Clinical trial NCT02318784
Conditions: Neuroendocrine Cancer
Keywords: neuroendocrine malignancies pancreatic neuroendocrine tumors (PNETs) gastrointestinal (GI) carcinoids carfilzomib Kyprolis proteasome inhibitors
Sponsor: SCRI Development Innovations, LLC
Start date: 2015-07-15; Completion date: 2021-05-15
Enrollment: 62 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if carfilzomib is safe and effective in the treatment of patients with advanced neuroendocrine tumors.

Detailed description:
Neuroendocrine malignancies such as pancreatic neuroendocrine tumors (PNETs) and gastrointestinal (GI) carcinoids, are generally rare but their incidences are increasing. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. Carfilzomib (Kyprolis®) is an irreversible proteasome inhibitor with a favorable safety profile that has been studied in a variety of hematologic and solid tumors. Carfilzomib received accelerated approval from the U.S. FDA in 2012, based on a favorable response rate, for the treatment of patients with multiple myeloma who received at least two prior therapies, and demonstrated disease progression within 60 days of completing the last therapy. In this multi-center study, the investigators propose to evaluate carfilzomib for the treatment of patients with advanced neuroendocrine cancers.

Arms: arm 1: Carfilzomib will be administered as intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle.

Cycle 1: First two doses of Carfilzomib 20 mg/m2 IV; subsequent doses at 56 mg/m2 IV

Cycle 2 onwards: Carfilzomib 56 mg/m2 IV
Interventions: intervention 1: Carfilzomib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CONFIDENTIAL 
This document is confidential and is the property of the SCRI Development Innovations, LLC.  No part of this 
document may be transmitted, reproduced, published, or used by other persons without prior written authorization 
from SCRI Development Innovations, LLC. 
Page 1 of 70 
 
GI 195 
Phase II Study of Carfilzomib for the Treatment of Patients with Advanced 
Neuroendocrine Cancers 
SCRI INNOVATIONS STUDY NUMBER: 
GI 195 
 
STUDY DRUG: 
Carfilzomib 
SPONSOR: 
SCRI Development Innovations, LLC 
(SCRI Innovations) 
3322 West End Avenue , Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
STUDY CHAIR: 
Johanna Bendell, MD 
Director, GI Oncology Research 
Associate Director, Drug Development Unit 
Sarah Cannon Research Institute 
 
3322 West End Avenue, Suite 900 
Nashville, TN 37203 
jbendell@tnonc.com  
 
DATE FINAL: 
16 NOVEMBER 2014 
AMENDMENT 1 
17 DECEMBER 2014 
AMENDMENT 2 
25 FEBRUARY 2015 


 
 
CONFIDENTIAL 
STUDY DRUG(S): CARFILZOMIB 
  
SCRI INNOVATIONS STUDY NUMBER: GI 195 
AMENDMENT 2 DATE:  25 FEBRUARY 2015 
 
 
 
 
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Clinical Study Statement of Compliance 
Phase II Study of Carfilzomib for the Treatment of Patients with Advanced 
Neuroendocrine Cancers 
 
 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. 
 


 
 
 
CONFIDENTIAL 
STUDY DRUG(S): CARFILZOMIB 
  
SCRI INNOVATIONS STUDY NUMBER: GI 195 
AMENDMENT 2 DATE:  25 FEBRUARY 2015 
 
 
 
 
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Clinical Study Signature Approval Page 
Phase II Study of Carfilzomib for the Treatment of Patients with Advanced 
Neuroendocrine Cancers 
SCRI INNOVATIONS STUDY NUMBER: 
 
GI 195 
STUDY DRUG: 
Carfilzomib   
DATE FINAL: 
16 NOVEMBER 2014 
AMENDMENT 1 
17 DECEMBER 2014 
AMENDMENT 2 
25 FEBRUARY 2015 
 
__________________________ 
__________________________         ______________  
Study Chair 
 
Study Chair Signature 
 
Date 
 
 
 
 
__________________________ 
__________________________         ______________  
SCRI Development Innovations, LLC 
 
 
SCRI Development Innovations, LLC  
Representative Signature 
 
Date 
 
 
 
Johanna Bendell, MD 
Sheetal Khedkar 
 


 
 
 
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STUDY DRUG(S): CARFILZOMIB 
  
SCRI INNOVATIONS STUDY NUMBER: GI 195 
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Clinical Study Principal Investigator Signature Form 
Phase II Study of Carfilzomib for the Treatment of Patients with Advanced 
Neuroendocrine Cancers 
SCRI INNOVATIONS STUDY NUMBER: 
 
GI 195 
DATE FINAL: 
16 NOVEMBER 2014 
AMENDMENT 1 
17 DECEMBER 2014 
AMENDMENT 2 
25 FEBRUARY 2015 
 
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: 
 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Attn:  GI 195 Study Team  
Nashville, TN 37203 


 
CONFIDENTIAL 
STUDY DRUG(S): CARFILZOMIB 
  
SCRI INNOVATIONS STUDY NUMBER: GI 195 
AMENDMENT 2 DATE:  25 FEBRUARY 2015 
 
 
 
 
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GI 195 Summary of Changes 
 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        17 DECEMBER 2014 
Section 3.1 Inclusion Criterion #3 
Patients currently receiving or previously treated with single agent somatostatin analogues (e.g. 
sandostatin LAR® or lanreotide) are eligible.  However, this is not a mandatory criterion to be 
included in the study. 
 
Section 3.2 Exclusion Criterion #2 
Patients who have had radiation therapy, hormonal therapy, biologic therapy, or chemotherapy 
for cancer within 21 days or 5 half-lives of any chemotherapy or biologic/targeted agent, 
whichever is longer, prior to first treatment day of the study.  (Refer to exclusion criterion #8 
for restrictions associated with radiation therapy in patients with brain metastases) 
 
Section 3.2 Exclusion Criterion #4 
History or known presence of central nervous system (CNS) metastases.  
 
Section 5 
“Subject” changed to “Patient” 
 
Section 7.6.1 Follow-up for Patients Who Discontinue Prior to Disease Progression 
• Physical examination, including measuring your weight and vital signs (includes blood 
pressure, heart rate, breathing rate, and oral temperature) 
• CBC, including 3-part differential and platelets.  Blood samples for routine laboratory 
testing.  
• Blood samples for CMP testing 
• You will have CT scan of the chest, a CT scan of the abdomen/ pelvis done 
 
Appendix D, Footnote o  
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. 
 
Minor typographical and grammatical corrections were done throughout the protocol.  


 
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STUDY DRUG(S): CARFILZOMIB 
  
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AMENDMENT NUMBER: 
2 
AMENDMENT DATE:        25 FEBRUARY 2015 
Section 2.3: Exploratory objective 
The following objective was deleted. 
To perform whole exome sequencing analysis in optional tumor biopsy samples.  
 
Section 4: Patient registration 
Registration fax number changed from (866) 699 0258 to (866) 346 1062 
Registration Email address was added: CANN.SCRIInnovationsEnr@scri-innovations.com 
 
Section 5.4.1: Tumor Tissue Samples 
Archival tumor samples will may be collected during the study with the purpose of identifying 
molecular alterations relevant to carfilzomib.  For patients who participate in the study, whole 
exome sequencing analysis in optional tumor biopsy samples will be done.  This material should 
be provided as a tissue block or 10 paraffin-dipped unstained slides.  The status of gene mutation 
and protein expression by IHC will be tested to explore whether these are correlated with the 
response to treatment.  
We hope to have evaluable biopsy data in approximately 10% of the patients.  In order to do this, 
we plan to collect biopsies in 20% of patients.  A pre-treatment biopsy and a repeat biopsy on 
Day 15(± 1) Cycle 1 will be optional but preferable.  The samples will be analyzed in house at 
Onyx.  
For collection, shipment, handling, etc. of tumor biopsy samples see the Laboratory Manual. 
 
Section 7.2: Baseline study assessment 
Fresh (optional) tumor biopsy sample, if applicable 
 
Section 7.3.1: Days 1, 8, and 15 of each cycle 
Optional biopsy (Cycle 1, Day 15), if applicable 
 
Appendix D: Study assessment table 
Fresh biopsy collection and footnote “i” has been deleted to reflect the changes. 


 
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STUDY DRUG(S): CARFILZOMIB 
  
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GI 195 PROTOCOL SYNOPSIS 
Title of Study: 
Phase II Study of Carfilzomib for the Treatment of Patients with Advanced Neuroendocrine 
Cancers 
SCRI Innovations 
Study Number: 
GI 195 
Sponsor: 
SCRI Development Innovations, LLC.  Nashville, TN 
Study Duration: 
The total duration of the study is planned to be 24 months. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at multiple sites.   
Number of 
Patients: 
Up to 62 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is to: 
• 
To evaluate the overall response rate (ORR) of patients with advanced 
neuroendocrine tumors treated with carfilzomib. 
 
Secondary Objectives 
The secondary objectives of this study are: 
• 
To evaluate the disease control rate (DCR) in patients with advanced 
neuroendocrine cancers treated with carfilzomib. 
• 
To evaluate the progression free survival (PFS) of patients with advanced 
neuroendocrine cancers treated with carfilzomib. 
• 
To further evaluate toxicities associated with this regimen.  
Exploratory Objective 
The exploratory objective of this study is: 
• 
To determine the status of gene mutation and protein expression by 
immunohistochemistry (IHC) on the tumor samples to explore the correlation with 
the response to treatment will be done. 
Study Design: 
This Phase II open-label, non-randomized clinical study will be conducted by participating 
sites in the Sarah Cannon Research Institute network.  This study will evaluate the use of 
carfilzomib for patients with advanced neuroendocrine tumors.  Patients will receive 
treatment by intravenous (IV) infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each 
cycle.  Cycles are 28 days in length.  Patients will be evaluated for response to treatment 
every 3 cycles; responding and/or stable patients will continue treatment, with re-evaluations 
every 3 cycles, unless tumor progression or intolerable toxicity occurs.  Response to therapy 
will be assigned using RECIST v1.1 criteria. 
Study Drugs, 
Doses, and Modes 
of Administration: 
Carfilzomib will be administered as IV infusion.  Patients will receive 20 mg/m2 on Days 1 
and 2 of Cycle 1.  Thereafter, patients will receive 56 mg/m2 on Days 8, 9, 15 and 16.  
Starting from Cycle 2 patients will receive 56 mg/m2 on Days 1, 2, 8, 9, 15 and 16.   


