Conditions: Major Liver Resection
Keywords: Octreotide, Major Liver Resection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
This will be a prospective, randomized, double blind trial enrolling patients who will undergo major liver resection. Patients will be randomized in a 1:1 ratio to receive either octreotide or placebo in the postoperative period. The patients will receive octreotide intravenously continuously for five days after operation. During this period the patients' health will be monitored by performing blood tests including complete metabolic profile, Complete Blood Count (CBC) with/diff., INR and PTT. The functioning of heart will also be monitored post-operatively by EKG. Up to 80 participants will be accrued over a 2 year period. Volumetric CT scans will be performed prior to hepatectomy, 1 week after hepatectomy and 3 months after hepatectomy to evaluate liver regeneration.

Detailed description:

Arms:
arm 1: Octreotide will be administered post-operatively until day 5 arm 2: Normal saline will be administered post-operatively until day 5

Interventions: intervention 1: Octreotide intervention 2: Placebo
Intervention descriptions: intervention 1: Octreotide will be administered 50 µg intravenously per hour for up to five days postoperatively, starting at the time of vascular inflow disruption. intervention 2: Normal saline will be administered in the same fashion as Octreotide

Protocol document:
Prot_SAP_000.pdf: 
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GI-072 Randomized controlled trial of the Use of Octreotide to Enhance Liver Recovery after Major 
Hepatectomy
Sponsor-Investigator:
Sanjay Reddy, MD
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
Phone: 215-214-1437
Fax: 215-728-2773
Email: Sanjay.Reddy@fccc.edu
Co-Investigator:                                     Jordan Anaokar, MDFox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
                                                                 Email: Jordan.Anaokar@fccc.edu
Sub-site Principal Investigator:            Kwan Nang Lau, MD
Fox Chase Cancer Center at Temple University
3401 N Broad Street
Philadelphia PA 19140
                                                                 Email: KwanNang.Lau@tuhs.temple.edu
Statistician:
Karthik Devarajan, PhD
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
Phone: 215-728-2794
Fax: 215-728-2553
Email: karthik.devarajan@fccc.edu
Study Development:                              Manisha Saini, PhD
                                                                 Phone: 215-214-1439
                                                                 Email: Manisha.saini@fccc.edu 
                                                                 
Initial Version Date: 04/13/2016
Version date: 10/25/2017
Amendment 3: 05 Feb 2019


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Amendment 4: 26 Feb 2019
Amendment 5: 24 Apr 2019
Amendment 6: 14 Jun 2019


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Schema  
Population:
80 patients
40 in each arm
Patient Assessment
Evaluation will be done daily while in 
inpatient and 2 weeks postoperatively
Continue treatment until:
5 days postoperatively or discharge 
Unacceptable toxicity
Patient preference
Follow up
All patients will be followed until 6 months 
after discharge from hospital
Treatment:
Octreotide 50 µg/h or Placebo (saline 
solution) starting intraoperatively until 
POD#5 or discharge


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Table of Contents
Schema .....................................................................................................................................................ii
Table of Contents..................................................................................................................................3
1.0
Introduction ..................................................................................................................................5
1.1. Study Disease...................................................................................................................5
1.2. Agent under Investigation ..............................................................................................6
1.3. Preclinical and Clinical Data...........................................................................................6
1.3.1.
Pre-Clinical Data...........................................................................................................6
1.3.2.
Clinical Data ..................................................................................................................7
1.4. Study Rationale ................................................................................................................7
2.0
Objectives......................................................................................................................................7
2.1. Primary Objective.............................................................................................................7
2.2. Primary Endpoints:..........................................................................................................8
2.3. Secondary Objective........................................................................................................8
2.4. Secondary Endpoints ......................................................................................................8
3.0
Study Plan .....................................................................................................................................8
3.1. Description of Study Design, Population and Duration of Study Therapy .............8
4.0
Patient Selection Inclusion & Exclusion...........................................................................8
4.1. Inclusion Criteria..............................................................................................................8
4.2. Exclusion Criteria.............................................................................................................9
4.3. Inclusion of Women and Minorities...............................................................................9
4.4. Pregnancy .........................................................................................................................9
4.5. Patient Registration .......................................................................................................10
5.0
Treatment Plan..........................................................................................................................10
5.1. Treatment Administration .............................................................................................11
5.2. Concomitant Medications, Supportive Care, and Excluded Therapies.................11
5.3. Blinding............................................................................................................................11
5.3.1.
Unblinding....................................................................................................................11
5.4. Duration of Therapy .......................................................................................................12
5.5. Follow up .........................................................................................................................12
5.6. Criteria for Discontinuation ..........................................................................................12
6.0
Dose Modifications .................................................................................................................12
6.1. General Principles..........................................................................................................12
7.0
Study Agent Information.......................................................................................................13
7.1. Study Drug: Octreotide acetate....................................................................................13
7.1.1.
Product description ....................................................................................................13
7.1.2.
Availability....................................................................................................................13
7.1.3.
Solution preparation...................................................................................................13
7.1.4.
Stability ........................................................................................................................13
7.1.5.
Route of administration..............................................................................................13
7.2. Placebo Information: Saline Solution .........................................................................13
7.2.1.
Product description ....................................................................................................13


