-
Spheres®) 
Sarah Cannon 
Innovations Study 
Number: 
GI 221 
Sponsor: 
Sarah Cannon Development Innovations, LLC – Nashville - TN 
Study Duration: 
The total duration of the study is planned to be 3 years. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at approximately 5 sites in the Sarah Cannon network in the 
United States. 
Number of 
Patients: 
Up to 25 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is to: 
• 
Evaluate the safety of concomitant administration of lanreotide for patients 
undergoing liver-directed radioembolization with yttrium-90 microspheres (SIR-
Spheres). 
Secondary Objectives 
The secondary objective of this study is to: 
• 
Evaluate the objective response rate (ORR), disease control rate (DCR), 
progression-free survival (PFS), and overall survival (OS). 
 
Study Design: 
This is an open-label, prospective, multi-center Phase II study for patients with metastatic 
well-to-moderately differentiated neuroendocrine tumors (including typical carcinoid and 
pancreatic neuroendocrine tumors) who are candidates for liver-directed radioembolization.  
Patients will receive treatment with lanreotide (120 mg subcutaneously (SQ) every 28 days) 
in combination with SIR-Spheres treatment (dose and treatment day to be determined by 
treating radiation oncologist). 
 
Study Drugs, 
Doses, and Modes 
of Administration: 
Lanreotide 120 mg Day 1 of every cycle (every 28 days) by deep subcutaneous injection. 
SIR-Spheres TBD 


 
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GI 221 PROTOCOL SYNOPSIS 
Inclusion Criteria: 
1. Metastatic well-to-moderately differentiated (or low-grade) neuroendocrine carcinoma, 
including typical carcinoid or pancreatic islet cell carcinoma. 
2. Computerized tomography (CT) scan evidence of liver metastases which are not treatable 
by surgical resection or local ablation with curative intent at the time of study entry.  If a 
CT scan is not possible, then an MRI may be used. 
3. Patients who are currently receiving or have previously received lanreotide or another 
somatostatin analogue are eligible.  Previous treatment with lanreotide or another 
somatostatin analogue is not required for study entry. 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(Appendix A). 
5. Adequate hematologic function defined as: 
• 
Absolute neutrophil count (ANC) ≥1500/μL 
• 
Hemoglobin (Hgb) ≥9 g/dL 
• 
Platelets ≥100,000/µL 
6. Adequate liver function defined as: 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN) 
• 
Total bilirubin ≤1.2 x ULN (unless the patient has Grade 1 bilirubin elevation due to 
Gilbert’s disease or a similar syndrome involving slow conjugation of bilirubin) 
7. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR 
calculated creatinine clearance ≥50 mL/min as calculated by Cockcroft and Gault 
Formula. 
8. 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 3 months (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 3 months (90 days) after the last 
dose of study drug (Appendix C). 
9. Life expectancy ≥ 3 months. 
10. Age ≥18 years. 
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. 


 
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GI 221 PROTOCOL SYNOPSIS 
Exclusion 
Criteria: 
1. Anti-cancer therapy with the exception of lanreotide or another somatostatin analogue 
within 21 days or 5 half-lives (whichever is shorter) of starting study treatment. 
2. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to Cycle 1 
Day 1 or has not recovered from side effects of such therapy. 
3. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
4. 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.   
5. Clinically significant ascites, cirrhosis, portal hypertension, or thrombosis as 
determined by clinical or radiologic assessment. 
6. Pregnant or lactating 
7. Acute or chronic liver, renal, or pancreas disease. 
8. Any of the following cardiac diseases currently or within the last 6 months: 
- 
Left Ventricular Ejection Fraction (LVEF) <45% as determined by Multiple Gated 
Acquisition (MUGA) scan or echocardiogram (ECHO) 
- 
QTc interval >480 ms on screening electrocardiogram (ECG) 
- 
Unstable angina pectoris 
- 
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 
9. 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). 
10. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low 
molecular weight heparin is allowed. 
11. 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. 
12. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.  
Laboratory test results ≤1 year will be confirmed by the treating physician prior to 
study enrollment. If results are ≥1 year old, a fresh blood sample will be required for a 
new test. 
13. Presence of other active cancers, or history of treatment for invasive cancer ≤5 years.  
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. 
14. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 


 
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Statistical 
Methodology: 
This study will test no formal hypothesis.  The sample size of 25 patients is based on 
clinical practicalities rather than statistical reasoning, in order to evaluate the safety of 
administration of lanreotide and SIR-Spheres. 


 
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GI 221 CONTACT INFORMATION 
Sarah Cannon Innovations 
Contact Information: 
Sarah Cannon Development Innovations 
1100 Charlotte Avenue, Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
Study Chair: 
Johanna Bendell, MD 
Sarah Cannon  
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 
Sarah Cannon Innovations Enrollment Phone #: 
Sarah Cannon Innovations Enrollment Fax #: 
Sarah Cannon Innovations Enrollment Email: 
1-877-MY-1-SCRI 
1-866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsENR@scri-innovations.com 


 
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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 
DCR 
Disease control rate 
DMC 
Data Monitoring Committee 
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 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
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 
PFS 
Progression-free survival 
PR 
Partial response/remission 
QA 
Quality assurance 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 