 
CONFIDENTIAL 
STUDY DRUG(S): CARFILZOMIB 
  
SCRI INNOVATIONS STUDY NUMBER: GI 195 
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GI 195 PROTOCOL SYNOPSIS 
Inclusion Criteria: 
1. Patients with biopsy-proven advanced, unresectable or metastatic, well-to-moderately 
differentiated (or low-grade) neuroendocrine carcinoma, including typical carcinoid, 
pancreatic islet cell and other well-to-moderately differentiated neuroendocrine 
carcinomas. 
2. Patients must have at least one unidimensional measurable lesion definable by 
magnetic resonance imaging (MRI) or computerized tomography (CT) scan.  Disease 
must be measurable per Response Evaluation Criteria in Solid Tumors RECIST 
version 1.1 criteria (Appendix E).  
3. Patients currently receiving or previously treated with single agent somatostatin 
analogues (e.g. sandostatin LAR® or lanreotide) are eligible.  However, this is not a 
mandatory criterion to be included in the study. 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ECOG 
PS 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) ≤ 2.5 x ULN or <5.0 x ULN in patients 
with liver metastases 
- 
Aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5.0 x ULN in patients 
with liver metastases 
- 
Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin 
elevation due to Gilbert’s disease or a similar syndrome involving slow 
conjugation of bilirubin) 
7. Adequate renal function defined as serum creatinine ≤2.0mg/dL or calculated 
creatinine clearance ≥30 mL/min as calculated by Cockcroft and Gault Formula. 
8. Women of childbearing potential (WoCBP) must have a negative serum or urine 
pregnancy test.  Serum pregnancy test should be performed ≤7 days or urine 
pregnancy test will be performed within ≤3 days prior to start of treatment.  Another 
pregnancy test will be performed within 30 days following last dose of study drug.  
WoCBP or men with partners of childbearing potential must use effective birth 
control measures during treatment (Appendix C).  If a woman becomes pregnant or 
suspects she is pregnant while participating in this study, she must agree to inform 
her treating physician immediately. 
9.  Predicted life expectancy > 12 weeks 
10. Age ≥18 years. 
11. All patients must be willing to and have the ability to comply with the study and 
related follow-up procedures. 
12. All patients must be able to understand the nature of the study and give written 
informed consent prior to study entry. 


 
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GI 195 PROTOCOL SYNOPSIS 
Exclusion 
Criteria: 
1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade 
neuroendocrine carcinoma, adenocarcinoid, globlet cell carcinoid, atypical carcinoid, 
anaplastic carcinoid, pulmonary neuroendocrine and small cell carcinoma are not 
eligible 
2. Patients who have had radiation therapy, hormonal therapy, biologic therapy, or 
chemotherapy for cancer within 21 days or 5 half-lives of any chemotherapy or 
biologic/targeted agent, whichever is longer, prior to first treatment day of the study.  
(Refer to exclusion criterion #8 for restrictions associated with radiation therapy in 
patients with brain metastases) . 
3. Patients who have received any other investigational agents within the 21 days or 5 
half-lives, whichever is longer, prior to first treatment day of the study.   
4. Women who are pregnant or lactating. 
5. Patients with poorly controlled or clinically significant atherosclerotic vascular disease 
including the following: 
- 
Congestive heart failure (New York Heart Association [NYHA] ≥ Class 3 and 4 
heart failure (Appendix B) 
- 
Patients with known LVEF<40% 
- 
Unstable angina pectoris requiring nitrates within the last 12 months 
- 
Acute myocardial infarction, cerebrovascular accident, or transient ischemic attack 
within the last 12 months 
- 
Angioplasty (coronary or vascular) within the last 12 months 
- 
Cardiac or vascular stenting in the past 12 months 
- 
Ventricular arrhythmia requiring medication within the last 12 months 
6. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active 
infection, or psychiatric illness/social situations that would impair the ability of the 
patient to receive protocol treatment. 
7. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
8. 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.   
9. Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C. 
10. 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 at least 3 
years previously, 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. 
11. Infection requiring IV antibiotics. 
Statistical 
Methodology: 
This is a multicenter, Phase II study of carfilzomib for the treatment of patients with 
advanced neuroendocrine cancers.  Demographic data and baseline disease characteristics 
will be summarized using appropriate descriptive statistics (e.g., mean, median, standard 
deviation or percentages and frequency counts).  The primary endpoint, ORR, will be 
determined using RECISTv1.1 criteria.  The median and 25% and 75% percentiles for PFS 
will be summarized with associated 95% CI, and the distribution of PFS will be presented 
graphically using the Kaplan-Meier approach.  Progression-free survival will be evaluated 
six and 12 months after the last patient is enrolled on the trial. 


 
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GI 195 CONTACT INFORMATION 
SCRI Innovations 
Contact Information: 
SCRI Innovations 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
 
Study Chair: 
Johanna Bendell. MD 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
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 
SCRI Innovations Enrollment Phone #: 
SCRI Innovations Enrollment Fax #: 
SCRI Innovations Enrollment Email: 
1-877-MY-1-SCRI 
1-866-346-1062 
CANN.SCRIInnovationsEnr@scri-innovations.com 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST  
Aspartate aminotransferase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMP 
Comprehensive metabolic profile 
CR 
Complete response 
CT 
Computerized tomography 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
HGFR 
Hepatocyte growth factor receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
PD 
Progressive disease 
PDGFR 
Platelet-derived growth factor receptors  
PHI 
Protected health information 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PNET 
Pancreatic neuroendocrine tumors 
PR 
Partial response 
PT 
Prothrombin 
PTT 
Partial thromboplastin time 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 


 
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LIST OF ABBREVIATIONS (continued) 
SCRI 
Sarah Cannon Research Institute 
SD 
Stable disease 
SUSAR 
Suspected unexpected serious adverse reaction 
TLS 
Tumor lysis syndrome 
UAE 
Unexpected Adverse Event 
ULN 
Upper limit of normal 
WoCBP 
Women of childbearing potential 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 18 
1.1 
Background ........................................................................................................... 18 
1.2 
Treatment for pancreatic neuroendocrine tumors (PNET) and gastrointestinal 
carcinoid tumors .................................................................................................... 18 
1.3 
Carfilzomib ............................................................................................................ 19 
1.3.1 
Safety Pharmacology and Toxicology .................................................................. 19 
1.3.2 
Clinical Experience ............................................................................................... 20 
1.4 
Rationale for the Study .......................................................................................... 20 
2. 
STUDY OBJECTIVES ......................................................................................... 21 
2.1 
Primary Objective.................................................................................................. 21 
2.2 
Secondary Objectives ............................................................................................ 21 
2.3 
Exploratory Objectives .......................................................................................... 21 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 21 
3.1 
Inclusion Criteria ................................................................................................... 21 
3.2 
Exclusion Criteria .................................................................................................. 23 
3.3 
Discontinuation from Study Treatment ................................................................. 24 
4. 
PATIENT REGISTRATION ................................................................................ 24 
5. 
STUDY DESIGN .................................................................................................. 25 
5.1 
Treatment Plan ...................................................................................................... 26 
5.1.1 
Carfilzomib ............................................................................................................ 26 
5.2 
Treatment Duration ............................................................................................... 27 
5.3 
Concomitant Medications...................................................................................... 27 
5.3.1 
Permitted Concomitant Medications ..................................................................... 28 
5.3.2 
Prohibited Concomitant Medications .................................................................... 28 
5.4 
Correlative Studies ................................................................................................ 28 
5.4.1 
Tumor Tissue Samples .......................................................................................... 28 
6. 
DOSE MODIFICATIONS .................................................................................... 28 
6.1 
Dose Modifications Due to Hematologic Toxicity ............................................... 29 
6.2 
Dose Modifications for Non-Hematologic Toxicity ............................................. 31 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 33 
7.1 
Overview ............................................................................................................... 33 
7.2 
Baseline Study Assessments ................................................................................. 33 


 
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7.3 
Study Treatment Assessments ............................................................................... 34 
7.3.1 
Days 1, 8, and 15 of each cycle ............................................................................. 34 
7.3.2 
Days 2, 9, and 16 of each cycle ............................................................................. 35 
7.4 
Response Assessment Every 3 Cycles .................................................................. 35 
7.5 
End of Study Treatment ........................................................................................ 35 
7.6 
Follow-up .............................................................................................................. 36 
7.6.1 
Follow-up for Patients Who Discontinue Prior to Disease Progression ............... 36 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 36 
8.1 
Carfilzomib ............................................................................................................ 36 
8.1.1 
Labeling, Packaging, and Supply .......................................................................... 36 
8.1.2 
Preparation and Administration of Carfilzomib .................................................... 37 
8.1.3 
Infusion reaction .................................................................................................... 37 
8.1.4 
Precautions and Risks Associated with Carfilzomib ............................................. 38 
8.2 
Accountability for All Study drugs ....................................................................... 38 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 38 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 38 
10.1 
Statistical Design ................................................................................................... 38 
10.2 
Sample Size Considerations .................................................................................. 38 
10.3 
Analysis Population ............................................................................................... 39 
10.4 
Data Analysis ........................................................................................................ 39 
10.4.1 
Efficacy Analysis .................................................................................................. 39 
10.5 
Analysis Time Points............................................................................................. 40 
10.5.1 
Final Analysis ........................................................................................................ 40 
10.5.2 
Planned Interim Analysis ...................................................................................... 40 
10.5.3 
Efficacy Review .................................................................................................... 40 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 41 
11.1 
Definitions ............................................................................................................. 41 
11.1.1 
Adverse Events ...................................................................................................... 41 
11.1.2 
Serious Adverse Event .......................................................................................... 41 
11.1.3 
Adverse Reaction .................................................................................................. 42 
11.1.4 
Suspected Adverse Reaction ................................................................................. 42 
11.1.5 
Recording and Reporting of Adverse Events ........................................................ 42 
11.1.6 
Assessment of Adverse Events.............................................................................. 43 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 44 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 45 
11.3.1 
Diagnosis vs. Signs and Symptoms ....................................................................... 45 


 
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11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 45 
11.3.3 
Abnormal Laboratory Values ................................................................................ 45 
11.3.4 
Deaths .................................................................................................................... 45 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 46 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 46 
11.3.7 
New Cancers.......................................................................................................... 46 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 47 
11.3.9 
Carfilzomib Overdose ........................................................................................... 47 
11.4 
Sponsor Serious Adverse Event Reporting Requirements .................................... 47 
11.4.1 
SCRI Innovations Assessment of Unexpected Adverse Events (UAE) ................ 47 
11.4.2 
SCRI Innovations Reporting for Clinical Studies Under an Investigational 
New Drug Application .......................................................................................... 48 
12. 
REGISTRATION ON CLINICALTRIALS.GOV ................................................ 48 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 49 
13.1 
Study Monitoring, Auditing, and Inspecting ......................................................... 49 
14. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 49 
14.1 
Institutional Review Board Approval.................................................................... 49 
14.2 
Regulatory Approval ............................................................................................. 50 
14.3 
Informed Consent .................................................................................................. 50 
14.3.1 
Confidentiality ....................................................................................................... 50 
14.4 
Financial Information ............................................................................................ 51 
15. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 51 
15.1 
Amendments to the Protocol ................................................................................. 51 
15.2 
Documentation Required to Initiate the Study ...................................................... 52 
15.3 
Study Documentation and Storage ........................................................................ 53 
15.4 
Data Collection ...................................................................................................... 55 
15.5 
Disclosure and Publication Policy ......................................................................... 55 
16. 
REFERENCES ...................................................................................................... 56 
17. 
APPENDICES ....................................................................................................... 61 
 


