Conditions: Neuroendocrine Tumors Carcinoid Tumors
Keywords: advanced metastatic unresectable carcinoma gastrointestinal tract lungs colon liver rectum small intestine stomach pancreatic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if the study drug, Pasireotide LAR can shrink or slow the growth of Metastatic Neuroendocrine Carcinomas. The safety of this drug will also be studied. The patient's physical state, changes in the size of the tumor, and laboratory findings taken while on-study will help us decide if Pasireotide LAR is safe and effective.

Detailed description:
This is a multi-institutional, prospective phase II open-label trial.

The investigational drug used in this study is pasireotide LAR 60 mg. Pasireotide will be administered as an intramuscular injection at the beginning of every cycle which is defined as 28 days (+/- 3 days). Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent. Safety and efficacy will be assessed throughout the treatment period.

Arms:
arm 1: The investigational drug used in this study is pasireotide long acting release (LAR) 60 mg.

Interventions: intervention 1: Pasireotide Long Acting Release (LAR)
Intervention descriptions: intervention 1: Pasireotide will be administered as an intramuscular injection at the beginning of every cycle which is defined as 28 days (+/- 3 days). Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Phase II Study of Pasireotide LAR in Patients with Metastatic Neuroendocrine 
Carcinomas 
 
NCT01253161 
 
Version 14 
December 11, 2020 


 
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Medical Affairs 
SOM230C  
Clinical Trial Protocol CSOM230DUS23T 
 Phase II Study of Pasireotide LAR in Patients with 
Metastatic Neuroendocrine Carcinomas 
Author: 
Jonathan Strosberg, MD 
Version number: 
14 
Release date: 
12/11/2020 


 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables 
 .................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
 1 
Introduction .............................................................................................................. 6 
 
1.1 
Overview of neuroendocrine tumors ........................................................ 6 
 
1.2 
Somatostatin analogs ................................................................................ 7 
 
1.3 
Pasireotide (SOM 230) ............................................................................. 8 
 
1.4 
Clinical experience ................................................................................... 9 
     1.4.1 Pasireotide s.c. .......................................................................................... 9 
     1.4.2 Pasireotide LAR ..................................................................................... 10 
2 
Study objectives ...................................................................................................... 11 
 
2.1 
Selection of doses ................................................................................... 11 
3 
Endpoints ................................................................................................................ 12 
 
3.1 
Primary endpoints ................................................................................... 12 
 
3.2 
Secondary endpoints ............................................................................... 12 
 
3.3 
Exploratory endpoint .............................................................................. 12 
4 
Study design ........................................................................................................... 12 
 
4.1 
Treatment ................................................................................................ 12 
 
     4.1.1 Rescue treatment for breakthrough diarrhea and other hormonal 
symptoms ............................................................................................................... 12 
 
4.2 
Follow-up................................................................................................ 13 
5 
Population ............................................................................................................... 13 
 
5.1 
Inclusion/exclusion criteria ..................................................................... 13 
 
     5.1.1 Inclusion criteria ..................................................................................... 13 
 
     5.1.2 Exclusion criteria .................................................................................... 14 
 6 
Study medication .................................................................................................... 15 
 
6.1 
Study drug: Pasireotide (SOM 230) ....................................................... 15 
  
6.2 
Permitted study drug adjustments........................................................... 16 
 
6.3 
Follow-up for Toxicities ......................................................................... 16 
 
     6.3.1 Management guidelines for hyperglycemia ........................................... 17 
 
     6.3.2 Management guidelines for QTc prolongation on ECG ......................... 17 
 
     6.3.3  Management Guidelines for Abnormal Liver Function ......................... 17 
 
     6.3.4 Concomitant therapy............................................................................... 18 
 
     6.3.5 Study drug discontinuation ..................................................................... 18       
 
6.4 
End of Treatment .................................................................................... 18 


 
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 7 
Visit schedule and assessments .............................................................................. 19 
  
7.1 
Pretreatment evaluation .......................................................................... 18 
 
7.2 
Evaluations during treatment .................................................................. 20 
 
7.3 
End of treatment evaluation .................................................................... 20 
8 
Outcome Measures ................................................................................................. 23 
 
8.1 
RECIST criteria for response ................................................................. 22 
 
8.2 
Guidelines for evaluation of measureable disease .................................. 25 
 
8.3 
Confirmation of Measurement/Duration of Response ............................ 25 
 
8.4 
PFS and censoring .................................................................................. 26 
9 
Safety Monitoring ................................................................................................... 27 
 
9.1 
Adverse events ........................................................................................ 27 
 
     9.1.1 Serious adverse events ............................................................................ 27 
 
     9.1.2 Recordati Inc. instructions for rapid notification .................................... 28 
 
     9.1.3 Pregnancies ............................................................................................. 28 
 
9.2 
Data monitoring board ............................................................................ 28 
10 
Data Collection ....................................................................................................... 29 
11 
Statistical Methods and Data Analysis ................................................................... 29 
 
11.1 
Sample size ............................................................................................. 29 
 
11.2 
Sample size justification ......................................................................... 29 
 
11.3 
Subset analyses ....................................................................................... 30 
12 
Exploratory Analysis .............................................................................................. 30 
13 
Quality of Life Assessments ................................................................................... 31 
14 
Protocol amendments, or changes in study conduct ............................................... 31 
15 
Procedures and Instructions .................................................................................... 32 
 
     15.1.1   Publication of results ............................................................................ 32 
 
     15.1.2   Disclosure and confidentiality .............................................................. 32 
 
     15.1.3   Discontinuation of study ....................................................................... 32 
 
15.2      Ethics and good clinical practice ............................................................... 32 
 
     15.2.1    Institutional Review Board .................................................................. 33 
 
     15.2.2    Informed consent ................................................................................. 33 
       
     15.2.3    Decleration of Helskinki ...................................................................... 33 
16 
References  ............................................................................................................. 33 
Appendix A......................................................................................................................... 35 
Appendix B ......................................................................................................................... 36 
Appendix C ......................................................................................................................... 38 
Appendix D........................................................................................................................ 39 
Appendix E  ....................................................................................................................... 40 


 
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List of tables 
Table 1-1 
Binding profile for octreotide and pasireotide at sst1-5 (IC50, M) ............ 8 
Table 6-1 
Handling and preparation of pasireotide LAR dose .............................. 15 
Table 6-2 
Criteria for dose modification of pasireotide ........................................ 16 
Table 6-3-2 
Guidelines for management of QTc prolongation ................................ 17 
Table 6-3-3 
Guidelines for management of abnormal liver function ....................... 17 
Table 6-3-3-1 
SOM230 Abnormal liver function discontinuation criteria .................. 17 
Table 7-3 
Visit evaluation schedule ...................................................................... 21 
Table 8-1 
Evaluation of best overall response....................................................... 24 
Table 8-4 
Classification of primary outcome ........................................................ 26 
 


 
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List of abbreviations  
5-HIAA 
Urinary 5-hydroxyindole acetic acid 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT 
BG 
Blood Glucose 
CPO 
Clinical Pharma Organization 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CT 
Computer Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practices 
GEP 
Gastroenteropancreatic 
GI 
Gastrointestinal 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
IM 
Independent Ethics Committee 
Intramuscular 
ITT 
Intent to Treat 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
LAR 
Long Acting Release 
MRI 
Magnetic Resonance Imaging 
MTD 
PFS 
Maximum tolerated dose 
Progression-Free Survival 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
SSA 
Somatostatin Analog 
SOP 
Standard Operating Procedure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
 
 


 
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1 
Introduction 
1.1 
Overview of Neuroendocrine Tumors  
Neuroendocrine tumors are a heterogeneous group of neoplasms which include carcinoid 
tumors and pancreatic neuroendocrine tumors.  The majority are characterized by a relatively 
indolent rate of growth and a propensity to produce and secrete a variety of hormones and 
other vasoactive substances, giving rise to diverse clinical syndromes.  Histologically, 
carcinoid tumors arise from the endocrine (enterochromaffin) cells of the gastrointestinal tract 
and airways.  Carcinoid tumors have distinct features depending on their site of origin.  In the 
1960s, Williams et al classified carcinoid tumors based on embryologic derivation, 
distinguishing between foregut (bronchial, stomach, duodenal), midgut (jejunal, ileal, cecal, 
appendiceal) and hindgut (distal colon and rectal) tumors.1  As a rule of thumb, metastatic 
midgut carcinoid tumors produce serotonin and other vasoactive substances which give rise to 
the typical carcioid syndrome.2  This syndrome manifests primarily as diarrhea and flushing, a 
vasomotor phenomenon which causes redness and warmth in the face and upper torso. 
Carcinoid heart disease, characterized by fibrosis of the tricuspid and pulmonic heart valves, 
can also occur in patients with severe and prolonged elevations of circulating serotonin.   In 
contrast, hindgut carcinoid tumors are rarely, if ever, associated with a hormonal syndrome.  
Tumor growth rates also correlate with site of origin.  In the metastatic setting, midgut 
carcinoid tumors tend to behave in the most indolent fashion, whereas neuroendocrine tumors 
originating in the foregut or hindgut regions tend to behave more aggressively once they have 
metastasized. 
 