 
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LIST OF ABBREVIATIONS (continued) 
SAR 
Suspected adverse reaction 
Sarah Cannon Innovations 
Sarah Cannon Development Innovations, LLC 
SD 
Stable disease 
SUSAR 
Suspected unexpected serious adverse reaction 
UAE 
Unexpected Adverse Event 
ULN 
Upper limit of normal 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 17 
1.1 
Background ........................................................................................................... 17 
1.2 
Rationale for the Study .......................................................................................... 17 
2. 
STUDY OBJECTIVES ......................................................................................... 17 
2.1 
Primary Objective.................................................................................................. 17 
2.2 
Secondary Objectives ............................................................................................ 18 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 18 
3.1 
Inclusion Criteria ................................................................................................... 18 
3.2 
Exclusion Criteria .................................................................................................. 19 
3.3 
Discontinuation from Study Treatment ................................................................. 20 
4. 
STUDY REGISTRATION.................................................................................... 21 
5. 
STUDY DESIGN .................................................................................................. 21 
5.1 
Treatment Plan ...................................................................................................... 21 
5.1.1 
Lanreotide .............................................................................................................. 21 
5.1.2 
SIR-Spheres Microspheres Administration ........................................................... 22 
5.2 
Treatment Duration ............................................................................................... 22 
5.3 
Concomitant Medications...................................................................................... 23 
5.3.1 
Permitted Concomitant Medications ..................................................................... 23 
5.3.2 
Prohibited Concomitant Medications .................................................................... 23 
5.3.3 
Medications Affecting Metabolism via Cytochrome P450 ................................... 24 
6. 
DOSE MODIFICATIONS .................................................................................... 24 
6.1 
Dose Modifications Due to Hematologic Toxicity ............................................... 24 
6.2 
Specific Recommendations for Management of Clinical Events Related to 
Lanreotide .............................................................................................................. 25 
6.2.1 
Cholelithiasis and Gallbladder Sludge .................................................................. 25 
6.2.2 
Hyperglycemia and Hypoglycemia ....................................................................... 25 
6.2.3 
Thyroid Function Abnormalities ........................................................................... 25 
6.2.4 
Cardiovascular Abnormalities ............................................................................... 25 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 26 
7.1 
Overview ............................................................................................................... 26 
7.2 
Baseline Study Assessments ................................................................................. 26 
7.3 
Study Treatment Assessments ............................................................................... 27 
7.3.1 
Day 1 of each cycle ............................................................................................... 27 
7.3.2 
14 - 4 Days Prior to SIR-Spheres Cycle ................................................................ 27 


 
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7.4 
Response Assessment ............................................................................................ 27 
7.5 
End of Study Treatment ........................................................................................ 27 
7.6 
Follow-up .............................................................................................................. 28 
7.6.1 
Follow-up for Patients Who Discontinue Prior to Disease Progression ............... 28 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 28 
8.1 
Lanreotide .............................................................................................................. 28 
8.1.1 
Labeling, Packaging, and Supply .......................................................................... 28 
8.1.2 
Preparation and Administration of Lanreotide ...................................................... 29 
8.1.3 
Precautions and Risks Associated with Lanreotide ............................................... 29 
8.2 
SIR-Spheres® Microspheres .................................................................................. 29 
8.2.1 
Labeling, Packaging, and Supply .......................................................................... 29 
8.2.2 
Preparation and Administration of SIR-Spheres® Microspheres .......................... 29 
8.2.3 
Precautions and Risks Associated with SIR-Spheres® Microspheres ................... 29 
8.3 
Accountability for Lanreotide ............................................................................... 29 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 30 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 30 
10.1 
Statistical Design ................................................................................................... 30 
10.2 
Sample Size Considerations .................................................................................. 30 
10.3 
Analysis Population ............................................................................................... 30 
10.4 
Data Analysis ........................................................................................................ 30 
10.4.1 
Demographics and Baseline Characteristics ......................................................... 31 
10.4.2 
Efficacy Analysis .................................................................................................. 31 
10.4.3 
Safety Analysis ...................................................................................................... 31 
10.5 
Analysis Time Points............................................................................................. 32 
10.5.1 
Final Analysis ........................................................................................................ 32 
10.5.2 
Planned Interim Analysis ...................................................................................... 32 
10.5.3 
Safety Review........................................................................................................ 32 
10.5.4 
Efficacy Review .................................................................................................... 32 
10.6 
Data Monitoring Committee ................................................................................. 32 
10.7 
Steering Committee ............................................................................................... 32 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 32 
11.1 
Definitions ............................................................................................................. 33 
11.1.1 
Adverse Events ...................................................................................................... 33 
11.1.2 
Serious Adverse Event .......................................................................................... 33 
11.1.3 
Adverse Reaction .................................................................................................. 34 
11.1.4 
Suspected Adverse Reaction ................................................................................. 34 


 
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11.1.5 
Recording and Reporting of Adverse Events ........................................................ 34 
11.1.6 
Assessment of Adverse Events.............................................................................. 35 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 35 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 36 
11.3.1 
Diagnosis versus Signs and Symptoms ................................................................. 36 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 36 
11.3.3 
Abnormal Laboratory Values ................................................................................ 37 
11.3.4 
Deaths .................................................................................................................... 37 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 37 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 38 
11.3.7 
New Cancers.......................................................................................................... 38 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 38 
11.3.9 
Lanreotide Overdose ............................................................................................. 38 
11.4 
Sponsor Serious Adverse Event Reporting Requirements .................................... 39 
11.4.1 
Sponsor Assessment of Unexpected...................................................................... 39 
11.4.2 
Sponsor Reporting for Clinical Studies Under an Investigational New Drug 
Application ............................................................................................................ 40 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 40 
12.1 
Study Monitoring, Auditing, and Inspecting ......................................................... 40 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 40 
13.1 
Institutional Review Board Approval.................................................................... 40 
13.2 
Regulatory Approval ............................................................................................. 41 
13.3 
Informed Consent .................................................................................................. 41 
13.3.1 
Confidentiality ....................................................................................................... 41 
13.4 
Financial Information ............................................................................................ 42 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 42 
14.1 
Amendments to the Protocol ................................................................................. 42 
14.2 
Documentation Required to Initiate the Study ...................................................... 43 
14.3 
Study Documentation and Storage ........................................................................ 44 
14.4 
Data Collection ...................................................................................................... 45 
14.5 
Disclosure and Publication Policy ......................................................................... 46 
15. 
REFERENCES ...................................................................................................... 47 
16. 
APPENDICES ....................................................................................................... 48 
 


 
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LIST OF TABLES 
Table 1 
Dose Modifications for Toxicities Suspected to be Related to 
Lanreotide ................................................................................................ 25 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 48 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 49 
Appendix C: 
Guidelines for Female Patients of Childbearing Potential and Fertile 
Male Patients ............................................................................................ 50 
Appendix D: 
Schedule of Assessments ......................................................................... 52 
Appendix E: 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1... 54 
Appendix F: 
Common Substrates for CYP3A .............................................................. 58 
 