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7.2.2.
Availability....................................................................................................................13
7.2.3.
Route of administration..............................................................................................13
7.3. Drug Ordering, Storage and Handling ........................................................................14
7.4. Destruction of Drug........................................................................................................14
7.5. Records to be kept at Site; Dispensing and Accountability....................................14
8.0
Study Calendar .........................................................................................................................15
9.0
Adverse Events.........................................................................................................................16
9.1. Definitions .......................................................................................................................16
9.2. Severity Rating ...............................................................................................................16
9.3. Attribution/Relationship to study drug:......................................................................16
9.4. Expectedness .................................................................................................................17
9.5. Recording and Reporting Responsibilities................................................................17
9.5.1.
Investigative Site Recording Responsibilities:........................................................17
9.5.2.
Investigative Site Reporting Responsibilities: ........................................................17
9.5.3.
Sponsor Reporting Responsibilities:........................................................................18
9.6. Pregnancy........................................................................................................................19
10.0 Measures of Effect...................................................................................................................19
10.1.Definitions .......................................................................................................................19
11.0 Statistical Considerations....................................................................................................20
11.1.1.
Primary Efficacy Analysis..........................................................................................20
11.1.2.
Early Stopping for Toxicity ........................................................................................20
11.1.3.
Secondary Analyses ..................................................................................................20
11.1.4.
Randomization............................................................................................................21
11.2.Sample Size/Accrual Rate.............................................................................................21
11.3.Stratification Factors .....................................................................................................21
11.4.Reporting and Exclusions ............................................................................................21
12.0 Data and Safety Monitoring Plan.......................................................................................21
12.1.Monitoring Plan ..............................................................................................................21
12.2.Data Safety Monitoring Board......................................................................................21
13.0 Administrative...........................................................................................................................22
13.1.Data Reporting................................................................................................................22
13.2.Retention of Records.....................................................................................................22
13.3.Study Agents...................................................................................................................22
13.4.Informed Consent...........................................................................................................22
14.0 References..................................................................................................................................23


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1.0 Introduction
1.1. Study Disease 
Major liver resections are becoming more prevalent for treatment of benign and malignant 
liver disease. Post-hepatectomy liver failure has been characterized by jaundice, 
coagulopathy and hepatic encephalopathy.1 Post-hepatectomy liver failure after major 
liver resection, defined as removing at least three anatomical segments, is associated with 
increased portal flow and pressure in the liver remnant.2  Allard et al looked at non-
cirrhotic patients undergoing major liver resection and found that a post-hepatectomy 
portal venous pressure greater than 21 mmHg was an independent predictor of liver failure 
as well as 90-day mortality.3 Post-operative liver failure, after major liver resection 
(similar to the “small for size syndrome”) is related to an increase in portal flow and 
pressure into the liver remnant. Post-hepatectomy liver failure is associated with 20-50% 
mortality. 
Other research has studied the pathophysiology of liver failure in the context of increased 
portal pressure or “small-for-size syndrome”. Demetris et al reviewed patients who 
underwent adult liver donor liver transplantation and developed unexplained cholestasis, 
coagulopathy and ascites. In those patients with post-hepatectomy portal hyperperfusion 
they found portal vein and periportal sinusoidal endothelium denudation, severe 
congestion with thrombosis of periportal sinusoids, and poor hepatic arterial flow and 
vasospasm, 4 thus portal venous hyperperfusion is a significant factor in allograft 
dysfunction. Attempts to decrease portal hyperperfusion in hepatic transplantation 
patients include portal decompression surgically with portocaval or mesocaval shunts, 
splenectomy and splenic artery ligation.5-9 However, little research had been done on 
using medications to decrease portal hyperperfusion after major hepatectomy.
Several human and animal studies show that octreotide can decrease portal venous 
pressure. The pathophysiology of this action is believed to be due to interaction of 
somatostatin with the receptors SSTR-2 and SSTR-1.15 The effect of somatostatin on 
SSTR-1 causes glucagon suppression and increased effect of protein kinase-C dependent 
vasoconstrictors therefore resulting in splanchnic vasoconstriction leading to decreased 
portal flow15. The effect of SSTR-2 is decrease of hepatic resistance by acting on hepatic 
stellate cells.15,16 Bosch and colleagues described that somatostatin use results in decrease 
in hepatic venous wedge pressure and hepatic blood flow with minimal effect systemically 
in patients with severe portal hypertension.10 These observations have been substantiated 
in other studies as well.11-13 Busani et al examined the use of octreotide in living donor 
liver transplantation patients with “small-for-size” syndrome.  They showed a 25% 
decrease in hepatic venous pressure and 13% decrease in portal venous flow after 
administration of octreotide in the postoperative period.14 However, they did not report if 
this decrease improved graft survival or prevented liver failure.
The progression of liver regeneration has been most recently studied in living liver donors. 
Liver resection in humans results in rapid regeneration. In 3 months the liver has restored 
74 -79% of preoperative volume.17.