Pancreatic neuroendocrine tumors arise from the islets of Langerhans.  These heterogeneous 
neoplasms can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, and 
vasoactive intestinal peptide (VIP).2  In contemporary studies, most pancreatic 
neuroendocrine tumors are unassociated with a hormonal syndrome, and are termed 
“nonfunctioning.”   
 
Treatment options for metastatic neuroendocrine tumors have evolved in recent years.  
Somatostatin analogs such as octreotide were initially developed to palliate hormonal 
symptoms such as the flushing and diarrhea caused by the carcinoid syndrome.3 More 
recently, accumulating data has supported their role as antiproliferative agents, capable of 
stabilizing tumor growth in patients with metastatic neuroendocrine malignancies.4  Last year, 
results of a phase III, randomized, placebo-controlled trial were published, demonstrating that 
long-acting octreotide (Sandostatin LAR 30 mg) significantly prolonged time to tumor 
progression among patients with metastatic midgut carinoid tumors.5   
 
Emerging evidence supports the use of other targeted agents, although none yet is considered 
standard of care.  Sunitinib, a multitargeted tyrosine kinase receptor inhibitor, has recently 
been demonstrated to prolong progression-free survival in patients with metastatic pancreatic 
neuroendocrine tumors. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) 
has shown promise in several phase II studies.6  Results of randomized, placebo-controlled 
phase III studies are pending.  Bevacizumab, an inhibitor of circulating vascular-endothelial 
growth factor (VEGF) is also being tested in phase III studies based on encouraging phase II 


 
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evidence.  Cytotoxic chemotherapy appears to produce high response rates in metastatic 
pancreatic neuroendocrine tumors7; however responses in carcinoid tumors have been 
discouraging. 
 
Among the various emerging treatments, somatostatin analogs appear to be associated with 
the most favorable side effect profile and ease of administration.  Their convenient mode of 
administration and tolerability are particularly important in patients with metastatic 
neuroendocrine tumors who often remain on treatment for many years.   
 
1.2 
Somatostatin analogs in the treatment of patients with 
Neuroendocrine Carcinomas 
 
The human hormone somatostatin was initially identified as a hypothalamic inhibitor of 
growth hormone.8 It was subsequently discovered to be a universal endocrine “off switch” due 
to its exocrine, endocrine, paracrine and autocrine inhibitory effects.9  In the digestive tract, it 
reduces secretion and motility, decreases portal blood flow, and reduces the secretion of other 
gastrointestinal hormones.  The effects of somatostatin are mediated through interaction with 
five somatostatin receptors (sst1-5), belonging to a family of G-protein coupled receptors with 
seven transmembrane domains.10   
 
The clinical use of native human somatostatin is limited by its short half life of approximately 
two minutes. In order to improve the pharmacokinetic profile, synthetic somatostatin analogs 
(SSAs) have been developed by shortening the polypeptide chain while retaining binding 
affinity to somatostatin receptors.11  The two commercially available analogs, octreotide and 
lanreotide, are octapeptides that bind with high affinity to somatostatin receptor 2 (sst2) and 
with moderate affinity to sst5.  
 
Octreotide has been used in clincial practice since the 1980s when it was shown to effectively 
palliate the carcinoid syndrome, as well as other syndromes caused by metastatic 
neuroendocrine tumors including VIPomas and glucagonomas.  Octreotide was initially 
available in an immediate-release subcutaenous formulation.  During the past decade, a long-
acting repeatable (LAR) depot formulation of octreotide (Sandostatin LAR) has been 
available allowing for monthly intramuscular dosing.12 
 
In recent years, evidence of the antineoplastic activity of SSAs has emerged.  Although 
objective radiographic responses associated with these agents are rare, many cases of 
prolonged disease stability have been documented in the literature, leading to the hypothesis 
that SSAs exert an inhibitory effect on tumor growth.  Last year, results of a phase III 
randomized, placebo-controlled study, the PROMID trial, were published.  In this trial, 85 
patients with well-differentiated carcinoid tumors originating in the distal intestine and 
proximal colon (midgut) were randomized to receive either octreotide LAR 30 mg or placebo.  
Median progression-free survival was 14.3 months in the octreotide LAR group versus 6.0 
months in the placebo group (p=0.000072), confirming the antiproliferative effect of 
octreotide in this patient population.5   
 


 
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Pasireotide (SOM230) is a novel somatostatin analog with a similar binding affinity to 
somatostatin sst2 and substantially stronger binding affinities to ssts1, 3 and 5  (see section 
1.3).13  Preclinical data suggests that ssts 1, 3 and 5 play an important role in cell cycle arrest 
and induction of apoptosis.14  Thus, we hypothesize that pasireotide LAR may prove to be a 
more potent inhibitor of neuroendocrine tumor proliferation than octreotide LAR. 
 
1.3 
Pasireotide (SOM230) 
 
Pasireotide is an injectable somatostatin analogue. It is a novel cyclohexapeptide with the 
following chemical name: (2-Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-
(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-
hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl 
ester, di[(S)-2-aminosuccinic acid] salt.   
Like natural somatostatin and other somatostatin analogues (SSAs), pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (ssts). There are five known 
somatostatin receptors: ssts1-5. Somatostatin receptors are expressed in different tissues under 
normal physiological conditions. Somatostatin analogues activate these receptors with 
different potencies15 and this activation results in a reduced cellular activity and inhibition of 
hormone secretion. Somatostatin receptors are strongly expressed in many solid tumors, 
especially in neuroendocrine tumors. The SSAs currently approved for use in the clinic 
(octreotide and lanreotide) have a high affinity to the sst2, with moderate or no affinity to the 
remaining subtypes. Pasireotide is a novel cyclohexapeptide somatostatin analogue that 
exhibits a unique binding profile, binding with high affinity to four of the five known human 
somatostatin receptors. (Table 1.1). Compared to Sandostatin® (octreotide acetate), 
pasireotide exhibits a binding affinity which is 30-40 times higher for human sst1 and sst5, 5 
times higher for human sst3, and 2.5 times lower for human sst2. A detailed summary of 
available preclinical data is provided in the Investigators' Brochure. 
Table 1.1 
Binding profile for octreotide and pasireotide at sst1-5 (IC50, M) 
Compound 
sst 1 
sst2 
sst3 
sst4 
sst5 
octreotide 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50: 
octreotide to 
pasireotide 
30 
0.4 
5 
-- 
40 
 
Additionally, preclinical studies suggest anti-tumor activity of pasireotide.  Pasireotide has 
been found to significantly reduce cell proliferation of the neuroendocrine tumor cell line 
NCI-H727, whereas the conventional analogue octreotide did not.16 


 
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1.4 
Clinical experience with pasireotide 
Pasireotide is available as a short-acting subcutaneous (s.c) formulation and a long acting 
release (LAR) intramuscular (IM) formulation.   
1.4.1 
Pasireotide s.c. 
Pasireotide when given subcutaneously (s.c.) was well-tolerated at doses up to 600 µg b.i.d., 
900 µg b.i.d. and 1200 µg b.i.d by acromegalic, Cushing’s disease and carcinoid tumor 
patients, respectively. In addition, healthy volunteers have received pasireotide s.c. as a 
continuous infusion for seven days with total daily doses of up to 2025 µg being well 
tolerated. For all indications the most frequently reported adverse events were gastrointestinal, 
predominantly diarrhea, nausea and abdominal pain. Generally these events were mild, 
transient and only occasionally caused patients to discontinue treatment. 
Hyperglycemia was also observed for patients in all three indications. In general HbA1c was 
observed to increase by approximately 1%, corresponding to a blood glucose increase of 
approximately 30 mg/dL. Blood glucose increases tended to occur with increasing dose, and 
appeared to be more notable in patients who had a history of hyperglycemia or diabetes 
mellitus prior to receiving pasireotide. However hyperglycemia in these patients was 
responsive to appropriate diabetic management such as adjustments in oral antidiabetic 
treatment, or in some cases the addition of insulin. 
Occasionally laboratory abnormalities in liver function tests and pancreatic enzymes have 
been observed at higher doses of pasireotide. These events however have been transient. 
Further details on pasireotide s.c. can be found in the Investigator Brochure. 
 