 
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LIST OF TABLES 
Table 1 
Overall Treatment Plan ............................................................................ 27 
Table 2 
Dose Level Modifications ........................................................................ 29 
Table 3 
Carfilzomib Dose Modifications for Hematologic Toxicities ................. 30 
Table 4 
Carfilzomib Dose Reductions for Grade 3 or 4 Non-Hematologic 
Toxicities.................................................................................................. 32 
Table 5  
Recommended Action for Renal Dysfunction ......................................... 33 
LIST OF FIGURES 
Figure 1 
Study Schema........................................................................................... 26 


 
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LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 61 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 62 
Appendix C: 
Guidelines for Female Patients of Childbearing Potential and Fertile 
Male Patients ............................................................................................ 63 
Appendix D: 
Schedule of Assessments ......................................................................... 65 
Appendix E: 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1... 67 
 


 
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1. 
INTRODUCTION 
1.1 
Background 
Neuroendocrine malignancies refer to a diverse group of diseases that are generally rare 
however, their incidences are rapidly increasing.  Among these, pancreatic neuroendocrine 
tumors (PNETs, islet cell tumor, islet cell carcinoma, or pancreatic carcinoid) account for up to 
5% of all pancreatic malignancies.  Functional PNET tumors make extra amounts of hormones 
(e.g. gastrin, insulin, and glucagon) and cause symptoms.  Non-functional PNETs do not make 
extra amounts of hormones, and the symptoms are caused by the tumors as they grow.  The 
majority of the non-functional tumors are malignant.  
Gastrointestinal (GI) carcinoids are well-differentiated endocrine neoplasms that consist of a 
diverse group of tumors arising from cells of the diffuse endocrine system within the GI tract.  
These tumors are generally slow-growing and can be present throughout the GI tract.  All GI 
carcinoids share common pathologic features that characterize them as well-differentiated 
neuroendocrine tumors (NETs) (Levy and Sobin. 2007).  The World Health Organization 
(WHO) classification of GI NETs is clinically and prognostically useful for newly diagnosed 
patients with GI NETs because it accounts for specific biological behavior according to location 
and tumor differentiation.  The specific biological behavior of a particular tumor type varies 
according to the cell of origin (Capella et al. 1995; Solcia et al. 2000). 
1.2 
Treatment for pancreatic neuroendocrine tumors (PNET) and gastrointestinal 
carcinoid tumors 
Standard therapy for pancreatic neuroendocrine tumors (PNET) and gastrointestinal carcinoid 
tumors generally consists of chemotherapy combinations with streptozocin and either flurouracil 
or adriamycin, which are not very effective (Cheng and Saltz, 1999; McCollum et al. 2004).  
Neuroendocrine tumors are characterized by high vascularity along with high expression of 
several pro-angiogenic factors and growth factors and growth receptors (PDGFR), fibroblast 
growth factor receptor (FGFR), hepatocyte growth factor receptor (HGFR), insulin-like growth 
factor 1 (IGF-1) receptor, epidermal growth factor receptor (EGFR).  One of the major signalling 
pathways implicated in driving these tumors is the PI3K-AKT-mTOR pathway (Bergers et al. 
1999; Phan et al. 2006; Chaudhry et al. 1992; Wulbrand et al. 2000; Nilsson et al. 1992; 
Papouchado et al. 2005; Vignot et al. 2005).  This complex molecular signature led to a 
randomized phase III trial of sunitinib, a VEGFR tyrosine kinase inhibitor, versus best 
supportive care in patients with advanced PNET.  Results of this trial reported an improvement 
in response rate (9.3% vs. 0%, p=0.0066) and progression-free survival (PFS, 11.4 vs. 5.5 
months, p=0.0001, hazard ratio 0.418 [0.263, 0.662]) with sunitinib in patients with advanced, 
well-differentiated PNETs (Niccoli et al. 2010; Raymond et al. 2011).  Based on this 
information, sunitinib was approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of progressive, well-differentiated PNET in patients with unresectable locally 
advanced or metastatic diseases.  The RADIANT-3 study randomized patients to everolimus 
versus best supportive care (Yao et al. 2011, Afinitor (everolimus) PI 2102).  Everolimus 


 
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treatment resulted in an improved PFS (11.0 vs. 4.6 months, HR 0.35 [0.27, 0.45] and response 
rate (5 vs. 2%).  Everolimus has also been FDA approved for this patient population.  
Clinical trial data for patients with gastrointestinal carcinoid tumors are still emerging.  
Octreotide, which binds to somatostatin receptors that are ubiquitously expressed in most 
neuroendocrine tumors, has been shown to control symptoms and delay tumor growth in these 
patients (Leong et al. 2002; Imtiaz et al. 2000).  A recent randomized phase III study with 
octreotide LAR vs. placebo for patients with metastatic neuroendocrine cancers (PROMID 
study) showed an improvement in median time to progression (Rinke et al. 2009).  In the 
randomized, double-blind, multicenter trial of everolimus plus octreotide and best supportive 
care (BSC) vs. placebo plus octreotide and best supportive care for patients with advanced 
carcinoid tumors (RADIANT-2), a small improvement in progression-free survival was seen for 
patients treated with everolimus (16.4 versus. 11.3 months, HR 0.77, [0.59, 1.0]) (Pavel et al. 
2011).  Response rate was 2% for both treatment groups.  The use of bevacizumab for these 
patients is also under evaluation in a large randomized Southwest Oncology Group (SWOG) 
study whose results are anticipated shortly. 
1.3 
Carfilzomib 
Carfilzomib (KYPROLIS, Onyx Pharmaceuticals, Inc.), an irreversible proteasome inhibitor, is 
currently approved by the FDA for the treatment of patients with multiple myeloma who have 
received at least two prior therapies, including bortezomib and an immunomodulatory agent and 
have demonstrated disease progression on or within 60 days of completion of the last therapy 
(Siegel et al. 2012; Herndon et al. 2013; Kyprolis® (carfilzomib) PI 2012).  This approval was 
accelerated based on response rate.  In addition, carfilzomib has been studied in other cancer 
types such as Waldenstrom’s macroglobulinemia, non-Hodgkin’s lymphoma, mantle cell 
lymphoma, and a variety of solid tumors. Carfilzomib has a favorable safety profile according to 
the reported clinical studies. 
Carfilzomib is a tetrapeptide epoxyketone-based inhibitor of the chymotrypsin like activity of the 
20S proteasome. It is structurally and mechanistically different from the dipeptide boronic acid 
proteasome inhibitor bortezomib.  Carfilzomib also demonstrated less off-target activity 
compared to bortezomib when measured against a broad panel of proteases including metallo-
proteases, aspartyl-proteases, and serine proteases.  This selectivity of carfilzomib may 
contribute to the reduced myelosuppression and neuropathy observed in preclinical studies when 
compared with bortezomib. 
1.3.1 
Safety Pharmacology and Toxicology 
Based upon in vitro and in vivo studies, it is anticipated that carfilzomib can induce more intense 
and sustained proteasome inhibition compared to bortezomib, resulting in potent cytotoxic and 
pro-apoptotic activity across a broad panel of tumor-derived cell lines in culture (Demo et al. 
2007). Treatment of several hematologic tumor cell lines with carfilzomib for as little as 1 hour 
led to rapid inhibition of proteasome activity followed by an accumulation of polyubiquitinated 
proteins and induction of apoptosis. Interestingly, carfilzomib also demonstrated cytotoxicity 
towards tumor cells lines that have acquired resistance to bortezomib (Suzuki et al. 2011; Kuhn 
et al. 2007). Preclinical studies were done in rats and monkeys where carfilzomib was 


 
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administered intravenously (IV) for 5 consecutive days followed by a rest period of 9 days for 2 
cycles, showing a proteasome inhibition of more than 80% (Yang et al. 2011).   
However, bolus administration of carfilzomib has produced several adverse effects in rats and/or 
monkeys including cardiovascular, renal, gastrointestinal, renal, hepatic and hematopoietic 
toxicities, which were reduced with a longer infusion time (Herndon et al. 2013).  Carfilzomib 
also caused embryofetal toxicities in rats and rabbits, but has not shown any signs of 
teratogenicity. For this reason, pregnancy category D has been assigned for this agent, as the 
potential benefits in pregnant patient populations outweigh the potential harm to the fetus. 
Lastly, carfilzomib has been administered to rats and monkeys for 6 and 9 months, respectively, 
(once daily dosing on Days 1 and 2 for three consecutive weeks on a 28-day cycle), and was 
found to be well tolerated at the doses administered, showing more than 80% proteasome 
inhibition, with no behavioral changes or histological evidence of peripheral neuropathy and no 
neutropenia.  For details refer to the Investigator’s Brochure (IB).  In contrast, rats and monkeys 
treated with bortezomib in chronic toxicity studies demonstrated reduced motor activity, 
convulsions, tremors, and hind-limb paralysis accompanied by histological degeneration in 
peripheral nerves, as well as significant neutropenia. 
1.3.2 
Clinical Experience 
In the single-arm, multicenter trial of 266 multiple myeloma patients, carfilzomib produced an 
overall response rate (ORR) of 22.9% (95% confidence interval [CI]:18, 28.5) with a median 
duration of response of 7.8 months (95% CI: 5.6, 9.2).  In this and other studies, carfilzomib was 
well tolerated and did not seem to cause clinically meaningful peripheral neuropathy.  The most 
commonly reported adverse events (AEs) were fatigue, anemia, nausea, thrombocytopenia, 
dyspnea, diarrhea, and pyrexia.  Subsequent studies confirming the benefit of carfilzomib in the 
treatment of multiple myeloma are ongoing. 
In a clinical study, the pharmacokinetics and safety of carfilzomib were evaluated in patients 
with normal renal function vs. those with mild, moderate, and severe renal impairment, as well 
as in patients on chronic dialysis, treated with carfilzomib doses of 15 mg/m2 during cycle 1, 20 
mg/m2 during cycle 2, and 27 mg/m2 for cycles 3 and beyond (Badros et al. 2013).   
Pharmacokinetics data available for the 15 and 20 mg/m2  dose indicated that the Cmax and AUC 
of carfilzomib were similar across all renal function categories following carfilzomib doses of 15 
and 20 mg/m2.  Moreover, the overall safety profile was similar in patients in all renal function 
categories during mean treatment duration of 5.5 months.  However, a recent report indicated 6 
patients with baseline renal impairment had further renal function deterioration during the study 
period. 
1.4 
Rationale for the Study 
Proteasomes are multi-catalytic proteinase complexes responsible for degradation of a wide 
variety of protein substrates, and play many crucial roles in cell proliferation and survival.  
Intracellular proteins targeted for degradation by the proteasome are first ubiquitinated via the 
ubiquitin conjugation system.  Ubiquitinated proteins are cleaved within the proteasome by one 
or more of three separate N-terminal threonine protease activities: a chymotrypsin-like activity, a 
trypsin-like activity, and a caspase-like activity. 