 
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1. 
INTRODUCTION 
It is estimated that 8,000 people are diagnosed with neuroendocrine tumors (NETs) and cancers 
originating in the gastrointestinal tract (the stomach, intestine, appendix, colon, or rectum) each 
year in the United States (US).  The US Food and Drug Administration (FDA) has approved 
lanreotide (Somatuline® Depot Injection, Ipsen Pharma) to treat advanced gastrointestinal 
neuroendocrine tumors and advanced pancreatic neuroendocrine tumors.   
1.1 
Background 
For patients with unresectable liver metastases from NETs, radioembolization (RE) can achieve 
durable hepatic tumor response while alleviating symptoms.  Radioembolization with yttrium-90 
microspheres (SIR-Spheres® therapy) is FDA approved for the treatment of unresectable 
metastatic liver tumors from primary colorectal cancer with adjuvant intra-hepatic artery 
chemotherapy (IHAC) of floxuridine (FUDR).  SIR-Spheres therapy enables multiple liver 
metastases to be targeted in a single procedure, and delivers targeted radiation to these tumors 
while limiting the dose experienced by normal liver parenchyma (Kennedy et al 2012(a), 
Kennedy et al 2012(b)).   
An objective response rate (ORR) of 63% was reported in a retrospective review of 148 patients 
with unresectable liver metastases from NETs who received SIR-Spheres therapy; two-thirds of 
patients did not experience acute or delayed grade 3/4 toxicity (Kennedy et al 2008).  A 
prospective Phase II trial was conducted, in which SIR-Spheres were administered in 
combination with a 7-day infusion of 5-fluorouracil to 34 patients with unresectable metastatic 
NETs (mNETs) (King et al 2008).  A radiographic response by Response Evaluation Criteria in 
Solid Tumors (RECIST) was reported in 50% of these patients. 
In NETs that express somatostatin receptors, somatostatin analogues can control hypersecretion 
and help manage symptoms.  In addition, some of these agents have recently been shown in 
controlled trials to have some anti-proliferative effects.  Lanreotide is a somatostatin analogue 
which was shown to significantly prolong progression-free survival (PFS) in patients with 
gastroenteropancreatic NETs compared to placebo in the CLARINET trial (Caplin et al. 2014).   
1.2 
Rationale for the Study 
To our knowledge, there have not been studies conducted to formally assess the safety of co-
administration of lanreotide and RE with SIR-Spheres.  However, given the promising results of 
each of these individual treatments in this patient population, it is important to determine how to 
optimize these therapies for patients with NETs. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to: 


 
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• Evaluate the safety of concomitant administration of lanreotide for patients undergoing 
liver-directed radioembolization with yttrium-90 microspheres (SIR-Spheres). 
2.2 
Secondary Objectives 
The secondary objective of this study is to: 
• Evaluate the objective response rate (ORR), disease control rate (DCR), progression-free 
survival (PFS), and overall survival (OS). 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Metastatic well-to-moderately differentiated (or low-grade) neuroendocrine carcinoma, 
including typical carcinoid or pancreatic islet cell carcinoma. 
2. Computerized tomography (CT) scan evidence of liver metastases which are not treatable 
by surgical resection or local ablation with curative intent at the time of study entry.  If a 
CT scan is not possible, then an MRI may be used. 
3. Patients who are currently receiving or have previously received lanreotide or another 
somatostatin analogue are eligible.  Previous treatment with lanreotide or another 
somatostatin analogue is not required for study entry. 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 
(Appendix A). 
5. Adequate hematologic function defined as: 
- Absolute neutrophil count (ANC) ≥1500/μL 
- Hemoglobin (Hgb) ≥9 g/dL 
- Platelets ≥100,000/µL 
6. Adequate liver function defined as: 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN) 
- Total bilirubin ≤1.2 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin) 
7. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR 
calculated creatinine clearance ≥50 mL/min as calculated by Cockcroft and Gault 
Formula. 
8. Male patients with female partners of childbearing potential and women patients of 
childbearing potential are required to use two forms of acceptable contraception, 


 
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including one barrier method, during their participation in the study and for 3 months (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 3 months (90 days) after the last dose 
of study drug (Appendix C). 
9. Life expectancy ≥ 3 months. 
10. Age ≥18 years. 
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. Anti-cancer therapy with the exception of lanreotide or another somatostatin analogue 
within 21 days or 5 half-lives (whichever is shorter) of starting study treatment. 
2. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to Cycle 1 
Day 1 or has not recovered from side effects of such therapy. 
3. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
4. 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.   
5. Clinically significant ascites, cirrhosis, portal hypertension, or thrombosis as determined 
by clinical or radiologic assessment. 
6. Pregnant or lactating 
7. Acute or chronic liver, renal, or pancreas disease. 
8. Any of the following cardiac diseases currently or within the last 6 months: 
- Left Ventricular Ejection Fraction (LVEF) <45% as determined by Multiple 
Gated Acquisition (MUGA) scan or echocardiogram (ECHO) 
- QTc interval >480 ms on screening electrocardiogram (ECG) 
- Unstable angina pectoris 
- Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2 
[Appendix B]) 
- Acute myocardial infarction 
- Conduction abnormality not controlled with pacemaker or medication 


 
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- 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 
9. 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). 
10. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low molecular 
weight heparin is allowed. 
11. 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. 
12. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.  
Laboratory test results ≤1 year will be confirmed by the treating physician prior to study 
enrollment.  If results are ≥1 year old, a fresh blood sample will be required for a new 
test. 
13. Presence of other active cancers, or history of treatment for invasive cancer ≤5 years.  
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. 
14. 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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After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 calendar 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 patient’s 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] v4.03) 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.  Institutional Review Board (IRB) 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 Sarah Cannon Development Innovations (Sarah Cannon 
Innovations).  Registration may be made via email CANN.SCRIInnovationsEnr@scri-
innovations.com or fax 866-346-1062, 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 is an open-label, prospective, multi-center Phase II study for patients with metastatic well-
to-moderately differentiated neuroendocrine tumors (including typical carcinoid and pancreatic 
neuroendocrine tumors) who are candidates for liver-directed radioembolization.  Patients will 
receive treatment with lanreotide (120 mg subcutaneously [SQ] every 28 days) in combination 
with SIR-Spheres treatment (dose and treatment day to be determined by treating radiation 
oncologist).  Patients who are currently receiving or have previously received lanreotide are 
eligible, and treatment with lanreotide can continue monthly until disease progression or 
unacceptable toxicity.   
5.1 
Treatment Plan 
5.1.1 
Lanreotide 
Lanreotide 
120 mg Day 1 of every cycle (every 28 days) by deep subcutaneous injection 
Lanreotide will be given every 28 days, irrespective of when SIR-Spheres is administered.  No 
waiting or adjusting of the schedule is required. 