1.4.1.1 
Phase II studies of pasireotide s.c. in neuroendocrine tumors 
Preliminary safety data are available from a Phase II study [CSOM230B2202] in 45 patients 
with symptomatic metastatic carcinoid disease who received pasireotide s.c. doses from 300 
µg s.c. b.i.d. up to 1200 µg b.i.d. for a mean of 20 weeks. Overall pasireotide s.c. has been 
found to be generally well-tolerated by these patients, with the most common adverse events 
being mild diarrhea, nausea and abdominal pain. Blood glucose increases tended to occur with 
increasing dose, but were moderate and generally managed easily by adjustment in oral 
hypoglycemic medications. Weight loss was also observed in 18 patients. Maximum weight 
loss occurred within 4 to 6 months on the study drug, with a stabilization of effect after 
approximately 6 months. There was no apparent relationship between the weight loss and 
pasireotide dose. 
Preliminary efficacy data from this study also support that pasireotide is active in patients 
refractory/resistant to Sandostatin LAR, as partial or complete symptom control was observed 
in 12 of 44 patients (27%). Complete symptomatic response was achieved in two patients at 
the pasireotide 600 µg s.c. b.i.d. dose and one at the 900 µg s.c. b.i.d. dose. Nine patients 
achieved partial symptomatic response to treatment, three at each of the following doses: 600, 
750, 900 µg s.c. b.i.d. 
 


 
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1.4.2 
Pasireotide LAR 
Most of the experience with pasireotide comes from healthy volunteer and patient studies 
evaluating the subcutaneous formulation of pasireotide.  Pasireotide LAR is being evaluated 
in two studies, one healthy volunteer study and one study involving patients with acromegaly 
and carcinoid disease. 
1.4.2.1 
Pasireotide LAR in healthy volunteers 
Preliminary data from the healthy volunteer study found single IM doses of pasireotide LAR, 
at doses of up to 40 mg and 60 mg, respectively to be well-tolerated.  The most common 
adverse events were gastrointestinal.  Diarrhea was experienced by most of the subjects and 
was sometimes associated with abdominal pain, flatulence, and/or nausea.  The 
gastrointestinal events were mild or moderate in severity.  About 38% of subjects reported 
mild injection site pain and about 15% reported headaches. 
Transient elevations in liver function tests and/or pancreatic enzymes were observed in two 
subjects, both of which resolved and were not accompanied by any clinical symptoms.  Mild 
increases in fasting blood glucose were observed in some subjects during the pasireotide LAR 
treatment period.  All elevations were asymptomatic, considered not clinically significant and 
generally returned to normal within 3 to 4 weeks after the pasireotide LAR IM injection. 
 
1.4.2.2 
Pasireotide LAR in acromegalic patients 
Preliminary safety data are available from 18 acromegalic patients treated with pasireotide 
LAR in an ongoing study [CSOM230C2110]. These patients had received pasireotide LAR at 
doses of 20 (n=5), 40 (n=6) or 60 mg (n=7) for about six weeks at the time of the summary.  
Pasireotide LAR was well-tolerated by acromegalic patients in this study. The most common 
drug-related adverse events were gastrointestinal, predominantly diarrhea. Mild erythema 
reported as drug-related was experienced by three patients. Two patients on the 60 mg dose 
were reported to experience drug-related increases in blood glucose: mild diabetes mellitus 
was reported for one patient and mild hyperglycemia was reported for the other patient who 
also had a history of diabetes mellitus at baseline. A further patient who received the 20 mg 
dose experienced hyperglycemia, however this event was considered to be unrelated to study 
drug by the investigator. All three patients were given oral hypoglycemic agents and all 
continued in the trial.  
Following 2-3 injections of pasireotide LAR in acromegaly patients [CSOM230C2110], 
steady-state concentrations of pasireotide were achieved.  The trough plasma concentrations 
of pasireotide at steady state (Cmin.ss) on day 84 were 3.8 ± 2.1, 5.6 ± 2.4, and 13.8 ± 10.2 
ng/mL for 20 mg (N=9), 40 mg (N=9), and 60 mg (N=11) LAR, respectively, indicating an   
approximate dose proportionality. 
   
1.4.2.3 
Pasireotide LAR in carcinoid patients 
Preliminary safety data are available from nine carcinoid patients treated with pasireotide 
LAR in an ongoing study [CSOM230C2110]. These patients had received pasireotide LAR at 


 
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doses of 20 (n=1), 40 (n=4) or 60 mg (n=4) for about six weeks at the time of the summary. 
Pasireotide LAR was well-tolerated by carcinoid patients. Six out of nine treated patients 
reported at least one AE and the most commonly reported AEs were gastrointestinal.  
However, most of these events were considered unrelated to study drug.  Two patients 
reported hyperglycemia judged as related to study drug, one was mild and one moderate.  The 
patient who experienced moderate hyperglycemia had a past history of diabetes mellitus at 
entry to the study and died due to carcinoid tumor progression. 
Although pasireotide exposures appear to be higher in patients than in healthy volunteers, the 
data from studies assessing the subcutaneous formulation of pasireotide support that 
pasireotide LAR at doses of 60 mg and below are expected to be well-tolerated by patients.  A 
healthy volunteer study of pasireotide s.c. by continuous infusion tested doses of up to 2,025 
mcg per day [SOM230B2108].  The dose of 2,025 mcg by s.c. infusion per day was well-
tolerated and is equivalent to a dose of 56.7 mg from a single 28 day IM depot injection of 
pasireotide LAR.  Data resulting from studies [SOM230B2108] and [SOM230B2202] are 
described fully in the Pasireotide s.c Investigator’s Brochure. 
The effects of high doses of pasireotide on cardiac repolarization in healthy volunteers was 
tested in study CSOM230B2113.  The dose of s.c pasireotide selected was 1950mcg bid. This 
dose was compared to moxifloxacin and placebo.  The results of the study suggested the 
presence of an effect of pasireotide on QTcF intervals due to the fact that the upper bound of 
the 95% one-side CI for the difference from placebo was greater than 10ms at 1-2 hours post 
dose.      
Given the tolerable side-effect profile of pasireotide LAR, its enhanced affinity for 
somatostatin receptors compared to octreotide LAR, and its putative antiproliferative effects 
in patients with neuroendocrine tumors, we propose a phase II study investigating pasireotide 
LAR in patients with metastatic neuroendocrine tumors.  Unlike prior studies focusing on 
palliation of hormonal symptoms, the primary goal of this study is to assess radiologic 
progression-free survival (PFS). 
 
2 
Study objectives 
The primary purpose of the study is to investigate the progression-free survival associated 
with pasireotide LAR in treatment-naïve patients with metastatic carcinoid and pancreatic 
neuroendocrine tumors. 
Secondary objectives are to assess the overall survival (OS) associated with pasireotide LAR, 
overall radiographic response rate (ORR), adverse events (AEs), changes in tumor markers 
and changes in quality of life (QOL). 
2.1 
Selection of doses 
Based on the tolerable side-effect profile of pasireotide LAR at doses of 60mg every 4 weeks 
(see section 1.4.2.3) and pharmacokinetic data demonstrating therapeutic drug levels at that 
level, the dose of pasireotide in this study will be 60mg IM every 4 weeks.  No doses of 
pasireotide LAR exceeding 60mg will be tested in this trial.  If tolerability issues occur, the 
treatment dose may be reduced to 40mg. 


