Clinical trial NCT03043664
Conditions: Gastroenteropancreatic Neuroendocrine Tumors
Keywords: GEP-NET pembrolizumab lanreotide PD-1 Keytruda Somatuline Depot PD-L1 anti-PD-1
Sponsor: Duke University
Start date: 2017-07-01; Completion date: 2022-06-07
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for patients with non-resectable, recurrent, or metastatic well or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

The study will be conducted in two stages: 1) Safety Run-In and 2) Expanded Cohort.

1. Safety run-in: The first stage will include a safety run-in of 6 patients treated with pembrolizumab 200 mg intravenous (IV) every 3 weeks and lanreotide depot 90mg subcutaneous (SQ) every 3 weeks. Up to 6 patients at the Duke Cancer Institute will be accrued at the starting dose level. If one or less subject meets treatment-related discontinuation criteria (as specified in the protocol) during Cycle 1, then the study will proceed to the second stage, Expanded Cohort.
2. Expanded Cohort: Patients will be treated with pembrolizumab 200mg IV every 3 weeks and lanreotide depot 90mg SQ every 3 weeks as determined by the Safety Run-In Cohort.

Detailed description:

Arms: arm 1: Keytruda (pembrolizumab) 200 mg intravenous (IV) infusion every 3 weeks and Somatuline Depot (lanreotide) 90 mg subcutaneous (SQ) injection every 3 weeks.
Interventions: intervention 1: Lanreotide intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Somatuline depot (lanreotide) 90 mg SQ every 3 weeks intervention 2: Keytruda (pembrolizumab) 200 mg IV every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for 
Gastroenteropancreatic Neuroendocrine Tumors (PLANET) 
 
 
Trial: NCT03043664 
 
 
Protocol 
 
September 7, 2021 


 
 
 
 
 
 
Phase Ib/II Study of Pembrolizumab with 
Lanreotide Depot for Gastroenteropancreatic 
Neuroendocrine Tumors  
(PLANET) 
 
 
 Lead Principal Investigator:   
Michael Morse, MD 
Duke University Medical Center 
 
 
Durham, NC 27710 
 
Supported by:  
Merck & Co. 
Ipsen Biopharmaceuticals, Inc. 
 
 
 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to 
initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from the 
coordinating site and sponsor is required for disclosure otherwise. 


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PROTOCOL VERSIONS  
 
Version Number 
Version Date 
Version 1.0/ Initial 
28-OCT-2016   
Version 2.0/Amendment 1 
03-NOV-2017 
Version 3.0/Amendment 2 
29-NOV-2017 
Version 4.0/Amendment 3 
22-MAY-2020 
Version 5.0/Amendment 4 
06-JUL-2020 
Version 6.0/Amendment 5 
07-SEP-2021 
 
 
 
 
 
 
 


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SPONSOR CONTACT INFORMATION 
 
Lead Principal Investigator (PI): 
Michael Morse, MD 
Duke University Medical Center 
 
 
Durham, NC 27710 
Phone: 919-668-1861 
 
 
Email: michael.morse@duke.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNPOSIS  
Title 
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for Gastroenteropancreatic 
Neuroendocrine Tumors (PLANET) 
Objectives 
The primary objective is: 
1. To evaluate the objective response rate (ORR) by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 to pembrolizumab in combination with lanreotide depot in 
subjects with progressive, advanced or metastatic gastroenteropancreatic neuroendocrine 
tumors (GEP-NETs). 
The secondary objectives are: 
1. To assess the safety of pembrolizumab in combination with lanreotide depot in subjects 
with GEP-NETs. 
2. To assess progression free survival (PFS) of pembrolizumab in combination with 
lanreotide depot in subjects with GEP-NETs. 
3. To assess the overall survival (OS) of pembrolizumab in combination with lanreotide depot 
in subjects with GEP-NETs. 
4. To evaluate the ORR by Immune-Related Response Criteria (irRC) to pembrolizumab in 
combination with lanreotide depot in subjects with progressive, advanced or metastatic 
GEP-NETs. 
The exploratory objectives are: 
1. To characterize changes in circulating immune cells in subjects with GEP-NETs treated 
with pembrolizumab in combination with lanreotide depot.  
2. To determine whether safety and efficacy parameters (ORR, PFS, OS) correlate with PD-
L1 expression within the tumor in pre-treatment specimens. 
3. To explore the correlation between blood-based biomarkers and clinical outcomes. 
Patient Population 
Patients must have a non-resectable, recurrent, or metastatic well or moderately differentiated 
gastroenteropancreatic neuroendocrine tumor (GEP-NETs) with at least one measurable 
lesion of the disease on imaging and evidence of radiological tumor progression within the last 
12 months. 
Study Design 
The study will be conducted in two stages: 1) Safety Run-In and 2) Expanded Cohort. 
Safety Run-In:  The first stage will include a safety run-in of 6 patients treated with 
pembrolizumab 200 mg intravenous (IV) every 3 weeks and lanreotide depot 90mg 
subcutaneous (SQ) every 3 weeks.  Up to 6 patients at the Duke Cancer Institute will be 
accrued at the starting dose level.  If one or less subject meets treatment-related 


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discontinuation criteria (as specified in the protocol) during Cycle 1, then the study will proceed 
to the second stage, Expanded Cohort.  If more than one subject meets treatment-related 
discontinuation criteria (as specified in the protocol) during Cycle 1, then the study will be 
redesigned to include alternative dose levels. 
Expanded Cohort:  The second stage will include an expanded cohort of up to 20 patients 
enrolled at the Duke Cancer Institute and select Duke Cancer Network sites.  Patients will be 
treated with pembrolizumab 200mg IV every 3 weeks and lanreotide depot 90mg SQ every 3 
weeks as determined by the Safety Run-In Cohort. 
Number of Subjects 
In the Safety Run-In Cohort, there will be up to 6 evaluable subjects.  
In the Expanded Cohort, there will be up to 20 evaluable subjects.   
Estimated Length of Study Participation 
Patients may continue to receive study drug regimen until they experience unacceptable 
treatment-related toxicity, disease progression, or once they have been treated for 2 years (or 
received 35 administrations of pembrolizumab) at which they will revert to commercial use of 
lanreotide depot alone without pembrolizumab.   
Patients will be followed for survival for up to 48 weeks after the last subject has finished study 
drug regimen.     
Study Drug Regimen 
Cycle length is 21 days. 
Pembrolizumab is supplied as powder for solution for infusion in 50mg per vial, powder for 
solution for infusion. The dose and schedule is 200mg IV on Day 1 of each cycle.   
Lanreotide depot is supplied as 90 mg/0.3 mL single use prefilled syringes for injection.  The 
dose and schedule is 90mg SQ on Day 1 of each cycle.     
Study Assessments 
Toxicity and safety assessments will be monitored on an ongoing basis (refer to Study 
Calendar).  Assessments include vital signs, ECOG performance status, medical history, 
physical examination, review of adverse events and laboratory studies.  Toxicity management 
and supportive care will be provided as clinically indicated to ensure optimal patient care.   
Adverse event seriousness, grade, and relationship to study drug will be assessed by the 
Investigator using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
Tumor Assessments 
Disease response will be assessed using both RECIST 1.1 and Immune-Related Response 
Criteria (irRC).  Patients will undergo radiographic imaging every 4 cycles (ie.12 weeks) after 
the start of the study drug regimen. 


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Correlative Studies 
Tumor tissue will be assessed for level of PD-1 (infiltrating T cells) and PD-L1 expression 
(tumor and infiltrating immune cells).  Blood will be collected at specified time points (see 
Study Calendar) for circulating immune cells and protein multiplex arrays. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
PROTOCOL VERSIONS ..........................................................................................................2 
 
SPONSOR CONTACT INFORMATION ...................................................................................3 
 
PROTOCOL SYNPOSIS ..........................................................................................................4 
 
TABLE OF CONTENTS ...........................................................................................................7 
 
1.0             INTRODUCTION ..................................................................................................... 10 
1.1 
Background ............................................................................................................. 10 
1.2 
Study Drugs ............................................................................................................ 10 
1.2.1         Pembrolizumab ........................................................................................................ 10 
1.2.1.1    Pharmaceutical and Therapeutic Background ........................................................ 12 
1.2.1.2    Preclinical and Clinical Trial Experience ................................................................. 13 
1.2.1.3    Safety Profile .......................................................................................................... 14 
1.2.1.4    Dose Selection ....................................................................................................... 19 
1.2.2         Lanreotide Depot ..................................................................................................... 20 
1.2.2.1    Pharmaceutical and Therapeutic Background ........................................................ 20 
1.2.2.2    Preclinical and Clinical Trial Experience ................................................................. 21 
1.2.2.3    Safety Profile .......................................................................................................... 23 
1.2.1.4    Dose Selection ....................................................................................................... 23 
1.3  
Study Rationale ....................................................................................................... 24 
 
2.0            OBJECTIVES ........................................................................................................... 24 
2.1 
Primary Objective .................................................................................................... 24 
2.2 
Secondary Objectives ............................................................................................. 24 
2.3 
Exploratory Objectives ............................................................................................ 25 
 
3.0            STUDY DESIGN ....................................................................................................... 25 
3.1 
Study Description .................................................................................................... 25 
 
4.0            SUBJECT SELECTION ........................................................................................... 26 
4.1 
Inclusion Criteria ..................................................................................................... 26 
4.2   
Exclusion Criteria .................................................................................................... 27 
4.3 
Inclusion of Women and Minorities.......................................................................... 29 
 
5.0            STUDY ASSESSMENTS ......................................................................................... 29 
5.1 
Screening Period ..................................................................................................... 29 
5.2 
Treatment Period .................................................................................................... 30 
5.3 
Follow-up Period ..................................................................................................... 31 
5.4 
Laboratory Assessments ......................................................................................... 31 
5.5 
Adverse Event Assessment .................................................................................... 32 
5.6 
Tumor Assessments ................................................................................................ 32 
5.6.1        RECIST version 1.1 ................................................................................................. 32 
5.6.2        Immune-Related Response Criteria ......................................................................... 32 


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5.7 
Subject Discontinuation ........................................................................................... 33 
 
6.0            STUDY DRUGS ........................................................................................................ 34 
6.1 
Treatment Compliance and Study Drug Accountability ........................................... 34 
6.2 
Pembrolizumab ....................................................................................................... 35 
6.2.1      Storage and Handling ............................................................................................... 35 
6.2.2        Administration ........................................................................................................... 35 
6.3 
Lanreotide Depot ..................................................................................................... 35 
6.3.1      Storage and Handling ............................................................................................... 36 
6.3.2        Administration ........................................................................................................... 36 
6.4 
Concomitant Medications/Vaccinations ................................................................... 36 
6.4.1      Acceptable Concomitant Medications ....................................................................... 36 
6.4.2      Prohibited Concomitant Medications ........................................................................ 36 
 
7.0             DOSE MODIFICATION AND TOXICITY MANAGEMENT ...................................... 37 
7.1 
Dose Modifications .................................................................................................. 37 
7.1.1       Pembrolizumab Dose Modifications......................................................................... 38 
7.1.1       Lanreotide Depot Dose Modifications ...................................................................... 40 
7.2  
Toxicity Management .............................................................................................. 40 
7.2.1  
Pneumonitis ...................................................................................................... 41 
7.2.2  
Diarrhea/Colitis.................................................................................................. 41 
7.2.3  
Diabetes Mellitus ............................................................................................... 41 
7.2.4  
Hypophysitis ...................................................................................................... 41 
7.2.5  
Hyperthyroidism or Hypothyroidism .................................................................. 42 
7.2.6  
Hepatic .............................................................................................................. 42 
7.2.7  
Renal Failure or Nephritis ................................................................................. 42 
7.2.8  
Infusion Reactions ............................................................................................. 42 
 
8.0            CORRELATIVES ...................................................................................................... 44 
8.1 
Tumor Biomarkers ................................................................................................... 44 
8.2 
Circulating Immune Cells ........................................................................................ 44 
8.3 
Protein Multiplex Arrays .......................................................................................... 45 
8.4 
Future Use of Patient Samples ............................................................................... 45 
 
9.0            STATISTICAL ANALYSIS ....................................................................................... 45 
9.1 
General Analysis Considerations ............................................................................ 45 
9.1.1        Primary Endpoint ...................................................................................................... 45 
9.1.2        Secondary Endpoints ............................................................................................... 46 
9.1.3        Exploratory Endpoints .............................................................................................. 46 
 
10.0          SAFETY ................................................................................................................... 47 
10.1 
Adverse Events ....................................................................................................... 47 
10.2 
Serious Adverse Events .......................................................................................... 47 
10.3 
Events of Clinical Interest ........................................................................................ 49 
10.3.1      Medication Overdose and Error ............................................................................... 50 
10.4 
Other Safety Considerations ................................................................................... 51 
10.4.1      Pregnancy and Lactation ......................................................................................... 51 


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11.0          ADMINISTRATIVE RESPONSIBILITIES ................................................................. 52 
11.1 
Institutional Review Board/Independent Ethics Committee ..................................... 52 
11.2 
Protocol and Protocol Revisions ............................................................................. 52 
11.3          Protocol Deviations and Violations .......................................................................... 52 
11.4 
Informed Consent .................................................................................................... 53 
11.5 
Source and Study Documentation ........................................................................... 53 
11.6 
Case Report Forms ................................................................................................. 54 
11.7 
Monitoring and Audits/Inspections .......................................................................... 54 
11.8 
Study Closeout ........................................................................................................ 56 
11.9 
Records Retention................................................................................................... 56 
 
12.0  REFERENCES .............................................................................................................. 57 
 
Appendix A.  RECIST 1.1 ..................................................................................................... 59 
Appendix B.  Immune-Related Response Criteria ............................................................. 65 
Appendix C.  ECOG Performance Status ........................................................................... 66 
Appendix D.  Study Calendar .............................................................................................. 67 
Appendix E.  Laboratory Tests ............................................................................................ 68 
 
 
 