 
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Radioembolization using SIR-Spheres Microspheres 
Patients must be assessed with a hepatic angiogram and “break-through” scan to determine 
suitability for SIR-Spheres.  These “mapping” procedures will be completed by the radiation 
oncologist 14-4 days prior to SIR-Spheres treatment. 
Hepatic Angiogram 
The patient will undergo a preliminary angiogram of the liver to determine the vascular 
anatomy of the liver.  The hepatic angiogram will provide a road map of the arterial supply of 
the liver in order to plan delivery of the SIR-Spheres microspheres.  The hepatic angiogram 
should be performed together with the “break-through” scan and results must be available 
prior to radioembolization with SIR-Spheres (see Appendix D). 
Liver-Lung Break-Through Nuclear Scan 
In order to mitigate the possibility of including patients who exhibit excessive liver-to-lung 
shunting a nuclear medicine “break-through” scan using 99mTechnetium (Tc) macroaggregated 
albumin will be performed in all patients prior to SIR-Spheres treatment.   
If either the hepatic angiogram or the liver-lung break-through nuclear scan shows that a patient 
is ineligible to receive SIR-Spheres, then the patient will be removed from study. 
5.1.2 
SIR-Spheres Microspheres Administration 
SIR-Spheres microspheres will be administered by a certified radiation oncologist, interventional 
radiologist, or nuclear medicine physician to the patient by injection through a trans-femoral 
catheter into the hepatic artery.  All areas of tumor within the liver will be targeted with SIR-
Spheres microspheres which usually involves treating both lobes of the liver.  However, it is vital 
that the SIR-Spheres microspheres are not delivered to other organs such as the duodenum, 
stomach, pancreas, etc. 
If metastases are present in both lobes, then it is preferable that SIR-Spheres treatment to both 
lobes be done during the same visit.  If the metastases are limited to only one lobe, the 
radiologist can insert the catheter selectively into the lobar artery supplying only that lobe that 
contains the metastases.  The SIR-Spheres microspheres will then be delivered only to the lobe 
containing the metastases with sparing of the other normal lobe.  The SIR-Spheres microspheres 
are injected slowly into the hepatic artery to avoid reflux back down the hepatic artery and 
placement in the pancreas, stomach and other organs. 
5.2 
Study Duration 
The end of the study is defined as the 12-month time point after the final patient is enrolled. 
Patients will be evaluated for toxicity at the start of each cycle.  Every 2 cycles, restaging will 
occur with imaging, laboratory chemistries, and tumor markers as defined in Appendix D.  
Patients will continue on treatment until progression as defined in Appendix E or intolerance to 
side effects.   


 
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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 
Premedication with anti-emetics is allowed 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 
• Anticoagulation with coumarin-derivatives will not be permitted.  However, a maximum 
daily dose of 1 mg will be permitted for port line patency.  Should a thrombotic event 
occur while the patient is receiving treatment the patient may continue, but low molecular 
weight heparin (LMWH) will be the preferred treatment.  However, other non-coumarin 
anticoagulants (Xarelto®) are acceptable. 
• Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of 
insulin and glucagon.  Therefore, blood glucose levels should be monitored when 
lanreotide treatment is initiated or when the dose is altered, and antidiabetic treatment 
should be adjusted accordingly.  Patients who develop hyperglycemia during the study 
should be treated according to the American Diabetes Association guidelines.   
• Concomitant administration of cyclosporine with lanreotide may decrease the relative 
bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine 
dose to maintain therapeutic levels. 
• Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have 
an additive effect on the reduction of heart rate associated with lanreotide.  Dose 
adjustments of concomitant medication may be necessary. 
The pharmacological gastrointestinal effects of lanreotide may reduce the intestinal absorption of 
concomitant drugs.  Limited published data indicate that concomitant administration of a 
somatostatin analog and bromocriptine may increase the availability of bromocriptine. 
Vitamin K absorption was not affected when concomitantly administered with lanreotide. 
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the investigator with the exception of those listed in Section 5.3.2. 
5.3.2 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 


 
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• 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. 
5.3.3 
Medications Affecting Metabolism via Cytochrome P450 
The limited published data available indicate that somatostatin analogs may decrease the 
metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, 
which may be due to the suppression of growth hormone.  Since it cannot be excluded that 
lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a 
low therapeutic index (e.g. quinidine, terfenadine; see Appendix F) should therefore be used with 
caution.  Drugs metabolized by the liver may be metabolized more slowly during lanreotide 
treatment and dose reductions of the concomitantly administered medications should be 
considered. 
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_4.03_2010-06-14_QuickReference_5x7.pdf), 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. 
6.1 
Dose Modifications Due to Hematologic Toxicity 
If hematologic toxicity occurs, hold all study drugs and re-evaluate in 1 week.  Absolute 
neutrophil count (ANC) and platelets should be monitored weekly until recovery.  If ANC and/or 
platelets do not recover within 3 weeks, the patient will be discontinued from the study. 
Dose modifications on Day 1 of each cycle will be based on blood counts determined on the day 
of scheduled treatment.  Nadir blood counts will not be used to determine dose modifications.  
Treatment on Day 1 of any cycle will proceed if blood counts demonstrate ANC >1500/µL and 
platelets>100,000/µL. 


 
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Table 1 
Dose Modifications for Toxicities Suspected to be Related to Lanreotide 
6.2 
Specific Recommendations for Management of Clinical Events Related to 
Lanreotide 
6.2.1 
Cholelithiasis and Gallbladder Sludge 
Lanreotide may reduce gallbladder motility and lead to gallstone formation; therefore, patients 
may need to be monitored periodically. 
6.2.2 
Hyperglycemia and Hypoglycemia 
Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other 
somatostatin analogues, inhibits the secretion of insulin and glucagon.  Hence, patients treated 
with lanreotide may experience hypoglycemia or hyperglycemia.  Blood glucose levels should be 
monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic 
treatment should be adjusted accordingly. 
6.2.3 
Thyroid Function Abnormalities 
Slight decreases in thyroid function have been seen during treatment with lanreotide in 
acromegalic patients, though clinical hypothyroidism is rare (<1%).  Thyroid function tests are 
recommended where clinically indicated. 
6.2.4 
Cardiovascular Abnormalities 
In patients without underlying cardiac disease, lanreotide may lead to a decrease in heart rate 
without necessarily reaching the threshold of bradycardia.  In patients suffering from cardiac 
disorders prior to lanreotide treatment, sinus bradycardia may occur.  Care should be taken when 
initiating treatment with lanreotide in patients with bradycardia. 
Toxicity 
Grade 
Actions 
Non-hematological 
1 or 2 
Continue lanreotide therapy at full dose with optimal supportive care. 
 