 
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In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety 
of tumor types.  Proteasome inhibitors are known to have antiproliferative, proapoptotic, 
antiangiogenic, and antitumor effects across multiple tumor models (Boccadoro et al. 2005).  
Preclinical data showed antitumor activity of proteasome inhibitor bortezomib in the PC-12 
neuroendocrine cell line (Fenteany and Schreiber. 1996).  A subsequent phase II study of 
bortezomib in 16 patients with PNET or carcinoid resulted in no objective responses (Shah et al. 
2004).  However, patient numbers were small and there was heterogeneity in tumor type as well 
as tumor marker status of the patients.   
Carfilzomib is an irreversible proteasome inhibitor that showed activity in patients who have 
failed to respond to bortezomib treatment and it exhibits antiproliferative and proapoptotic 
activity in solid and hematologic tumor cells in vitro.  We propose this phase II study to evaluate 
carfilzomib for patients with advanced neuroendocrine cancers.   
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objectives of this study are: 
• To evaluate the overall response rate (ORR) of patients with advanced 
neuroendocrine tumors treated with carfilzomib. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the Disease Control Rate (DCR) in patients with advanced neuroendocrine 
cancers treated with carfilzomib. 
• To evaluate the progression free survival (PFS) of patients with advanced neuroendocrine 
cancers treated with carfilzomib. 
• To further evaluate toxicities associated with this regimen.  
2.3 
Exploratory Objective 
The exploratory objective of this study is: 
• To determine the status of gene mutation and protein expression by 
immunohistochemistry (IHC) on the tumor samples to explore the correlation with the 
response to treatment.  
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. Patients with biopsy-proven advanced, unresectable or metastatic, well-to-moderately 
differentiated (or low-grade) neuroendocrine carcinoma, including typical carcinoid, 


 
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pancreatic islet cell and other well- to-moderately differentiated neuroendocrine 
carcinomas. 
2. Patients must have at least one unidimensional measurable lesion definable by magnetic 
resonance imaging (MRI) or computed tomography (CT) scan.  Disease must be 
measurable per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria 
(Appendix E).  
3. Patients currently receiving or previously treated with single agent somatostatin 
analogues (e.g. sandostatin LAR® or lanreotide) are eligible.  However, this is not a 
mandatory criterion to be included in the study. 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ECOG PS 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) ≤ 2.5 x upper limit of normal (ULN) or <5.0 x 
ULN in patients with liver metastases 
- Aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5.0 x ULN in patients with 
liver metastases 
- Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin) 
7. Adequate renal function defined as serum creatinine ≤2.0mg/dL or calculated creatinine 
clearance ≥30 mL/min as calculated by Cockcroft and Gault Formula. 
8. Women of childbearing potential (WoCBP) must have a negative serum or urine 
pregnancy test.  Serum pregnancy test should be performed ≤7 days or urine pregnancy 
test should be performed within ≤3 days prior to start of treatment.  Another pregnancy 
test will be performed within 30 days following last dose of study drug.  WoCBP or men 
with partners of childbearing potential must use effective birth control measures during 
treatment (Appendix C).  If a woman becomes pregnant or suspects she is pregnant while 
participating in this study, she must agree to inform her treating physician immediately. 
9. Predicted life expectancy > 12 weeks 
10. Age ≥18 years. 
11. All patients must be willing to and have the ability to comply with the study and related 
follow-up procedures. 


 
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12. All patients must be able to understand the nature of the study and give written informed 
consent prior to study entry. 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine 
carcinoma, adenocarcinoid, globlet cell carcinoid, atypical carcinoid, anaplastic 
carcinoid, pulmonary neuroendocrine and small cell carcinoma are not eligible. 
2. Patients who have had radiation therapy, hormonal therapy, biologic therapy, or 
chemotherapy for cancer within 21 days or 5 half-lives of any chemotherapy or 
biologic/targeted agent, whichever is longer, prior to first treatment day of the study.  
(Refer to exclusion criterion #8 for restrictions associated with radiation therapy in 
patients with brain metastases) 
3. Patients who have received any other investigational agents within the 21 days or 5 half-
lives, whichever is longer, prior to first treatment day of the study.   
4. Women who are pregnant or lactating. 
5. Patients with poorly controlled or clinically significant atherosclerotic vascular disease 
including the following: 
-  Congestive heart failure (New York Heart Association [NYHA] ≥ Class 3 and 4 heart 
failure) (Appendix B) 
-  Patients with known LVEF<40% 
-  Unstable angina pectoris requiring nitrates within the last 12 months 
-  Acute myocardial infarction, cerebrovascular accident, or transient ischemic attack within 
the last 12 months 
-  Angioplasty (coronary or vascular) within the last 12 months 
-  Cardiac or vascular stenting in the past 12 months 
-  Ventricular arrhythmia requiring medication within the last 12 months 
6. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active 
infection, or psychiatric illness/social situations that would impair the ability of the 
patient to receive protocol treatment. 
7. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
8. 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.   
9. Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C. 
10. 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 at least 3 years 
previously, and are considered unlikely to recur are eligible.  All patients with previously 


 
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treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of 
non-melanoma skin cancer. 
11. Infection requiring intravenous (IV) antibiotics. 
3.3 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression (patients who are receiving clinical benefit in the opinion of the 
treating investigator may be allowed to stay on study after consultation with the Medical 
Monitor.) 
• 
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 (as indicated in 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 
• 
If a patient becomes pregnant during the study period, treatment will be discontinued to 
avoid harm to fetus. 
After discontinuation from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of carfilzomib.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the investigator, these values are 
not likely to improve, because of the underlying disease.  In this case, the investigators must 
record his or her reasoning for this decision in the patients’ medical records and as a comment in 
the electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] 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. 
PATIENT REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, treatment alternatives, side-effects, risks, 
and discomforts.  Human protection committee (Institutional Review Board [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. 


 
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Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled through the SCRI Innovations Central Enrollment Desk.  The 
enrollment desk may be reached by calling (877) MY-1-SCRI.  Registration may be done via fax 
(866) 346-1062 Monday through Friday, 8:30 a.m. to 4:30 p.m., Central Standard Time, or via 
email to CANN.SCRIInnovationsEnr@scri-innovations.com.  Patient registration will be 
confirmed via email within 24 hours, or by the next business day. 
5. 
STUDY DESIGN 
This Phase II open-label, non-randomized clinical study will be conducted by participating sites 
in the Sarah Cannon Research Institute network.  This study will evaluate the use of carfilzomib 
for patients with advanced neuroendocrine tumors.  For the purpose of this study, patients will 
receive treatment by IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle.  
Cycles are 28 days in length.  Patients will receive 20 mg/m2 on Days 1 and 2 of Cycle 1.  
Thereafter, patients will receive 56 mg/m2 on Days 8, 9, 15 and 16.  Starting from Cycle 2 
patients will receive 56 mg/m2 on Days 1, 2, 8, 9, 15 and 16.  Patients will be evaluated for 
response to treatment every 3 cycles; responding and/or stable patients will continue treatment, 
with re-evaluations every 3 cycles, unless tumor progression or intolerable toxicity occurs.  
Response to therapy will be assigned using RECIST v1.1criteria (see Appendix E).   
The doses to be administered on specific treatment days are outlined in the table below.  Patients 
will receive dexamethasone (4 mg for 20 mg/m2 and 8 mg for 56 mg/m2) prior to receiving all 
carfilzomib doses in Cycle 1 and as needed throughout the study to reduce the severity of 
infusion reactions associated with carfilzomib.  The primary endpoints for this study are ORR 
and PFS. 
The planned enrollment for this study is 62 patients.   
The study schema is presented in Figure 1. 
 


 
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Figure 1 
Study Schema 
 
 
 
5.1 
Treatment Plan 
5.1.1 
Carfilzomib 
Patients receiving carfilzomib treatment must be hydrated in Cycle 1, and as needed from Cycle 
2 onwards, and pre-treated with dexamethasone as indicated below.   
Pre-treatment Hydration and Fluid Monitoring 
Intravenous (IV) hydration will be given immediately prior to each dose of carfilzomib during 
Cycle 1; 250 to 500 mL normal saline or other appropriate IV fluid should be given to reduce the 
risk of renal toxicity and of tumor lysis syndrome (TLS).  An additional 250 mL to 500 mL of IV 
fluids will be given as needed following carfilzomib administration.  If lactate dehydrogenase 
(LDH) or uric acid is elevated (and/or in patients considered still at risk for TLS) at Cycle 2 Day 
1, then the recommended IV hydration should be given additionally before each dose in Cycle 2.  
The goal of the hydration program is to maintain robust urine output (e.g., ≥ 2 L/day).  Patients 
should be monitored periodically during this period for evidence of fluid overload.  After Cycle 
2, patients will be hydrated at the Investigator’s discretion.   
If the patient has a dedicated line for carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration. 
Pre-treatment Dexamethasone 
Dexamethasone (4 mg for the 20 mg/m2 carfilzomib dose and 8 mg for the 56 mg/m2 carfilzomib 
dose) PO/IV will be administered prior to all carfilzomib doses during the first cycle and as 
needed in Cycle 2 and beyond.  If treatment-related fever, rigors, chills, and/or dyspnea are 
observed post any dose of carfilzomib after dexamethasone has been discontinued, 
dexamethasone (8 mg PO/IV) should be re-started and administered prior to subsequent doses. 
TREATMENT SCHEDULE 
Carfilzomib 20 mg/m2 IV will be administered over 30 minutes (± 5 minutes) on Days 1 and 2 of 
Cycle 1, followed by escalation to 56 mg/m2 IV over 30 minutes (± 5 minutes) on Days 8, 9, 15, 
and 16 of Cycle 1.  For patients who have adequately tolerated dosing during Cycle 1, 
carfilzomib 56 mg/m2 IV will be administered over 30 minutes (± 5 minutes) on Days 1, 2, 8, 9, 
15, and 16 of Cycle 2 and beyond.  Patients may continue study treatment until intolerable 
Day 1 Day 2 Day 8 Day 9 Day 15 Day 16 
20 mg/m 2 
56 mg/m 2 
56 mg/m 2 
Cycle 1
Cycle 2 and beyond
Carfilzomib
Carfilzomib
Carfilzomib 
Day 1 Day 2 Day 8 Day 9 Day 15 Day 16