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1.0 
INTRODUCTION 
1.1 
Background 
Neuroendocrine tumors of the gastrointestinal (GI) tract and pancreas (GEP-NETs) are generally 
indolent tumors which are nonetheless lethal once they become metastatic (1,2). Treatments include 
surgery, ablative procedures including embolization for liver metastases, systemic therapies targeting 
mammalian target of rapamycin (mTOR) or the vascular endothelial growth factor (VEGF) receptors 
(3).  For patients with symptoms associated with hormone hypersecretion in neuroendocrine tumors, 
somatostatin analogues (SSA) are generally used (4).  Furthermore, recent studies suggest 
somatostatin analogues also have antitumor effects (5,6).  For example, the CLARINET study 
demonstrated that first-line treatment with Lanreotide Autogel/Depot, a somatostatin analogue (SSA), 
significantly prolonged progression free survival (PFS) among patients with metastatic nonfunctioning, 
somatostatin receptor-positive enteropancreatic NETs of grade 1 or 2 (Ki-67 <10%) (6). However, 
patients ultimately have progression of disease, indicating the need for additional therapies that could 
be combined. Because immune cells have been demonstrated to infiltrate neuroendocrine tumors (7), 
one class of therapies that may be potential partners for lanreotide includes immunotherapies. Indeed, 
while the anti-proliferative effects are likely direct effects mediated through the somatostatin receptors, 
somatostatin analogues such as lanreotide also may have immunomodulatory effects as somatostatin 
receptors are present on human lymphocytes and monocytes (8).  Interferon alpha also has been used 
to treat neuroendocrine tumors with anti-tumor benefit similar to that of the somatostatin analogues (9).  
It is not known whether interferon is acting through immune mechanisms or other anti-proliferative or 
anti-angiogenic mechanisms. Interferon and lanreotide have been tested as a combination which was 
tolerable, but did not yield additive benefits; however, because the immunomodulatory molecules PD-
1 and PD-L1 have been identified within neuroendocrine carcinomas (10), we hypothesize that a 
combination of an immunotherapy (anti-PD-1 antibody) with a different mechanism of action when 
combined with lanreotide will have greater anti-tumor activity. 
1.2 
Study Drugs 
1.2.1 Pembrolizumab 
The programmed cell death 1 (PD-1) pathway represents a major immune control switch, which may 
be engaged by tumor cells to overcome active T-cell immune surveillance. Pembrolizumab 
(KEYTRUDA®, MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of 
the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 
and its ligants, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). 
This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and 
ultimately immune rejection. 
Merck, Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc. (Merck), is studying 
pembrolizumab for various oncology indications. Overall, as of 03-Mar-2016, 16,496 patients have been 
treated in the pembrolizumab development program, of which approximately 9833 patients have been 
exposed to pembrolizumab in Merck sponsored clinical trials (approximately 6713 subjects received 
pembrolizumab monotherapy, approximately 876 subjects received pembrolizumab in combination with 
one or more other chemotherapy or biologic agents, and approximately 2244 subjects received 
comparator treatment alone). As of the various data cutoff dates for the KEYTRUDA® Investigator 
Brochure (IB) Version 11 dated 01-Sep-2016, pembrolizumab monotherapy and combination therapy 


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have been administered to subjects with hematologic malignancies and solid tumors, in a total of 48 
ongoing, Phase 1, 2, and 3 clinical trials sponsored by Merck. 
On 04-Sep-2014 the United States (US) Food and Drug Administration (FDA) granted accelerated 
approval to KEYTRUDA® for treatment of patients with advanced or unresectable melanoma who are 
no longer responding to other drugs. KEYTRUDA® is the first approved drug that blocks PD-1. 
KEYTRUDA® is intended for use following treatment with ipilumumab (IPI), a type of immunotherapy. 
For melanoma patients whose tumors express a gene mutation called BRAF V600, KEYTRUDA® is 
intended for use after treatment with IPI and a BRAF inhibitor, a therapy that blocks activity of BRAF 
gene mutations. The recommended dose of KEYTRUDA® is 2 mg/kg administered as an intravenous 
(IV) infusion over 30 minutes every 3 weeks (Q3W). 
On 22-Jul-2015 the European Commission (EC) approved KEYTRUDA® for the treatment of advanced 
(unresectable or metastatic) melanoma in adults. The EC approval of KEYTRUDA® was based on data 
from 3 clinical studies (KEYNOTE [KN]001, KN002, and KN006) conducted in more than 1,500 first-line 
and previously-treated patients with advanced melanoma. KEYTRUDA® received EC regulatory 
approval based on Phase 3 data that showed it as the first and only anti-PD-1 therapy to provide a 
statistically superior survival benefit as a monotherapy compared to IPI, the current standard of care for 
advanced melanoma. This approval allowed marketing of KEYTRUDA® in all 28 EU member states at 
the approved dose of 2 mg/kg Q3W. With the EC decision, KEYTRUDA® is now approved in more than 
35 countries for the treatment of advanced melanoma. 
On 02-Oct-2015 the US FDA granted accelerated approval for KEYTRUDA® to treat patients with 
advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other 
treatments ans with tumors that express a protein called PD-L1. KEYTRUDA® is approved for use with 
a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 
expression in non-small cell lung tumors. The FDA-approved dose of KEYTRUDA® is 2 mg/kg Q3W. 
On 18-Dec-2015, the US FDA expanded the label to include the approval of KEYTRUDA® for the 
treatment of patients with unresectable or metastatic melanoma. This expansion now includes the initial 
treatment of patients with unresectable or metastatic melanoma with pembrolizumab. The FDA-
approved dose of KEYTRUDA® is 2 mg/kg Q3W. 
On 02-Aug-2016 the EC approved KEYTRUDA® for patients with locally advanced or metastatic 
NSCLC, at a dose of 2 mg/kg Q3W, in patients whose tumors express PD-L1 and who have received 
at least 1 prior chemotherapy regimen. Patients with EGFR or ALK positive tumor mutations should 
also have received approved therapy for these mutations prior to receiving KEYTRUDA®. The EC 
approval allows marketing of KEYTRUDA® in all 28 EU member states. The approval is based on 
findings from KN010, a pivotal study which showed KEYTRUDA® significantly improved overall survival 
(OS) compared to standard of care chemotherapy. 
On 05-Aug-2016 the US FDA approved KEYTRUDA®, at a fixed dose of 200 mg Q3W, for the treatment 
of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease 
progression on or after platinum-containing chemotherapy. Under the FDA’s accelerated approval 
regulations, this indication for KEYTRUDA® is approved based on tumor response rate and durability 
of response. For HNSCC patients, PD-L1 testing is not needed prior to use of KEYTRUDA®. The FDA-
approved dose of KEYTRUDA® is 200 mg Q3W. 
Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA® both as 
a monotherapy and in combination with other therapies across more than 30 tumor types and enrolling 
more than 16,000 patients. Immune-related adverse events (irAEs) are expected based on the nature 


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of the compound, its mechanism of action, and reported experience with immunotherapies that have a 
similar mechanism of action. 
1.2.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-
4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD L2).  The structure of murine PD-1 has been resolved.  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  
Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells 
as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors.  Both ligands are type I transmembrane receptors containing both IgV- 
and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-
cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment 
of patients with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. 


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1.2.1.2 Preclinical and Clinical Trial Experience 
For complete study information, refer to the current Pembrolizumab Investigator’s Brochure (IB).   
 
Non-Clinical Toxicology Summary 
In the 1-month and 6-month toxicology study in cynomologus monkeys, pembrolizumab, intravenously 
administered once a week and once every other week respectively up to a dose of 200mg/kg, resulted 
in no adverse treatment-related effects. In tissue cross-reactivity studies of pembrolizumab in human 
and monkey tissues, the expected on-target staining of mononuclear leukocytes membranes was 
demonstrated in both species. Off-target cross-reactivity staining was also noted in both species but 
was limited to the cytoplasm of various cell types/tissues and the stroma (extracellular connective tissue 
matrix), and was considered related to experimental methodological artifacts, i.e. tissue processing for 
IHC, which are well recognized limitations of tissue cross-reactivity studies and, thus not considered 
toxicologically relevant.  
There was no impact seen on male or female fertility based on evaluation of the Cynomolgus monkeys 
used in the 1-month and 6-month studies. Reproductive risk assessment was performed using a 
literature-based approach. In light of the identified potential risk related to inhibition of the PD-1 pathway, 
no reproductive or developmental toxicity studies were conducted with pembrolizumab. Therefore, 
inclusion of women of childbearing potential in clinical trials should be in accordance with the study 
protocol and applicable regulatory guidance (e.g., ICH M3(R2): Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals). 
Clinical Trial Summary 
As of the data cutoff dates for Version 11 (01-Sep-2016) of the Pembrolizumab Investigator’s Brochure, 
pembrolizumab monotherapy and combination therapies have been administered to approximately 
9833 subjects, with hematologic malignancies and solid tumors, in Merck sponsored trials. 
Clinical Pharmacology 
The PK profile of pembrolizumab, with low clearance and limited volume of distribution, is typical for 
therapeutic antibodies. Exposure to pembrolizumab is approximately linear in the dose range of clinical 
relevance (1 to 10 mg/kg and at 200 mg). Furthermore, pembrolizumab has a low potential fo eliciting 
the formation of ADAs. 
Efficacy 
For this Pembrolizumab IB (Version 11, 01-Sep-2016), efficacy data are available for a total fo 1572 
melanoma subjects treated with pembrolizumab in KN001, KN002, and KN006; 1529 subjects with 
NSCLC treated with pembrolizumab in KN001 and KN010; and 174 subjects with HNSCC treated with 
pembrolizumab in KN012. 
KN001 was an open-label, Phase 1, first-in-human study conducted to evaluate clinical activity of 
pembrolizumab as a single agent in two cancers, melanoma and NSCLC. The ORR demonstrated the 
antitumor activity of pembrolizumab in subjects with melanoma (ipilumumab-naïve and previously 
treated with ipilumumab). 


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KN002 was a randomized Phase 2 study comparing two doses of pembrolizumab to investigator’s 
choice chemotherapy in subjects with unresectable or metastatic (advanced) melanoma, who had 
progressed after prior treatment with IPI and BRAF (and/or MEK) inhibitor in subjects with BRAF-mutant 
melanoma. The study demonstrated superior PFS for both pembrolizumab treatment arms compared 
to the chemotherapy control arm. Treatment with pembrolizumab led to an ORR that was >4-fold higher 
than the response rate fo the chemotherapy control arm. This difference was highly statistically 
significant. 
KN006 was a randomized Phase 3 pivotal study, designed to test whether pembrolizumab was superior 
to IPI in the co-primary efficacy endpoints of PFS and OS in IPI-naïve subjects with unresectable or 
metastatic melanoma. This study demonstrated statisticaly significant improvements in OS and PFS for 
subjects randomized to pembrolizumab compared to subjects randomized to IPI. In the 10 mg/kg 
treatment groups (Q2W and Q3W), 185 subjects experienced objective responses that ranged from 1.4 
months to 8.2 months in duration. 
KN010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 2 dose levels vs 
docetaxel in subjects with NSCLC with PD-L1 positive tumors, who have experienced disease 
progression after platinum-containing systemic therapy. 
KN012 was a Phase 1b study of pembrolizumab in subjects with advanced solid tumors, including 
subjects with HPV-negative and HPV-positive head and neck cancer. The primary population for 
analysis included HNSCC subjects previously exposed to platinum therapy. 
The ORRs for pembrolizumab treatment in KN001, KN002, KN006, KN010, and KN012 compared 
favorably to historical response rates for available treatments for melanoma, NSCLC, and HNSCC, 
respectively, particularly in subjects who have progressed after multiple prior therapies. 
1.2.1.3 Safety Profile 
Pembrolizumab is safe and well tolerated, as evidenced by a low rate of toxicity Grade 3 to 5 drug-
related AEs (13.8%), discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (3.9%). 
Furthermore, the frequency of immune-mediated adverse reactions (AEOSIs) is low, and these events 
are readily managed in the clinical setting. 
The safety and efficacy data generated to date provide a favorable benefit-risk assessment for the use 
of pembrolizumab as a treatment for subjects with advanced/metastatic melanoma, NSCLC, and 
HNSCC. 
There are no specific safety concerns based on the results of nonclinical studies. Pembrolizumab has 
the same mechanism of action as other anti-PD-1 monoclonal antibodies. Preclinical studies have 
suggested similar potency, and PK modeling has suggested similar human PK in the class. Accordingly, 
the AEs observed with other anti-PD-1 antibodies may serve as an indicator for the AEs to expect in 
cancer subjects. 
Pembrolizumab is generally well-tolerated and demonstrates a favorable safety profile in comparison 
to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this mechanism of 
action, immune-mediated AEs are of primary concern. The important identified risks for pembrolizumab 
are of an immune-mediated nature, and include the following: pneumonitis; colitis; hepatitis; nephritis; 
endocrinopathies that include hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism) and Type 1 diabetes mellitus; uveitis; 
myositis; Guillain-Barré syndrome; pancreatitis; and severe skin reactions. Information on the nature 
and frequency of these identified risks is included in the Reference Safety Information of Version 11 of 


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the Investigator’s Brochure. The majority of immune-mediated adverse events were mild to moderate 
in severity, manageable with appropriate care, and rarely required discontinuation of therapy. 
In addition, two important potential risks have been identified, although the data available thus far for 
these events does not provide sufficient evidence of a causal relationship to pembrolizumab. The two 
important potential risks are: a) myasthenic syndrome, and b) an increased risk of severe complications 
(such as early severe graft versus host disease and venoocclusive disease) of allogenic transplant in 
patients with hematologic malignancies who have previously been treated with PD-1 inhibitors. The 
Sponsor continues to monitor and collect data on these potential risks in order to further characterize 
their potential relationship to pembrolizumab. 
Further details regarding reporting and management of immune-related AEs (irAEs) in general are 
described below. 
In addition to the immune-related risks noted above, infusion-related reactions are also an important 
identified risk for pembrolizumab; however, they are not considered immune-mediated. Information 
regarding the nature and frequency of infusion-related reactions is included in the Reference Safety 
Information in Version 11 of the Investigator’s Brochure. 
Immune-Related Adverse Events 
Based on the mechanism of action of pembrolizumab and similar immunomodulatory agents, the 
Sponsor is interested in all potential irAEs, and encourages appropriate investigation of signs and 
symptoms suggestive of these.  
Consultation with the appropriate medical specialist should be considered when investigating a possible 
irAE. These events can occur after the first dose to several months after the last dose of treatment. Mild 
irAEs are usually treated symptomatically and infrequently require dosing delays or discontinuation. 
Higher grade and persistent lower grade irAEs typically necessitate withholding or discontinuing 
treatment and administration of systemic steroids or other immunosuppressive agents (such as tumor 
necrosis factor blockers), when systemic steroids are not effective. Early recognition of irAEs and 
initiation of treatment are critical to reduce the risk of complications, since the majority of irAEs are 
reversible with the use of steroids and other immune suppressants. 
 