 
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3 
Endpoints 
3.1 
Primary endpoints 
• Progression-free survival (PFS) 
• Rate of PFS at one year 
3.2 
Secondary endpoints 
• Overall survival (OS) 
• Overall radiographic response rate (ORR) 
• Adverse events (AEs) 
• Changes in neuroendocrine tumor markers (such as chromogranin A or pancreatic 
polypeptide), or hormonal assays (such as urine 5-HIAA, gastrin, insulin, glucagon, 
vasoactive intestinal peptide, etc) if elevated at baseline.   
• Changes in quality of life (as measured by EORTC questionnaires EORTC QLQ-C30 
and QLQ GI.NET21 
3.3 
Exploratory endpoint 
• To assess the correlation between somatostatin receptor profiling (via 
immunohistochemistry) and PFS 
4 
Study design 
This is a multi-institutional, prospective phase II open-label trial.  
4.1 
Treatment 
The investigational drug used in this study is pasireotide LAR 60mg.  Pasireotide will be 
administered as an intramuscular injection at the beginning of every cycle which is defined as 
28 days (+/- 3 days).  Study treatment should begin within 14 days following enrollment into 
the study and continue until disease progression, unacceptable toxicity, or withdrawal of 
consent.  Safety and efficacy will be assessed throughout the treatment period.   
 
4.1.1 
Rescue treatment for diarrhea and other breakthrough hormonal 
symptoms 
 
Patients with hormonal symptoms caused by neuroendocrine tumors (such as the carcinoid 
syndrome) may experience symptom flares requiring short-acting rescue medications.  For 
these patients, short-acting pasireotide sc may be prescribed at the discretion of the 
investigator at a dose of 600 mcg bid prn.  Patients who continue to experience 
breakthrough diarrhea due to carcinoid syndrome or other hormonal syndromes may use 
antidiarrheal medications such as loperamide or diphenoxylate and atropine.  SOM230 may 


 
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cause malabsorption and steatorrehea which can be controlled with pancreatic enzyme 
supplementation.   
 
4.2 
Follow-up 
All patients will be followed for adverse events and serious adverse events for 28 days 
following the last dose of pasireotide, or until resolution or stabilization of the event, 
whichever comes first.  
5 
Population 
The study population will consist of patients with advanced (metastatic or unresectable) well 
and moderately differentiated neuroendocrine tumors of the gastrointestinal tract and lungs 
(carcinoid tumors) and pancreatic neuroendocrine tumors.  
5.1 
Inclusion/exclusion criteria 
The investigator or his/her designee must ensure that all patients who are offered enrollment 
in the study meet all of the following inclusion and exclusion criteria: 
5.1.1 
Inclusion criteria 
 
1. Locally unresectable or metastatic carcinoid or pancreatic neuroendocrine tumors. 
2. Tumors must be considered well or moderately differentiated (or low to intermediate 
grade).  Patients with poorly differentiated neuroendocrine carcinomas or small cell 
carcinomas are excluded from the study. 
3. No prior systemic antineoplastic neuroendocrine tumor treatment (including prior 
somatostatin analogs).  However patients who have received a short course of SQ 
octreotide (<10 days) in the past are eligible if > 1 week has elapsed from their last 
octreotide injection.   
4. Age ≥ 18 years. 
5. Minimum of four weeks since any major surgery. 
6. Measureable disease by RECIST. 
7. ECOG performance status ≤1 
8. Life expectancy 12 weeks or more. 
9. Adequate bone marrow function as shown by: ANC ≥ 1.0 x 109/L, Platelets ≥ 75 x 109/L, 
Hgb > 8 g/dL. 
10. Adequate liver function as shown by: serum bilirubin ≤ 2.0 x upper limit of normal 
(ULN), and serum transaminases activity ≤ 2 x ULN, with the exception of serum 
transaminases (< 3 x ULN) if the patient has liver metastases. 
11. Adequate renal function as shown by serum creatinine ≤ 2.0 x ULN. 


 
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12. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only 
be included after initiation of appropriate lipid lowering medication. 
13. Women of childbearing potential must have a negative serum pregnancy test within 14 
days of the administration of the first study treatment.  Women must not be lactating. Both 
men and women of childbearing potential must be advised of the importance of using 
effective birth control measures during the course of the study. 
14. Signed informed consent to participate in the study must be obtained from patients after 
they have been fully informed of the nature and potential risks by the investigator (or 
his/her designee) with the aid of written information. 
 
5.1.2 
Exclusion criteria 
 
1. Uncontrolled brain or leptomeningeal metastases, including patients who continue to 
require glucocorticoids for brain or leptomeningeal metastases. 
2. Patients with prior or concurrent malignancy except for the following: adequately treated 
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any 
other cancer from which the patient has been disease free for five years. 
3. Patients with uncontrolled diabetes mellitus or a fasting plasma glucose > 1.5 ULN or 
HbA1c >8%. Note: At the principle investigator’s discretion, non-eligible patients can be 
re-screened after adequate medical therapy has been instituted. 
4. Patients with symptomatic cholelithiasis 
5. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, or a 
history of acute myocardial infarction within the six months preceding enrollment.  
6. Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
• 
Severely impaired lung function 
• 
Any active (acute or chronic) or uncontrolled infection/ disorders.   
• 
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy 
7. Known hypersensitivity to somatostatin analogues or any component of the pasireotide 
LAR formulation  
8. Corrected QT interval (QTcF) of >470msec on screening ECG 
9. Risk factors for Tosades de Pointes such as cardiac failure, clinically 
significant/symptomatic bradycardia. 
10. Clinically significant hypokalemia or hypomagnesemia that are not correctable. 
11. History of sustained ventricular tachycardia, ventricular fibrillation, advanced heart block, 
idiopathic syncope thought to be related to ventricular arrhythmia, or congenital long QT 
syndrome. 


 
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12. Concomitant medication(s) known to increase the QT interval (see appendix A) 
13. History of noncompliance to medical regimens or unwillingness to comply with the 
protocol. 
6 
Study Medication 
6.1 
Study drug: Pasireotide (SOM 230) 
 
Study drug: pasireotide LAR (long-acting release) i.m. depot injection 
Inactive ingredients of pasireotide LAR include: mannitol, carmellose sodium 
(carboxymethylcellulose sodium), poloxamer 188 and water for injection. For detailed 
information on pasireotide, please refer to Sections 1.3 and 1.4 or the pasireotide 
Investigator Brochures.  
How supplied 
Study drug, Pasireotide LAR i.m. depot injections will be supplied in open-label 
packaging by Recordati Inc. as a powder in vials containing 20 mg and 40 mg  labeled as 
SOM230 LAR, with ampules containing 2 mL of vehicle (for reconstitution). No syringes 
or needles will be provided with the pasireotide study drug supplies.  
Preparation and storage 
Prior to reconstitution, vials should be brought to room temperature.  Pasireotide LAR 
should then be prepared as follows: 
Table 6-1   Handling and preparation of pasireotide LAR dose 
Dose  
Volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60 mg 
1 x 20 mg vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be injected 
Doses should be prepared and administered immediately after preparation.   
 
Recordati Inc. will supply pasireotide LAR as long as the patient remains on study, shows 
continuous benefit from treatment, and there are no safety concerns. Medication labels will 
comply with the legal requirements of the U.S. and will be printed in English. The storage 
conditions for pasireotide LAR will be described on the medication label. Bottles must be 
stored in a safe, secure location.  
All study medication will be supplied to each site directly by Recordati Inc. Under the 
responsibility of each site’s lead investigator, drug supplies must be kept in an appropriate, 
secure area (e.g. locked cabinet) and stored in accordance with the conditions specified on 
the drug labels. The investigator must maintain an accurate record of the shipment and 
dispensing of the study drug in a drug accountability ledger. An accurate record of the date 
and amount of study drug dispensed to each subject must be available for inspection at any 
time. 


 
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All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Recordati Inc., the investigator must not destroy any drug labels, 
or any unused drug supply. 
 
The storage condition for the study drug will be described on the medication label. 
Administration 
Pasireotide LAR will be administered i.m., intragluteally, every 4 weeks. The starting dose 
will be 60 mg.  The reconstitution has to be performed just prior to administration of the 
suspension. A minimal standing time can be tolerated for the reconstituted suspension in the 
vial. Prior to administration, the reconstituted suspension in the vial should be shaken again 
before withdrawal in the syringe. The i.m. injection must be given immediately after 
withdrawal of the reconstituted suspension from the vial to the syringe.  All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded.  Recordati Inc. will supply pasireotide free of charge for study participants. 
6.2 
Permitted study drug adjustments 
 
Toxicity will be assessed using the NCI-CTC for Adverse Events, version 4.0 (CTCAEv4.0, 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html)). For patients who are unable to tolerate 
pasireotide 60mg every 4 weeks, the dose may be changed to 40mg every 4 weeks (see table 
6-2). 
 