 
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toxicity, confirmed progressive disease (PD), withdrawal of consent, death, or study closure, 
whichever occurs earliest.  The treatment schedule is provided in the table below. 
Table 1 
Overall Treatment Plan 
DRUG 
DOSE 
CYCLE 
FREQUENCY 
Route of 
Administration 
Carfilzomiba, c 
20 mg/m2 
Cycle 1 only 
Days 1, 2 
IV over 30 minutes 
Carfilzomiba 
56 mg/m2 
Cycle 1 only 
Days 8, 9, 15, 16 
IV over 30 minutes 
Carfilzomibb, c 
56 mg/m2 
Cycle 2 and beyond 
Days 1, 2, 8, 9, 15, 16 IV over 30 minutes 
 
a Carfilzomib 20 mg/m2 IV will be infused over 30 minutes (± 5 minutes) on Days 1 and 2 of Cycle 1, followed by 
escalation to 56 mg/m2 infused over 30 minutes (± 5 minutes) on Days 8, 9, 15, and 16 of Cycle 1. 
b Carfilzomib 56 mg/m2 IV will be infused over 30 minutes (± 5 minutes) on Days 1, 2, 8, 9, 15, and 16 of Cycle 2 
and beyond. 
c Study drug will be taken within ± 2 days of the scheduled study day for Day 1 of each Cycle. 
Carfilzomib will be administered within ± 2 days of the scheduled study day for Day 1 of each 
Cycle.  Every effort should be made to maintain the dosing schedule as outlined above, and if 
this is not possible due to extenuating circumstances then priority should be given to maintain 
consecutive dosing days.  If a mid-cycle dose is missed, that dose should be administered no 
more than 2 days after the scheduled dosing day.  Anticipated treatment changes outside of the 2-
day window must be discussed with the Medical Monitor or designee. 
5.2 
Treatment Duration 
Patients will be evaluated for toxicity at the start of each cycle.  Every 3 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. 
5.3 
Concomitant Medications 
Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, therefore 
the pharmacokinetics (PK) profile of carfilzomib should not be affected by concomitant 
administration of cytochrome P450 (CYP) inhibitors and inducers. Carfilzomib is not expected 
to influence exposure of other drugs. However, 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. 


 
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5.3.1 
Permitted Concomitant Medications 
Premedication with anti-emetics should be given according to institutional practice. 
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: 
• Allopurinol (or other approved uric acid-lowering agent) in patients at high risk for TLS 
due to high tumor burden may be prescribed at the investigator’s discretion. 
• Prophylactic antiviral therapy (e.g., valacyclovir) per institutional standard practice is 
strongly recommended for patients at increased risk of herpes zoster. 
• Patients may receive antiemetics and antidiarrheal agents as necessary.  
• Myeloid growth factors (e.g., granulocyte-colony stimulating factor [G-CSF]) may be 
used if neutropenia occurs in accordance with American Society of Clinical Oncology 
(ASCO) Guidelines (Smith et al. 2006), but should not be given prophylactically. 
• Patients may receive RBC transfusions, erythropoietic stimulating agents, or platelet 
transfusions at any time.  
• Palliative radiation for pain management is permitted with the written approval of the 
Study Chair.  The radiation field cannot encompass a target lesion. 
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: 
• 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. 
5.4 
Correlative Studies 
5.4.1 
Tumor Tissue Samples 
Archival tumor samples may be collected during the study with the purpose of identifying 
molecular alterations relevant to carfilzomib.   
6. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v4.03 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), and appropriate supportive care treatment will be 
administered to decrease the signs and symptoms thereof.  Dose adjustments will be based on the 
organ system exhibiting the greatest degree of toxicity. 


 
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Doses of carfilzomib will be modified based on hematologic and non-hematologic toxicity.  If 
dose reductions are necessary, they will be permanent for the remainder of the treatment.  
Carfilzomib may be adjusted according to the dose modification tables that follow.  If the patient 
is receiving the lowest allowable dose and experiences a toxicity requiring a dose reduction, the 
offending study drug should be discontinued.  Any patient requiring a toxicity-related dose delay 
of more than 21 days from the intended day of the next scheduled dose must be discontinued 
from the study. 
If patients experience any dose-related toxicity at 20 mg/m2, they must be discontinued from the 
study. 
A maximum of two dose reductions are allowed in this study.  If more than two dose reductions 
are necessary for a patient, the patient will be discontinued from study treatment. 
The dose level reductions to be used in this study are presented in Table 2. 
 
Table 2 
Dose Level Modifications 
Dose Level 
Carfilzomib 
Starting Dose  
56 mg/m2 
Dose Level -1 
45 mg/m2 
Dose Level -2 
36 mg/m2 
 
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.  
Dose reductions for hematological toxicities are show in Table 3. 


 
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Table 3 
Carfilzomib Dose Modifications for Hematologic Toxicities 
AE Term and Description 
Dose Modification 
THROMBOCYTOPENIA 
Grade 3  
(25 - <50 x 109/L) 
 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.   
2. If improves in ≤ 7 days, maintain same 
dose, if > 7 days reduce dose 1 level. 
Grade 4 (<25 x 109/L) 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.  
2. Restart treatment with a 1 level dose-
reduction. 
Recurrent Grade 3/4 Event After Initial Dose 
Reduction 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.  
2. Restart treatment with a second 1 level 
dose-reduction. 
Recurrent Grade 3/4 Event After 2 Dose Reductions   Discontinue 
 
NEUTROPENIA 
Grade 3  
(0.5 x 109/L ≤ ANC <1.0 x 109/L) 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.   
2. If improves in ≤ 7 days, maintain same 
dose, if >7 days reduce dose 1 level. 
Grade 4   
(ANC <0.5 x 109/L) 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.   
2. Restart treatment with a 1 level dose-
reduction. 
Recurrent Grade 3/4 Event After Initial Dose 
Reduction 
1. Interrupt study treatment until toxicity 
reduced to ≤ Grade 2a.   
2. Restart treatment with a 1 level dose-
reduction. 
Recurrent Grade 3/4 Event After 2 Dose Reductions   Interrupt until toxicity ≤ Grade 2a and  
restart treatment with a 1 level dose-reduction 
if possible, or discontinue. 
a Hold carfilzomib treatment; do at least weekly CBC with differential until toxicity resolves (ANC recovery ≥1.0 x 109/L and 
platelets ≥75 x 109/L). 
b Re-treatment criteria = ANC recovery ≥1.0 x 109/L and platelets ≥75 x 109/L. 
c Patients who require a treatment delay of more than 3 weeks due to treatment-related toxicity will be discontinued from study 
treatment, unless the treating physician and the Study Chair agree that continued treatment at lower doses is in the best interest 
of the patient. 


 
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Table 3 
Carfilzomib Dose Modifications for Hematologic Toxicities (continued) 
AE Term and Description 
Dose Modification 
FEBRILE NEUTROPENIA 
Grade 3   ANC <1.0 x 109/L, fever ≥38.5°C 
 
1.  Interrupt study treatment until ANC 
recovery to ≤ Grade 2a (ANC ≥ 1.0 x 
109/L) and resolution of fever <38.5°C.  
2. Restart treatment with a 1 level dose-
reduction. 
Grade 4    ANC <1.0 x 109/L, fever ≥38.5°C and life-
threatening consequences 
1.  Interrupt study treatment until ANC 
recovery to ≤ Grade 2a (ANC ≥ 1.0 x 
109/L) and resolution of fever <38.5°C and 
any complications.  
2. Restart treatment with a 1 level dose-
reduction. 
a Hold carfilzomib treatment; do at least weekly CBC with differential until toxicity resolves (ANC recovery ≥1.0 x 109/L and 
platelets ≥75 x 109/L). 
b Re-treatment criteria = ANC recovery ≥1.0 x 109/L and platelets ≥75 x 109/L. 
c Patients who require a treatment delay of more than 3 weeks due to treatment-related toxicity will be discontinued from study 
treatment, unless the treating physician and the Study Chair agree that continued treatment at lower doses is in the best interest of 
the patient.. 
6.2 
Dose Modifications for Non-Hematologic Toxicity 
The dose reduction guidelines for non-hematologic toxicities are shown in Table 4. 


 
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Table 4 
Carfilzomib Dose Reductions for Grade 3 or 4 Non-Hematologic Toxicities 
Event  
Action to be Taken 
Allergic reaction/hypersensitivity 
Grade 2 – 3  
Grade 4 
Hold until ≤ Grade 1, reinstitute at full dose.  
Discontinue 
Tumor lysis syndrome  
(≥ 3 of following: ≥ 50% increase in creatinine, 
uric acid, or phosphate; ≥ 30% increase in 
potassium; ≥ 20% decrease in calcium; or 
≥ 2-fold increase in LDH 
 
Hold carfilzomib until all abnormalities in serum 
chemistries have resolved.  Reinstitute at full doses. 
Infection  
Grade 3 or 4 
Hold carfilzomib (no more than 3 weeks) until 
systemic treatment for infection complete.  If no 
neutropenia, restart at full dose.  If neutropenic, follow 
neutropenic instructions (Table 3). 
Herpes zoster or simplex of any grade 
Hold carfilzomib until lesions are dry. Reinstitute at 
full dose. 
Neuropathy 
Grade 2 treatment emergent neuropathy with 
pain or Grade 3 neuropathy 
 
Grade 4 neuropathy 
 
Continue to dose.  If neuropathy persists for more than 
two weeks hold carfilzomib until resolved to ≤ Grade 
2 without pain. Then restart at 1 dose decrement. 
Discontinue carfilzomib 
Renal Dysfunction 
Please refer to Table 5. 
Congestive heart failure 
Any patient with symptomatic congestive heart 
failure, whether or not drug related, must have the 
dose held until resolution or return to baseline, after 
which treatment may continue at a reduced dose, or 
the patient may be withdrawn from the study.  If no 
resolution after 2 weeks, the patient will be withdrawn 
from the study. 
Other non-hematologic toxicity assessed as 
carfilzomib-related > Grade 3 
Hold dose until toxicity resolves to ≤ Grade 1 or 
baseline.  Restart at 1 dose decrement. 
a Carfilzomib should be held until toxicity resolves to ≤ Grade 1.  Patients who develop irreversible Grade 3/4 non-hematologic 
toxicity, or toxicity that does not resolve to ≤ Grade 1 within 3 weeks, should be removed from the study. 
b No more than 2 dose reductions of carfilzomib are allowed.  
 