 


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Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab   
(Presented by Decreasing Frequency of AEOSI Category) 
 
 
 


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cont. Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab 
(Presented by Decreasing Frequency of AEOSI Category)  
 
 
 


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cont. Table 1.2.1.3.1 All AEOSI Adverse Reactions Considered Expected for Pembrolizumab 
(Presented by Decreasing Frequency of AEOSI Category) 
 
Nephritis: Five additional cases of the AEOSI nephritis were observed in the Reference Safety Dataset; 
however, they are not contained in the preceeding table because the reported AE coding at the time 
did not include an AEOSI nephritis term. The coding for each of these 5 cases has since been updated 
after the data-lock of the Reference Safety Dataset as follows, and each of the terms below is 
considered an AEOSI adverse reaction expected for pembrolizumab: 
 
Tubulointerstitial nephritis: n=2 (in addition to 4 cases already included in above table), for an 
overall frequency of n=6 (0.2%) 
 
Nephritis: n=2 (0.1%) 
 
Autoimmune nephritis: n=1 (0%) 
Therefore, based on the addition of the above 5 cases, the overall frequency for the AEOSI nephritis in 
the Reference Safety Dataset should be n=9 (0.3%) 
Colitis: One event in the Reference Safety Dataset was initially counted as an AEOSI of colitis. 
However, it was later determined that the subject did not have colitis, and had been included in the 
Reference Safety Dataset summary of colitis due to data entry errors. Therefore, the overall frequency 
of the AEOSI colitis should be n=48 (1.7%), and the frequency for the individual event of colitits should 
be n=45 (1.6%) 


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Infusion-Related Reactions: One subject had an event of anaphylactoid reaction that was not counted 
as an infustion-related reaction since this term was not part of the terms list for the AEOSI infusion-
related reactions at the time of reporting. Therefore, the incidence of AEOSI infusion-related reactions 
in the Referense Safety Dataset should be n=71 (2.5%). The term “anaphylactoid reaction” (n=1 [0%]) 
is considered an AEOSI expected for pembrolizumab. 
Table 1.2.1.3.2 All Additional Adverse Reactions Considered Expected for Pembrolizumab 
1.2.1.4 Dose Selection 
PN001 is being conducted to evaluate the safety and clinical activity of single agent pembrolizumab.  
The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were 
well tolerated and no dose-limiting toxicities were observed.  This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this 
protocol to test for initial tumor activity.  Recent data from other clinical studies within the pembrolizumab 
program has shown that a lower dose of pembrolizumab and a less frequent schedule may be sufficient 
for target engagement and clinical activity. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release 


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assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body weights.  
Pembrolizumab has been found to have a wide therapeutic range based on the melanoma indication.  
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between different 
indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors 
is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg 
Q3W in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor 
burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK 
model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
1.2.2 Lanreotide Depot 
Lanreotide is an octapeptide analogue of somatostatin. 
1.2.2.1 Pharmaceutical and Therapeutic Background 
Lanreotide is a well-established peptide analogue of the natural hormone somatostatin, in which the 
biochemical stability of the peptide has been increased by incorporation of modified amino acids. Like 
native somatostatin, lanreotide inhibits the secretion of many hormones (including GH), and has anti-
proliferative activity. Somatostatin is a peptide naturally produced by the hypothalamus and neurons of 
the GI tract. Somatostatin produced by the hypothalamus acts on the pituitary gland to inhibit the 
synthesis and release of GH and thyroid stimulating hormone (TSH). Therefore, in diseases involving 
increases of GH, such as acromegaly and some cancers, somatostatin has a use in inhibiting GH 
production. Somatostatin produced by neurons of the GI tract acts to inhibit numerous digestive 


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endocrine and exocrine secretions. Therefore, the compound can also inhibit secretions from digestive 
fistulae which, if left untreated, prevent fistula closure leading to risk of skin damage and sepsis. 
Receptors for somatostatin are expressed on the surface of most NETs, and since somatostatin inhibits 
cell proliferation, the compound can also be used to treat these tumors. The therapeutic use of 
somatostatin is, however, limited by its short halflife of only 2 to 3 minutes. Therefore, synthetic SSAs 
with increased specificity and half-life duration have been developed for medicinal use. Lanreotide is a 
synthetic octapeptide with a biological activity similar to naturally occurring somatostatin. The compound 
is characterised by the presence of D-Tryptophan in the amino acid ring, increasing stability, and by the 
presence of D-beta Nal outside of this ring, which increases its selectivity. The terminal amine function 
reduces binding to central nervous system (CNS) receptors. Lanreotide exhibits high affinity for the 
somatostatin Type 2 (SSTR2) and Type 5 (SSTR5) receptors found in the pituitary gland, GH secreting 
pituitary tumors, NETs and the digestive tract. The product has a much lower affinity for somatostatin 
Type 1, 3 and 4 receptors. 
Lanreotide has been developed in the following formulations: 
 
Immediate release 
 
Microparticle prolonged release (lanreotide PR 30 and 60 mg) 
 
Lanreotide Autogel 60, 90 and 120 mg 
Marketing authorisation has been granted for lanreotide MPF (indicated for the treatment of acromegaly, 
NETs, and also for thyrotropic adenoma and digestive fistulae in some countries), and for lanreotide 
Autogel formulation (indicated for acromegaly and NETs). The immediate release formulation (IRF) is 
not registered. The lanreotide PR 30 mg (MPF) is administered by intramuscular (i.m.) injection every 
7, 10 or 14 days. The 7-day dose interval is only registered in a few countries, and the lanreotide PR 
60 mg formulation, a monthly formulation, is no longer registered in any country. 
Lanreotide Autogel was developed to extend the duration of lanreotide release, obtaining at least a 28-
day dosing interval. This formulation can be administered by deep subcutaneous injection into the 
external quadrant of the buttock by a healthcare professional. A clinical variation has been approved in 
several countries, whereby patients who are well controlled by SSAs can be treated with lanreotide 
Autogel 120 mg every 42 to 56 days rather than every 28 days. 
Lanreotide Autogel was first launched in France in 2001, and is registered in approximately 60 countries 
worldwide including countries in Africa, Asia, Central and Eastern Europe, the Middle East, Australasia, 
and North, Central and South America. 
Lanreotide depot for injection is available as 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL single-
use prefilled syringes 
Lanreotide depot injection is a somatostatin analog indicated for: 1) the long-term treatment of 
acromegalic patients who have had aninadequate response to or cannot be treated with surgery 
and/orradiotherapy; and 2) the treatment of patients with unresectable, well-or moderately-
differentiated, locally advanced or metastatic gastroenteropancreaticneuroendocrine tumors (GEP-
NETs) to improve progression-free survival.   
1.2.2.2 Preclinical and Clinical Trial Experience 
For complete study information, refer to the Lanreotide Investigator’s Brochure (IB).   
Non-Clinical Toxicology Summary 


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Toxicology data have been assessed based on plasma lanreotide concentrations in animals compared 
with humans after administration of lanreotide Autogel 120 mg (1.7 mg/kg based on a body weight of 
70 kg). 
The toxicity of lanreotide was extensively studied in rodents and dogs and no acute or chronic toxicity 
hazard was detected. Repeated subcutaneous injection of lanreotide Autogel for up to 26 weeks in rats 
and up to 39 weeks in dogs did not cause systemic target organ toxicity at plasma concentrations of 
approximately 200- to 400-fold (rats) and 16- to 23-fold (dogs), the exposure observed after 
administration of lanreotide Autogel 120 mg to humans. Chronic administration of lanreotide produced 
a reduction in growth rate (decreased body weight gain, decreased weight of some organs) in rats and 
dogs and gallbladder dilatation in dogs which were considered related to the pharmacological activity 
of the product. 
The effects on the GI tract of animals were similar to those in humans. No overt signs of pancreatic or 
gallbladder toxicity were observed in the chronic toxicity studies in rats and dogs. 
In standard tests, lanreotide showed no tendency to cause damage to deoxyribonucleic acid (DNA). 
Two-year rodent carcinogenicity studies of lanreotide administered once daily by subcutaneous 
injection did not result in systemic neoplastic changes despite achieving 12- to 30-fold (at 10 mg/kg/day 
in mice) and 2.5- to 2.7-fold (at the highest dose tested of 0.5 mg/kg/day in rats) the human plasma 
concentration after administration of the MRHD of 120 mg. An increase in neoplastic changes with 
lanreotide compared to controls was observed at the injection sites for doses of approximately 20- and 
90-fold (mice) and 1.8-fold (rats) the human plasma level at the MRHD. The neoplastic changes 
observed at the injection site of rodents were probably caused by long-term irritation of the 
subcutaneous tissue rather than damage to DNA and are not considered a cause for concern with 
regard to the safe use of lanreotide Autogel in patients. 
Reproductive toxicity studies in rats and rabbits showed that lanreotide did not interfere with normal 
embryonic development in pregnant animals despite the presence of lanreotide metabolites in the 
amniotic fluid and foetal tissues. There was a tendency to reduce female fertility but only at doses that 
reduced body weight gain. At these doses this effect is an expected outcome of inhibition of GH 
secretion. The fertility of males was unaffected by the treatment and the behavioural and reproductive 
characteristics of 2 subsequent generations were unaffected by administration of the drug to the parents 
despite the excretion of unchanged lanreotide and 1 of its metabolites in the maternal milk. 
The local tolerance of lanreotide Autogel after chronic subcutaneous injection in rats and dogs revealed 
the presence of nodules at the injection site after each administration. The histopathological changes 
(granulomatous inflammation and/or fibrosis) observed at the injection site following lanreotide Autogel 
administration appear to be a normal reaction of the subcutaneous tissue to the presence of a foreign 
body.  
Studies with lanreotide Autogel or IRF indicate that lanreotide is not harmful to the immune system of 
animals. Lanreotide causes less stimulation to the immune system of humans than in rats and dogs. 
Toxicology studies of the impurities present in lanreotide Autogel were conducted using high doses 
compared to those intended for human use. No safety concerns were identified during these studies. 
Based upon the pharmacology, PK, safety pharmacology and toxicology studies (including 
cardiovascular tolerance), lanreotide Autogel is considered to be safe for chronic use in humans. 
Clinical Trial Summary 


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In terms of NET, the main effects of lanreotide are reducing carcinoid syndrome symptoms associated 
with NET and tumor stabilization. As of May 14, 2014 (Lanreotide IB Version 14.0), the main efficacy 
parameters used to assess the effect of lanreotide in NET studies were the number of symptom 
episodes (mainly diarrhoea and flushing) and PFS. Reductions in tumor biomarkers have also been 
observed in patients with NET. 
The efficacy of lanreotide Autogel (60, 90 and 120 mg) in the treatment of symptoms associated with 
carcinoid NET was investigated in an open, multicentre, dose titration clinical study (Study 718).  
Lanreotide Autogel was administered by deep subcutaneous injection at 4-week intervals for 6 months 
to assess the relief of clinical symptoms in patients diagnosed with symptomatic carcinoid NET. 
Seventy-one patients were treated and included in the ITT population, 35 were included in the Per 
Protocol (PP) population, and 71 were included in the Safety population. The primary efficacy endpoint 
of the study was the proportion of patients whose target symptom responded at Month 6. The 
investigator identified the symptom that was most troublesome to each patient and this became the 
“target symptom”. A response was defined as a reduction of ≥50% in the mean daily number of episodes 
of the target symptom (i.e., the number of episodes of diarrhea or the number of episodes of moderate 
or severe flushing) compared with baseline. Symptom assessments were recorded in patient diaries. 
The response rate was approximately 40%. 
The secondary efficacy analyses included an evaluation of the efficacy of lanreotide Autogel in the relief 
of clinical symptoms (diarrhoea and/or flushing) after each month of treatment. The changes from 
baseline for both flushing and diarrhoea were clinically and statistically significant for each month 
(Months 1 to 6). In Study 166, 9/30 patients had NET-related symptoms at baseline; after lanreotide 
treatment, symptoms were totally controlled in 4 of these patients. 
A long-term retrospective study has been conducted with lanreotide Autogel in patients with malignant 
carcinoid syndrome, assessing clinical and objective response and tolerance. A 9-year study included 
76 patients with metastatic midgut NETs and carcinoid syndrome. Clinical response was based on 
symptom score with radiological assessment based on RECIST (Response Evaluation Criteria In Solid 
Tumors). In this study, lanreotide Autogel provided good symptomatic control of diarrhoea and flushing 
in patients with malignant carcinoid syndrome.  
Another phase III study (Study 726) has been completed, which investigated the effect of lanreotide 
Autogel 120 mg on PFS in patients with well- or moderately well-differentiated, non-functioning entero-
pancreatic, neuroendocrine tumors.   
1.2.2.3 Safety Profile 
The safety results from NET studies were similar to those from acromegaly studies. The most common 
treatment emergent adverse events (TEAEs) were GI disorders, including diarrhea and abdominal pain. 
Other common TEAEs were asthenia, fatigue, headache, vomiting, nasopharyngitis, nausea, anorexia, 
cholelithiasis, flatulence, intestinal obstruction, injection site pain, back pain, hyperglycaemia and 
dizziness. 
1.2.1.4 Dose Selection 
According to prescribing information (revised date 12/2004), the recommended dose of lanreotide depot 
is 120 mg administered every 4 weeks by deep subcutaneous injection. There is no recommended dose 
adjustment for mild or moderate renal impairment. There is insufficient information to recommend a 
dose for patients with severe renal impairment or with hepatic impairment of any severity. However, in 
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administered every 3 weeks (same dose intensity as the 120mg every 4 week dose) by deep 
subcutaneous injection will be used for the current study. 
1.3  
Study Rationale 
In the proposed study, we aim to study the combination of pembrolizumab with lanreotide depot (the 
formulation available in the US) in patients with unresectable, recurrent, or metastatic GEP-NETs, who 
have had progression in the prior 12 months in order to establish that full dose of each agent is tolerable 
in combination and to explore the clinical activity of this combination on outcome measures including 
response rate, disease free survival/progression free survival, and overall survival, and we will also 
study the side effect profile of pembrolizumab in this setting.  Furthermore, in order to understand the 
effect of pembrolizumab and lanreotide depot on immune parameters, we will explore the effect of this 
combination on circulating immune cells and determine correlations of clinical parameters with PD-L1 
expression in tumor. 
The response rate to lanreotide depot was not reported in the final publication of the CLARINET trial 
but in a prior study of lanreotide (9) one of 25 patients experienced a partial response to single agent 
and two of 28 patients experienced a response to interferon plus lanreotide depot. In a more recent 
study, the response rate was 4% (11). Therefore, the response rate to lanreotide depot is likely to be 
10% or less. Further, this study may enroll patients who have previously progressed on somatostatin 
analogues so it is unlikely that lanreotide depot alone will lead to clinical responses in these patients. 
The response rate to pembrolizumab for neuroendocrine tumors is not reported as there have been few 
patients with neuroendocrine tumors treated with pembrolizumab. Thus far, the malignancies for which 
anti-PD-1 therapy is indicated or will likely become indicated have demonstrated greater than 10% 
response rates and in general, response rate of 20% or greater. With the projected number of 
participants (n=26), the difference between 10% and 25% in the proportion of patients responding can 
be detected with adequate power. 
Because the immune profile (including regulatory T cells, myeloid derived suppressor cells, T cell 
subsets, dendritic cells) in the peripheral blood of neuroendocrine tumor patients in general and the 
immune response to anti-PD-1 therapy in these patients in particular have not been well described, we 
will analyze these cell populations in the peripheral blood of patients on the clinical trial (12). Further, 
because the validity of PD-L1 as a biomarker of response to anti-PD-1 antibody therapy is still under 
evaluation and has been observed to be associated with outcome in some tumors but not others (13), 
we propose to correlate clinical responses (tumor regression) with PD-L1 expression within pre-
treatment tumor specimens. 
2.0 
OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this trial is: 
1. To evaluate the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 to pembrolizumab in combination with lanreotide depot in subjects with 
progressive, advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-
NETs). 
2.2 
Secondary Objectives 
The secondary objectives of this trial are: 


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1. To assess the safety of pembrolizumab in combination with lanreotide depot in subjects with 
GEP-NETs. 
2. To assess progression free survival (PFS) of pembrolizumab in combination with lanreotide 
depot in subjects with GEP-NETs. 
3. To assess the overall survival (OS) of pembrolizumab in combination with lanreotide depot in 
subjects with GEP-NETs.  
4. To evaluate the ORR by Immune-Related Response Criteria (irRC) to pembrolizumab in 
combination with lanreotide depot in subjects with progressive, advanced or metastatic GEP-
NETs. 
2.3 
Exploratory Objectives 
The exploratory objectives of this trial are: 
1. To characterize changes in circulating immune cells in subjects with GEP-NETs treated with 
pembrolizumab in combination with lanreotide depot.  
2. To determine whether safety and efficacy parameters (ORR, PFS, OS) correlate with PD-L1 
expression within the tumor in pre-treatment specimens. 
3. To explore the correlation between blood-based biomarkers and clinical outcomes. 
3.0 
STUDY DESIGN 
3.1 
Study Description 
This open-label, non-randomized, phase II trial is designed to assess the safety and efficacy of 
pembrolizumab in combination with lanreotide depot in patients with progressive, advanced or 
metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who have progressed on front 
line somatostatin analogue (SSA) therapy.   
The study will be conducted in two stages: 1) Safety Run-In Cohort and 2) Expanded Cohort. 
1. Safety Run-In Cohort: The first stage is a safety run-in cohort of patients treated with pembrolizumab 
200 mg intravenous (IV) every 3 weeks and lanreotide depot 90mg subcutaneous (SQ) every 3 
weeks (+/-7 day treatment window).  Up to 6 patients at the Duke Cancer Institute will be accrued 
at the starting dose level.  If one or less subject meets treatment-related discontinuation criteria 
(refer to Section 5.7) during Cycle 1, then the study will proceed to the second stage, Expanded 
Cohort.  If more than one subject meets treatment-related discontinuation criteria (refer to Section 
5.7) during Cycle 1, then the study will be redesigned to include alternative dose levels. 
 