Table 6-2 Criteria for dose-modification of pasireotide  
Adverse event 
Action 
*Grade ≤ 2  
No study drug adjustments 
*Grade ≥ 3 and 
judged as at least 
possibly drug 
related 
• Reduce dose to 40mg 
• If AE improves to grade ≤2 before the next administration, increase 
dose to 60mg.  If the dose is increased and that AE recurs at CTC 
grade ≥ 3 the dose will be reduced back to the lower dose and shall 
not be increased again during the study period. 
• If AE does not improve to grade ≤2 on the lower dose befoe the next 
administration, the patient will discontinue the study drug and be 
followed for safety. 
*This guidance should be use for all probably related AEs except for changes in blood glucose 
which should be addressed as described in Section 6.3.1 and changes in QTc interval which 
should be addressed as described in Section 6.3.2.. 
 
 
6.3 
Follow-up for toxicities 
Patients who interrupt or permanently discontinue pasireotide due to an adverse event or 
abnormal laboratory value must be followed at least weekly for 28 days after the last dose of 
pasireotide, and subsequently at monthly intervals until resolution or stabilization of the event, 


 
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whichever comes first. If a patient requires a dose delay of > 21 days from the intended day of 
the next scheduled dose, then the patient should be discontinued from the study. 
All patients will be followed for adverse events and serious adverse events for 28 days 
following the last dose of pasireotide. 
 
 
6.3.1 
Management Guidelines for Hyperglycemia 
 
During the study, all patients with HbA1c ≥ 7 % and or fasting plasma glucose (FPG) > 130 
mg/dL (7.2 mmol/L), should be considered for the following: 
 
• 
Provided information and receive teaching on diabetes disease management 
• 
Initiation of drug therapy with anti-hyperglycemic medications 
• 
Referral to a diabetes specialist for evaluation and appropriate management 
• 
Monitoring of blood glucose by fingerstick twice daily (fasting morning blood glucose 
and 2-hour post-meal) if not already done. Patients, who monitor blood glucose should 
keep a diary of their glucose values and present the collected data to their physician/ 
diabetes specialist for evaluation and appropriate management. 
 
6.3.2 
Management Guidelines for QTc prolongation on ECG 
 
Table 6-3-2 provides guidelines for management of prolonged QTc interval. 
 
Table 6-3-2 Guidelines for Management of QTc Prolongation 
 
QTc CTC grade 1 (≤ 480 msec) 
No study drug adjustments 
QTc CTC grade 2 (> 480 or ≤ 500 msec) 
either drug related or drug unrelated 
Patient is to be referred to a cardiologist for evaluation and 
appropriate management, and the patient can remain in the study 
Patient’s study drug dose will be reduced to 40 mg. 
QTc CTC grade ≥ 3 (> 500 msec), or 
increase in QTcF ≥60ms over baseline 
Discontinue study drug 
Follow patient for safety 
 
  6.3.3    Management Guidelines for Abnormal Liver Function 
 
Table 6-3-3: SOM230 Abnormal liver function management  
Perform within 72 hours of awareness of abnormal LFTs:  
 Perform liver-directed medical history and physical examination (i.e. assess occupational hazards, concomitant 
medications including OTC meds, intercurrent illness, etc)  
 Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if total bilirubin is > 2.0x ULN), Alb, 
PT (INR), ALP, and GGT  
 Perform hepatitis screen: anti-HAV, IgM (to confirm acute hepatitis A), HbsAg, Anti-HBc, anti-HCV (if positive PCR viral 
load should be assessed), Anti-HEV, ANA antibodies, anti-smooth muscle anti-bodies, CMV, EBV  
 Perform abdominal ultrasound (liver and biliary tree)  
 Collect PK sample and record the dose level and the dosing time for the last dose the patient has taken prior to PK 
sampling.  
 


 
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Liver chemistry tests should be monitored every 3-4 days for s.c. and LAR studies until resolution or return to baseline 
status.  
 For ALT or AST > 5x ULN and ≤ 8x ULN:  
o Study medication should be temporarily interrupted and liver chemistry tests monitored every 3-4 days for s.c. and LAR 
studies until resolution or return to baseline  
o If resolution or return to baseline does not occur after 2 weeks, the patient should be discontinued.  
o If ALT or AST returns to less than 5x ULN, study drug can be resumed and patient can continue study per protocol  
o If ALT or AST rises above 5x ULN anytime after study drug is resumed, then study drug should be discontinued 
immediately.  
 
 
Table 6-3-3-1: SOM230 Abnormal liver function discontinuation criteria 
Hepatic-related discontinuation criteria for all ongoing studies  
Study medication should be discontinued immediately if any of the discontinuation criteria below are 
met:  
 ALT or AST > 3x ULN and Total Bilirubin > 2x ULN and ALP < 2x ULN  
 ALT or AST > 5x ULN and ≤ 8x ULN persistent for more than 2 weeks  
 ALT or AST > 8x ULN  
 
Re-challenge of study medication is prohibited once discontinuation criteria are met.  
 
6.3.4    Concomitant therapy 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At 
each visit, the investigator will ask the patient about any new medications he/she is or has 
taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be 
recorded. 
The use of concomitant medications that might lead to QT prolongation (appendix A) is 
prohibited and requires the discontinuation of the patient prior to starting the respective QT 
prolonging medication. 
Pasireotide is a moderate inhibitor of CYP2C9 and 2D6.  Substrates of CYP2C9 and 2D6 
(appendix D) with a narrow therapeutic index should be used with caution.  Patients on 
Warfarin should have their INR monitored more closely while receiving SOM230. 
 
     6.3.5    Study drug discontinuation 
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator 
considers directly attributable to the study drug should have their dose adjusted as per dose 
modification guidelines in Table 6-2. If a patient has already decreased 1 dose level, no 
further dose reduction is permitted, and the patient will be permanently discontinued from 
treatment.  For QTc related protocol discontinuation, please see section 6.3.2.   For LFT 
related protocol discontinuation, see section 6.3.3. 


 
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6.4 
End of treatment 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients will be withdrawn from the study if any of the following 
occur: 
• Disease progression 
• Death 
• Withdrawal of consent 
• Delay of treatment >21 days. 
• Uncontrolled diabetes mellitus (DM) 
• Pregnancy 
• Adverse event(s) ≥grade 3 despite dose reduction 
• QTc prolongation (see section 6.3.2) 
7 
Visit schedule and assessments 
 
7.1 
Pretreatment Evaluation 
 
Baseline tumor and patient characteristics including: 
 
• Patient demographics: age, gender and race (Caucasian, Black, Hispanic, Asian, 
other). 
• Medical history 
• Medications 
• ECOG performance status. 
• Type of neuroendocrine tumor: primary site (if known) vs. unknown.  
• Differentiation or grade (if available). 
• Known sites of metastases. 
• Estimation of tumor burden in the liver (none vs. <10% vs. >10%).   
• Presence or absence of radiotracer uptake on OctreoScan (if available). 
• Presence or absence of hormonal syndrome (carcinoid syndrome, gastrinoma 
syndrome, insulinoma syndrome, etc.) 
• Presence or absence of a pathologically elevated hormone or biomarker.   
• EORTC QLQ C-30 and EORTC QLQ GI-NET21 questionnaires 
 
Tests to be performed within 28 days prior to initiation of therapy (if day 28 falls on a 
weekend or holiday the deadline may be extended to the next working day): 
 
• Radiologic assessment of tumor burden by CT scan or MRI 
• Assessment of secretory proteins. All patients will undergo an initial assessment of 
chromogranin A.  Patients with suspected serotonin-producing tumors (and all patients 
with midgut carcinoid tumors) will have a 24 hour urine 5-HIAA measured at 


 
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baseline.  Other possible neuroendocrine tumor markers/hormones (e.g. pancreatic 
polypeptide, gastrin, glucagon, etc.) may be collected at the discretion of the 
investigator based on clinical symptoms and tumor location.   
 