 
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Table 5  
Recommended Action for Renal Dysfunction 
Renal Dysfunction 
Recommended Action 
≥ 0 and < 25% decrease in CrCl 
over baseline 
Based on investigator judgment; no dose 
modification may be necessary. 
≥ 25% and < 50% decrease in 
CrCl over baseline 
Hold carfilzomib dose until CrCl is stable. 
If attributable to carfilzomib, resume carfilzomib 
at one dose decrement. 
If not attributable to carfilzomib, restart at dose 
used prior to the event. 
≥ 50% decrease in CrCl over 
baseline or CrCl < 15 mL/minute 
(NCI-CTC Grade 4) 
Hold carfilzomib dose until CrCl improves to < 
25% decrease over baseline and CrCl returns to ≥ 
15 mL/ minute (if CrCl dropped to < 15 ml/min). 
If attributable to carfilzomib, resume carfilzomib 
at one dose decrement. 
If not attributable to carfilzomib, restart at dose 
used prior to the event. 
If dialysis is required, may resume at a maximal 
dose of 20 mg/m2 and administer the carfilzomib 
after dialysis. 
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, 12-lead electrocardiogram (ECG), complete blood 
counts (CBC), differential and platelets, complete metabolic profile (CMP), prothrombin/partial 
thromboplastin time/international normalization ratio (PT/PTT/INR), and serum pregnancy test 
should be done ≤7 days prior to initiation of treatment. If urine pregnancy test is being done, it 
must be performed within 72 hours of Cycle 1 Day 1.  However, if these initial examinations are 
obtained within 72 hours of Cycle 1 Day 1 they do not have to be repeated on Cycle 1 Day 1.  
CT scans and LVEF assessment should be performed ≤28 days prior to initiation of treatment, as 
should tumor markers, if appropriate.   
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 other study-related procedures 


 
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• Medical history (including clinical tumor assessment as appropriate) 
• Physical examination, measurements of height (first visit), weight, 
• Vital signs (resting heart rate, blood pressure [BP], respiratory rate, and oral temperature) 
• ECOG performance status (see Appendix A) 
• 12-lead electrocardiogram (ECG) 
• Echocardiogram (ECHO) with calculated left ventricular ejection fraction (LVEF) (repeat 
if/when clinically indicated).  Multigated acquisition (MUGA) scan is acceptable if 
ECHO is not available. 
• Concomitant medication review 
• CBC including hemoglobin, hematocrit, WBC with 3-part differential and platelets 
• CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), ALT, AST, alkaline phosphatase (ALP), total 
bilirubin, total protein, and albumin. 
• PT/PTT/INR 
• Fasting serum chromogranin A (overnight fasting required) 
• Serum (within 7 days) or urine (within 72 hours) pregnancy test must be done before 
Cycle 1 Day 1  
• CT scans of the chest, abdomen and pelvis ≤28 days prior to initiation of study treatment; 
CT scan of abdomen and pelvis is preferred, but CT scan of abdomen is acceptable. 
• Archival tumor tissue or 10 unstained slides will be obtained if available 
7.3 
Study Treatment Assessments  
7.3.1 
Days 1, 8, and 15 of each cycle 
• Physical examination including measurement of weight, (Day 1 only) 
• 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) 
• Fasting serum chromogranin A (Day 1 only) 
• 24-hour urine for 5-HIAA (Day 1 only) 


 
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7.3.2 
Days 2, 9, and 16 of each cycle  
• Vital signs 
• AE assessment 
• Concomitant medication review 
7.4 
Response Assessment Every 3 Cycles  
Patients will be evaluated for response to treatment after every 3 cycles of treatment.  The 
following assessments will be performed:  
• CT scans of chest, abdomen and pelvis (if abnormal at baseline) 
• 24 hour urine for 5-HIAA 
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. 
After withdrawal from or completion of protocol treatment, patients must be followed up 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 
• Medical history 
• Vital signs 
• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• CBC, including 3-part differential and platelets 
• CMP  
• Serum or urine pregnancy test 
• CT scans of chest, abdomen and pelvis, if no disease progression or not done within prior 
6 weeks. 


 
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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.  Patients will not be followed up 
for survival if they start any subsequent therapy.  
The following tests will be done during follow up visits:  
• Medical history will be updated 
• Physical examination, including weight and vital signs (includes blood pressure, heart 
rate, breathing rate, and oral temperature) 
• CBC, including 3-part differential and platelets 
• CMP  
• 24-hour urine collection for 5-HIAA testing 
• CT scan of the chest, a CT scan of the abdomen/pelvis . 
 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
Carfilzomib 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-
4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Carfilzomib 
60 mg  
Onyx Therapeutics, Inc. 
 
8.1.1 
Labeling, Packaging, and Supply 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials 
packaged in multi-vial cartons.  Institutional pharmacies will be supplied with open stock vials 
with full-disclosure labels. 
The immediate packaging will contain a statement to conform with U.S. Food and Drug 
Administration (FDA) Investigational New Drug (IND) requirements as follows: Caution: New 
Drug - Limited by Federal (or United States) law to investigational use. 


 
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All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for carfilzomib are included on the investigational product label. 
SCRI Innovations must be granted access on reasonable request to check drug storage, 
dispensing procedures, and accountability records. 
8.1.2 
Preparation and Administration of Carfilzomib 
For the purpose of this study, carfilzomib will be administered as an IV infusion over 30 
minutes. 
Preparation and administration instructions will be provided in the pharmacy instruction. 
8.1.3 
Infusion reaction 
Infusion reactions associated with IV administration of carfilzomib were characterized by a 
spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial 
edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or 
angina. These reactions can occur immediately or up to 24 hours after administration.  
Administration of dexamethasone prior to carfilzomib dosing reduce the incidence and severity 
of reactions. Inform patients of symptoms and ask them to contact physician if symptoms of an 
infusion reaction occur.  Infusion reactions should be treated as per institutional protocol. 
Infusion reactions (e.g., rash, urticaria, erythema, pruritus, bronchospasm, and hypotension) can 
occur with the agent used in this study.  To identify the grade of a reaction, refer to the list below 
adapted from the General Disorders and Administration Site Conditions section of the NCI 
CTCAE v 4.03: 
• 
Grade 1:  Mild transient reaction; infusion interruption not indicated; 
intervention not indicated. 
• 
Grade 2:  Therapy or infusion interruption indicated but responds promptly 
to symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, IV fluids 
indicated for ≤24 hours). 
• 
Grade 3:  Prolonged (e.g., not rapidly responsive to symptomatic mediation 
and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae.  
Note:  any infusion that is interrupted and not resumed within the visit will 
be considered a Grade 3 reaction. 
• 
Grade 4:  Life-threatening consequences; urgent intervention indicated. 
Minor symptoms such as flushing, skin reactions, dyspnoea, lower back pain, hypotension, or 
tachycardia may require temporary interruption of the infusion.  However, severe reactions, such 
as hypotension requiring treatment, dyspnoea requiring bronchodilators, angioedema or 
generalized urticaria may require immediate treatment discontinuation and aggressive 
symptomatic therapy.  Patients who experience a severe reaction should not be re-challenged.  


 
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Patients who experience an allergic/infusion reaction may be pre-medicated for subsequent 
cycles per local guidelines and clinical practice. 
  
8.1.4 
Precautions and Risks Associated with Carfilzomib 
Precautions and risks are located in the IB. 
8.2 
Accountability for All Study drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by SCRI Innovations or its 
representatives and regulatory agency inspectors upon request. 
At the end of the study, all SCRI Innovations Drug Accountability Record Form(s) will be 
completed by the site and sent to the SCRI Innovations Regulatory Department.  Study drug 
supplies must not be destroyed unless prior approval has been granted by SCRI Innovations.  
Please contact SCRI Innovations regarding disposal of any study drug. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using the Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 (see Appendix E).  Lesions are either measurable or non-
measurable according to the criteria.  The term “evaluable” in reference to measurability will not 
be used, as it does not provide additional meaning or accuracy. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a multicenter, Phase II study of carfilzomib for the treatment of patients with advanced 
neuroendocrine cancers.  
Demographic data and baseline disease characteristics will be summarized using appropriate 
descriptive statistics (e.g., mean, median, standard deviation or percentages and frequency 
counts). 
The primary endpoint, ORR, will be determined using RECIST v1.1 criteria.  The median and 
25% and 75% percentiles for PFS will be summarized with associated 95% CI, and the 
distribution of PFS will be presented graphically using the Kaplan-Meier approach.  Progression-
free survival will be evaluated six and 12 months after the last patient is enrolled on the trial. 
 
10.2 
Sample Size Considerations 
This study will enroll up to 62 patients.  Simon’s optimal two-stage design (Simon, 1989) will be 
used for go/no go decision making.  The null hypothesis that the true response rate is 0.05 will be 


 
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tested against a one-sided alternative.  In the first stage, 23 patients will be accrued.  If there is 1 
or no response in these 23 patients, the study will be stopped.  Otherwise, 33 additional patients 
will be accrued for a total of 56.  The null hypothesis will be rejected if at least 6 responses are 
observed in 56 patients.  This design yields a type I error rate of 0.05 and power of 80% when 
the true response rate is 0.15.  The sample size will be increased by 10% to an accrual of 62 
patients, to account for potential non-evaluability.   
 
10.3 
Analysis Population 
The following analysis populations will be used: 
• The Full Analysis Set (FAS) will consist of all enrolled patients who receive at least one 
full or partial dose of study group and who have measurable disease at baseline. 
• The Evaluable Population will consist of the subset of the FAS who receive at least 2 full 
cycles of study drug and who no major protocol violations or deviations. 
• The Safety Population is defined as all patients who have received at least one full or 
partial dose of study treatment and for whom post baseline safety assessments are 
available.   
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.  For time to event outcomes, the median and 25% and 75% 
percentiles will be summarized with associated 95% confidence intervals.  All statistical analyses 
will be performed using SAS 9.1 or higher.  Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized.  Data to be tabulated will 
include demographic features such as age, sex and race, as well as disease-specific 
characteristics. 
The number and percentages of patients enrolled, treated, completing the treatment/study and 
withdrawn from treatment/study for any reasons will be summarized.  
10.4.1 
Efficacy Analysis 
Efficacy analyses will be reported for FAS population.  Additionally, the ORR, Clinical Benefit 
Rate (CBR), and PFS will be summarized for the Evaluable Population.  The following outcomes 
will be used to evaluate the clinical benefit of the study treatment: 
• 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 RECIST v1.1 criteria.  
 
• Clinical Benefit Rate (CBR) is defined as the proportion of patients with CR, PR or stable 
disease (SD) (≥ 6 cycles) according to RECIST v1.1 criteria. 
 