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To our knowledge no studies have investigated the potential role of octreotide in liver 
recovery and liver regeneration after major hepatectomy. We hypothesize that 
administration of octreotide will modulate portal venous pressure and aid in liver recovery 
and regeneration as well as potentially decrease the possibility of liver failure. In addition 
this may lead to safer extended hepatectomies for primary or metastatic tumors of the 
liver. Ultimately our goals are to improve the safety of major liver surgery and potentially 
expand the pool of patients who may undergo surgery for patients with metastatic or 
primary liver tumors. It is well established that complete resection is the major 
determinant of long term survival for patients with primary (that are not transplant 
candidates) or metastatic liver tumors.
1.2. Agent under Investigation
Octreotide acetate is a somatostatin analog. Octreotide suppresses secretion of multiple 
hormones including pituitary growth hormone, thyrotropin and decreases release of 
pancreatic islet hormones. In addition octreotide reduces splanchnic blood flow, 
gastrointestinal motility, and gastric acid secretion.23 The plasma half-life is 100 minutes 
and has a duration of action up to 12 hours. 
1.3. Preclinical and Clinical Data
1.3.1. Pre-Clinical Data
Limited number of animal studies have been published regarding the hepato-protective 
effect of octreotide. However, somatostatin has been shown to improve survival, improve 
liver function and decrease portal hypertension in some animal studies. Xu et al tested the 
hypothesis that somatostatin can rescue “small-for-size” liver grafts after transplantation 
in rats. Somatostatin was given 5 minutes before total hepatectomy and immediately after 
reperfusion in the recipient (20 g/kg). Graft survival, portal hemodynamics, intragraft gene 
expression and hepatic ultrastructural changes were compared between the rats with or 
without somatostatin treatment. Seven-day graft survival rates in the somatostatin 
treatment group were significantly improved compared to the control group (66.7% vs. 
16.7%, P 0.036). In the treatment group, portal pressure and hepatic surface blood flow 
were significantly decreased within the first 30 minutes after reperfusion, whereas in the 
control group, transient portal hypertension and excessive hepatic blood flow were 
observed. Intragraft expression (both messenger RNA and protein) of endothelin-1 was 
significantly downregulated accompanied with upregulation of heme oxygenase-1 and 
A20. Better preservation of liver function was found in the treatment group. Hepatic 
ultrastructure, especially the integrity of sinusoids, was well protected in the treatment 
group. The authors concluded that low-dose somatostatin rescues “small-for-size” grafts 
from acute phase injury in liver transplantation by attenuation of acute-phase shear stress 
that resulted from transient portal hypertension.25 Jia and colleagues used rat models that 
underwent major hepatectomies and showed greater reduction of ALT and AST with 
administration of somatostatin and PGE1 than the control group. The study also showed 
that administration of somatostatin and PGE1 resulted in down-regulation of Bax and 
caspase-3 and upregulation of Bcl-2, which are the proteins involved in the apoptosis 
pathway, leading to suppression of apoptosis.26 Therefore in animal models somatostatin 
has been used to improve liver recovery after major hepatectomy.


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1.3.2. Clinical Data
Octreotide is very commonly used in every day practice in patients with and without liver 
disease for control of variceal bleeding. According to the American College of 
Gastroenterology, somatostatin and analogues such as octreotide cause splanchnic 
vasoconstriction at pharmacological doses. Although this effect is considered to be due to 
an inhibition of the release of vasodilatory peptides (mainly glucagon), recent studies 
suggest that octreotide has a local vasoconstrictive effect. The advantage of somatostatin 
and analogues such as octreotide is that they are safe when given intra-operatively and can 
be used continuously for many days. Of the analogues that have been administrated 
subcutaneously or intravenously, only octreotide is available in the United States and it has 
been used most often as an initial IV bolus of 50 μg followed by a continuous infusion of 
25-50 μg/hour.27 
Combination of pharmacological therapy and endoscopic therapy are the most rational 
approach in the treatment of acute variceal hemorrhage. The use of pharmacological agents 
with few side effects allows prolonging therapy for 5 days, the period during which the risk 
of re-bleeding is the highest. A meta-analysis of 8 trials showed that, compared to 
endoscopic therapy alone, endoscopic plus pharmacological (octreotide, somatostatin, 
vapreotide) therapy improved the initial control of bleeding and 5-day hemostasis without 
differences in mortality or severe adverse events.28 Accumulating evidence on the use of 
octreotide in thousands of patients with liver disease, show that its use is safe and has very 
limited adverse events. Furthermore, octreotide has been studied extensively in 
postoperative patients, especially in patients after pancreatectomy and again its safety has 
been well documented18-20. 
1.4. Study Rationale 
Laboratory and animal studies show that somatostatin analogues decrease portal venous 
pressure. In addition, somatostatin analogues have been used to decrease or stop variceal 
bleeding in patient with cirrhosis. We therefore hypothesize that the administration of 
octreotide will be beneficial in liver recovery and regeneration and potentially decrease 
the incidence of liver failure after a major hepatectomy.
2.0 Objectives
The main objective of this study is to evaluate the use of octreotide in patients undergoing 
major hepatectomy (at least three segments) to determine whether liver recovery will be 
improved.
2.1. Primary Objective
1. To compare the rates of liver recovery in patients treated with octreotide vs placebo 
after a major hepatectomy. 