Tests to be performed within 14 days prior to initiation of therapy (if day 14 falls on a 
weekend or holiday the deadline may be extended to the next working day): 
 
• History and physical evaluation including height, weight, vital signs and performance 
status. 
• Baseline hematological and biochemical profiles including CBC with differential and 
comprehensive metabolic panel (fasting glucose, sodium, potassium, chloride, 
bicarbonate, creatinine, blood urea nitrogen, albumin, SGOT (AST) SGPT (ALT) total 
bilirubin, alkaline phosphatase, calcium and magnesium). 
• Hemoglobin A1c 
• Serum pregnancy test for women of childbearing potential 
• Electrocardiogram 
 
7.2 
Evaluations During Treatment 
 
 
Beginning of every cycle (defined as 28 days +/- 3 days) (every 6 months after 5 years on 
therapy) 
 
• Physical examination 
• Toxicity assessment 
• Vital signs 
• ECOG performance status 
• CBC with differential 
• Fasting comprehensive metabolic panel 
• Assessment of adverse events 
 
Data to be obtained every 3 cycles of treatment (every 12 months after 5 years on therapy): 
 
• Radiologic assessment of tumor burden by CT scan or MRI.  Patients who have been 
on study for > 2 years will undergo scans every 6 cycles. Patients who have been on 
study for > 5 years will undergo scans every 12 cycles, at treating physician discretion.  
• Electrocardiogram (baseline, 6 hours after 1st injection, 21days after 1st injection, 21 
days after 3rd injection, Cycle 6, and every 3 cycles thereafter. ) 
• Liver function testing 21 days after 1st injection and 21 days after 3rd injection 
• Assessment of chromogranin A and/or other tumor markers or hormones if elevated at 
baseline (see section 7.1).  
• EORTC QLQ C-30 and EORTC QLQ GI-NET21 questionnaires 
7.3 
 End of Treatment Evaluation 
 


 
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Data to be obtained at completion of study: 
 
• Physical examination 
• Toxicity assessment 
• Vital signs 
• Weight 
• ECOG PS 
• CBC with differential 
• Comprehensive metabolic panel 
• Glycosylated hemoglobin 
• ECG 
• Assessment of adverse events 
• Radiologic assessment of tumor burden (if patient is discontinued for any reason other 
than radiographic disease progression). 
 
Table 7-3 lists all of the assessments and indicates the visits at which they are to be performed 
with an “X”. All data obtained from these assessments must be supported in the patient’s 
source documentation.  
Table 7-3 
Visit evaluation schedule 
Evaluation 
Screening/ 
Baselinea 
6 hours 
after 1st 
injection, 
21 days 
after 1st  
and 3rd 
injections 
Each Cycle 
(day 1)k 
Cycle 6 
Every 3 
Cycles 
Endb 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Relevant medical 
history/ current 
medical 
conditions 
X 
 
X 
 
 
X 
Diagnosis and 
extent of cancer  
X 
 
 
 
 
 
Physical exam  
X 
 
X 
 
 
X 
Vital signs  
X 
 
X 
 
 
X 
ECGc  
X 
X 
 
X 
X 
X 
LFT testing 
 
X 
 
 
 
 
ECOG 
Performace 
Status 
X 
 
X 
 
 
X 
CBC with 
differentiald 
X 
 
X 
 
 
X 
Glycosylated 
hemoglobin 
X 
 
 
 
 
X 
Fasting 
X 
 
X 
 
 
X 


 
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Comprehensive 
metabolic panele 
Pregnancy test 
and review of 
contraceptionf 
X 
 
 
 
 
X 
Secretory 
hormonesg and 
serum 
chromogranin A 
X 
 
 
 
X 
 
Radiologic 
assessment of 
tumor burdenh 
X 
 
 
 
X 
X 
Adverse eventsi 
X 
 
X 
 
 
X 
Concomitant 
medicationsj 
X 
 
X 
 
 
X 
EORTC QLQ C-
30 and EORTC 
QLQ GI-NET21 
questionnaires 
X 
 
 
 
X 
 
 
a  Screening includes review of: demography/informed consent, inclusion/exclusion criteria, 
relevant medical history/concomitant medications, diagnosis and extent of cancer. 
 
b Patients who interrupt or permanently discontinue pasireotide due to an adverse event or 
abnormal laboratory value must be followed at least weekly for 28 days after the last dose of 
SOM230, and subsequently at monthly intervals until resolution or stabilization of the event, 
whichever comes first. 
 
c All ECGs should be done before SOM230 injection on the same day. ECG should be done at 
any time when clinically indicated. 
 
d Complete blood count must include: hemoglobin, hematocrit, platelets, total while blood cell 
count and differential. 
  
e Comprehensive metabolic panel should include fasting glucose, sodium, potassium, chloride, 
bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT 
(ALT), total bilirubin, alkaline phosphatase, calcium and magnesium.  Patients are to fast 
overnight for 8 hours prior to all biochemistry samples being taken. Blood samples are to be 
taken in the morning. Water is allowed during this time.  Clinically significant electrolyte 
abnormalities are to be addressed prior to each SOM230 administration. 
 
f For women of child-bearing potential: Women of childbearing potential must have a 
negative serum preganancy test within 14 days of enrollment.  Acceptable contraception must 
be used while on study and for at least 60 days after last dose of pasireotide. 
 
g If patients present with hormonally active tumor, secretory hormone levels corresponding to 
the syndrome (e.g. urine 5-HIAA, gastrin, glucagon, insulin, etc.) should be measured at 
baseline and each restaging cycle. 
 


 
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h Baseline radiologic tests (CT or MRI with iv contrast) should include all known sites of 
metastatic disease.  For most midgut carcinoid tumors, a CT or MRI scan of the abdomen and 
pelvis is indicated.  For pancreatic neuroendocrine tumors, a CT or MRI scan of the abdomen 
may be sufficient. Patients who have been on study for > 2 years will undergo scans every 6 
cycles. Patients who have been on study for > 5 years will undergo scans every 12 cycles.  
 
i See section 9.1 for definitions of adverse events 
 
j All concomitant medications, including over the counter drugs, should be documented each 
visit.  Particular attention should be paid to dose of diabetic medications.  Patients with 
diabetes are to be instructed to check blood glucose levels via a fingerstick several times 
daily, particularly for the first few days of treatment. 
 
k For patients who have been on study for >5 years, all procedures, with the exception of vitals 
and treatment administration, will occur only once every 6 months (EP, labs, EKGs, 
questionnaires); scans will occur once every 12 months.  
8 
Outcome Measures 
 
The primary efficacy endpoint is progression-free survival, defined as the time from the date 
of first study treatment to the date of the first documented disease progression (by RECIST 
criteria) or death due to any cause.  If a patient has not progressed or died at the date of the 
analysis cut-off or when he/she receives any further anti-cancer therapy, PFS is censored at 
the time of the last tumor assessment before the cut-off or the anti-cancer therapy date. 
  
8.1 
RECIST Criteria for response 
The Response Evaluation Criteria in Solid Tumors (RECIST 1.0) guidelines will be employed 
in this study.  For the purposes of this study, target lesions are defined as metastatic lesions 
that are bidirectionally measurable with one diameter measuring at least 2 cm (or 1 cm with 
spiral CT scan).  All lesions up to a maximum of 10 lesions representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repetitive measurements (either by imaging techniques or 
clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. 
 
Measurable disease: lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as > 2 cm with conventional techniques or as > 1 cm with spiral CT 
scan. 
 
Non-measurable disease: all other lesions, including small lesions (longest diameter < 2 cm 
with conventional techniques or < 1 cm with spiral CT scan). 
 


 
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Complete response (CR): complete disappearance of all target lesions, confirmed by repeat 
assessments at no less than 4 weeks after the criteria for response are first met. 
 
Partial response (PR): at least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. This must be confirmed by 
repeat assessment at no less than 4 weeks after the criteria for response are first met. 
 
Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of target 
lesions, taking as reference the smallest sum longest diameter recorded since the treatment 
started or the appearance of one or more new lesions. 
 
Stable Disease (SD): neither sufficient decrease to qualify for partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started. 
 
Non-target Lesions: all other lesions (or sites of disease) not included in the “target disease” 
definition should be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as “present” or “absent”. 
 