 
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o For ORR and CBR, patients without a post-baseline tumor assessment will be 
classed as not evaluable (NE) and considered as non-responders. 
 
• Progression-free Survival (PFS) is defined as the time from the first day of study drug 
administration (Day 1) to disease progression as defined by 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. 
 
For ORR and CBR, the estimates and the associated 95% CI based on the Clopper-Pearson 
method will be calculated.  For PFS, Kaplan-Meier curves will be generated and the median time 
to event and the associated 95% CI be provided.  
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 v4.03.  A copy of CTCAE scoring system may be 
downloaded from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE. 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized using system organ class and preferred term for all patients in the Safety Population.  
In addition, summaries of serious adverse events (SAEs), AEs leading to treatment 
discontinuation, AEs by maximum NCI CTCAE grade, and AEs related to study treatment will 
also be presented.  
Other safety endpoints including changes in laboratory results, vital signs and ECG findings will 
be summarized for the safety population.  Summaries of laboratory abnormalities based on 
maximum CTCAE grading will also be produced.   
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur when all patients progress or, for any patients with a 
sustained response or stable disease, a minimum of 3 treatment cycles have been completed. 
10.5.2 
Planned Interim Analysis 
No interim analyses are planned.  Interim results may be presented at congress prior to final 
study report, if applicable.  The design follows that of Simon et al. 1989.  If < 2 of the initial 23 
patients enrolled in the study fail to achieve a response, the study will be stopped and the 
remaining 33 additional patients will not be enrolled.  Patients will be evaluated for response to 
treatment every 3 cycles.  Patients will be removed from treatment at the time of disease 
progression.  Patients demonstrating an extended period of stable disease will be considered non-
responders after 12 cycles of treatment. 
10.5.3 
Efficacy Review 
Not applicable. 


 
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11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and 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 AEs to the SCRI 
Innovations Safety Department (SCRI Innovations SD) (see Section 11.1.5).  It is SCRI 
Innovations SD’s responsibility to report relevant SAEs to the applicable local or national 
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. 
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, defined as any adverse experience that places the subject, in the 
view of the Investigator, at immediate risk of death at the time of occurrence; i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
• 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 


 
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or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.   
It is important to distinguish between “serious” and “severe” AE, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
11.1.3 
Adverse Reaction 
An adverse reaction (AR) 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 (SAR) 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.  An SAR 
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 v4.03, and changes will be documented. 
If the AE is serious, it should be reported immediately to SCRI Innovations SD.  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). 


 
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Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment, and/ or test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the investigator. 
Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to carfilzomib 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). 


 
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11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to SCRI Innovations SD in order to comply with regulatory requirements.  
Determination of life-threatening or serious is based on the opinion of either the Sponsor or the 
Investigator.   
Serious AEs may occur at any time from the start of study treatment through the 30 days after the 
last dose of study drug.  The SCRI Innovations SD must be notified of all SAEs, regardless 
of causality, within 24 hours of the first knowledge of the event by the treating physician or 
research personnel.   
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to SCRI Innovations SD via fax or e-mail using the using the 
following contact information (during both business and non-business hours): 
SCRI 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. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to SCRI Innovations SD as soon as it is available; these reports should be 
submitted using the SCRI Innovations SAE Report Form.  The detailed SAE reporting process 
will be provided to the sites in the SAE reporting guidelines contained in the study reference 
manual. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
Expedited Reporting by Investigator to Onyx 
Expedited reporting will be completed by the Sponsor Safety Department of SCRI Innovations 
Safety Department.  Expedited reports will not be sent to Onyx by the Site investigator.  SAE 
reports are submitted by the participating site investigator with 24 hours of awareness to the 
SCRI Innovations Safety Department.  The Expedited Reporting responsibilities belong to SCRI 
Innovations Safety Department.  
CAR-XXX and the institutional protocol number should be included on all reports to Onyx.   
Onyx Drug Safety and Pharmacovigilance Contact Information: 
Onyx Fax:  
(800) 783-7954 
Email:  Adverse.Events@onyx.com 
 


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


 
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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 SCRI 
Innovations SD. 
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. 


 
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11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study or within 3 months after the last dose of 
study drug, a Pregnancy Form (a paper report form, not available within the eCRF) should be 
completed and faxed to the SCRI Innovations SD.  SCRI Innovations SD 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 SCRI Innovations 
SD. 
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 SCRI Innovations SD immediately.  Every effort should 
be made to follow the pregnancy for the final pregnancy outcome.  Newborns should be followed 
for a minimum of 12 weeks. 
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. 
If the subject becomes pregnant, the drug will be immediately discontinued.  The investigator 
will discuss the risks and concerns of investigational drug exposure to a developing fetus and 
counsel the subject and/or pregnant partner (or ensure that such counseling is provided).  
SCRI Innovations SD will notify Onyx DS within 24 hours of learning of any pregnancy. 
11.3.9 
Carfilzomib 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 SCRI Innovations SD 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 carfilzomib, see the IB. 
11.4 
Sponsor Serious Adverse Event Reporting Requirements 
SCRI Innovations SD will forward SAE information to Onyx Drug Safety and 
Pharmacovigilance, either via Fax:  (800) 783-7954 or via email: Adverse.Events@onyx.com 
within 1 business day of SCRI Innovations SD personnel becoming aware of the SAE. 
SCRI 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. 
11.4.1 
SCRI Innovations Assessment of Unexpected Adverse Events (UAE) 
SCRI Innovations SD 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: 


 
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• Event(s) is not mentioned in the IB (or 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 SAR that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation 
When applicable, an unexpected 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 suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
IB or USPI), and are serious (as defined by the protocol) and require expedient submission to 
relevant health authorities within 7 days (fatal or life-threatening event) or 15 days (all serious 
events), or as defined by law.  The term SUSAR is used primarily in the reporting of events to 
regulatory authorities. 
Expected AEs are those events that are listed or characterized in the Package Insert or current IB. 
11.4.2 
SCRI Innovations Reporting for Clinical Studies Under an Investigational New 
Drug Application 
All written IND Safety Reports submitted to the FDA by the SCRI Innovations Safety 
Department must also be faxed to pharmaceutical company(ies) that are supporting the study 
with either funding or drug supply: 
Onyx Drug Safety and Pharmacovigilance  
Contact Information: 
Onyx Fax:  (800) 783-7954 
E-mail:  Adverse.Events@onyx.com 
12. 
REGISTRATION ON CLINICALTRIALS.GOV 
This study will be registered on ClinicalTrials.gov by the sponsor, SCRI Development 
Innovations within 21 days of the enrollment of the first patient as required by the Food And 
Drug Administration Amendments Act of 2007.  Updates and changes will be submitted to 
ClinicalTrials.gov in compliance with regulations.  The Primary Completion Date for this study 
will be the date upon which the last patient undergoes an assessment for response [the primary 
outcome variable is Overall Response Rate (ORR) which is defined as the proportion of patients 
with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 
criteria].  Patients will be evaluated for response every 3 cycles.  Patients demonstrating an 
extended period of stable disease will be considered non-responders after 12 cycles of treatment. 


 
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Study results will be posted on ClinicalTrials.gov within 12 months of the Primary Completion 
Date 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL 
13.1 
Study Monitoring, Auditing, and Inspecting 
The investigator will permit study-related monitoring, quality audits, and inspections by SCRI 
Innovations 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 SCRI Innovations 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, SCRI Innovations or its representative(s). 
14. 
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). 
14.1 
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/SCRI Innovations and/or designee will follow all necessary 
regulations to ensure appropriate, initial, and on-going, IRB study review.  The Principal 
Investigator/SCRI Innovations (as appropriate) must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the informed 
consent document.  Investigators will be advised by SCRI Innovations or designee whether an 
amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB. 


 
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Safety updates for carfilzomib, will be prepared by SCRI Innovations or its representative as 
required, for distribution to the Investigator(s) and submission to the relevant IRB. 
14.2 
Regulatory Approval 
As required by local regulations, SCRI Innovations will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, 
SCRI Innovations 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. 
14.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form (ICF). 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
FDA, as well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
14.3.1 
Confidentiality 
14.3.1.1 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 
• 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 
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• 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 SCRI Innovations, 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 SCRI Innovations.  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. 
14.3.1.2 Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the SCRI 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, SCRI 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 
14.4 
Financial Information 
The finances for this clinical study will be patient to a separate written agreement between the 
SCRI Development Innovations, LLC and applicable parties.  Any Investigator financial 
disclosures as applicable to 21CFR Part 54 shall be appropriately provided. 
15. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
15.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by SCRI Innovations or its representatives.  All amendments require review and approval of all 
pharmaceutical companies and the Principal Investigator supporting the study.  The written 


 
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amendment must be reviewed and approved by SCRI Innovations, and submitted to the IRB at 
the investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by SCRI 
Innovations 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. 
15.2 
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: 


 
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SCRI Innovations 
Regulatory Department 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current Curricula Vitae for the principal investigator and any associate investigator(s) 
who will be involved in the study 
• Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB-approved consent form (and patient information sheet, if applicable) 
containing permission for audit by representatives of  SCRI 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)  
 
15.3 
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 


 
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representatives from SCRI Innovations 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, 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. 
SCRI Innovations 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 SCRI Innovations 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 SCRI 
Innovations 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 
SCRI Innovations.  The investigator must obtain SCRI Innovations’ written permission before 
disposing of any records, even if retention requirements have been met.  All study files will be 
maintained by SCRI Innovations (SCRI Innovations) throughout the study, and will be held by 
SCRI Innovations at the conclusion of the study. 


 
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15.4 
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 SCRI Innovations 
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 SCRI 
Innovations and replaced instead with the patient number and patient’s initials.  The investigator 
will maintain a personal patient identification list (patient numbers with corresponding patient 
identifiers) to enable records to be identified and verified as authentic.  Patient data/information 
will be kept confidential, and will be managed according to applicable local, state, and federal 
regulations. 
All data requested in the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The investigator will electronically 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. 
15.5 
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.  SCRI Innovations reserves the 
right to release literature publications based on the results of the study.  Results from the study 
will be published/presented as per SCRI Innovations’ 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, patient to the notice requirements described 
herein and patient to acknowledgement of SCRI Innovations as appropriate.  Investigator shall 
provide SCRI Innovations 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 SCRI 
Innovations requests in writing, the investigator shall withhold any publication or presentation an 
additional sixty (60) days solely to permit SCRI Innovations to seek patent protection and to 
remove any SCRI Innovations Confidential Information from all publications. 