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2.2. Primary Endpoints:
Liver recovery after hepatectomy will be measured by comparing area under the curve 
(AUC) for total bilirubin and INR for each group separately.
2.3. Secondary Objective
1.
To compare the rates of hepatic parenchymal regeneration in patients treated 
with octreotide Vs placebo after major liver hepatectomy.
2.
Evaluate the incidence of post-hepatectomy liver failure, bile leak, overall as 
well as 30-day and 90 day morbidity and mortality using American College of 
Surgeons-National Surgical Quality Improvement Definitions (ACS-NSQIP).
2.4. Secondary Endpoints
1.
Hepatic parenchymal regeneration will be evaluated by hepatic volume 
measured by CT scan preoperatively, at 1 week (could be done within 2 
weeks) post-operatively and at 3 months postoperatively.
3.0 Study Plan 
3.1. Description of Study Design, Population and Duration of Study Therapy 
This will be a prospective, randomized, double blind trial enrolling patients who will 
undergo major liver resection. Patients will be randomized in a 1:1 ratio to receive either 
octreotide or placebo in the postoperative period. The patients will receive octreotide 
intravenously continuously for five days (120 hrs.) after operation. During this period the 
patients’ health will be monitored by performing blood tests including complete metabolic 
profile, CBC with/diff., INR and PTT. The functioning of heart will also be monitored 
post-operatively by EKG. Up to 80 participants will be accrued. Volumetric CT scans will 
be performed prior to hepatectomy, 1 week after hepatectomy and 3 months after 
hepatectomy to evaluate liver regeneration.
4.0 Patient Selection Inclusion & Exclusion
4.1. Inclusion Criteria  
4.1.1 Patients must have liver tumors requiring a major liver resection, defined as 
removing at least three anatomical segments in patients without liver disease 
and two segments in patients with cirrhosis/fibrosis of the liver.
 
4.1.2 Age > 18 years.
4.1.3 ECOG performance status 0 or 1.
4.1.4 Patients must have acceptable organ and marrow function as defined below:
WBC
> 1500/mcL
ANC
> 500/mcL
PLTs
> 40,000/mcL


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Alk Phosphatase 
< 3 times institutional upper limit of normal
AST/ALT
< 10 times institutional upper limit of normal
INR
< 1.8 times institutional upper limit of normal
4.1.5 Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document.
4.1.6 Q-T Interval of ≤ 450 ms as measured by EKG. 
4.2. Exclusion Criteria  
4.2.1 Patients with known hypersensitivity to octreotide or somatostatin.
4.2.2 Patients who are receiving any other investigational agents.
 
4.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements.
4.2.4 Pregnant or breast feeding. Refer to section 4.4 for further detail.
NOTE: In 5-8% of cases scans fail to detect metastatic disease and it is only revealed at 
the time of surgery. If such a case happens and the liver cancer is found to be metastatic 
at the time of surgery, such patients will not be operated upon and will be considered as 
screen failures. Such patients will be replaced.
4.3. Inclusion of Women and Minorities
Men and women, regardless of race, ethnic group or sexual orientation are eligible for 
this study.  
4.4. Pregnancy
The effects of octreotide on the developing human fetus at the recommended therapeutic 
dose are unknown.  For this reason, women of child-bearing potential (WOCBP) and men 
must agree to use adequate contraception prior to study entry, for the duration of treatment, 
and for at least 3 months after the completion of treatment.  
WOCBP is defined as follows: Any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma 
follicle-stimulating hormone (FSH) level > 35 mIU/ml).  Even women who are using oral, 
implanted, or injectable contraceptive hormones or mechanical products (diaphragm, 


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condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g. vasectomy), should be considered to be WOCBP.
Should a woman become pregnant or suspect she is pregnant while participating in this study, 
she must inform her treating physician immediately.
Prior to study enrollment, WOBCP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy.  In 
addition, men enrolled on this study should understand the risks to any sexual partner of 
childbearing potential.
All WOCBP must have a negative serum pregnancy test within 28 days prior to receiving 
the first dose of the investigational agent(s).  If the pregnancy test is positive, the patient must 
not receive protocol treatment and must not be enrolled in the study.
4.5. Patient Registration
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the Investigator-Sponsored Research Unit (ISRU) at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email:

Completed registration form 

Consent and HIPAA signature pages 

Eligibility checklist
Following registration, participants must begin protocol treatment within 30 calendar days 
of registration.  Issues that would cause treatment delays must be discussed with the 
Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The Study 
Monitor must be notified as soon as possible if a participant does not begin protocol 
treatment 
as 
scheduled. 
For 
additional 
registration 
questions, 
please 
email 
FCCC.MONITOR@fccc.edu or call (215) 728-5544.
The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received a 
sequence number prior to the initiation of treatment.  
Each patient’s sequence number encodes their assignment to one of the arms of the study, 
according to the randomization schedule generated prior to the study by the Biostatistics 
Department at Fox Chase Cancer Center.  Each participant will be dispensed blinded study 
treatment, labeled with his or her unique sequence number, throughout the study
Exceptions to the current registration policies will not be permitted. 