 
3 or 4 
Delay lanreotide until recovery to Grade ≤ 1 with optimal supportive 
care.   
 
If symptoms recur, discontinue the study. 
Hematological 
 
1 or 2 
Continue lanreotide therapy at full dose, with optimal supportive care 
 
3 or 4 
Delay study treatment until neutrophils ≥0.75 x109/L (750/mm3), 
platelets ≥50 x109/L (50,000/mm3) and Hgb ≥ 9.0 g/dL 
 
If toxicity recurs, discontinue the study. 


 
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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, electrocardiogram (ECG), 
complete blood counts (CBC), 3-part differential and platelets, comprehensive metabolic profile 
(CMP),  and prothrombin time (PT)/partial thromboplastin time (PTT)/International 
Normalization Ratio (INR) 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.   
7.2 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
screening: 
• Written informed consent prior to any study-related procedures (≤28 days prior to 
initiation of treatment) 
• Medical history 
• Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, blood pressure [BP], and oral temperature) 
• Results of HIV, hepatitis B, and hepatitis C tests will be confirmed if taken within the 
past 1 year. If test results are >1 year old, patient will be required to provide a fresh blood 
sample for a new test. 
• ECOG performance status (see Appendix A) 
• 12-lead ECG 
• Concomitant medication review 
• CBC with 3-part differential and platelets 
• CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (APT), AST, ALT, total 
bilirubin, total protein, and albumin. 
• PT/PTT/INR 
• Serum or urine pregnancy test (must be performed within 72 hours of Cycle 1 Day 1) 
• CT scans of the chest, abdomen/pelvis ≤28 days prior to initiation of study treatment.  If a 
CT scan is not possible, then an MRI may be used. 


 
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7.3 
Study Treatment Assessments  
7.3.1 
Day 1 of each cycle 
• Physical examination, including measurement of weight and vital signs 
• ECOG performance status 
• Adverse event (AE) assessment 
• Concomitant medication review 
• CBC, including 3-part differential and platelets (may be done up to 72 hours prior to 
treatment) 
• CMP (may be done up to 72 hours prior to treatment) 
7.3.2 
14 - 4 Days Prior to SIR-Spheres Cycle 
The following tests will be obtained 14-4 days prior to SIR-Spheres treatment: 
• Hepatic angiogram 
• 
99mTc MAA lung shunt scan 
7.4 
Response Assessment  
It is recommended, but not required, for patients to have CT scans prior to and 6 weeks 
following treatment with SIR-Spheres.  Patients will have CT scans performed 12 weeks after 
SIR-Spheres treatment. 
After the post-SIR-Spheres 12-week scans, patients will be evaluated for response to treatment 
after every 2 cycles of lanreotide.  The following assessments will be performed:  
• CT scans of chest, abdomen and pelvis.  If CT chest is normal at baseline this does not 
have to be repeated with each restaging unless there is a clinical reason to do so.  If a CT 
scan is not possible, then an MRI may be used. 
Patients with progressive disease or unacceptable toxicity should be discontinued from the study; 
patients with stable disease or response to therapy will continue treatment. 
7.5 
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 fulfill 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: 
• Physical examination, including measurement of weight and vital signs 


 
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• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• CBC, including 3-part differential and platelets 
• CMP  
• CT scans/MRI of chest, abdomen and pelvis (unless taken within the previous 8 weeks) 
7.6 
Follow-up 
7.6.1 
Follow-up for Patients Who Discontinue Prior to Disease Progression 
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed every 3 months (±1 month) from the date of last dose of study drug until disease 
progression.  Tests to be performed are listed in Appendix D.  No follow up will be done for 
survival or if the patient starts a subsequent therapy. 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
Lanreotide 
 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Lanreotide 
120 mg 
Ipsen Pharma Biotech 
 
8.1.1 
Labeling, Packaging, and Supply 
Lanreotide is supplied in strengths of 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL in a 
single, sterile, prefilled, ready-to-use, polypropylene syringe (fitted with an automatic needle 
guard) fitted with a 20 mm needle covered by a low density polyethylene sheath. 
Each prefilled syringe is sealed in a laminated pouch and packed in a carton. 
NDC 15054-1060-3 60 mg/0.2 mL, sterile, prefilled syringe 
NDC 15054-1090-3 90 mg/0.3 mL, sterile, prefilled syringe 
NDC 15054-1120-3 120 mg/0.5 mL, sterile, prefilled syringe 
Lanreotide must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light 
in its original package.  Thirty (30) minutes prior to injection, remove sealed pouch of lanreotide 
from refrigerator and allow it to come to room temperature.  Keep pouch sealed until injection. 


 
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Each syringe is intended for single use.  Do not use lanreotide beyond the expiration date on the 
packaging. 
8.1.2 
Preparation and Administration of Lanreotide 
Lanreotide is provided in a single-dose, prefilled syringe affixed with an automatic needle 
protection system.  Inject lanreotide via the deep subcutaneous route in the superior external 
quadrant of the buttock.  Alternate the injection site between the right and left sides from one 
injection to the next.  Remove lanreotide from the refrigerator 30 minutes prior to administration.  
Keep pouch sealed until just prior to injection. 
8.1.3 
Precautions and Risks Associated with Lanreotide 
Please refer to the prescribing information for information regarding precautions and risks 
associated with lanreotide 
(http://www.somatulinedepot.com/static/download/Somatuline%20Depot%20Full%20Prescribin
g%20Information.pdf). 
8.2 
SIR-Spheres® Microspheres 
SIR-Spheres microspheres are to be administered in accordance with the terms of its marketing 
authorization and in accordance with institutional standard of practice.  Please refer to the US 
Package Insert http://www.sirtex.com/us/clinicians/package-insert for detailed information on 
how to prepare and administer SIR-Spheres microspheres. 
8.2.1 
Labeling, Packaging, and Supply 
Each site will procure a supply of SIR-Spheres microspheres, which is commercially available. 
All study medications must be kept in a secure place under appropriate storage conditions.  
Storage conditions for SIR-Spheres microspheres can be found in the relevant US Package 
Insert.  The product must not be used after the expiration date on the label. 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
8.2.2 
Preparation and Administration of SIR-Spheres® Microspheres 
SIR-Spheres microspheres should be prepared and administered in accordance with information 
in the approved labeling.   
8.2.3 
Precautions and Risks Associated with SIR-Spheres® Microspheres 
Please refer to the US Package Insert 
http://www.accessdata.fda.gov/cdrh_docs/pdf/P990065c.pdf for detailed information on the risks 
associated with the use of SIR-Spheres microspheres. 
8.3 
Accountability for Lanreotide 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
lanreotide drug supplies at the site. 
All lanreotide drug inventories must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 