2. Expanded Cohort:  The second stage is an expanded cohort of up to 20 patients enrolled at the 
Duke Cancer Institute and select Duke Cancer Network sites.  Patients will be treated with 
pembrolizumab 200mg IV every 3 weeks and lanreotide depot 90mg SQ every 3 weeks as 
determined by the Safety Run-In Cohort. 






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3. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
4. Known history of active TB (Bacillus Tuberculosis). 
5. Hypersensitivity to pembrolizumab or lanreotide or any of their excipients. 
6. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study drug or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously 
administered agent. 
7. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to 
the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. Patients with ≤ Grade 2 neuropathy are an exception 
to this criterion and may qualify for the study. 
8. Prior major surgery within 2 weeks prior to the first dose of study drug or who has not recovered 
adequately from the toxicity and/or complications from the intervention.     
9. Known additional malignancy that is progressing or requires active treatment.  Exceptions include 
basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 
10. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to the first dose of study drug.  
This exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability.   
11. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
12. Known history of, or any evidence of active, non-infectious pneumonitis. 
13. Active infection requiring systemic therapy. 
14. History or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is 
not in the best interest of the subject to participate, in the opinion of the treating physician.   
15. Known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
16. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration 
of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of 
study drug. 
17. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 


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18. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
20. Live vaccine within 30 days of planned start of study drug regimen. Seasonal influenza vaccines for 
injection are generally inactivated flu vaccines and are allowed; however intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
21. History of intolerance to somatostatin analogues. 
4.3 
Inclusion of Women and Minorities 
Men and women of all races and ethnic groups are eligible for this trial.  
5.0 
STUDY ASSESSMENTS 
Note:  After Cycle 1, if the subject is unable to have a study assessment or treatment taken within the 
defined time window due to an event outside of his or her control (e.g., clinic closure, personal 
emergency, inclement weather, vacation), the assessment should be performed as close as possible 
to the required schedule. 
Refer to Appendix D for Study Calendar.    
5.1 
Screening Period 
During the Screening Period, subjects are consented and screened for the study. Informed consent 
must be obtained before initiation of any screening procedure that is performed solely for the purpose 
of determining eligibility for this study.  Evaluations performed as part of routine care before informed 
consent can be considered as screening evaluations if done within the defined screening period, and if 
permitted by the local Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) policies. 
Study eligibility is based on meeting all of the inclusion criteria and none of the exclusion criteria (refer 
to Section 4.0) before the first dose of study drug on Cycle 1 Day 1.   
The following study procedures must be done within 28 days prior to Cycle 1 Day 1:   
 
Demographics 
 
Medical and cancer history 
 
Physical examination 
 
Height 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Thyroid function tests 
 
Adverse event assessment (review of baseline symptoms) 
 
Tumor assessment (CT and/or MRI scans)  
 
Chromogranin A (blood tumor marker) 
 
Tumor tissue (archived tumor if available. If archived tissue is not available, a fresh tissue 
biopsy will be attempted provided that the subject has tumor amenable to safe biopsy. If 
archived tissue is not available, and subject does not have tumor amenable to safe biopsy, 
they are still eligible to participate). 


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 
Circulating immune cells  
 
Protein multiplex arrays 
 
The following study procedures must be done within 7 days prior to Cycle 1 Day 1: 
 
 
CBC with differential 
 
Chemistries including liver function tests (LFTs) 
 
Urinalysis 
 
Serum pregnancy test for women of childbearing potential 
Subject eligibility is determined using lab results obtained up to 7 days prior to Cycle 1 Day 1.  Any 
laboratory assessments repeated on Cycle 1 Day 1 must meet eligibility requirements.  The Screening 
Period ends upon receipt of the first dose of study drug or final determination that the subject is ineligible 
for the study. 
5.2 
Treatment Period 
During the Treatment Period, subjects will receive pembrolizumab on Day 1 and lanreotide depot on 
Day 1 of each 21-day cycle until either: 1) disease progression; 2) the occurrence of unacceptable 
treatment-related toxicity; 3) completion of 2 years of study treatment (or 35 administrations of 
pembrolizumab); or 4) other reason(s) for subject discontinuation as described in Section 5.7.  Toxicity-
related dose modifications of pembrolizumab and lanreotide may occur during the Treatment Period.  
Dose modification guidelines are described in Section 7.1.  
In each cycle after Cycle 1, subjects will have study procedures on Day 1, +/-7 days and may have 
laboratory assessments obtained up to 3 days prior to the treatment visit.  If clinically indicated, 
additional visits and/or safety assessments may be warranted. 
The following study procedures must be completed on Day 1 of each cycle (±7 days):    
 
Physical examination 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Adverse event assessment  
 
CBC with differential 
 
Chemistries including LFTs 
 
Urinalysis 
 
Pembrolizumab and Lanreotide administration 
The following study procedures must be completed every 12 (± 1) weeks:   
 
Thyroid function tests  
 
Serum pregnancy test for women of childbearing potential 
 
Tumor assessment (CT and/or MRI scans)  
 
Chromogranin A (blood tumor marker) 
 
Circulating immune cells - first restaging only  
 
Protein multiplex arrays 


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Restaging scans will be performed every 4 cycles (ie. every 12 weeks) and disease reponse will be 
assessed using guidelines described in Section 5.6.  
The Treatment Period ends when a subject receives his or her last dose of study treatment; the subject 
then enters the Follow-up Period. 
5.3 
Follow-up Period 
Subjects should return 30 (±7) days after their last dose of study drug for an off-treatment visit to 
complete the following study procedures: 
 
Physical examination 
 
Vital signs and weight 
 
Concomitant medications 
 
ECOG performance status 
 
Adverse event assessment  
 
CBC with differential 
 
Chemistries including LFTs 
 
Urinalysis 
 
Thyroid function tests (if clinically indicated) 
 
Serum pregnancy test for women of childbearing potential 
 
Circulating immune cells  
 
Protein multiplex arrays 
Additional follow-up may occur for subjects with adverse events (AEs) related to study drug that are 
ongoing at the time of this off-treatment visit unless AE is deemed unresolveable or subject has started 
a new anti-cancer treatment regimen. 
For subjects that are discontinued from study treatment for reasons other than disease progression, 
subjects will have disease status (chromogranin A and restaging scans per standard of care schedule) 
followed until disease progression or start of new anti-cancer treatment regimen.  Disease status may 
be collected by personal interviews or review of medical records. 
Subjects will be followed for survival for up to 48 weeks after the last subject has finished study drug 
regimen or until the study is closed (whichever comes first).  Survival status may be collected by 
personal interviews or review of medical or public records. 
5.4 
Laboratory Assessments 
Local laboratories will perform all clinical laboratory tests using standard procedures, and results will be 
provided to the Investigator. Abnormalities in clinical laboratory tests that lead to a change in subject 
management (e.g., dose modification, requirement for additional medication, treatment or monitoring) 
are considered clinically significant for the purposes of this study, and will be recorded on the case 
report form (CRF).  If laboratory values constitute part of an event that meets criteria defining it as 
serious, the event (and associated laboratory values) must be reported as a serious adverse event 
(SAE). 
Refer to Appendix E for details of laboratory tests for this study.  In addition, chromogranin A, a blood 
tumor marker, will be obtained at baseline and at every restaging. 


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5.5 
Adverse Event Assessment 
AE definition is described in Section 10.1.  AEs will be documented throughout the study.  AE 
seriousness, grade, and relationship to study drug will be assessed by the Investigator using NCI 
CTCAE version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-
14 QuickReference 5x7.pdf).   
SAE definitions and reporting requirements are described in Section 10.2. 
Select non-serious and serious adverse events also known as Events of Clinical Interest (ECI) must 
be recorded and reported as described in Section 10.3.   
5.6 
Tumor Assessments 
Tumor response will be assessed using RECIST version 1.1 and irRC.  Radiographic imaging will be 
performed with CT scan of chest/abdoment/pelvis with and without contrast and/or MRI scan of 
abdomen/pelvis every 12 (±1) weeks or every 4 cycles after the start of study treatment.  The same 
method for tumor assessment should be employed at every assessment.  
5.6.1   RECIST version 1.1 
RECIST is a set of published rules that define when cancer patients improve ("respond"), stay the same 
("stabilize"), or worsen ("progression") during treatments. The original criteria were published in 
February 2000 by an international collaboration including the European Organization for Research and 
Treatment of Cancer (EORTC), National Cancer Institute (NCI) of the United States and the National 
Cancer Institute of Canada Clinical Trials Group. RECIST 1.1, published in January 2009, is an update 
to the original criteria and will be used for this study.   
Refer to Appendix A for definition of target lesions, methods of measurement and all other related 
criteria for RECIST version 1.1. The following summarizes the definitions of the criteria used to 
determine objective tumor response for target lesions:  
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.   
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression).  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
5.6.2  Immune-Related Response Criteria 
The responses that are seen with immunotherapeutic agents may extend beyond those of cytotoxic 
agents and could include responses after disease progression that is not captured by RECIST.  To 


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account for this, for this study, immune-related response criteria (irRC) will be used to allow for more 
comprehensive evaluation of clinical activity. Conventional response criteria may not adequately assess 
the activity of immunotherapeutic agents because PD (progressive disease) by initial radiographic 
evaluation does not necessarily reflect therapeutic failure, thus stopping the study treatment with initial 
perceived PD may be premature.  
Refer to Appendix B for definitions and guidelines of the irRC.  The overall response according to the 
irRC is derived from time-point response assessments (based on tumor burden) as follows:  
 
irCR:  complete disappearance of all lesions (whether measurable or not, and no new lesions) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented  
 
irPR:  decrease in tumor burden ≥50%relative to baseline confirmed by a consecutive assessment 
at least 4 weeks after first documentation  
 
irSD:  not meeting criteria for irCR or irPR, in absence of irPD  
 
irPD:  increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented     
5.7 
Subject Discontinuation 
Subjects will receive study treatment until treatment discontinuation for one of the reasons listed below. 
However, subjects may discontinue study treatment or withdraw their consent to participate in the study 
at any time without prejudice.  All reasons for discontinuation or withdrawal from trial will be recorded. 
Reasons for subject discontinuation by the Investigator may include, but are not limited to, the following:   
 
Death 
 
Confirmed radiographic disease progression (Note: With approval of the Lead PI, a subject may be 
granted an exception to continue on study treatment with confirmed radiographic progression if 
clinically stable or clinically improved.) 
 
Completed 2 years of study treatment or 35 administrations of pembrolizumab 
 
Significant noncompliance by subject or Investigator 
 
Investigator or Lead PI determination that it is no longer safe and/or no longer in the subject’s best 
interest to continue participation 
 
Withdrawal of consent 
 
Lost to follow-up 
 
Necessity for treatment with other anticancer treatment prohibited by protocol 
 
Sexually active subjects who refuse to use medically accepted methods of contraception during the 
course of the study and for 120 days following the last dose of study drug 
 
Women who become pregnant or are breast feeding 
 
Request by regulatory agencies for termination of treatment of an individual subject or all subjects 
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 
The following Treatment-Related Discontinuation Criteria attributed to pembrolizumab, 
lanreotide depot, or both: 
– 
Any Grade 2 uveitis, eye pain, or blurred vision that does not respond to topical therapy and 
does not improve to Grade 1 OR requires systemic treatment. 
– 
Any Grade 3 non-skin adverse event lasting > 7 days, with the following exceptions for 
treatment-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reactions, and infusion reactions: 
 
Grade 3 uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
 
Grade 3 laboratory abnormalities do not require treatment discontinuation except 
Grade 3 thrombocytopenia > 7 days OR associated with bleeding requires 
discontinuation 
– 
Any liver function test (LFT) abnormality that meets the following criteria: 
 
AST or ALT > 8 x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
– 
Any Grade 4 adverse event or laboratory abnormality, except for the following events: 
 
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis  
 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 3 days of their onset 
 
Grade 4 endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid 
hormones) or glucose controlling agents, respectively, retreatment can be 
considered 
– 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
Dosing interruptions to allow for prolonged steroid tapers to manage treatment-
related adverse events are allowed  
 
Dosing interruptions > 6 weeks that occur for non-treatment-related reasons may be 
allowed 
– Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued 
pembrolizumab or lanreotide depot dosing 
6.0 
STUDY DRUGS  
6.1 
Treatment Compliance and Study Drug Accountability 
The Investigator will maintain accurate records of receipt of all study drugs, including dates of receipt. 
In addition, accurate records will be kept regarding when and how much study drug is dispensed and 
used by each subject in the study. Reasons for deviation from the expected dispensing regimen must 
also be recorded. At completion of the study, to satisfy regulatory requirements regarding drug 