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5.0 Treatment Plan
Treatment will be administered while the patient is hospitalized after hepatectomy as described 
below.  Missed days will not be made up. This is a randomized study therefore dosing 
instructions for the individual patient’s treatment assignment must be followed.
5.1. Treatment Administration
The dosage of octreotide will be 50 µg intravenously per hour for up to five days (120 
hrs) postoperatively, starting intra-operatively after portal vein ligation as directed by the 
operating surgeon. There is no requirement for any special IV access for this drug 
administration and central or peripheral IV could be used.  If randomized to the placebo 
arm, patients will receive an equal volume of 0.9% saline solution alone to be started at 
the same time as octreotide.
5.2. Concomitant Medications, Supportive Care, and Excluded Therapies
Patients will receive full supportive care therapies concomitantly during the study 
including transfusions of blood and blood products, antibiotics, anti-emetics when 
appropriate.  
The effects of Octreotide injection on QT interval has been observed mostly in 
acromegalic patients that receive somatostatin analogues for months or years.  Currently, 
use of octreotide for 5 days does not necessitate measurement of QT.  The patients will be 
monitored in the ICU for at least 24 h postoperatively. Medications that prolong QT 
interval are not excluded but should be used with caution in the study. Whenever QT 
prolonging drugs are used, EKG should be done daily to monitor QT interval.
5.3. Blinding
This is a double blinded study – Patients, treating physicians, the Sponsor Investigator and 
all site personal except the pharmacy will be blinded to the treatment arm.  Investigators 
will remain blinded to each participant’s assigned study treatment throughout the course 
of the study.
A copy of the randomization table will be held by the ISRU and each site’s pharmacy.  In 
order to maintain the blind, each pharmacy will prepare and label solution bags in such a 
way that the blinding is maintained.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to 
unblinded study treatment records at the site to verify that randomization/dispensing has 
been done accurately.
5.3.1. Unblinding
If, in the opinion of an investigator, it is in a patient’s best interest that the blind on their 
treatment assignment be broken, the Sponsor-Investigator must be contacted for approval 
prior to unblinding.


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If identification of the study treatment is required for a medical emergency in which the 
knowledge of treatment with octreotide will affect the immediate management of the 
participant’s condition, the Sponsor Investigator must be notified within 24 hours after 
breaking the blind. 
The date and reason that the blind was broken must be recorded in the source 
documentation and eCRF, as applicable. The patient may continue to be in the study and 
receive assigned treatment/placebo after the unblinding has been done, at the sponsor-
investigator’s discretion.
5.4. Duration of Therapy
Patients will receive octreotide or placebo until discharge or for up to 5 days (120 hrs.) 
post-surgery, whichever occurs first. The therapy will be discontinued if patient:

Withdraws consent  

Unacceptable adverse events

Disease Progression

Intercurrent illness that prevents further administration of treatment

Patient becomes pregnant

General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator.
5.5.
Follow up
All patients will be followed for adverse events, 2 weeks after the discharge by a clinic 
visit. A 3 month post-discharge follow-up will be done to evaluate liver regeneration and 
overall health of patients. A 6 month post-discharge follow-up will be done to monitor 
overall health of the patients.
5.6. Criteria for Discontinuation
Patients will be removed from study when any of the criteria listed in Section 5.4 applies. 
The reason for study removal and the date the patient was removed must be documented in 
the medical record and case report form.
6.0 Dose Modifications
6.1. General Principles 
There are no planned dose modifications for this trial. Toxicities due to octreotide during 
short course of treatments are rarely seen. Long-term treatment (up to 1 year treatment) 
with this drug can result in toxicities that are manageable with supportive care. 
For grade 1-2 toxicities in this study, patients will be given supportive care, if needed, and 
will continue to receive the study treatment. Since this is a double blind trial the treating 
physician would not know whether the patient received octreotide or placebo. Unblinding 
could be done for grade 3 or 4 toxicities, if the investigator suspects that the toxicity is 
possibly related to octreotide and it is in the best interest of the patient. Prior permission 


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is required from sponsor-investigator for unbliding except in the case of emergency. For 
octreotide related grade 3 or 4 toxicities the patients may be discontinued from the 
treatment administration. For grade 3 or 4 toxicities that are not related to octreotide the 
treatment may continue at the treating physician’s discretion.
7.0 Study Agent Information
7.1. Study Drug: Octreotide acetate
7.1.1. Product description
Octreotide acetate is a somatostatin analog. Octreotide suppresses secretion of 
multiple hormones including pituitary growth hormone, thyrotropin and decreases 
release of pancreatic islet hormones. In addition octreotide reduces splanchnic blood 
flow, gastrointestinal motility, and gastric acid secretion.23 The plasma half-life is 
100 minutes and has a duration of action up to 12 hours. It mimics natural 
somatostatin by inhibiting serotonin release, and the secretion of gastrin, VIP, insulin, 
glucagon, secretin, motilin, and pancreatic polypeptide. Octreotide decreases growth 
hormone and IGF-1 in acromegaly. Octreotide provides more potent inhibition of 
growth hormone, glucagon, and insulin as compared to endogenous somatostatin. 
Also suppresses LH response to GnRH, secretion of thyroid-stimulating hormone and 
decreases splanchnic blood flow.
The drug name on the label of the solution bags will be prepared in such a way that 
the treatment blind is maintained.
7.1.2. Availability 
This product is commercially available. 
7.1.3. Solution preparation
The concentration of an octreotide solution is 1500 g in 500ml of normal saline. 
µ
7.1.4. Stability
Octreotide is stable in sterile isotonic saline solutions for 24 hours. 
7.1.5. Route of administration 
Continuous IV infusion at 50µg/hr
7.2. Placebo Information: Saline Solution
7.2.1. Product description
The placebo used in this study will be 500ml normal saline solution.  The drug 
name on the label of the solution bags will be prepared in such a way that the 
treatment blind is maintained.