Complete Response:  Disappearance of all non-target lesions. 
 
Non-complete response/Non-progression:  Persistence of one or more non-target lesions. 
 
Progression:  Appearance of one or more new lesions.  Unequivocal progression of existing 
non-target lesions. 
 
Cytology and Histology: if the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should ideally be confirmed by cytology or histology.  These techniques can 
be used to differentiate between PR and CR in rare cases. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response, stable disease, and progressive disease 
 
Evaluation of Best Overall Response: the best overall response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  In general, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
Table 8.1 
Evaluation of best overall response 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 


 
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CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
Note:  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
8.2 
Guidelines for Evaluation of Measurable Disease 
 
Clinical Lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. 
 
CT scan:  Conventional CT scan should be performed with cuts of 10mm or less in slice 
thickness contiguously.  Spiral CT scan should be performed using a 5mm contiguous 
reconstruction algorithm.   
 
8.3 
Confirmation Measurement/Duration of Response 
 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed no less than 4 weeks after the criteria 
for response are first met.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks. 
 


 
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Duration of Overall Response:  The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
 
Progression Free Survival (PFS): PFS is defined as the time from the date of first study 
treatment to the date of the first documented disease progression or death due to any cause.  If 
a patient has not progressed or died at the date of the analysis cut-off or when he/she receives 
any further anti-cancer therapy, PFS is censored at the time of the last tumor assessment 
before the cut-off or the anti-cancer therapy date. 
 
8.4 
   PFS and Censoring 
Since disease progression is assessed periodically, the true date of disease progression is 
known only to occur at a time point after the last radiological assessment of stable disease (or 
better) and prior to the date of the scan detecting progression.  Table 8.4 provides instructions 
on classification of the primary endpoint (PFS) depending on various clinical scenarios. 
 
Table 8.4: Classification of Primary Outcome 
 
Situation 
Outcome 
Date of Progression or Censoring 
Progression documented 
between scheduled visits 
Progressed 
Earliest of: 
Date of radiologic assessment showing 
new lesion (if progression is based 
on new lesion); or 
Date of last radiologic assessment of 
measured lesions (if progression is 
based on increase in sum of 
measured lesions) 
No progression 
Censored 
Date of last radiologic assessment of 
measured lesions 
Treatment discontinuation for 
undocumented progression 
Censored 
Date of last radiologic assessment of 
measured lesions 
Treatment discontinuation for 
Censored 
Date of last radiologic assessment of 


 
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toxicity or other reason 
measured lesions 
New anticancer treatment started 
Censored 
Date of last radiologic assessment of 
measured lesions 
Death before first progressive 
disease assessment 
Progressed 
Date of death 
Death between adequate 
assessment visits 
Progressed 
Date of death 
Death after one to two missed 
visits 
Progressed 
Date of death 
Progression after one to two 
missed visits 
Progressed 
Earliest of: 
Date of radiologic assessment showing 
new lesion (if progression is based 
on new lesion); or 
Date of last radiologic assessment of 
measured lesions (if progression is 
based on increase in sum of 
measured lesions) 
Death or progression after more 
than two missed visits 
Censored 
Date of last radiologic assessment of 
measured lesions 
 
9 
Safety monitoring 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters and 
regular physical examinations.  Adverse events will be evaluated continuously throughout the 
study.  Safety and tolerability will be assess according to the NIH/NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) that is available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
9.1 
 Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug. Abnormal laboratory 


 
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values or test results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigators’ Brochure or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
9.1.1 
Serious adverse events 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety each serious adverse event must also be reported to Recordati Inc. within 24 hours of 
learning of its occurrence. A serious adverse event is an undesirable sign, symptom or medical 
condition which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
9.1.2 
Recordati Inc. instructions for rapid notification of serious 
adverse events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Recordati Inc. Pharmaceuticals Integrated Medical Safety (IMS). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  
All events must be reported, by FAX (888-299-4565), to Recordati Inc. Pharmaceuticals IMS 
Department within 24 hours of learning of its occurrence. This includes serious, related, 
labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences, all deaths 
during treatment or within 30 days following completion of active protocol therapy.   
Any serious adverse event occurring after the patient has provided informed consent and until 
4 weeks after the patient has stopped study participation must be reported. This includes the 
period in which the study protocol interferes with the standard medical treatment given to a 
patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Recordati Inc. study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
9.1.3 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Recordati Inc. within 24 hours of learning of 
its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications. 
9.2 
Data Monitoring Board 
The participating investigator will report all adverse events and serious adverse events to the 
Principal Investigator (or Protocol Chair) and to the IRB according to the local IRB’s policies 
and procedures in reporting adverse events.  
10 
Data collection  
Once eligibility has been established and the participant successfully registered, the 
participant is assigned a protocol case number.  This number is unique to the participant on 
this trial and must be used for case report form (CRF) completion. 


 
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Investigators must enter the information required by the protocol onto CRFs.  
11 
Statistical methods and data analysis 
 
11.1 
Sample size 
 
35 patients will be enrolled, with up to 3 additional patients to account for potential dropouts. 
 
11.2 
Sample size justification 
 
We plan to conduct a single-arm phase II trial, with the 12-month progression-free survival 
rate as the primary endpoint, and using a one-sided alpha level of 10%.   
 
The null hypothesis is that PFS rate at 12 months will be 19%. With n=30 (plus up to 3 
additional patients (10%) to account for early dropouts), we will have 90% power to reject the 
null, if the true 1-year PFS rate from this treatment regimen is 40% (these PFS rates 
correspond to null and alternative hypothesis median PFS of 5 and 9 months, respectively).  
The sample size calculations were conducted using nQuery Advisor 6.01. 
 
The sample size was derived for the estimation of PFS at 1-year using binomial theory.  If the 
survival distribution is exponential, a much tighter confidence interval for the 1-year survival 
is possible.  We will first test for the exponentiality of the survival distribution using the 
Hollander=Proschan17 test.  If the p-value for this preliminary test is greater than 0.20, we will 
provide the 90% lower confidence bound assuming an exponential distribution. 
 
11.3 
Subset analyses 
 
Neuroendocrine tumors are characterized by a heterogeneous rate of growth. Tumors 
originating in the distal small intestine and proximal colon (midgut carcinoid tumors) are 
characterized by a slower rate of metastatic growth than neuroendocrine tumors of other sites, 
including the lungs, stomach, pancreas and rectum.  Therefore, a post-study subset analysis 
will evaluate PFS data based on site of primary tumor, distinguishing between two subsets: 
 
Subset 1: Patients with neuroendocrine tumors of the distal small intestine and cecum (midgut 
carcinoids).  Patients with mesenteric masses whose primary tumors are unidentified will be 
considered to have midgut carcinoid tumors. 
 
Subset 2: Patients with advanced (metastatic or unresectable) neuroendocrine tumors of other 
primary sites (lung, stomach, duodenum, distal colon, rectum, pancreas) or unknown primary 
site. 
 


 
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Other subset analyses will distinguish patients with low-grade (grade 1) tumors versus 
intermediate grade (grade 2) tumors, and patients with low hepatic tumor burden (<10%) 
versus high hepatic tumor burden (>10%). 
12 
Exploratory Analysis 
 
If available, archival tissue containing a tumor block (preferred) or 10 unstained slides (3-5 
micron thick) representing biopsies from patient’s primary or metastatic neuroendocrine 
tumor should be sent to Moffitt Cancer Center for correlative immunohistochemical studies.  
Specimens should be placed in a secure, airtight container, labeled with the patient name and 
study number. 
Site should contact Moffitt Cancer Center at (813) 745-3275 with expected delivery date. 
 
Shipping address: 
Attention Dr. Domenico Coppola 
Anatomic Pathology Dept. 
H. Lee Moffitt Cancer Center 
12902 Magnolia Ave 
Tampa, FL 33612  
 
Immunohistochemistry (IHC) will be used to evaluate the expression of somatostatin 
receptors (SSTs 1-5).   Sections of 3-4 microns in thickness will be cut from the selected 
formalin-fixed paraffin embedded tissue and subjected to IHC staining protocol using the 
Dakocytomation Autostainer (DakoCytomation, Carpitenria, Calif).  Microwave antigen 
retrieval with IHC Select EDTA buffer, pH 7.5, will be utilized.  Rabbitt polyclonal primary 
antibodies against SST 1-5 with cross-reactivity against human SST subtypes will be diluted 
and incubated for 60 minutes at room temperature.  Using a semiquantitative scoring system, 
the intensity of IHC staining for various SST subtypes will be scored as either 0 (negative), 1+ 
(mild positive staining), 2+ (moderate positive) and 3+ (strong positive staining).  The 
correlation between SST staining patterns and clinical outcomes (PFS) will be analyzed in a 
descriptive fashion. 
 