 
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16. 
REFERENCES 
Afinitor (everolimus) PI 2102 
Product information. Afinitor (everolimus). East Hanover, NJ: Novartis Pharmaceuticals 
Corporation, 2012 (accessed 2013 June 20). http://www.pharma.us.novartis.com/product/ 
pi/pdf/afinitor.pdf. 
 
Badros et al. 2013 
Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, et al. Carfilzomib in multiple 
myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia 2013; 
27(8):1707-1714. 
 
Bergers et al. 1999 
Bergers, G, Javaherian K, Lo KM, Folkman J, Hanahan D . Effects of angiogenesis inhibitors on 
multistage carcinogenesis in mice. Science 1999 :284(5415): 808-812. 
 
Boccadoro et al. 2005 
Boccadoro M, Morgan G, Cavenagh J.  Preclinical evaluation of the proteasome inhibitor 
bortezomib in cancer therapy.  Cancer Cell Int 2005: 5(1):18. 
 
Capella et al. 1995 
Capella C, Heitz PU, Höfler H, Solcia E, Kloppel G..: Revised classification of neuroendocrine 
tumours of the lung, pancreas and gut. Virchows Arch 1995: 425 (6): 547-560. 
 
Chaudhry et al. 1992 
Chaudhry, A., Papanicolaou V, Oberg K, Heldin CH, Funa K.  Expression of platelet-derived 
growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res 
1992 :52(4):1006-1012. 
 
Cheng and Saltz, 1999 
Cheng, P.N. Saltz,L.B. Failure to confirm major objective antitumor activity for streptozocin and 
doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 1999: 
86(6):944-948. 
 


 
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Demo et al. 2007 
Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN et al. Anti-tumor activity of PR-
171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007: 67(13):6383–6391. 
 
Fenteany and Schreiber. 1996 
Fenteany G, Schreiber SL.  Specific inhibition of the chymotrypsin-like activity of the 
proteasome induces a bipolar morphology in neuroblastoma cells.  Chem Biol 1996: 3(11):905-
912. 
 
Herndon et al. 2013 
Herndon T, Deisseroth AB, Kaminskas E, Kane RC, Koti KM, Rothmann MD, et al.  U.S. Food 
and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.  Clin 
Cancer Res2013;19(17):4559-4563. 
 
Imtiaz et al. 2000 
Imtiaz F, Worthington V, Champion M, Beesley C, Charlwood J, Clayton P et al.  Genotypes 
and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1.  
J Inherit Metab Dis 2000: 23(2):162-174. 
 
Kyprolis® (carfilzomib) PI 2012 
Product information. Kyprolis (carfilzomib). South San Francisco, CA: Onyx Pharmaceuticals, 
Inc, 2012 (accessed 2013 June 18). http://www.kyprolis.com/Content/ 
pdf/PrescribingInformation.pdf 
 
Kuhn et al. 2007 
Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of 
carfilzomib, a novel, irreversibleinhibitor of the ubiquitin proteasome pathway, against 
preclinical models of multiple myeloma. Blood 2007: 110(9):3281–3290. 
 
Leong et al. 2002 
Leong WL, Pasieka JL.  Regression of metastatic carcinoid tumors with octreotide therapy: two 
case reports and a review of the literature. J Surg Oncol 2002: 79(3):180-187. 
 


 
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Levy and Sobin. 2007 
Levy AD, Sobin LH: From the archives of the AFIP: Gastrointestinal carcinoids: imaging 
features with clinicopathologic comparison. Radiographics 2007: 27 (1): 237-257. 
 
McCollum et al. 2004 
McCollum, A.D., et al., Lack of efficacy of streptozocin and doxorubicin in patients with 
advanced pancreatic endocrine tumors. Am J Clin Oncol 2004: 27(5):485-488. 
 
Niccoli et al. 2010 
Niccoli, P., Raoul J, Bang Y, Borbath I, Lombard-Bohas J, Valle W, et al. Updated safety and 
efficacy results of the phase III trial of sunitinib (SU) versus. placebo (PBO) for the treatment of 
pancreatic neuroendocrine tumors (NET). in J Clin Oncol. 2010.28(15s):abstr4000.. 
 
Nilsson et al. 1992 
Nilsson, O., Wangberg B, Theodorsson E, Skottner A, Ahlman H, et al., Presence of IGF-I in 
human midgut carcinoid tumours--an autocrine regulator of carcinoid tumour growth? Int J 
Cancer, 1992 :51(2):195-203. 
 
Papouchado et al. 2005 
Papouchado, B., Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, et al., 
Epidermal growth factor receptor and activated epidermal growth factor receptor expression in 
gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol, 2005: 
18(10):1329-35. 
 
Pavel et al. 2011 
Pavel ME, Hainsworth JD, Baudin E, et al.  Everolimus plus octreotide long-acting repeatable 
for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome 
(RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011: 378(9808):2005-
2012. 
 
Phan et al. 2006 
Phan, A.T., Wang L, Xie J, Zhang A, Rashid D, Evans J et al. Association of VEGF expression 
with poor prognosis among patients with low-grade neuroendocrine carcinoma. J Clin Oncol 
2006; 24:18s: abstr 4091. 


 
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Raymond et al. 2011 
Raymond E, Dahan L, Raoul JL, Bang Y, Borbath I, Lombar-Bohas C, et al.  Sunitinib malate 
for the treatment of pancreatic neuroendocrine tumors.  N Engl J Med 2011;364:501-513. 
 
Rinke et al. 2009 
Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M,et al.  Placebo-controlled, 
double-blind, prospective, randomized study on the effect of octreotide LAR in the control of 
tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the 
PROMID study group.  J Clin Oncol 2009 27(28):4656-4663. 
 
Shah et al. 2004 
Shah MH, Young D, Kindler HL, Webb I, Kleiber B, Wright J, Grever M.  Phase II study of the 
proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors.  
Clin Cancer Res 2004;10(18 Pt 1):6111-6118. 
 
Siegel et al. 2012 
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S,et al., A phase 2 study of single-
agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.  
Blood 2012. 120:2817-2825. 
 
Simon et al. 1989 
Simon R. Optimum two-stage designs for Phase II clinical trials. Controlled Clinical Trials 1989. 
10:1-10. Co Controlled l Trials 10:1-10 (1989) 
 
Smith et al. 2006 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 
2006;24(19):3187–205. 
 
Solcia et al. 2000 
Solcia E, Kloppel G, Sobin LH, et al.: Histological Typing of Endocrine Tumours. 2nd ed. New 
York, NY: Springer, 2000. 
 


 
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Suzuki et al. 2011 
Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib resistant adenocarcinoma 
cells. PLoS One 2011: 6(12):e27996. 
 
Vignot et al. 2005 
Vignot, S., Faivre S, Aguirre D, Raymond E et al., mTOR-targeted therapy of cancer with 
rapamycin derivatives. Ann Oncol 2005: 16(4): 525-537. 
 
Wulbrand et al. 2000 
Wulbrand, U., Remmert G, Zofel P, Wied M, Arnold R, Rehmann HC et al., mRNA expression 
patterns of insulin-like growth factor system components in human neuroendocrine tumours. Eur 
J Clin Invest 2000; 30(8):729-739. 
 
Yang et al. 2011 
Yang J, Wang, Z, Kirk C, et al. Pharmacokinetics, pharmacodynamics, metabolism,distribution, 
and excretion of carfilzomib in rats. Drug Metab Dispos 2011; 39(10):1873-1882. 
 
Yao et al. 2011 
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E,et al.  Everolimus for advanced 
pancreatic neuroendocrine tumors.  N Engl J Med 2011: 364(6):514-523. 
 
 
 


 
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17. 
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)  
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 SCRI 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 new 
born complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to SCRI 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  
 
 
ASSESSMENTS 
Pre-
Treatment 
 
STUDY TREATMENT  (Cycles repeated every 28 days)  
FOLLOW-UP 
Day 1 
Day 2 
Day 8 
Day 9 
Day 15 
Day 16 
End of Study 
Evaluationm 
Prior to disease 
progressionn 
Baselinea 
Tests and Observations 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
X 
X 
Physical examb    
X 
X 
 
 
 
 
 
X 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS  
X  
X 
 
X 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
ECHOd 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival status 
  
 
 
 
 
 
 
 
 
Laboratory Assessments 
CBC, 3-part differential, and platelets 
X 
X 
 
X 
 
X 
 
X 
X 
CMP e 
X 
X 
 
X 
 
X 
 
X 
X 
PT, PTT, INRf 
X  
 
 
 
 
 
 
 
 
Serum or Urine Pregnancy Testg 
X 
 
 
 
 
 
 
X 
 
Archival Tumor Tissue Samples 
Xh 
 
 
 
 
 
 
 
 
Fasting serum chromagranin Ai 
Xi 
Xi 
 
 
 
 
 
 
 
24 hour urine for 5-HIAAj 
 
Xj 
 
 
 
 
 
 
X 
Staging  (Every 3 cycles) 
CT Scan chestk 
X 
 
 
 
 
 
 
X 
X 
CT Scan abdomen /pelvisl 
X 
 
 
 
 
 
 
X 
X 


 
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Appendix D: Schedule of Assessments (continued)   
 
a 
Baseline procedures including medical history, physical examination, peripheral neuropathy assessment, 12-lead ECG, ECOG PS, CBC, CMP,  
PT/PTT/INR, and serum or urine pregnancy test 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.  Scans should be performed ≤ 28 days prior to initiation of treatment, to 
document measurable or evaluable disease. 
b 
Physical examination will include measurements of height (pre-treatment visit only), weight, and vital signs.   
c 
Vital signs will include resting heart rate, blood pressure, respiratory rate, and temperature. 
d 
ECHO with calculated LVEF (repeat if/when clinically indicated).  MUGA is acceptable if ECHO is not available. 
e 
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, 
and albumin.   
f 
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. 
g 
Serum or urine pregnancy tests are to be conducted in women of childbearing potential at the beginning of the study and at the end of study visit or 30 
days post last dose..   
h 
If available, archival tissue samples will be requested by study site personnel. 
i 
Fasting (overnight) serum chromagranin A test will be done during screening and then on Day 1 of each cycle.  
j 
24 hour urine for 5-HIAA will be done during screening and then every 3 cycles to assess response. 
k 
CT scans of the chest ≤4 weeks prior to initiation of treatment and then every 3 cycles during the treatment and at the end of study visit, if no PD and 
not done within prior 6 weeks. 
l 
CT scans of the abdomen/pelvis ≤4 weeks prior to initiation of  treatment and then every 3 cycles during the treatment and at the end of study visit.   
m 
Patients should visit the study center ≤30 days for end-of-treatment assessments.  Patients must be followed for AEs for 30 calendar days after the last 
dose of study drug. 
n 
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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SCRI INNOVATIONS STUDY NUMBER: GI 195 
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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. 
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. 


 
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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 
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.