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7.2.2. Availability 
This product is commercially available.
7.2.3. Route of administration 
Continuous IV infusion at 50µg/hr
7.3. Drug Ordering, Storage and Handling
Octreotide is commercially available and will be provided for this trial. For prolonged 
storage, octreotide ampules and multi-dose vials should be stored at refrigerated 
temperatures 2-8°C (36-46°F) and protected from light. At room temperature, (20-30°C 
or 70-86°F), octreotide is stable for 14 days if protected from light. The solution can be 
allowed to come to room temperature prior to administration. Do not warm artificially. 
After initial use, multiple-dose vials should be discarded within 14 days. Ampules should 
be opened just prior to administration and the unused portion must be discarded.
Following submission and approval of the required regulatory documents, participation in 
the study initiation meeting and receipt of the site activation letter from the FCCC ISRU, 
the initial order may be placed.  Drug order forms and ordering procedure will be presented 
at the site initiation meeting.
7.4. Destruction of Drug 
At the time of study closure, the unused and expired study drug will be destroyed at the site 
per Institutional SOPs unless otherwise specified. Expired study medication may be 
destroyed on site, as per institution SOPs, during the study. 
7.5. Records to be kept at Site; Dispensing and Accountability
It is the responsibility of the Site Principal Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where investigational 
product is inventoried and disposed.  Records or logs must comply with applicable 
regulations and guidelines, and should include:

Amount received and placed in storage area.

Amount currently in storage area.

Lot number or batch number.

Dates and initials of person responsible for each investigational product 
inventory entry/movement.

Amount dispensed to each patient.

Non-study disposition (e.g., lost, wasted, broken).
8.0 Blood for future research and banking
Optional plasma and sera will be collected from consenting patients for future research and 
banking. The samples will be collected before surgery and after surgery on the same day. The 
samples will be collected and handles according to the instructions specified in the Fox Chase 
Cancer Center Protocol Support Lab manual. 


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9.0 Study Calendar
Follow-up 
 
Pre-Study A
During 
Treatment 
(Days 1 - 5)
1 week 
Post-surgery
2 Weeks 
Post-Discharge
(+/- 7 days)
3 Months 
Post-Discharge
(+/-7 days)
6 Months 
Post-Discharge
(+/- 15 days)
Informed Consent 
X
 
 
 
 
Medical history
X
 
 
 
 
β-HCG
X B
 
 
 
 
Serum Chemistryc
X
X
X
X
X
INR
X
X
X
X
X
PTT
X
X
X
X
X
CBC w/diff, plts
X
X
X
Height
X
 
 
 
 
Weight
X
 
X
X
X
Physical exam
X
XF
X
X
X
EKG 
X
X
 
 
 
Vital signs (T, P, R, BP)
X
X
X
X
X
Concurrent meds
X
X
X
X
X
ECOG status
X
XG
X
X
X
MRI/CT scan of the liver
X
 
 XE
 
X
 
Adverse event evaluation
 
X
X
 
 
Plasma and sera D
X
X
Footnotes
A.
Pre-study H&P, radiologic tumor imaging, and all labs must be ≤ 60 days prior to registration.  
B.
Serum pregnancy test (women of childbearing potential) must be completed <28 days before 
registration.
C.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.
D.
This is optional plasma and sera collection for future research and banking. It should be collected 
before surgery and after surgery on the same day.
E.
Could be done within 2 weeks of surgery
F.
Only on day2 post-surgery. Day 1 PE will not take place since patient will be in ICU.
G.
ECOG on day 1 after surgery may not happen since patient will be in ICU.


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10.0
Adverse Events
10.1. Definitions
Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (NCI CTEP Guidelines March 28, 2011).
Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization (for > 24 hours), persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or is a congenital anomaly/ birth defect, or results in any important medical 
event that may not result in death, be life threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the above 
outcomes.  A “life-threatening” adverse event places the patient at immediate risk of death 
in the judgment of the investigator or sponsor.
10.2. Severity Rating 
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions:
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL.
Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL.
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE
For this study abnormal LFT and INR will not be recorded as AE and will not be graded. 
The primary endpoint of the study is liver recovery based upon LFT and INR and 
therefore these will be included in the analyses rather than AE.
10.3. Attribution/Relationship to study drug: 

Definite – clearly related

Probable – likely related

Possible – may be related

Unlikely – doubtfully related


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
Unrelated – clearly not related
10.4. Expectedness
An Expected Adverse Event is one where the specificity or severity is consistent with 
the current information available from the resources.
An Unexpected Adverse Event is one where the nature, severity, or frequency of the 
event is related to participation in the research is not consistent with either:
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the protocol-
related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts
OR
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the 
subjects(s) predisposing risk factor profile for the adverse event.
(OHRP Guidance on reviewing unanticipated problems 2007)
10.5. Recording and Reporting Responsibilities
10.5.1. Investigative Site Recording Responsibilities:
1. Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event.  Each category listed 
above must be recorded for each event.
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) 
and in progress reports with details about the grade and attribution of each 
episode, action taken with respect to the study drug, and the patient’s 
outcome will be recorded in the CRF.  All events will be recorded on case 
report forms for the duration of the study until they resolve.
3. All reportable SAEs will be recorded on the FDA MedWatch form 3500a.  
After submitting the initial report it may be necessary to submit follow up 
reports to the Sponsor should the event require further investigation.
10.5.2. Investigative Site Reporting Responsibilities:
1. The investigator/ site is responsible to report all SAEs that occur on or 
after the first day of study treatment to the sponsor within 24 hours of 
becoming aware of the event.  All subsequent SAEs must be reported for 
up to 14 days after the last treatment.