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accountability, all unused study drug will be reconciled and destroyed in accordance with applicable 
state and federal regulations. 
6.2 
Pembrolizumab 
Pembrolizumab will be provided for this study by Merck & Co., a sterile, non-pyrogenic lyophilized 
powder for intravenous infusion supplied in single-use Type I glass vial containing 50 mg of 
pembrolizumab. The product is preservative-free, white to off-white powder and free from visible foreign 
matter.  It is reconstituted with 2.3 mL sterile water for injection (WFI) to yield a 2.4 mL solution 
containing 25 mg/mL of pembrolizumab. The reconstituted vial contains an excess fill of 10 mg 
(equivalent to 0.4 mL of reconstituted solution) to ensure the recovery of label claim of 50 mg 
pembrolizumab per vial (equivalent to 2 mL of reconstituted solution). 
6.2.1   Storage and Handling 
Pembrolizumab Powder for Solution for Infusion vials should be stored at refrigerated conditions (2 – 8 
°C). Prior to reconstitution, the vial of lyophilized powder can be out of refrigeration (temperatures at or 
below 25°C (77°F) for up to 24 hours. Following reconstitution with sterile water for injection, 
Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal 
saline) or regional equivalent and the final concentration of pembrolizumab in the infusion solutions 
should be between 1 mg/mL and 10 mg/mL.  If normal saline is not available, 5% Dextrose Injection, 
USP or regional equivalent (5% dextrose) is permissible.  The preferred diluent is 0.9% Sodium Chloride 
and 5% dextrose is only permissible if normal saline is not available. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 hours. 
This includes room temperature storage of reconstituted drug product solution in vials, room 
temperature storage of admixture solutions in the IV bags and the duration of infusion.  In addition, 
reconstituted vials and/or IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for 
up to 20 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.   
Refer to Pembrolizumab Pharmacy Manual for additional drug product stability and handling guidelines. 
6.2.2 Administration 
Pembrolizumab 200 mg will be administered in an outpatient setting as a 30 minute IV infusion on Days 
1 of each cycle (+/-7 days for C2 and all subsequent cycles).  Every effort should be made to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of infusion 
pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
Refer to Pembrolizumab Pharmacy Manual specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
6.3 
Lanreotide Depot 
Lanreotide depot will be provided by Ipsen.  It is provided in a single-dose, prefilled syringe affixed with 
an automatic needle protection system. The prefilled syringes contain a white to pale yellow, semi-solid 
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6.3.1   Storage and Handling 
Lanreotide depot must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light 
in its original package. Thirty (30) minutes prior to injection, the sealed pouch of lanreotide depot must 
be removed from the refrigerator to allow it to come to room temperature. The pouch should remain 
sealed until injection. 
Each syringe is intended for single use and not be used beyond the expiration date on the packaging. 
6.3.2 Administration 
Lanreotide depot 90 mg will be administered in an outpatient setting as a deep subcutaneous injection 
(in the superior external quadrant of the buttock) on Day 1 of each cycle (+/- 7 days for C2 and all 
subsequent cycles).  The injection site should be alternated between the right and left sides from one 
injection to the next. 
6.4 
Concomitant Medications/Vaccinations 
Concomittant medications will be documented throughout the study.  Medications or vaccinations 
specifically prohibited in the exclusion criteria are not allowed during the ongoing trial.  If there is a 
clinical indication for one of these or other medications or vaccinations specifically prohibited during the 
trial, discontinuation from trial therapy or vaccination may be required.  The Lead PI should discuss any 
questions regarding this with the Merck Clinical team.. The final decision on any supportive therapy 
or vaccination rests with the Lead PI and/or the subject's primary physician (ie. Investigator).  
6.4.1 Acceptable Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the Investigator in keeping with the local standards of medical care.  All concomitant 
medication received from the date of signed informed consent through 30 days after the last dose of 
study drug will be documentedincluding all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications.   
Subjects must agree to use two birth control methods after informed consent is signed through 120 
days after the last dose of study drug.  The two methods can either be two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Medically acceptable contraceptives include: 
(1) surgical sterilization (such as a tubal ligation, hysterectomy, or vasectomy), (2) approved hormonal 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as 
a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable 
methods for routine use. 
6.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Period of this study: 
 
Antineoplastic systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 


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 
Chemotherapy not specified in this protocol 
 
Investigational agents other than pembrolizumab or lanreotide depot 
 
Radiation therapy (Note: Radiation therapy to a symptomatic solitary lesion may be allowed with 
the approval of the Lead PI.)   
 
Live vaccines within 30 days prior to the first dose of study drug and while participating in the 
study.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Lead PI. 
Subjects who, in the assessment by the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the Investigator deems to be medically necessary. 
The Exclusion Criteria may describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Follow-up Period. 
7.0 
DOSE MODIFICATION AND TOXICITY MANAGEMENT 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last dose 
of study drug.  Subjects will be instructed to notify their treating physician of any and all AEs. Toxicity 
will be graded according to NCI CTCAE version 4.0.   
All AEs should also be managed with supportive care at the earliest signs of toxicity considered related 
to study drug(s). 
7.1 
Dose Modifications  
Subjects experiencing one or more AEs due to the study drug(s) may require dose modification(s) as 
described in Section 7.1.1 and Section 7.1.2.  At the discretion of the Investigator, dose modifications 
are permitted outside of the those provided in the protocol if the Investigator feels it is in the interest of 
the subject’s safety (e.g., due to multiple toxicities, persistent toxicities, intercurrent illness, or short term 
compliance or monitoring issues, etc.). 
Subjects may need to be followed at least weekly when any study drug is held for toxicity until the 
toxicity returns to Grade ≤ 1 or is determined to be chronic or irreversible.   
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 4 weeks of the scheduled 
interruption, unless otherwise discussed with the Lead PI. The reason for interruption should be 
documented in the patient's study record. 
If pembrolizumab is permanently discontinued, the subject will be discontinued from study treatment. 
All dose modifications and reasons for modification must be recorded in the CRF. 








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7.2.1  Pneumonitis 
 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional anti-
inflammatory measures, as needed. 
 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
7.2.2  Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).   
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.   
 
For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose oral 
steroids.   
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
7.2.3  Diabetes Mellitus 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or Grade 3-4 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
Insulin replacement therapy is recommended.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
7.2.4  Hypophysitis 
 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 


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7.2.5  Hyperthyroidism or Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, 
is indicated per standard of care. 
 
Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
7.2.6  Hepatic 
 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline values 
(consider weekly). 
 
Treat with IV or oral corticosteroids 
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks. 
7.2.7  Renal Failure or Nephritis 
 
For Grade 2 events, treat with corticosteroids. 
 
For Grade 3-4 events, treat with systemic corticosteroids. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.  
7.2.8  Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Appropriate resuscitation equipment should be 
available in the room and a physician readily available during the period of drug administration. 
Table 7.2.8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 






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Refer to Study Manual for collection, processing, and submission details. 
8.3 
Protein Multiplex Arrays 
Peripheral blood will be collected from each subject at baseline, at each restaging, at the time of disease 
progression (or treatment discontinuation) and at 30-day off treatment visit for plasma biomarkers.  
Plasma will be stored by the Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew 
Nixon.   
 
Refer to Study Manual for collection, processing, and submission details. 
8.4 
Future Use of Patient Samples 
Any remaining biological materials at the end of the study will be deidentified and retained for possible 
use in biomarker research. 
9.0 
STATISTICAL ANALYSIS 
9.1 
General Analysis Considerations 
Percentage of PD-L1 + cells by IHC, the percentages of the lymphoid and myeloid cells in peripheral 
blood, and levels of the cytokines/angiogenesis/inflammatory serum and plasma markers  will be listed 
and summarized using the descriptive statistics (minimum, maximum, mean median, std).  The PD-L1 
expression and peripheral blood lymphoid and myeloid cell percentages will be correlated with the 
response by comparing the means of different groups using either 2-sample t-tests or non-parametric 
Wilcoxon rank-sum test, or the Chi-square test based on the distribution and structure of the data (i.e., 
either parametric or non-parametric methods will be used depending on the measurement of the 
corresponding endpoints). 
A cohort of patients will be enrolled to assess the primary endpoint of objective response rate (ORR) in 
this patient population. A safety run-in will be conducted in the first 6 patients enrolled. A starting dose 
level (full, standard doses of each drug) is planned for this study. If one or fewer subjects meet 
discontinuation criteria, this dose level will be determined to be safe and the trial will continue. If 
discontinuation criteria are met in  2/6 patients at the starting dose level, then the study will be 
redesigned. This study is expected to accrue a minimum of 6 evaluable subjects in the safety run-in 
portion of the study.  
9.1.1  Primary Endpoint 
Objective Response Rate (ORR). CT or MRI scans and blood tumor markers will be repeated every two 
cycles.  Tumor response defined as complete response (CR) or partial response (PR) will be assessed 
using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).   
ORR will be estimated by the 90% Exact Lower Confidence Bound (LCB) for the binomial proportion. 
An ORR of less than 10% will be considered not to be of clinical value, If the 90% LCB is >= 0.1, the 
regimen will be considered efficacious. With 26 patients studied the LCB will be approximately 0.1 if 5 
responses are observed. 
If a sufficient number of responses are observed, duration of response (DOR) will be summarized for 
subjects who achieve confirmed PR or CR using the Kaplan-Meier product-limit method. The median 
DOR (and two-sided 95% CI) will also be calculated. In addition, the percentage of responders still in 
response at different time points (3, 6 and 12 months) will be presented based on the KM plot. 


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The magnitude of reduction in tumor burden will be summarized descriptively (such as a waterfall plot) 
based on change in the sum of the longest diameters of target lesions relative to baseline. 
9.1.2  Secondary Endpoints 
PFS: defined as time from start of the treatment until documented disease progression or death from 
any cause (those for whom event of progression or death not observed will be censored at the time of 
the last response assessment). 
OS: defined as time from start of the treatment till the patient’s death from any cause (patient who are 
still alive at the end of the study will be censored). 
If sufficient events are observed, PFS and OS will be estimated by the Kaplan-Meier method. 
Safety and Tolerability Monitoring: The safety and tolerability of Lanreotide Depot plus pembrolizumab 
will be primarily assessed by the rate of treatment-related AEs leading to drug discontinuations during 
the first 12 weeks of treatment. The regimen will be considered safe if <33% of patients treated require 
dosing discontinuation for study drug related toxicity in the first 12 weeks (e.g., 0 of 3, ≤1 of 6, < 2 of 9, 
≤3 of 12 or ≤5 of 18 patients). This will be assessed continuously throughout the study. A patient will be 
considered evaluable for safety if treated with at least one dose of study regimen. In addition, safety 
and tolerability will be analyzed by the incidence of adverse events, serious adverse events, and specific 
laboratory abnormalities (worst grade). Toxicities will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Descriptive statistics (counts, percentages) will be used to summarize safety parameters (adverse 
events, serious adverse events, adverse events leading to discontinuation, deaths) for all treated 
subjects.  Safety summaries will be presented by the severity of the adverse event and by relationship 
to study drug. 
9.1.3  Exploratory Endpoints 
Descriptive statistics (minimum, maximum, mean median, std) will be provided for percentage of PD-
L1 + cells by IHC, the percentages of the lymphoid and myeloid cells in peripheral blood, and levels of 
the cytokines/angiogenesis/inflammatory serum and plasma markers.   
For analysis of the immune monitoring data from the 2 polychromatic flow cytometry panels, we will 
perform initial analysis using statistical graphics (e.g. box-plots) of the cell subset relative frequencies 
and trends over time. To assess the impact of cell subsets of interest (listed in Section 8.0 at baseline 
and on-treatment on treatment outcome, we will perform a one-way ANOVA of cell subset relative 
frequency against the RECIST 1.1 response categories to identify variables whose unadjusted p-values 
are statistically significant. Given the exploratory aim of the research, no correction for the number of 
independent variables will be performed, and a ranked list of cell subsets with uncorrected p-values will 
be tabulated. This list will be used for hypothesis generation, and to select candidates for independent 
validation studies.  
The PD-L1 expression and peripheral blood lymphoid and myeloid cell percentages will be correlated 
with the response by comparing the means of different groups using either 2-sample t-tests or non-
parametric Wilcoxon rank-sum test, or the Chi-square test based on the distribution and structure of the 
data (i.e., either parametric or non-parametric methods will be used as appropriate). 
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10.0 SAFETY 
Refer to Study Manual for required reporting forms. 
 
10.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether or 
not considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the supporting company product(s), is also an AE. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered AEs.  Examples of this may include, but are not 
limited to, teething, typical crying in infants and children and onset of menses or menopause occurring 
at a physiologically appropriate time. 
Supporting company product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by the 
supporting company for human use. 
AEs may occur during the course of the use of supporting company product(s) in clinical trials or within 
the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
Progression of the cancer under study is not considered an AE unless it is considered to be drug related 
by the Investigator. 
AEs will be documented from the date of first dose of study drug through 30 days after the last dose of 
study drug.  All Grade 2-5 AEs as well as special reporting circumstances, such as exposure via a 
parent during pregnancy or breast-feeding, overdose, medication error, misuse, abuse, off-label use or 
occupational exposure must be recorded on the CRF. 
10.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is immediately life-threatening (ie, in the opinion of the Investigator, the AE places the subject at 
immediate risk of death; it does not include a reaction that, had it occurred in a more severe form, 
might have caused death). 
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
4. Results in persistent or significant disability or incapacity. (Note: The term “disability” refers to 
events that result in a substantial disruption of a subject’s ability to conduct normal life function.) 
5. Is a congenital anomaly or birth defect. 


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6. Is an important medical event (Note: The term “important medical event” refers to an event that, 
based upon appropriate medical judgment, may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the subject or require intervention to prevent one of 
the other serious outcomes listed under the definition of SAE. Examples of important medical 
events include intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization; or development of product 
dependency or product abuse.) 
SAEs and/or follow up to SAEs including death due to any cause other than progression of the cancer 
under study, that occurs from the date of the first dose of study drug through 30 days following the last 
dose of study drug, whether or not related to study drug(s), must be recorded on the CRF and must be 
reported within 2 working days to supporting companies. External sites should report SAEs to the Duke 
study team within 24 hours. Reporting instructions for external sites can be found in the REDCap study 
eManual.  
All SAEs must be followed until resolution, return to baseline condition, or stabilization.  Any SAEs that 
are ongoing at the time the clinical database is closed will be reported to supporting companies as 
unresolved. 
The initial report for each SAE or death should include at minimum the following information: 
 
protocol number and title 
 
patient initials, study identification number, sex, age 
 
date the event occurred 
 
description of the event 
 
seriousness criteria 
 
event causality or causal relationship 
 
study drug name(s) 
 
dose level and cycle number at the time the event occurred 
 
description of the patient’s condition 
 
study status of patient at time of report 
 
responsible investigator name and contact details 
The Investigator should report a diagnosis or a syndrome rather than individual signs or symptoms. The 
Investigator should also try to separate a primary AE considered as the foremost untoward medical 
occurrence from secondary AEs which occurred as complications. Whenever possible, the Investigator 
should also provide the batch or lot number of the study drug(s). 
SAE Reporting Procedure: 
Immediately upon awareness of a SAE, the Investigator (or designee) completes the DCI SAE Report 
Form and will submit the form within 2 business days of knowledge of the event to the funding 
companies. External sites should submit the form within 24 hours to the Duke study team via the 
REDCap SAE reporting tool. In accordance with applicable regulations, Investigators must report SAEs 
to their local IRB according to their institutional guidelines. 
 
Note:  It is imperative that initial SAE reports are submitted as soon as possible (within 2 business days 
of knowledge of the event) with available information to the supporting companies.  Missing and/or 
clarified event information may be provided in a follow-up report.   


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Follow-up information including severity, action taken, concomitant medications, and outcome should 
be communicated to the supporting company as soon as possible using the same form mentioned 
above. 
 
 
The Lead PI will review the report form with accompanying source document, sign page 5 of the form 
and promptly submit it to the funding companies.   
If the event meets the Duke University Health System (DUHS) IRB reporting requirements, the study 
team regulatory coordinator will submit information about the SAE including the Lead PI’s assessment 
as a safety event to the DUHS IRB within 5 business days. Any study-related death must be reported 
to the IRB within 24 hours of discovery.   
Within two business days of receipt, the study team will submit the SAE report form and other relevant 
safety information to the following supporting companies: 
Merck Global Safety 
ATTN: Worldwide Product Safety 
 
 
Ipsen Safety 
ATTN: Ipsen Call Center 
 
Expedited Reporting Procedure for Duke Cancer Institute (Coordinating Center): 
Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs to the 
FDA in accordance with 21CFR 312.32.  Any SAE that is possibly related and unexpected must be 
submitted to the FDA attached to the IND.  If the SAE meets criteria for reporting to the FDA, the study 
team will complete the Form FDA 3500A (MedWatch) and send to the Lead PI and the supporting 
companies that are noted above.  This submission of the Form FDA 3500A to the FDA attached to the 
IND will be completed by the Duke GI Oncology Clinical Trials Regulatory Coordinator. 
 