 
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At the end of the study, all Sarah Cannon Innovations Drug Accountability Record Form(s) will 
be completed by the site and sent to the Sarah Cannon Innovations Regulatory Department.  
Lanreotide drug supplies must not be destroyed unless prior approval has been granted by the 
Sponsor or its representative.  Please contact Sarah Cannon Innovations regarding disposal of 
lanreotide. 
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 (Eisenhauer et al. 2009) (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 is an open-label, prospective, multi-center study for patients with metastatic well-to-
moderately differentiated neuroendocrine tumors (including typical carcinoid and pancreatic 
neuroendocrine tumors) who are candidates for liver-directed radioembolization.  Patients will 
receive treatment with lanreotide (120 mg monthly injections) in combination with SIR-Spheres 
treatment (dose and treatment day to be determined by treating radiation oncologist).   
10.2 
Sample Size Considerations 
This study will test no formal hypothesis.  The sample size of 25 patients is based on clinical 
practicalities rather than statistical reasoning, in order to evaluate the safety of administration of 
lanreotide and SIR-Spheres. 
10.3 
Analysis Population 
The following analysis populations will be used: 
• The Safety Analysis Set (SAF) / Safety Population is defined as all patients who have 
received at least one dose of both study medication, i.e. at least one dose of lanreotide 
(120 mg subcutaneously [SQ] every 28 days) and at least one dose of SIR-Spheres 
treatment 
10.4 
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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10.4.1 
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. 
10.4.2 
Efficacy Analysis 
All efficacy analyses will be performed using the Safety Analysis Set. 
• 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 criteria.  
 
• Disease Control Rate (DCR) is defined as the proportion of patients with CR, PR or SD 
according to the RECIST v1.1 criteria. 
 
o For ORR and DCR, patients without a post-baseline tumor assessment will be 
classed as not evaluable (NE) and considered as non-responder. 
 
• Progression Free Survival (PFS), defined as the time from the first day of study drug 
administration (Day 1) to disease progression as defined by the RECIST v1.1 criteria, or 
death on study.  Patients who are alive and free from disease progression will be censored 
at the date of last tumor assessment. 
 
• Overall Survival (OS), defined as the time from the first day of study drug administration 
(Day 1) until death on study.  Patients who are alive will be censored at the date of last 
known date alive. 
For ORR and DCR, the estimates and the associated 95% CI (based on the Clopper-Pearson 
method) in each treatment group will be calculated.  The absolute and relative difference in ORR 
and DCR between the two treatment groups will also be presented. 
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and the 
associated 95% CI be provided.  The 95% CI for these endpoints will be calculated. 
10.4.3 
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 the CTCAE scoring system may be 
downloaded from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. 
The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized using system organ class and preferred term for all patients in the Safety Analysis 
Set.  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. 


 
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Other safety endpoints including laboratory results, vital signs and ECG findings will be 
summarized for all patients in the Safety Analysis Set.  
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized. 
The safety analysis is the primary endpoint of this study.   
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur 12 months after the last patient is enrolled. 
10.5.2 
Planned Interim Analysis 
The safety data will be reviewed periodically after every 6 patients received treatment for 3 
months. 
10.5.3 
Safety Review 
The study will stop if Grade 3/4 treatment-related AEs are seen in ≥33% of patients. 
10.5.4 
Efficacy Review 
There is no efficacy review planned. 
10.6 
Data Monitoring Committee 
There is no Data Monitoring Committee (DMC) planned for this study. 
10.7 
Steering Committee 
There is no Steering Committee planned for this study. 
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 hematology, clinical chemistry, 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 SAEs to the Sarah 
Cannon Innovations Safety Department (see Section 11.2).  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 
according to the policies of that IRB.  
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 


 
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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. 
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. 


 
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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. 
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 v4.0, and changes will be documented. 
If the AE is serious, it should be reported immediately to Sarah Cannon 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. 
All adverse events (serious and non-serious) as well as special reporting circumstances, such as 
exposure via a parent during pregnancy or breast-feeding, overdose, medication error, misuse, 
abuse, off-label use or occupational exposure should be collected on the relevant eCRF where 
appropriate. 
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 


 
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All AEs regardless of seriousness or relationship to lanreotide treatment (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. 
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”, regardless of causality, require 
expeditious handling and reporting to Sarah Cannon 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 30 days after the 
last dose of study.  The Sarah Cannon 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. 


 
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The SAE report should be sent to the Sarah Cannon Innovations Safety Department via fax or e-
mail using the using the following contact information (during both business and non-business 
hours): 
Sarah Cannon 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.  
SAE reports will be sent to Ipsen Biopharmaceuticals, Inc. from the Sarah Cannon Innovations 
Safety Department within 24 hours of receipt of the SAE report by Sarah Cannon Innovations. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Sarah Cannon Innovations Safety Department as soon as it is available; 
these reports should be submitted using the Sarah Cannon Innovations SAE Report Form.   
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
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. 


 
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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. 
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 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 
Innovations Safety Department. 


 
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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. 
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 (see Section 11.1.2).  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 (a paper report 
form, not available within the eCRF) should be completed and faxed to the Sarah Cannon 
Innovations Safety Department.  The Sarah Cannon 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 the Sarah Cannon 
Innovations Safety Department.  Sarah Cannon Innovations will forward the pregnancy form to 
Ipsen Biopharmaceuticals, Inc. 
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 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 
Lanreotide 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 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 (see Section 11.2) if the 
overdose is symptomatic. 
For information on how to manage an overdose of lanreotide, see the Investigator’s Brochure. 