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Each investigator is responsible to report all AEs/SAEs to their local IRB 
following guidelines set by that IRB.  The FCCC OCR reserves the right 
to request an event be reported to the IRB at their discretion.  Copies of 
events reviewed by the IRB must be sent email to SAE.FCCC@fccc.edu. 
2. If the investigator or IRB feels the event warrants a revision to the 
informed consent that was not already initiated by the OCR, draft 
revisions will be made in track changes and submitted to the OCR for 
consideration.  Any consent revisions must receive OCR approval prior to 
submission to the IRB.
3. Any investigator who is in doubt of whether a particular AE needs to be 
reported is directed to call the Study Monitor for confirmation with the 
Sponsor- Investigator
4. If the results of an investigator or OCR investigation show an adverse 
event not initially determined to be reportable is so reportable, the 
investigator will report the event following the above guidelines based on 
the date the determination is made.
5. Copies of all related correspondence and reporting documents must be 
submitted to the ISRU and will be maintained in the trial master file. 
The participating sites should report events to:
Investigator-Sponsored Research Unit
Office of Clinical Research
 
           Fox Chase Cancer Center
SAE.FCCC@fccc.edu
10.5.3. Sponsor Reporting Responsibilities:
1. Adverse events which meet all of the following criteria must be reported 
to all participating institutions for IRB submission within 2 weeks of 
notification of the event.  
i.
Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied;
ii. Possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the 
research); and
iii. Serious (refer to above definition) or otherwise one that suggests that 
the research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized.


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2. If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the 
form of an amendment from the OCR for each site’s IRB of record along with 
the report of the adverse event.  
3. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at OCR.
4. SAEs that are related, unexpected, fatal, or life-threatening are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information.  Further information on the timing of submissions are as directed 
by FDA guidelines  (http://www.fda.gov/medwatch/index.html).  Serious, 
unexpected events that suggest significant clinical risk will be submitted to 
within 15 calendar days after initial receipt of this information.
Food and Drug Administration:
Telephone 1-800-332-1088
Fax 1-800-332-0178
http://www.fda.gov/medwatch/report.htm
10.6. Pregnancy 
All WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation.
In the event of a confirmed pregnancy in a patient participating in the study, the 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor who 
will notify Sanjay Reddy, MD, PhD. 
11.0
Measures of Effect
11.1. Definitions
The effect of the Octreotide will be measured by the timing of improvement of liver 
function postoperatively. The liver regeneration will be measured by direct volumetry.  All 
patients will undergo preoperatively CT or MRI. The liver volumes will be measured in 
the venous phase. The liver volume will be measured within a week after liver resection 
and also at 3 months. The liver volume will be calculated after marking the liver contours 
on the cross-section images. Large vessels, including the inferior vena cava and the 
extrahepatic portal vein, the major fissures, and the gallbladder fossa will be excluded. For 
this study, the following volumes will be calculated: the total liver volume and the 
estimated remnant liver volume (RLV) at Post-operative day (POD) 0 and the regenerated 
residual liver volume after liver resection at POD 7 and POD 90. The RLV at POD 0 will 
be calculated by performing a virtual dissection on preoperative images according to the 
dissection margins identified by reviewing the postoperative images and based on the 
surgical report, as well as the liver weight.  The RLV at POD 7 and POD 90 will be 
measured on postoperative images and corresponds to the liver volume 7 and 90 days after 
liver resection.


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Evaluable for adverse events:  All patients will be evaluable for adverse events from the 
time of their first treatment. All AE will be recorded but for the purpose of this trial only 
AE that are at least possibly related to drug/placebo will be graded and reported. AE that 
are unrelated or unlikely related to the treatment will not be graded or reported.
Evaluable for Efficacy: Only patients who receive at least 24 hrs of infusion with the 
drug/placebo will be evaluable for response. Patients who are not evaluable for response 
will be replaced. A maximum of 5 patients can be replaced in the trial for being not 
evaluable for efficacy.
Patients considered as screen failures due to detection of metastatic disease at the time of 
surgery, will not be operated upon and will be replaced. There is no cap on replacement 
of such patients but they are only estimated to be about 5-8% of total accrual.
12.0
Statistical Considerations
12.1.1. Primary Efficacy Analysis
Newly diagnosed patients undergoing hepatectomy will be prospectively enrolled 
into the study over a period of 2 years and randomized into one of two groups, 
receiving octreotide treatment or placebo control. The area under the curve (AUC) 
for post-operative total bilirubin (TB) and INR levels will be computed separately for 
each group. Forty patients will be enrolled in each arm. There will be an interim 
analysis to determine lack of efficacy when approximately one-third of the patients 
have enrolled in the study.
With 40 patients in each arm, we would be able to detect a 28% reduction in the 
AUC for TB and a 25% reduction the AUC for INR between arms and achieve 82% 
power at the one-sided 2.5% significance level. These calculations assume that 2 
sequential tests will be made using the O-Brien-Fleming spending function to 
determine the test boundaries and are based on mean AUC (and standard deviations) 
of 8.89 (3.88) for TB and 7.08 (2.75) for INR in the control arm using pilot data. 
A two-sample z-test will be used to compare the mean AUC between arms. Means 
and standard deviations of the AUC for each variable were calculated based on pilot 
data on prior surgeries available from the FCCC database.
12.1.2.  Early Stopping for Toxicity
Evaluation of adverse events will be done in the Octreotide treatment arm. We will 
stop the study early if 3 or more of the first 11 patients enrolled into this arm suffer 
grade 3 or 4 treatment related toxicity. The table below lists the probability of early 
stopping due to adverse events based on pre-specified true probabilities of such 
events in these individuals.