All unexpected, drug related SAEs that are fatal or life-threatening will be reported to the FDA by 
phone or fax within 7 calendar days of initial receipt of the information and will provide a complete 
report within 8 days of the initial report submission (by calendar day 15).  
 
All unexpected, treatment-related SAEs that are not fatal or life-threatening will be reported in a 
written report to the FDA within 15 days of initial receipt of the information. 
The Duke study team will forward all expedited reports to all participating investigators in the form of 
an Investigator Alert. The Investigator Alert template is available on the DCI intranet titled “Safey 
Reporting for Multi-site IITs Notification Email”. 
10.3 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI). 
For the time period beginning with date of first dose of study drug through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, that occurs to any subject must be reported within 


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2 working days to Merck Global Safety if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Events of clinical interest for this trial include: 
1. A overdose of pembrolizumab, as defined below in Section 10.3.1, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal, and at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
*NOTE:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  
10.3.1 Medication Overdose and Error 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment of overdose 
of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of study drug(s), the adverse 
event(s) is reported as a SAE, even if no other seriousness criteria are met. Refer to SAE reporting 
procedures in Section 10.2. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious ECI, using 
the terminology “accidental or intentional overdose without adverse effect.” Refer to ECI reporting 
procedures. 
ECI Reporting Procedure: 
Immediately upon awareness of an ECI, the Investigator (or designee) completes the DCI SAE Report 
Form and will submit the form within 2 business days of knowledge of the event to the funding 
companies. External sites should submit the form within 24 hours to the Duke study team via the 
REDCap SAE reporting tool.  
 
 
Note:  It is imperative that initial ECI reports are submitted as soon as possible (within 2 business days 
of knowledge of the event) with available information to the funding companies.  Missing and/or clarified 
event information may be provided in a follow-up report.   


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Follow-up information including severity, action taken, concomitant medications, and outcome should 
be communicated to the funding companies as soon as possible using the same forms mentioned 
above. 
The Lead PI will review the report form with accompanying source document, sign page 5and the PI or 
designee will then promptly submit it to the funding companies.   
Within two business days of receipt, the study team will submit the SAE report form and other relevant 
safety information to the following supporting companies: 
Merck Global Safety 
ATTN: Worldwide Product Safety 
 
 
Ipsen Safety 
ATTN: Ipsen Call Center 
 
10.4 Other Safety Considerations 
The Investigator must also report in the same timelines as SAEs any incidence of medication error, 
occupational exposure, abuse or misuse that is associated with or result in an adverse event.  All 
related fatal outcomes must also be reported in the same timeline as a SAE.   
Refer to SAE reporting procedures in Section 10.2. 
10.4.1 Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the Investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 120 
days following cessation of funding companies’ product, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the Investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
Such events must be reported according to SAE reporting procedures (refer to Section 10.2).   


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11.0 ADMINISTRATIVE RESPONSIBILITIES 
11.1 Institutional Review Board/Independent Ethics Committee  
Before study initiation, the Investigator must have written and dated approval/favorable opinion from the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the protocol, consent form, 
subject recruitment materials/process (e.g., advertisements), and any other written information to be 
provided to subjects.  
The Investigator should provide the IRB/IEC with reports, updates, and other information (e.g., Safety 
Updates, Amendment IRB/IECs, and Administrative Letters) according to regulatory requirements and 
institution procedures. 
Copies of all IRB/IEC approvals, as well as annual re-approvals and approved/stamped informed 
consent forms must be submitted to Duke GI Oncology Clinical Trials Office. 
11.2 Protocol and Protocol Revisions 
All revisions to the protocol will be provided to the supporting companies by the Lead PI or designee(s) 
at the Duke GI Oncology Clinical Trials Office.  The Lead PI must have written and dated 
approval/favorable opinion from the Duke University Health System (DUHS) IRB of revised protocol 
prior to distribution to Investigators at external participating sites.   
Investigators must obtain written and dated and approval/favorable opinion from the IRB/IEC before 
conducting any updated protocol version.  Study must be conducted as described in the approved 
protocol.  The Investigator must not implement changes of the approved protocol without prior written 
agreement by the Lead PI and prior review and documented approval/favorable agreement by the 
IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the changes involve only logistical or administrative aspects of the study (e.g., 
changes in research personnel or change in phone numbers). 
Documentation of approval(s) from the IRB/IEC must be sent to Duke GI Oncology Clinical Trials Office.  
11.3  Protocol Deviations and Violations  
A protocol deviation is non-adherence to protocol specific study procedures or schedules that does not 
involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or Good Clinical Practice 
(GCP) guidelines.  
A protocol violation is any significant divergence from the protocol such as non-adherence on the part 
of the subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary 
objective evaluation criteria, and/or GCP guidelines.  
As a matter of policy, the Lead PI (ie. sponsor) will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study.  If it is found that a subject who did not meet protocol eligibility criteria 
was entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke GI Oncology 
Clinical Trials Office must be informed immediately.  Such subjects will be discontinued from the study, 
except in an exceptional instance following review and written approval by the Lead PI and the 
responsible IRB/IEC. 


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Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s) 
at the Duke GI Oncology Clinical Trials Office.   
In accordance with applicable regulations, Investigators must report protocol deviations and violations 
to their local IRB/IEC according to their institutional guidelines.  
11.4 Informed Consent 
The Investigator must ensure that subjects or their legally acceptable representatives are clearly and 
fully informed about the purpose, potential risks and other critical issues regarding clinical trials in which 
they volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator 
and must include all elements required by CFR 21 Part 50.25 and their IRB.  A copy of the proposed 
informed consent document must be submitted to the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office for review and comment prior to submission to the local IRB/IEC. 
Informed consent must be obtained prior to performing any study-related procedures that are not part 
of normal subject care, including screening and changes in medications. A copy of the signed informed 
consent form must be given to the study subject.  
11.5 Source and Study Documentation 
Source documents include all original recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical study.  
Accordingly, source documents include, but are not limited to, laboratory reports (including normal and 
abnormal results), radiology reports, subject diaries, biopsy reports, ultrasound photographs, subject 
progress notes, hospital charts or pharmacy records and any other similar reports or records of any 
procedure performed in accordance with the protocol. 
Whenever possible, the original recording of an observation should be retained as the source document; 
however, a photocopy is acceptable provided that it is a clear, legible, and exact duplication of the 
original certified document.   
When clinical observations are entered directly into an electronic medical record system (i.e. in lieu of 
original hardcopy records), the electronic record can serve as the source document if the system has 
must be validated to meet the FDA requirements for electronic records and signatures (i.e. meets 21 
CFR Part 11 compliant).   
Regulations require that Investigators maintain information in the study subject’s medical records which 
corroborate data recorded on the CRF.  In order to comply with these regulatory requirements, the 
following information will be maintained and made available as required by the Lead PI or designee(s), 
monitors, and/or regulatory inspectors: 
 
Medical history/physical condition of the study subject prior to involvement in the study sufficient 
to verify protocol entry criteria. 
 
Dated note that informed consent was obtained for the subject’s participation in the study. 
 
Dated and signed notes for each subject visit including results of examinations. 
 
Notations on abnormal lab results and their resolution. 
 
Dated reports of special assessments (e.g., ECG reports). 
 
Dated and signed notes regarding adverse events (includng event description, severity, onset 
date, duration, relation to study treatment, outcome and treatment for adverse event). 


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 
Dated notes regarding concomitant medications taken during the study (including start and stop 
dates). 
 
Subject condition upon completion of or withdrawal from the study. 
Study documentation includes all CRFs, data correction forms, source documents, monitoring logs and 
appointment schedules, sponsor-investigator correspondence and regulatory documents (e.g., protocol 
and amendments, IRB/IEC correspondence and approvals, approved and signed subject consent 
forms, Statement of Investigator form, and clinical study supplies receipts and distribution records). 
The Investigator will prepare and maintain complete and accurate study documentation in compliance 
with GCP guidelines and applicable federal, state, and local laws, rules and regulations; and, for each 
subject participating in the study, promptly complete all CRFs and such other reports as required by this 
protocol following completion or termination of the clinical study or as otherwise required pursuant to 
any agreement with the Lead PI and Duke Cancer Institute (DCI). 
The Investigator acknowledges that, within legal and regulatory restrictions and institutional and ethical 
considerations, study documentation will be promptly and fully disclosed to Lead PI or designee(s) by 
the Investigator upon request and also shall be made available at the Investigator’s site upon request 
for inspection, copying, review and audit at reasonable times by representatives of the Lead PI and DCI 
or responsible government agencies as required by law.  
The Investigator agrees to promptly take any reasonable steps that are requested by the Lead PI or 
designee(s) as a result of an audit to cure deficiencies in the study documentation and case report 
forms. 
11.6 Case Report Forms 
Subject data will be entered (ie. CRFs completed) into an electronic data capture (EDC) system called 
Medidata RAVE.  This database is maintained on a secure Duke University server and is accessible 
via internet with login and password.     
CRFs should be completed by trained study personnel according to guidelines provided by the Lead 
PI or designee(s) at the Duke GI Oncology Clinical Trials Office.  The Investigator or qualified 
designee is responsible for recording and verifying the accuracy of subject data.  The Investigator 
acknowledges that his/her electronic signature is the legally binding equivalent of a written signature. 
By entering his/her electronic signature, the Investigator confirms that all recorded data have been 
verified as accurate.   
In the event of discrepant data, the study monitor or study designee will request data clarification from 
the Investigator or designee for which may be resolved electronically in the EDC system. 
Accurate and reliable data collection will be ensured through verification and crosscheck of the CRFs 
against the Investigator’s study records (source document verification) by the study monitor or study 
designee. 
11.7 Monitoring and Audits/Inspections 
The study will be monitored both internally by the Lead PI and externally by the Duke Cancer Institute 
(DCI) Monitoring Team in accordance with their NCI-approved “Institutional Protocol Monitoring 
Procedures and Guidelines for NIH-sponsored Research Involving Human Subjects”.  


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In terms of internal review, the Lead PI and/or designee(s) will continuously monitor and tabulate 
adverse events.  Appropriate reporting to the DUHS IRB will be made. If an unexpected frequency of 
Grade 3 or 4 adverse events occurs, depending on their nature, action appropriate to the nature and 
frequency of these adverse events will be taken. This may require a protocol amendment, dose de-
escalation, or potentially closure of the study. The Lead PI of this study will also continuously monitor 
the conduct, data, and safety of this study to ensure that: 
 
Interim analyses occur as scheduled (if applicable); 
 
Stopping rules for toxicity and/or response are met; 
 
Risk/benefit ratio is not altered to the detriment of the subjects; 
 
Appropriate internal monitoring of adverse events and outcomes is done; 
 
Over-accrual does not occur; 
 
Under-accrual is addressed with appropriate amendments or actions; 
 
Data are being appropriately recorded on the CRF in a reasonably timely manner. 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety 
and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, GCP, and applicable regulatory requirements.  As specified in the DCI 
Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the 
third subject is enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to 
enrollment and subjects are no longer receiving study interventions that are more than minimal risk.   
An external site monitoring plan addendum describes monitoring at participating sites. 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and 
DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the 
sponsor, the Principal Investigator, or the IRB.  All study documents must be made available upon 
request to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited 
to the National Institute of Health, National Cancer Institute, and the FDA.  Every reasonable effort will 
be made to maintain confidentiality during study monitoring. 
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. 
DCI Quality Assurance personnel, or designee, may conduct audits at sites.  Audits will include, but not 
be limited to: audit trail of data handling and processes, SOPs, drug supply, presence of required 
documents, the informed consent process, and comparison of case report forms/database with source 
documents.  The Investigator agrees to accommodate and participate in audits conducted at a 
reasonable time in a reasonable manner, as needed. 
Regulatory authorities may also audit an Investigator during or after the study.  The Investigator should 
contact the Lead PI and designee(s) at the Duke GI Oncology Clinical Trials Office as well as their local 
IRB, immediately if this occurs, and must fully cooperate with governmental (e.g., FDA) audits 
conducted at a reasonable time in a reasonable manner. 
The Duke University Compliance Program - Human Subject Research Compliance (HSRC) section may 
conduct confidential audits to evaluate compliance with the protocol and the principles of GCP.  The 


PLANET Protocol Version 5.0  
   
                     PI: Morse    
 
 
 
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CONFIDENTIAL                                                                       Page 56 of 68                                  
 
Lead PI agrees to allow the HSRC auditor(s) direct access to all relevant documents and to allocate 
his/her time and the time of the study team at the Duke GI Oncology Clinical Trials Office to the CTQA 
auditor(s) in order to discuss findings and any relevant issues. 
11.8 Study Closeout 
Upon completion of the study (defined as all subjects have completed all follow-up visits, all CRFs are 
complete, and all queries have been resolved) the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office will notify the Investigator of closeout and a study closeout visit will be performed.   
The study monitor or study designee will ensure that the Investigator’s regulatory files are up to date 
and complete, and that any outstanding issues from previous visits have been resolved.  Other issues 
to be reviewed at the closeout visit include: retention of study files, possibility of site audits, publication 
policy, and study closure with local IRB. 
11.9 Records Retention 
The Investigator will maintain the records of study drug disposition, worksheets and all other study-
specific documentation (e.g., study files, source documentation) until notified by the Lead PI or 
designee(s) at the Duke GI Oncology Clinical Trials Office that records may be destroyed.  If the 
application is not filed or is withdrawn, the Investigator will maintain the records for at least two (2) 
years after the formal discontinuation of the clinical development program for this product(s).  
To avoid error, the Investigator will contact the Lead PI or designee(s) at the Duke GI Oncology 
Clinical Trials Office before the destruction of any records pertaining to the study to ensure they no 
longer need to be retained.  In addition, the Lead PI or designee(s) will be contacted if the Investigator 
plans to leave the institution so that arrangements can be made for the transfer of records. 


PLANET Protocol Version 5.0  
   
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Version Date_07Sept2021 
CONFIDENTIAL                                                                       Page 57 of 68                                  
 
12.0  REFERENCES 
1. Vinik AI. Advances in Diagnosis and Treatment of Pancreatic Neuroendocrine Tumors (PNETS). 
Endocr Pract. 2014 Oct 8:1-23. [Epub ahead of print] PubMed PMID: 25297671. 
2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, 
Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and prognostic factors 
for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 
20;26(18):3063-72. 
3. Strosberg JR. Systemic treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETS): 
current approaches and future options. Endocr Pract. 2014 Feb;20(2):167-75. 
4. Sun L, Coy DH. Somatostatin and its Analogs. Curr Drug Targets. 2014 Dec 5.[Epub ahead of 
print] 
5. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, 
Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-
controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control 
of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the 
PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63.  
6. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila 
J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. 
Lanreotide in metastatic enteropancreatic  neuroendocrine tumors. N Engl J Med. 2014 Jul 
17;371(3):224-33. 
7. Vikman S, Sommaggio R, De La Torre M, Oberg K, Essand M, Giandomenico V, Loskog A, 
Totterman TH. Midgut carcinoid patients display increased numbers of regulatory T cells in 
peripheral blood with infiltration into tumor tissue. Acta  Oncol. 2009;48(3):391-400. 
8. Bhathena SJ, Louie J, Schechter GP et al. Identification of human mononuclear leukocytes bearing 
receptors for somatostatin and glucagon. Diabetes 1981; 30: 127–131.  
9. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; 
International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial 
on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of 
metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and 
Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. 
10. Schultheis AM, Scheel AH, Ozretić L, George J, Thomas RK, Hagemann T, Zander T, Wolf J, 
Buettner R. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015 Jan 9. 
pii: S0959-8049(14)01166-6. 
11. Martín-Richard M, Massutí B, Pineda E, Alonso V, Marmol M, Castellano D, Fonseca E, Galán A, 
Llanos M, Sala MA, Pericay C, Rivera F, Sastre J, Segura A, Quindós M, Maisonobe P; TTD 
(Tumores del Tracto Digestivo) Study Group. Antiproliferative effects of lanreotide autogel in 
patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-
label, single arm phase II study. BMC Cancer. 2013 Sep 20;13:427.  