 
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11.4 
Sponsor Serious Adverse Event Reporting Requirements 
SAE and pregnancy information will be collected on the Sarah Cannon SAE Report Form and 
forwarded to Ipsen Biopharmaceuticals, Inc. Call Center, Fax:  866-792-7415 within 24 hours of 
Sarah Cannon Innovations Safety Department personnel becoming aware of the SAE. 
Sarah Cannon Innovations is responsible for reporting relevant SAEs to the competent authority, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonisation (ICH) guidelines, FDA regulations. 
In addition, Ipsen Biopharmaceuticals and Sarah Cannon Development Innovations will report to 
the other significant safety or efficacy information (i.e., information that may affect the safety of 
patients in the Study or receiving the Study Drug in any other environment, such as, without 
limitation, commercial supply) immediately and within a maximum of 24 hours of identification 
of the information. 
11.4.1 
Sponsor Assessment of Unexpected 
The Sponsor is responsible for assessing an adverse event or suspected adverse event as 
“unexpected.” 
An adverse event or suspected adverse reaction is considered “unexpected” when the following 
conditions occur: 
• Event(s) is not mentioned in the current US Package Insert 
• 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 SARs 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 adverse event may also apply to an event that is not listed in the 
current US Package Insert (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 are 
suspected (by the Investigator or Sponsor) to be related to the study drug, are unexpected (not 
listed in the Investigator’s Brochure 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 Package Insert or current IB. 


 
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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 Innovations Safety 
Department must also be faxed to pharmaceutical company(ies) that are supporting the study 
with either funding or drug supply: 
Ipsen Biopharmaceuticals, Inc. Call Center 
Fax:  866-792-7415 
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 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). 
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), IB, 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 


 
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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. 
Safety updates for lanreotide 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 that includes 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 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 
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 Innovations shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized party. 
13.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between 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. 


 
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If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representatives.  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, or 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 include, 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. 
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 Innovations 
Regulatory Department 
1100 Charlotte Avenue, Suite 800 
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 


 
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• 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 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 
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 
signed ICFs, 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, and 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. 


 
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The Sponsor shall maintain adequate investigational 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 marketing 
application has been approved by the FDA; or, in the event that the marketing application has not 
been approved by the FDA, 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 IRB shall maintain adequate documentation/records of IRB activities as per 21CFR Part 
56.115 for at least 3 years after completion of the research. 
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 
marketing application has been approved by the FDA; or, in the event that the marketing 
application has not been approved by the FDA, 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 Innovations) throughout the study, and will be held by the Sponsor at the 
conclusion of the study. 
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 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. 


 
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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 
sixty (60) days solely to permit the Sponsor to seek patent protection and to remove any Sarah 
Cannon Innovations Confidential Information from all publications. 


 
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15. 
REFERENCES 
Caplin et al. 2014 
Caplin, M. E., Pavel, M., Ćwikła, J. B., et al. Lanreotide in metastatic enteropancreatic 
neuroendocrine tumors. New Eng J of Med 2014: 371, 224-233. 
Eisenhauer et al. 2009 
Eisenhauer EA et al. New response evaluation criteria in solid tumours; revised RECIST 
guideline (version 1.1).  Eur J Cancer. 2009; 45 p. 228-47. 
Kennedy et al 2012(a) 
Kennedy, A., Coldwell, D., Sangro, B., et al. Integrating radioembolization into the treatment 
paradigm for metastatic neuroendocrine tumors in the liver. Am J Clin Oncol 2012: 35, 393-398. 
Kennedy et al 2012(b) 
Kennedy, A., Coldwell, D., Sangro, B., et al. Radioembolization for the treatment of liver tumors 
general principles. Am J Clin Oncol 2012: 35, 91-99. 
Kennedy et al 2008 
Kennedy, A. S., Dezarn, W. A., McNeillie, P., et al. Radioembolization for unresectable 
neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. 
Am J Clin Oncol 2008: 31, 271-279. 
King et al 2008 
King, J., Quinn, R., Glenn, D. et al. Radioembolization with selective internal radiation 
microspheres for neuroendocrine liver metastases. Cancer 2008: 113, 921-929.  
 


 
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16. 
APPENDICES 
 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 


 
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Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 


 
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Appendix C: Guidelines for Female Patients of Childbearing Potential and Fertile Male 
Patients 
 
Acceptable Contraception Methods:   
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 3 months after 
stopping treatment.   
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Sterilization  
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks prior to study entry.  In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 
Male Partner Sterilization When the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Use of a combination of any two of the following (one from a + one from b): 
a)  Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or established use of oral, injected or implanted hormonal 
methods of contraception. 
b)  Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
Fertile male patients, defined as all males physiologically capable of conceiving offspring, 
with female partners of child-bearing potential must use condoms plus spermicidal agent 
during the study treatment period and for 3 months after the last dose of study drug, and 
should not father a child during this period. 
Male patients must also refrain from donating sperm during their participation in the study. 
The following are acceptable forms of barrier contraception: 
• Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
Unacceptable Contraception Methods: for women of childbearing potential include: 
• IUD progesterone T 
• Female condom 


 
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• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported to 
the Sarah Cannon Innovations Safety Department within 24 hours of learning of its 
occurrence.  The pregnancy should be followed up for 3 months after the termination of the 
pregnancy to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the Sarah Cannon Innovations Safety Department.  Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the study drug of any pregnancy outcome.  Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not of Childbearing Potential are defined as follows:   
• Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms).  
• Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy).   
• Women who are >45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 12 months OR who have a 
follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value 
<40 pg/mL (140 pmol/L). 
• Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 


 
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Appendix D: Schedule of Assessments  
Procedures 
Screening 
Lanreotide 
Every cycle 
SIR-Spheres 
TBD 
Restaging 
Every 2 
cycles 
 
End of 
Treatmenti 
Follow-Up 
Baseline 
Day 
Day 
Prior to Disease 
Progressionj 
1 
TBD 
TESTS & OBSERVATIONS 
 
Informed Consenta  
X 
 
 
 
 
 
Medical history 
Xb 
 
 
 
 
 
Physical examination, vital 
signs, height, weightc 
Xb 
X 
 
 
X 
X 
ECOG Performance Status 
Xb 
X 
 
 
X 
X 
12-lead ECG 
Xb 
 
 
 
 
 
HIV/HBV/HCV Tests/Results 
Xb 
 
 
 
 
 
Adverse event evaluation 
 
X 
 
 
X 
X 
Concomitant medication review 
X 
X 
 
 
X 
X 
LABORATORY TESTS 
 
CBC, including 3-part 
differential and platelets 
Xb 
X 
 
 
X 
X 
CMPd 
Xb 
X 
 
 
X 
X 
PT/PTT/INRe 
Xb 
 
 
 