We will also explore the correlation between early biochemical response and PFS.  Early 
biochemical responders will be defined as patients with elevated chromogranin A (CgA) who 
experience a major reduction (>50%) or normalization of their CgA between their baseline 
(pretreatment) measurement and their follow-up assessment 3 months later.   
13 
Quality of Life Assessment 
 
 
Patient quality of life will be measured using the EORTC QLQ-C30 (version 3) and the 
EORTC QLQ GI.NET21 questionnaires (appendices B and C).  The EORTC QLQ-C30 
questionnaire is designed to assess the health-related quality of life of cancer patients 
participating in clinical trials.  It is composed of 5 functional scales, three symptom scales, a 
global health status scale, and six single items.  The EORTC QLQ GI.NET21 questionnaire is 


 
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designed to assess physical and psychological symptoms related to neuroendocrine tumors of 
the gastrointestinal tract. 
Both questionnaires will be scored and handled as recommended in the user manual.  Missing 
items will be imputed with the mean of the non-missing items scored at that assessment time 
point.  Ambiguous items will be considered as missing items.  At each assessment time point, 
summary statistics of the raw score and linear transformation score (on a 0-100 scale) will be 
provided.   
 
 
 
14 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Recordati Inc. and the investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation or the scientific quality of the study require additional approval by the IRB at 
each study center.  A copy of the written approval of the IRB must be provided to Recordati 
Inc. Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Recordati Inc. in the interests of preserving the safety of all 
patients included in the trial.  If an immediate change to the protocol is felt to be necessary by 
the investigator and is implemented for safety reasons Recordati Inc. must be notified and the 
IRB at the center must be informed immediately.    
15 
Procedures and Instructions 
15.1.1 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review 
and comment by Recordati Inc. and prior to any outside submission.  Recordati Inc. must 
receive copies of any intended communication in advance of publication (at least fifteen 
working days for presentational materials and abstracts and thirty working days for 
manuscripts).   These requirements acknowledge Recordati Inc.’s responsibility to provide 
peer input regarding the scientific content and conclusions of such publications or 
presentations.  Principal Investigation/Institution shall have the final authority to determine 
the scope and content of its publications, provided such authority shall be exercised with 
reasonable regard for the interests of Recordati Inc. and, in accord with the trial contract and 
shall not permit disclosure of Recordati Inc. confidential or proprietary information. 


 
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15.1.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Recordati Inc. in strict confidence 
and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study 
documents provided by Recordati Inc. (investigators' brochures and other material) will be 
stored appropriately to ensure their confidentiality. The information provided by Recordati 
Inc. to the investigator may not be disclosed to others without direct written authorization 
from Recordati Inc., except to the extent necessary to obtain informed consent from patients 
who wish to participate in the trial. 
15.1.3 
Discontinuation of study 
Recordati Inc. reserves the right to discontinue any study under the conditions specified in the 
clinical trial agreement. 
15.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Recordati Inc. standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
15.2.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Recordati Inc. before study initiation. Any amendments to the 
protocol, other than administrative ones, must be reviewed by Recordati Inc. approved by this 
committee. 
15.2.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 


 
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This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
15.2.3 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon 
request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
16 
References  
 
 
1. 
Williams ED, Sandler M. The classification of carcinoid tum ours. Lancet. Feb 2 
1963;1:238-239. 
2. 
Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic 
gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. May 2008;2(3):113-
125. 
3. 
Kvols LK. The carcinoid syndrome: a treatable malignant disease. Oncology 
(Huntingt). Feb 1988;2(2):33-41. 
4. 
Weckbecker G, Raulf F, Stolz B, Bruns C. Somatostatin analogs for diagnosis and 
treatment of cancer. Pharmacol Ther. Nov 1993;60(2):245-264. 
5. 
Rinke A, Muller HH, Schade-Brittinger C, 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. Oct 1 2009;27(28):4656-4663. 
6. 
Yao JC, Phan AT, Chang DZ, et al. Phase II study of RAD001 (everolimus) and depot 
octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine 
carcinoma (LGNET). Journal of Clinical Oncology. June 20 2006;24(18S):4042. 
7. 
Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in 
the treatment of patients with locally advanced and metastatic pancreatic endocrine 
carcinomas. J Clin Oncol. Dec 1 2004;22(23):4762-4771. 
8. 
Reichlin S. Somatostatin. N Engl J Med. Dec 15 1983;309(24):1495-1501. 
9. 
Evers BM, Parekh D, Townsend CM, Jr., Thompson JC. Somatostatin and analogues 
in the treatment of cancer. A review. Ann Surg. Mar 1991;213(3):190-198. 
10. 
Maurer R, Reubi JC. Somatostatin receptors. Jama. May 10 1985;253(18):2741. 
11. 
Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective 
octapeptide analogue of somatostatin with prolonged action. Life Sci. Sep 13 
1982;31(11):1133-1140. 


 
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12. 
Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus 
open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin 
Oncol. Feb 1999;17(2):600-606. 
13. 
Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel 
somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) 
receptor binding and a unique antisecretory profile. Eur J Endocrinol. May 
2002;146(5):707-716. 
14. 
Lattuada D, Casnici C, Venuto A, Marelli O. The apoptotic effect of somatostatin 
analogue SMS 201-995 on human lymphocytes. J Neuroimmunol. Dec 2002;133(1-
2):211-216. 
15. 
Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at 
human recombinant somatostatin receptor subtypes supports its usefulness in 
neuroendocrine tumors. Neuroendocrinology. 2004;80 Suppl 1:47-50. 
16. 
Ono K, Suzuki T, Miki Y, et al. Somatostatin receptor subtypes in human non-
functioning neuroendocrine tumors and effects of somatostatin analogue SOM230 on 
cell proliferation in cell line NCI-H727. Anticancer Res. Jul-Aug 2007;27(4B):2231-
2239. 
17. 
Hollander M, and Proschan F.  Testing to determine the underlying distribution using 
randomly censored data. Biometrics 1979:393-401. 
 


 
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Appendix A: List of Drugs Known to Promote QT Prolongation 
 
This is not a comprehensive list of medications which may prolong the QT interval.  
 
Albuterol* 
Amiodarone  
Arsenic trioxide  
Bepridil 
Chlorpromazine  
Chloroquine  
Cisapride 
Clarithromycin 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Halofantrine  
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine 
Methadone  
Pentamidine 
Pimozide 
Procainamide 
Quinidine 
Salbutamol* 
Sotalol  
Sparfloxacin 
Thioridazine 
 
*Parenteral preparations only; inhaled 
treatments at usual doses are acceptable 
 
 
 
 
 
 
 
 
 
 
Appendix B EORTC QLQ-C30 (version 3)  


 
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Appendix C EORTC QLQ-GLNET21  
 


 
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Appendix D: Substrates of CYP2C9 and 2D6: 
2C9 
NSAIDs: 
diclofenac 
ibuprofen 
piroxicam 
 
Oral Hypoglycemics: 
tolbutamide 
glipizide 
 
Angiotensin II Blockers: 
losartan 
irbesartan 
 
Others: 
celecoxib 
fluvastatin 
naproxen 
phenytoin 
rosiglitazone 
sulfamethoxazole 
tamoxifen 
tolbutamide 
torsemide 
warfarin I 
 
2D6 
Beta Blockers: 
S-metoprolol 
propafenone 
timolol 
 
Antidepressants: 
amitriptyline 
clomiprmine 
desipramine 
imipramine 
paroxetine 
 
Antipsychotics: 
haloperidol 
risperidone 
thioridazine 
 
Others: 
aripiprazole 
codeine 
dextromethorphan I 
duloxetine 
flecainide 
mexilletine 
ondansetron 
tamoxifen 
tramadol 
venlaxine 
 
 
 
 


 
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Appendix E: Pasireotide LFT managment algorithm