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12. Spranger S, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor 
microenvironment 
is 
driven 
by 
CD8(+) 
T 
cells. 
Sci 
Transl 
Med. 
2013; 
5:200ra116.10.1126/scitranslmed.3006504 
13. Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, Giannarelli 
D, Chilosi M, Bronte V, Scarpa A, Bria E, Tortora G. Differential Activity of Nivolumab, 
Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-
Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. 
PLoS One. 2015;10(6):e0130142. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 





















ICF_001.pdf: 
 
 
 
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for 
Gastroenteropancreatic Neuroendocrine Tumors (PLANET) 
 
 
Trial: NCT03043664 
 
 
Consent Form 
 
June 23, 2021 


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 1 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study because you have a neuroendocrine tumor of the 
gastrointestinal (GI) tract or pancreas (GEP-NET).  Research studies are voluntary and include only 
people who choose to take part.  Please read this consent form carefully and take your time making your 
decision. As your study doctor or study staff discusses this consent form with you, please ask him/her to 
explain any words or information that you do not clearly understand.  We encourage you to talk with 
your family and friends before you decide to take part in this research study.  The nature of the study, 
risks, inconveniences, discomforts, and other important information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Michael Morse will conduct the study and it is funded by Merck & Co and Ipsen 
Biopharmaceuticals, Inc.  The supporters of this study, Merck & Co and Ipsen, will pay Duke University 
to perform this research, and these funds may reimburse part of Dr. Morse’s salary.  Dr. Morse has 
received personal compensation from Ipsen Biopharmaceuticals, Inc and personal compensation 
for speaking and consulting for Merck & Co. in the past, and may receive personal compensation from 
these sponsors in the future.
CONCISE SUMMARY 
This is a research study to evaluate the safety and efficacy of pembrolizumab and lanreotide drug 
combination in subjects with progressive, advanced or metastatic gastroenteropancreatic 
neuroendocrine tumors (GEP-NETs) who have progressed on front line somatostatin analogue 
(SSA) therapy. 
If you are one of the first 6 subjects enrolled in this study, you will receive Pembrolizumab 200 mg 
intravenous (IV) every 3 weeks and Lanreotide depot 90 mg subcutaneous (SQ) every 3 weeks. 
These 21-day cycles will be repeated until your cancer gets worse or you are no longer able to 
tolerate the study drugs. If the first 6 subjects tolerate these doses well (have few or easily 
manageable side effects), 20 additional subjects will be enrolled at the same dose. If more than one 
of the first six subjects have bad side effects at this dose, the study will be stopped. You will have 
tests, exams and procedures that are part of your standard care and for study purposes. 
There are risks to this study drug that are described in this document. Some risks include: itching of 
the skin, loose or watery stools, cough, stomach pain, muscle pain, vomiting, headache and others. 
If you are interested in learning more about this study, please continue reading below. 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 2 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Morse will be your doctor for the study and will be in contact with your 
regular health care provider throughout the time that you are in the study and afterwards, if needed.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab and lanreotide drug 
combination in subjects with progressive, advanced or metastatic gastroenteropancreatic neuroendocrine 
tumors (GEP-NETs) who have progressed on front line somatostatin analogue (SSA) therapy.  The 
combination of these drugs is investigational.   The word “investigational” means the study drugs are 
still being tested in research studies and not approved by the U.S. Food and Drug Administration (FDA).
HOW DO THESE DRUGS WORK?

Pembrolizumab (KEYTRUDA) is an I.V. (intravenous, meaning given through a vein) drug 
that targets a factor called “PD-1” and allows your immune system to attack your cancer more 
effectively.  Pembrolizumab is FDA approved for indications including metastatic melanoma, 
advanced non-small cell lung cancer, metastatic head and neck cancer, classical Hodgkin 
Lymphoma, urothelial carcinoma, and MSI-H or mismatch repair deficient solid tumors that 
have progressed following prior treatment, but is considered investigational in GEP-NET. The 
word “investigational” means the study drugs are still being tested in research studies and not 
approved by the U.S. Food and Drug Administration (FDA).

Lanreotide (SOMATULINE DEPOT) is a drug that is injected subcutaneously (meaning given 
through the fat). This drug is a peptide analogue of the natural hormone somatostatin, which may 
prevent signals that help cancer cells survive and grow. Lanreotide is FDA approved for 
unresectable, locally advanced or metastatic GEP-NET. However, lanreotide is considered 
investigational in combination with pembrolizumab. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 50 people will take part in this study at Duke University Medical Center.
WHAT IS INVOLVED IN PARTICIPATING IN THE STUDY?
Once you understand what is involved with participating in this study and all your questions have been 
answered, you will be asked to sign and date this consent form to show that you want to take part in this 
research study. 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 3 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
For your safety, you will be monitored, or watched carefully, to be sure side effects are prevented or 
minimized. This will require regular clinic visits, blood and urine tests, and radiology tests (such as CT 
scans, which are a computerized series of x-rays). These tests to check you and your cancer are part of 
your routine care.  If you have side effects or have other medical problems, you may need more 
monitoring or procedures (tests).  
In addition, you will have some tests that are only for research purposes. These research tests are not 
part of your regular care and they will not affect your study regimen. All of the research tests performed 
are being done to help find out which subjects are most likely to benefit or have side effects from the 
study drug combinations. Thus, all of the blood, urine, and tumor tissue collections mentioned in this 
form are required in order for you to participate in this study.
Screening:

Recording of your demographic information, including your age, sex, and race/ethnicity

You will be asked some questions about your past health and medical history, your current cancer 
illness including your functional status, treatments you have received, how you are feeling and the 
medications, vitamins and herbal supplements you are taking right now.

A physical exam (including height and weight) will be done, and your vital signs (blood pressure, 
pulse, respiratory rate, and temperature) will be taken.

Review the medications you have taken and your current medications.

Have radiographic assessments of your cancer by Computed Tomography (CT) Scan (a 
computerized series of x-rays) or Magnetic Resonance Imaging (MRI, body pictures created by 
using magnetic energy rather than x-ray energy). 

Collect blood to measure Chromogranin A levels (a marker of your tumor) 

Collect blood and urine for safety tests

Collect blood for pregnancy testing 

Collect blood for exploratory research tests (markers of your tumor and immune system)

Collect tumor tissue for biomarker testing. If archived tissue is not available, a fresh tumor biopsy 
will be required to participate in the study. 
After completing the screening tests, your study team will check the results to determine whether you 
are eligible to participate in this study. 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 4 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Study drugs:
Pembrolizumab and lanreotide will be given in periods that will last for 3 weeks. This period of time is 
called a “cycle”. For this study each “cycle” will last about 21 days.   The doses that you will receive are 
based on when you enter the study. Your study doctor will tell you exactly what doses you will be 
receiving.
If you are one of the first 6 subjects enrolled in this study, you will be given:
Pembrolizumab 200 mg intravenous (IV) every 3 weeks and
Lanreotide depot 90 mg subcutaneous (SQ) every 3 weeks
These 21-day cycles will be repeated until your cancer gets worse or you are no longer able to tolerate 
the study drugs.
If the first 6 subjects tolerate these doses well (have few or easily manageable side effects), 20 additional 
subjects will be enrolled at the same dose. If more than one of the first six subjects have bad side effects 
at this dose, the study will be stopped. Your study doctor will discuss this with you further.
Assessments During Drug Regimen:
The following visits to the study center will occur during the study. Most of these tests and procedures 
are part of your regular medical care, but they may be done more often for this study. Study drug cycles 
will be repeated until the study is stopped or until your cancer gets worse.
Day 1 of every cycle (every 21 days): 

You will be asked some questions about your current cancer illness including your functional status, 
how you are feeling and the medications, vitamins and herbal supplements you are taking right now.

Review any side effects you are having.

A physical exam (including weight) will be done, and your vital signs (blood pressure, pulse, 
respiratory rate, and temperature) will be taken.

Collect blood and urine for safety tests

Collect blood for research tests (markers of your tumor and immune system)
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 5 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Every 12 weeks (every 4 cycles):

A CT scan or an MRI will be done to measure the amount and size of the tumors in your body

Collect blood to measure Chromogranin A levels (a marker of your tumor) 

Collect blood for pregnancy testing 

Collect blood for exploratory research tests (markers of your tumor and immune system)
Evaluations After You Stop Receiving Study Drug:
The following evaluations will take place approximately 30 days after you get your final dose of study 
drug:

You will be asked some questions about your current cancer illness including your functional status, 
how you are feeling and the medications, vitamins and herbal supplements you are taking right now.

Review any side effects you are having.

A physical exam (including weight) will be done, and your vital signs (blood pressure, pulse, 
respiratory rate, and temperature) will be taken.

Collect blood and urine for safety tests

Collect blood for research tests (markers of your tumor and immune system)
Continuing Study Drug Regimen After Disease Progression:
With most anti-cancer drugs, an increase in the size or number of tumors that is detected with CT or 
MRI scans or a physical examination is a signal that your disease has progressed and that you should 
consider switching to another therapy.
However, with immunotherapeutic drugs, including pembrolizumab, an early increase in the size or 
number of tumors may not always be a sign of disease progression.  Pembrolizumab is thought to work 
by stimulating your immune system to attack your tumors.  When cells from your immune system attack 
your tumors, one result can be an apparent increase in the size or number of those tumors.  In some 
subjects, an early increase can be followed by a later reduction in tumor size. Because of this possibility, 
you are permitted to continue receiving the study drugs even if a scan performed early in the course of 
your study regimen shows an increase in your tumors. However, you will only continue the study drug 
regimen if you and your doctor think you could benefit. 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 6 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
HOW LONG WILL I BE IN THIS STUDY?
You may receive the study drug regimen for up to two years (or 35 cycles) as long as your cancer does 
not get worse. Once you stop taking the study drug regimen, you may be followed for up to 48 weeks 
after the last patient completes study drug regimen. 
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose. All anti-cancer 
treatments may have side effects.  Most side effects from the drugs used in this study are expected to 
mild and reversible.  However, side effects may rarely be severe, long lasting, and very rarely may even 
be lethal.  Side effects may require additional treatments, procedures, hospitalization, or surgery. While 
the lists of side effects below are meant to be comprehensive, there can also be side effects not 
specifically listed or side effects that have not been seen before.  For these reasons, you will be watched 
closely and you should also let your medical team know right away if you have any new problems.
Risks associated with Pembrolizumab:
Pembrolizumab, which is approved in the USA and some other countries, is available by prescription to 
treat several different cancers, but is not approved to treat your type of cancer. Pembrolizumab works by 
helping your immune system to fight your cancer.
However, pembrolizumab can also cause your immune system to attack normal organs and tissues in 
your body and can affect the way they work, which can result in side effects that may become serious or 
life-threatening, and in some cases, may lead to death, and/or may occur after you stop taking 
pembrolizumab. These side effects can affect more than one of your normal organs and tissues at the 
same time.
Very common side effects seen in more than 20% of subjects who received  pembrolizumab 
include the following:

Itching of the skin (pruritus)

Loose or watery stools
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 7 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

Cough
Common side effects seen in 5% to 20% of subjects who received pembrolizumab include the 
following:

Joint pain

Fever

Back pain

Rash

Pain in your belly

Loss of skin color

Not enough thyroid hormone, so you may feel tired, gain weight, feel cold, or have infrequent or 
hard stools (hypothyroidism)

Low levels of salt in the blood that may cause you to feel tired, feel confused, have a headache, 
have muscle cramps, and/or feel sick to your stomach (hyponatremia)
Uncommon side effects seen in 1% to 5% of subjects who received pembrolizumab include the 
following:

Inflammation of the lungs, so you may feel short of breath and cough; rarely this may lead to 
death (pneumonitis)

Too much thyroid hormone, so you may feel anxious, feel angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, or have loose or watery stools (hyperthyroidism) 

Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever, feel 
short of breath, experience a decrease in your blood pressure at the time of receiving your 
infusion (IV) or just after, or pain at the site of infusion

Inflammation of the bowels/gut, which may cause you to feel severe pain in your belly with 
loose or watery stools, and stools that are black, tarry, sticky with blood or mucus (colitis)

Inflammation of the skin, so you may have peeling of the skin, itchiness, and/or skin redness. 
The skin inflammation (for example, peeling, itching and redness) could also be widespread 
throughout your body. More severe skin reactions may involve the inside of your mouth, the 
surface of your eye and genital areas, and/or may cause the top layer of your skin to peel from all 
over your body which can cause severe infection. These severe conditions can sometimes lead to 
death. (severe skin reactions, including Stevens-Johnson syndrome, a skin condition called 
pemphigoid and toxic epidermal necrolysis)
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 8 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Rare but potentially Serious side effects seen in less than 1% of subjects who received 
pembrolizumab include the following:

Inflammation of the nerves that may cause pain, weakness, or tingling in your hands and feet, 
and may spread to your legs, arms, and upper body, leading to severe muscle weakness and 
possible temporary paralysis (Guillain-Barré syndrome)

Inflammation of the muscles, so you may feel weak or have pain in your muscles (myositis)

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels), so you may 
have severe pain in the top part of your belly that may move to your back, feel sick to your 
stomach, and have vomiting that gets worse when you eat (pancreatitis)

Inflammation of the eye, so you may have eye redness, blurred vision, sensitivity to light, eye 
pain, see floaters, or have headaches (uveitis)

Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like not 
eating, feel tired, have a mild fever, have a pain in the right side of your belly, or have yellow 
eyes and skin and dark urine (hepatitis)

Inflammation of the pituitary gland, (a gland in the head) which may cause you to feel sick to 
your stomach or have headaches, changes in your behavior, double vision, few to no menstrual 
cycles, weakness, vomiting and dizziness, or fainting (hypophysitis)

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which could 
cause tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle, and belly 
aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes darkening of 
the skin like a suntan (adrenal insufficiency)

Type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier than 
usual, frequent urination, and weight loss. You are likely to need regular insulin shots.