 
 
Serum or urine pregnancy testf 
X 
 
 
 
 
 
DISEASE ASSESSMENT 
 
CT scan/MRI of the chest, 
abdomen, pelvisg 
X 
 
 
Xg 
X 
X 
Hepatic angiogram 
 
 
X 
 
 
 
99mTc MAA lung shunt scanh 
 
 
X 
 
 
 


 
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Appendix D: Schedule of Assessments (continued)   
 
a 
Informed Consent must be obtained ≤28 days prior to the initiation of study treatment. 
b 
Baseline procedures including medical history, physical examination, ECOG PS, 12-lead ECG, CBC, CMP, and PT/PTT/INR 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.  
Also at screening visit, treating physician will confirm results of HIV, hepatitis B, and hepatitis C tests if taken within the past 1 year. If results >1 year 
old, patient must provide a fresh blood sample for a new test.  
c 
Physical examination will include measurements of height (pretreatment visit only), weight, and vital signs (resting heart rate, blood pressure, and 
temperature).   
d 
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST (SGOT), ALT 
(SGPT), total bilirubin, total protein, and albumin.  CMP may be done up to 72 hours prior to treatment.     
e 
If PT/PTT/INR are normal at baseline they do not need to be repeated.  Patients requiring the initiation of an anti-coagulation therapy during study 
treatment should have coagulation tests performed according to standard practice guidelines. 
f 
Serum or urine pregnancy tests are to be conducted in women of childbearing potential within 72 hours of Cycle 1 Day 1.   
g 
CT scans of the chest, abdomen/pelvis ≤28 days prior to initiation of treatment.  It is recommended, but not required, for patients to have CT scans prior 
to and 6 weeks following treatment with SIR-Spheres.  Patients will have CT scans performed 12 weeks after SIR-Spheres treatment.  After the post-
SIR-Spheres 12 week scans, patients will be evaluated for response to treatment after every 2 cycles of lanreotide.  The following assessments will be 
performed: CT scans of chest, abdomen and pelvis.  If CT chest is normal at baseline this does not have to be repeated with each restaging unless there 
is a clinical reason to do so.  If a CT scan is not possible, then an MRI may be used. 
h 
Patients will be at assessed 14-4 days prior to SIR-Spheres treatment to determine the suitability for SIR-Spheres (see Section 7.3.2)  
i 
All patients will undergo the End of Treatment visit assessments listed within 30 days after treatment ends due to completion of the planned study 
treatment period, or once a patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or the study physician.  
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 fulfill 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. 
j 
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 3 months (±1 month) from the date of 
last dose of study drug until disease progression.  PFS will be evaluated for this trial 6 and 12 months after the last patient is enrolled.  No follow up will 
be done for survival or if the patient starts a subsequent therapy. 
 
  


 
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Appendix E: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Definitions 
Response and progression will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (Eisenhauer et al. 2009).  Lesions are either measurable or non-measurable using the criteria 
provided below.  The term “evaluable” in reference to measurability will not be used, as it does not provide 
additional meaning or accuracy. 
Baseline Eligibility 
Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of: 
• 
10 mm by CT by computerized tomography (CT scan slice thickness 
no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 
20 mm by chest x-ray. 
 
Skin lesions:  Documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by 
CT scan.  At baseline and in follow-up, only the short axis will be measured 
and followed.  
Non-Measurable Disease: 
All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10- to <15-mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses, 
abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.  
Target Lesions: 
The most reproducible measurable lesions, up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs should be 
identified as target lesions and recorded and measured at baseline.   
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), should be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible repeated 
measurements.  Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a short axis of 
≥15 mm by CT scan. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then as noted 
above, only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
response. 


 
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Non-Target Lesions: 
All other lesions should be identified as non-target lesions at baseline.  
Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
Guidelines for Evaluation of Measureable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment, as per protocol screening 
requirements. 
The same method of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up.  Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a treatment. 
 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter.  In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest X-ray: 
Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, a CT scan is 
preferable. 
Conventional CT and MRI: 
CT, MRI:  CT is the best currently available and reproducible method to 
measure lesions selected for response assessment.  This guideline has 
defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5mm or less.  When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).  
Ultrasound: 
When the primary study endpoint is objective response, ultrasound should 
not be used to measure tumor lesions.  It is, however, a possible alternative 
to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules.  Ultrasound may also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
Endoscopy and Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated.  Therefore, use of these techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers.  Such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper limit of normal, they must normalize for a subject to 
be considered in complete clinical response when all lesions have 
disappeared. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between partial response 
(PR) and complete response (CR) in rare cases (e.g., after treatment to 
differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 


 
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Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.   
Partial Response (PR):  
 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.. 
Stable Disease (SD):   
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest (nadir) sum of diameters 
since the treatment started. 
Progressive Disease (PD):   
 
At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest (nadir) sum since the treatment started, or the 
appearance of one or more new lesions.  Requires not only 20% increase, but 
absolute increase of a minimum of 5 mm over sum. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor markers.  
All lymph nodes must be non-pathological in size (<10 mm short axis). 
Stable Disease (SD):    
 
Persistence of one or more non-target lesions and/or persistence of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  When the subject also has measurable disease, to 
achieve “unequivocal progression” on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in the target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. 
 
Evaluation of Best Overall Response 
As detailed above, the best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).  
In general, the subject’s best response assignment will depend on the achievement of both measurement and 
confirmation criteria.   
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is required for studies in 
which response rate is the primary endpoint, but is not required in randomized studies or studies with primary 
survival endpoints (i.e., where response is not a primary endpoint).


 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
SD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
SD OR NE 
NO 
PR 
SD 
SD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the evaluation 
of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle 
aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” size (<10 mm), they 
may still have a measurement reported on scans.  This measurement should be recorded even though the nodes are 
normal in order not to overstate progression, should it be based on increase in size of the nodes.  As noted earlier, 
this means that subjects with CR may not have a total sum of “zero” on the eCRF. 


 
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Appendix F: Common Substrates for CYP3A 
The following list describes medications which are common substrates for CYP3A.   
This list should not be considered all-inclusive.   
 
CYP3A Substrates with Narrow Therapeutic Index 
Alfentanil 
Astemizole 
Cisapride 
Cyclosporine 
Dihydroergotamine 
Ergotamine 
Fentanyl 
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus  
Terfenadine 
 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#classSub (September 19, 2015)