Conditions: Locally Advanced Digestive System Neuroendocrine Carcinoma Locally Advanced Pancreatic Neuroendocrine Carcinoma Metastatic Digestive System Neuroendocrine Carcinoma Metastatic Pancreatic Neuroendocrine Carcinoma Refractory Digestive System Neuroendocrine Carcinoma Refractory Pancreatic Neuroendocrine Carcinoma Unresectable Digestive System Neuroendocrine Carcinoma Unresectable Pancreatic Neuroendocrine Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This phase II trial studies how well liposomal irinotecan, leucovorin, and fluorouracil work in treating patients with high grade neuroendocrine cancer of gastrointestinal, unknown, or pancreatic origin that does not respond to treatment and has spread to other places in the body. Lliposomal irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving liposomal irinotecan, leucovorin and fluorouracil may work better in treating patients with neuroendocrine cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the objective response rate liposomal irinotecan (nanoliposomal irinotecan \[Nal-IRI\]) + fluorouracil (5FU) and leucovorin in patients with refractory advanced high grade neuroendocrine cancer of gastrointestinal (GI), unknown or pancreatic origin.

SECONDARY OBJECTIVES:

I. To determine overall survival, progression-free survival, time to treatment failure, safety, clinical response and, quality of life (QOL) changes resulting from the combination treatment of nanoliposomal irinotecan (Nal-IRI) + fluorouracil (5FU) and leucovorin.

EXPLORATORY OBJECTIVES:

I. Genetic profiling for mutations will be conducted on all pre-study tumor samples and compared to changes in immune response.

OUTLINE:

Patients receive liposomal irinotecan intravenously (IV) over 90 minutes, leucovorin IV over 30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days for in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, then every 2 months thereafter.

Arms:
arm 1: Patients receive liposomal irinotecan IV over 90 minutes, leucovorin IV over 30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days for in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Fluorouracil intervention 2: Leucovorin intervention 3: Liposomal Irinotecan intervention 4: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Document Coversheet 
 
 Study Title:    Phase 2 Single-Arm Study of Nanoliposomal Irinotecan with Fluorouracil and Leucovorin in 
Refractory Advanced High Grade Neuroendocrine Cancer of GI, Unknown or Pancreatic Origin 
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
09/01/2022 
NCT Number: 
NCT03736720 
IRB Number 
I 64518 
 