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Probability of stopping the study early due to adverse events in the Octreotide treatment 
arm based on pre-specified true probabilities of such events
Probability of 
adverse event in 
an individual
10%
20%
30%
40%
Probability of 
stopping early 
due to adverse 
events
9%
38.3%
68.7%
88.1%
12.1.3. Secondary Analyses
The rate of liver generation between octreotide and placebo treated patients will be 
compared at 1 week (could be done within 2 weeks) and at 3 months after surgery. The 
liver volume will be calculated at baseline and postoperatively. We will compare the 
percentage of liver growth between the treatment and control arms.
Incidence of post-hepatectomy liver failure, bile leak, overall as well as 30-day and 90 
day morbidity and mortality will be analyzed using American College of Surgeons-
National Surgical Quality Improvement Definitions (ACS-NSQIP). Demographic and 
clinical variables will be summarized by treatment group using descriptive statistics. 
Variance stabilizing and normalizing transformations will be used as and when required. 
Categorical variables will be analyzed using Fisher’s exact tests or chi-square tests and 
continuous variables will be analyzed using the t-test or the Mann-Whitney test. Wherever 
appropriate, paired comparisons will be made using the paired t-test or the Wilcoxon test. 
All tests will be two-sided and will use a Type I error of 5%. 
12.1.4. Randomization
A randomization schedule for this study will be generated using permuted blocks of size 
6 stratified by treatment arm and extent of liver resection (see 11.3 for details).
12.2. Sample Size/Accrual Rate
We plan to accrue 80 patients, approximately 10 patients per year.
12.3. Stratification Factors
Treatment arm and extent of liver resection (1st subgroup- 3 segments resected; 2nd 
subgroup - ≥4 segments resected) will be used as stratification factor in this study. 
Patients will also be stratified based upon the underlying liver disease.
12.4. Reporting and Exclusions
Evaluation of toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment.
Evaluation of response:  All evaluable patients included in the study must be assessed 
for response to treatment, even if there are major protocol treatment deviations.
.  


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13.0
Data and Safety Monitoring Plan
13.1. Monitoring Plan 
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the ISRU will collect and report data to 
the Sponsor Investigator who will review these data on a regular basis at a rate dependent 
on subject accrual.  All serious adverse events (SAEs) will be reviewed on a real time 
basis first by the study site PI and subsequently by the ISRU and Sponsor Investigator as 
applicable.
13.2. Data Safety Monitoring Board  
Interim analysis of toxicity, outcome and ongoing scientific investigations may be 
performed at least every 6 months by the Fox Chase Cancer Center Data Safety 
Monitoring Board (FCCCDSMB).  In this capacity the FCCCDSMB will serve as an 
advisory committee to the sponsor-investigator.  The FCCCDSMB will review those 
aspects of this trial that are outlined in the responsibilities section of the Data and Safety 
Monitoring Plan (DSMP).  If the committee decides that changes should be made to this 
trial, it will make recommendations in writing to the Sponsor- Investigator, the Associate 
Director of Clinical Research, and the Protocol Management Executive Committee, 
which, in turn, have the authority to approve or disapprove these recommendations.  These 
changes will be discussed with the Sponsor- Investigator before they are implemented.  
These changes may include early termination of accrual.  Other changes might include 
altering the accrual goals or changing the eligibility criteria for the trial.
14.0
Administrative  
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines.
14.1. Data Reporting
The FCCC Study Monitor will request case report forms to be completed within 2 weeks 
of the protocol visit.  Participating sites are responsible to respond to queries prior to the 
next scheduled monitoring visit.  
The ISRU is responsible for compiling and submitting data to the sponsor investigator and 
statistician on an ongoing basis for monitoring as described in the data safety monitoring 
plan and reporting to the Data and Safety Monitoring Board.
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, 
such as case report files, produced will be stored in a secure location. 
 
The ISRU is responsible for distributing, tracking and review of all IND Action Letters, 
Safety Reports and study specific Serious Adverse Events.


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14.2. Retention of Records  
The Study Monitor must be notified of any plans to move records to an offsite location 
prior to doing so.
14.3. Study Agents
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol.  The 
agent may not be transferred to any party not participating in the clinical trial.
14.4. Informed Consent
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study.  A copy of the informed consent documents must be provided 
to the patient or the patient’s legally authorized representative.  If applicable, they will be 
provided in a certified translation of the local language.
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file.


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15.0
References
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postresection liver failure.”British Journal of Surgery.  2011; 98: 1188-1200.
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258:822–830.
4. Demetris AJ, Kelly DM, Eghtesad B, et al. “Pathophysiologic observations and histopathologic 
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5. Tu YL, Wang X, Wang DD, et al. “Impact of mesocaval shunt on safe minimal liver remnant: 
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13. Jenkins SA, Baxter JN, Corbett WA, Shields R. “Effects of a somatostatin analogue SMS 201-
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26. Jia C, Dai C, Bu X, et al. “Co-administration of prostaglandin E1 with somatostatin attenuates 
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