Inflammation of the kidneys, so you may pass less urine or have cloudy or bloody urine, 
swelling, and low back pain (nephritis) 

Inflammation of the middle layer of your heart wall that may cause your heart to have difficulty 
pumping blood throughout your body, which can cause chest pain, shortness of breath, and 
swelling of the legs. You may experience a fast or irregular heartbeat that may cause dizziness or 
fainting. Sometimes this condition can lead to death. (myocarditis)

Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the rate at 
which food is converted into energy. (thyroiditis)
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 9 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and legs, 
or difficulty breathing (myasthenic syndrome or myasthenia gravis, including exacerbation)

Formation of small clusters of immune cells (called granulomas) in parts of your body such as 
your lymph nodes, eyes, skin, or lungs (sarcoidosis)

Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness. 
(encephalitis)

Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or legs, 
bladder or bowel problems including needing to urinate more frequently, urinary incontinence, 
difficulty urinating,  constipation, and could include paralysis (myelitis)

Inflammation of the blood vessels (vasculitis)
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in which a 
person receives blood-forming stem cells from a donor), you may experience graft versus host disease 
(GvHD), which may include diarrhea, skin rashes, and liver damage, after receiving pembrolizumab. 
Sometimes this condition can lead to death.
If you have had a solid organ transplant (for example, if you have received a kidney or heart transplant), 
you may experience rejection of the transplanted organ. Your doctor will monitor you and should tell 
you what signs and symptoms you should report depending on the type of organ transplant you have 
had. 
Additionally, since pembrolizumab was approved in September 2014, the following side effects have 
been reported by people receiving pembrolizumab. These side effects were voluntarily reported from a 
group of people of unknown size. It is not possible to estimate the frequency of this side effect:

Inflammation of the joints which may include joint pain, stiffness and or swelling (arthritis)

Severe responses of the immune system that cause the body to attack its own blood cells, spleen, 
liver, lymph nodes, skin, and brain. This may include fever, rash, inflammation of the liver, 
yellowing of the skin, an enlarged liver and spleen, low blood counts, and enlarged lymph nodes.  
The nervous system may also be affected and cause confusion, seizures, and even coma. 
(hemophagocytic lymphohistiocytosis)

Changes in eyesight, eye pain or loss of vision may occur. There may also be neurological signs 
such as severe headache, dizziness, nausea, and drowsiness. Loss of hearing, loss of hair 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 10 of 19                                                  Subject*Initials:______________
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(alopecia) and skin color may occur along, with whitening (loss of pigmentation) of the hair and 
eyelashes (poliosis).  (Vogt-Koyanagi-Harada syndrome)

Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made in the 
liver).  This can cause symptoms similar to those seen with inflammation of the liver (hepatitis) 
such as pain in right side of your belly, yellow eyes and skin, feeling tired, and itching 
(sclerosing cholangitis).
Risks associated with lanreotide:
The data below reflect exposure to lanreotide in 101 subjects with GEP-NETs.
Very common side effects seen in greater than 10% of subjects include the following:

Stomach pain

Muscle pain

Vomiting

Headache

Injection site reaction

Low blood sugar (hypoglycemia)

High blood sugar (hyperglycemia)

Gallstones (cholelithiasis)
Common side effects seen in between 1 in 100 to 10 in 100 (1-10%) of subjects:

Dizziness

Depression

Shortness of breath (dyspnea) 
Risks from Study Procedures:
Some of the study procedures may have possible side effects, risks and discomforts. You may 
experience none, some, or all of those listed below.
Risks of Drawing Blood: 
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising.  
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely.
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 11 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
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M0345
Risks of Magnetic Resonance Imaging:
Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical images 
of the body. There have been no ill effects reported from exposure to the magnetism or radio waves used 
in this test. However, it is possible that harmful effects could be recognized in the future. A known risk 
is that the magnet could attract certain kinds of metal. Therefore, we will carefully ask you about metal 
within your body (this includes certain dyes found in tattoos). If there is any question about potentially 
hazardous metal within your body, you will be excluded from participation in this research study. We 
will also keep the examining room locked so that no one carrying metal objects can enter while you are 
in the scanner.
The study involves entering a large room in which a magnet is present. You will be placed on a narrow 
bed and then slid into a small tunnel approximately 6 feet in length and 25 inches in diameter. You will 
be asked to lie still for about one hour on this bed. You will hear a loud machine-like noise. You may be 
asked to have a harmless monitoring device applied during the study. During the study, you can have 
voice contact and physical contact with someone in attendance if you desire.
Risks of Magnetic Resonance Imaging with Contrast Dye: 
For some magnetic resonance imaging (MRI) scans, you may get a MRI contrast material (a dye). This 
is given in your vein using a small needle or plastic tube. You may feel local warmth or pain in the area 
where the dye is injected. The most common contrast material used for MRIs is gadolinium. Side effects 
from the dye may include nausea, vomiting, or headache.  Persons with decreased kidney function or 
chronic liver disease experiencing decreased kidney function may develop a severe disease called 
nephrogenic systemic fibrosis from gadolinium. Nephrogenic systemic fibrosis triggers thickening of the 
skin, organs and other tissues. The exact cause is unclear, and there is no effective treatment. The MRI 
contrast material will be given in amounts that have been approved by the FDA. You will not get the 
MRI contrast material if you have abnormal kidney function. Serious allergic reactions that may be life-
threatening are very rare.
Risks of Computed Tomography Scan with Contrast Dye: 
Computed Tomography (CT) is a way to make x-ray images of the inside of the body. The CT scanner is 
a doughnut-shaped machine that uses x-rays to create computer pictures that show structures inside your 
body more clearly than regular x-ray pictures. During the procedure, a technologist will take you into the 
CT scan room where you will lie down on the patient table (usually on your back) inside of the CT 
machine. You should get comfortable because it is very important that you not move during certain parts 
of the test.
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 12 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
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M0345
CT examinations differ depending on the part of your body being studied. For example, if your abdomen 
is being studied, a series of pictures will be taken from your lower chest to your lower pelvis. During the 
study, you will be asked to hold your breath so that the pictures will not be blurred. The machine will 
make some noise, and the table will move during the scan. Also, you may receive signals from the 
technologist or from the machine about your breathing. Before or during the study, you may be given an 
injection of a contrast liquid in your vein to allow the radiologist to obtain clearer images of your 
organs. If you have any discomfort during the test or after the injection, be sure to tell the technologist. 
Risks of Radiation:
You will have a number of CT scans and MRI scans that are part of the regular care for your condition, 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk due to participating in the research. However, if you have concerns about the overall radiation 
exposure or MRI safety issues, you should discuss them with your physician.
Risks of Core Needle Biopsy:
You may experience pain from this procedure that could also include bruising, soreness or scarring at 
the biopsy site. Rarely, a subject may experience infection and/or internal bleeding and depending on the 
location of the biopsy. The biopsy procedure is usually performed while the patient is under local 
anesthesia (for example lidocaine), meaning the skin site where the needle will be inserted is numbed. 
Side effects from the local anesthesia are rare but may include convulsions or seizures, breathing 
problems, chest pain, rapid heart rate, irregular heartbeat, dizziness, bluish lips and fingernails, 
drowsiness, headache, itching, nausea and/or vomiting, raised red swellings on the skin, lips, tongue, or 
in the throat, restlessness, unusual tiredness or weakness, back pain, difficulty in opening the mouth, 
inability to hold bowel movement and/or urine, loss of sexual function, temporary paralysis (loss of 
function) of legs, persistent or prolonged numbness or tingling (“pins and needles” sensations) of lips 
and mouth, and shivering.
Imaging equipment may be used to guide the needle to the desired site. This may involve ultrasound or 
CT. If CT is used, a subject will be exposed to a small dose of radiation. In addition, a patient may be 
injected with a contrast dye (for example iodine). This may cause some side effects including hives, 
itching, lightheadedness, nausea and a metallic taste in the mouth.  Rarely, the iodine may result in a 
severe allergic reaction, including shock, very low blood pressure and cardiac arrest. 
Risks of Liver Biopsy
For patients undergoing liver biopsy, there may be increased risk in certain circumstances. When doctors 
perform your liver biopsy, they do so by passing a needle into the liver usually through your side. 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 13 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
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M0345
Doctors are usually able to get a large enough piece of liver to examine under the microscope by taking 
a single biopsy of the liver. However, in some patients, only a small piece is retrieved (not enough to 
look at under the microscope) and in this case, a second specimen from the liver is taken. After the first 
attempt, if there is not enough for research purposes, a second piece will be taken.. Thus, by 
participating in this study, in a small fraction of patients undergoing liver biopsy (less than 5% of all 
subjects), there will be a chance that a second piece of liver will be taken for research purposes. The 
additional risk of an additional liver sampling is approximately 1 in 1,000 for increased bleeding, and 1 
in 2,000 for other complications such as puncture of a lung or colon. These complications are managed 
by observation and, in some circumstances, surgery.
If you undergo a liver biopsy you may require sedation. Sedation may include medications such as 
fentanyl or midazolam. These medications can lower blood pressure, slow down breathing, and decrease 
your heart rate. If concerning changes in your vital signs occur, a reversing medication can be given.  
Risks of Allergic Reaction
Occasionally, people have allergic reactions to medications which may require medical treatment.  A 
severe allergic reaction could be life-threatening.  Examples of an allergic reaction include: a rash; 
shortness of breath; wheezing; difficulty breathing; sudden drop in blood pressure; swelling around the 
mouth, throat, or eye; fast pulse; and sweating.  You should get immediate medical help and contact the 
study doctor if you have any of these or any other side effects during the study.
Drug and Food Interactions: 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
For those of reproductive potential:
Female
Being a part of this study while pregnant may expose the unborn child to significant risks, some of 
which may be currently unforeseeable.  Therefore, pregnant women will be excluded from the study.  If 
you are a woman of childbearing potential, a blood pregnancy test will be done (using 1 teaspoon of 
blood drawn from a vein by needle-stick), and it must be negative before you can continue in this study.  
If sexually active, you must agree to use two appropriate contraceptive measures for the duration of the 
study and for 120 days afterwards. Medically acceptable contraceptives include: (1) surgical sterilization 
(such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 14 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a 
spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for 
emergency use after unprotected sex, are not acceptable methods for routine use.  If you do become 
pregnant during this study or if you have unprotected sex, you must inform your study physician 
immediately.
Male
Your participation in this research may damage your sperm, which could cause harm to a child that you 
may father while on this study.  Such harm may be currently unforeseeable.  If you are sexually active, 
you must agree to use a medically acceptable form of birth control in order to be in this study and for 
120 days afterward. Medically acceptable contraceptives include: (1) surgical sterilization (such as a 
vasectomy), or (2) a condom used with a spermicide.  Contraceptive measures such as Plan B (TM), sold 
for emergency use after unprotected sex, are not acceptable methods for routine use. You should inform 
your partner of the potential for harm to an unborn child.  She should know that if pregnancy occurs, 
you will need to report it to the study doctor, and she should promptly notify her doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may be a direct medical benefit to you.  This drug may help 
shrink your cancer or keep it from growing.  However, we cannot guarantee any personal benefit.  Even, 
if you do not personally benefit, the knowledge learned from your participation may help doctors and 
researchers learn more about the use of these study drugs to help other people with cancer.
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
Your other choices may include the following:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting no treatment

Getting comfort care (also called palliative care) only; this type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer.  It does not treat the 
cancer directly.
Please talk to your doctor about these and perhaps other options.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 15 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law.
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to Merck and Ipsen and their affiliates. In addition, your records may be reviewed in order to 
meet federal or state regulations. Reviewers may include representatives from the Food and Drug 
Administration, representatives and affiliates of Merck and Ipsen, the Duke University Health System 
Institutional Review Board, and others as appropriate. If any of these groups review your research 
record, they may also need to review your entire medical record. 
As part of this study, you will be asked to have certain tests, x-rays, and procedures performed. Some of 
these tests, x-rays and procedures would have been done as part of your regular care. The study doctor 
will use these test results both to treat you and to complete this research. These test results will be 
recorded in your medical record and will be reported to representatives and affiliates of Merck and 
Ipsen. Results of tests and studies done solely for this research study and not as part of your regular care 
will not be included in your medical record. 
The study results will be retained in your research record for at least six years after the study is 
completed.  At that time either the research information not already in your medical record will be 
destroyed or information identifying you will be removed from such study results at DUHS.  Any 
research information in your medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study. If diclosed by the sponsor, the 
information is no longer covered by federal privacy regulations. If this information is disclosed to outside 
reviewers for audit purposes, it may be further disclosed by them and may not be covered by federal 
privacy regulations. 
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 16 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
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M0345
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. Morse.  At your request, a Financial Counselor in the clinic may provide you with an 
estimate of costs for routine services.
The study sponsor, Merck and Ipsen, have agreed to pay for services and procedures that are done solely 
for research purposes. Please talk with the study team about the specific services and procedures that the 
sponsor will pay for, and the ones for which you or your insurance will be responsible. 
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately. If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/ she can help fins a resolution. 
Merck and Ipsen will provide the study drug free of charge to you. At the end of the study, or if you 
decide to withdraw from the study before it ends, you may be asked to return all unused study drug.  
Your study doctor may request that you return for a checkup before you stop your study drug if he or she 
thinks that stopping it suddenly may harm you and may ask you to complete the tests that would 
ordinarily occur when a person completes the study.
WHAT ABOUT COMPENSATION?
You will not be paid for participating in this study.
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 17 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Duke University, Duke University Health System, Inc., your Duke physicians, or the study’s supporters 
Merck & Co and Ipsen Biopharmaceuticals, Inc., to provide monetary compensation or free medical 
care to you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Morse at (919) 668-1861 during 
regular business hours. After hours and on weekends and holidays, please call the Duke paging operator 
at (919) 684-8111, and ask the operator to page Dr. Morse.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
Participation in this study is voluntary.  You are free to withdraw your consent and to discontinue 
participation in the study at any time.  
If you withdraw from the study, no new data about you will be collected for study purposes unless the 
data concern an adverse event (a bad effect) related to the study.  If such an adverse event occurs, we 
may need to review your entire medical record.  All data that have already been collected for study 
purposes, and any new information about an adverse event related to the study, will be sent to the study 
sponsor.
If you decide to participate, you will be told of any important new information learned during the course 
of this research study that might affect your condition or your health, welfare, or willingness to stay in 
this study.  If you agree to continue participation, you will be asked to sign an updated consent form.
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you contact Dr. Morse in writing and let him know that you are 
withdrawing from the study.   His mailing address is: 
c/o Duke University Medical Center
 
    Protocol Office
    DUMC Box 2823
    Durham, NC 27710.
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 18 of 19                                                  Subject*Initials:______________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Morse at (919) 668-1861 during regular business hours.  
After hours and on weekends and holidays, please call the Duke paging operator at (919) 684-8111, and 
ask the operator to page Dr. Morse.
For questions about your rights as a research participant, or to discuss problems, concerns or 
suggestions related to the research, or to obtain information or offer input about the research, 
contact the Duke University Health System Institutional Review Board (IRB) Office at (919) 668-
5111.
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022


Consent to Participate in a Research Study
Phase Ib/II Study of Pembrolizumab with Lanreotide Depot for
Gastroenteropancreatic Neuroendocrine Tumors (PLANET)
PI: Michael Morse, MD
Page 19 of 19
                                                  *
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form.   
__________________________________________
Printed Name of Subject
      
__________________________________________
___________          _________
Signature of Subject
    
       Date
Time
“I have explained the research to the subject and answered all of his/her questions.” 
__________________________________________
Printed Name of Person Obtaining Consent
__________________________________________
__________        ___________
Signature of Person Obtaining Consent
      Date                    Time
DUHS IRB
IRB NUMBER: Pro00074917
IRB REFERENCE DATE: 06/23/2021
IRB EXPIRATION DATE: 03/09/2022