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PROTOCOL TITLE:
Phase 2 Single-Arm Study of Nanoliposomal Irinotecan with Fluorouracil and Leucovorin 
in Refractory Advanced High-Grade Neuroendocrine Cancer of GI, Unknown, or 
Pancreatic Origin
PROTOCOL NUMBER:
I-64518
PRINCIPAL INVESTIGATOR:
Renuka V. Iyer, MD
Roswell Park Comprehensive Cancer Center
Elm and Carlton Street
Buffalo, New York 14263
716-845-8195
Renuka.Iyer@roswellpark.org
VERSION NUMBER: INITIAL: DATE: 01 June 2018
AMENDMENT#1: 110818
AMENDMENT#2: 042419
AMENDMENT#3: 071119
AMENDMENT#4: 101719
AMENDMENT#5: 062620
AMENDMENT #6: 021921
AMENDMENT #7: 091421
AMENDMENT #8: 061022
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Institute). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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Table of Contents
1
Objectives ................................................................................................................................5
1.1
Primary Objective.................................................................................................................5
1.2
Secondary Objective.............................................................................................................5
1.3
Exploratory Objective...........................................................................................................5
2
Background..............................................................................................................................5
2.1
Nanoliposomal Irinotecan (Nal-IRI): Pharmaceutical and Therapeutic Background ..........5
2.1.1
Nal-IRI Preclinical Experience .........................................................................................6
2.1.2
Nal-IRI Preclinical Pharmacokinetics...............................................................................6
2.1.3
Nal-IRI Pharmacokinetics in Humans ..............................................................................7
2.1.4
Nal-IRI Safety in Humans...............................................................................................10
2.2
Fluorouracil and Leucovorin (5-FU/ LV)...........................................................................11
2.3
Rationale for Combination Therapy ...................................................................................12
3
Inclusion and Exclusion Criteria ...........................................................................................12
3.1
Inclusion Criteria ................................................................................................................12
3.2
Exclusion Criteria ...............................................................................................................14
3.3
Special Populations.............................................................................................................14
3.4
Inclusion of Women and Minorities...................................................................................14
4
Local and Study-Wide Number of Subjects ..........................................................................14
5
Local and Study-Wide Recruitment Methods .......................................................................15
6
Multi-Site Research ...............................................................................................................15
7
Study Timelines.....................................................................................................................15
8
Study Endpoints.....................................................................................................................15
8.1
Primary Endpoint................................................................................................................15
8.2
Secondary Endpoints ..........................................................................................................15
8.3
Exploratory Endpoint..........................................................................................................16
9
Design....................................................................................................................................16
10
Treatment...............................................................................................................................16
10.1
Dosing and Administration.................................................................................................16
10.1.1
Premedication..................................................................................................................16
10.1.2
Administration of Nal-IRI...............................................................................................17
10.2
Dose Modifications and Treatment Delays ........................................................................17
10.2.1
Diarrhea...........................................................................................................................18
10.2.2
Neutropenia.....................................................................................................................19
10.2.3
Hypersensitivity ..............................................................................................................19
10.2.4
Interstitial Lung Disease (ILD).......................................................................................19
10.2.5
Colitis/ Ileus ....................................................................................................................19
10.2.6
Thromboembolism..........................................................................................................19
10.2.7
Patients at Particular Risk ...............................................................................................19
10.2.8
Acute Infusion Associated Reactions .............................................................................20
10.2.9
Other Potential Toxicities ...............................................................................................20
10.2.10
Pregnancy ....................................................................................................................20
10.3
General Concomitant Medication and Supportive Care.....................................................20
10.3.1
Rescue Medications & Supportive Care .........................................................................20
10.3.2
Care of Intravenous Site..................................................................................................20
10.3.3
Management of Infusion Reactions ................................................................................20
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10.4
Prohibited Therapy .............................................................................................................22
10.5
Other Considerations ..........................................................................................................22
10.5.1
Contraception..................................................................................................................22
10.5.2
Use in Pregnancy ............................................................................................................23
10.6
Duration of Treatment ........................................................................................................23
11
Procedures Involved ..............................................................................................................24
11.1
Participant Registration: .....................................................................................................24
11.2
Schedule of Procedures and Observations..........................................................................24
11.2.1
Baseline/ Screening Visit................................................................................................24
11.2.2
On-Study Visits...............................................................................................................24
11.2.3
End of Treatment Visit....................................................................................................24
11.2.4
Long-term Follow-up......................................................................................................24
11.3
Clinical Procedures.............................................................................................................25
11.3.1
Medical History and Pre-existing Conditions.................................................................25
11.3.2
Physical Examination and Vital Signs............................................................................25
11.3.3
Performance Status .........................................................................................................25
11.3.4
Electrocardiogram (ECG) ...............................................................................................25
11.3.5
Adverse Event Assessment .............................................................................................25
11.3.6
Disease Evaluation..........................................................................................................25
11.3.7
EORTC-QLQ-C30..........................................................................................................26
11.4
Laboratory Procedures........................................................................................................26
11.4.1
Hematology.....................................................................................................................26
11.4.2
Chemistry........................................................................................................................26
11.4.3
UGT1A1*28....................................................................................................................26
11.4.4
Urine or Serum Pregnancy Test......................................................................................26
11.4.5
Comprehensive Genomic Profiling.................................................................................26
11.4.6
Central Pathology Review ..............................................................................................27
12
Withdrawal of Subjects..........................................................................................................28
13
Risks to Subjects....................................................................................................................28
14
Potential Benefits to Subjects ................................................................................................28
15
Data and Specimen Banking..................................................................................................28
16
Measurement of Effect ..........................................................................................................29
16.1
Response Parameters ..........................................................................................................29
17
Safety Evaluation...................................................................................................................29
17.1
Adverse Events ...................................................................................................................29
17.1.1
Diagnosis Versus Signs and Symptoms..........................................................................29
17.1.2
Adverse Events Occurring Secondary to Other Events ..................................................29
17.1.3
Abnormal Laboratory Values..........................................................................................30
17.1.4
Preexisting Medical Conditions (Baseline Conditions)..................................................30
17.2
Grading and Reporting Adverse Events .............................................................................30
17.2.1
Grading and Relationship to Drug ..................................................................................30
17.2.2
Reporting and Follow-Up of Pregnancy .........................................................................31
17.3
Reporting Adverse Events:.................................................................................................31
17.4
Serious Adverse Events ......................................................................................................31
17.4.1
Reporting Serious Adverse Events .................................................................................32
17.5
Investigator Reporting: Notifying the Study Sponsor ........................................................32
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17.6
Follow-Up for Serious Adverse Events..............................................................................32
17.7
Unanticipated Problems......................................................................................................32
17.7.1
Reporting Unanticipated Problems:................................................................................33
18
Data Management and Confidentiality..................................................................................33
18.1
Data Collection ...................................................................................................................33
18.2
Maintenance of Study Documents......................................................................................33
18.3
Revisions to the Protocol....................................................................................................33
18.4
Termination of the Study....................................................................................................34
18.5
Confidentiality ....................................................................................................................34
19
Statistical Plan .......................................................................................................................34
19.1
Sample Size Determination ................................................................................................34
19.2
Demographics and Baseline Characteristics.......................................................................34
19.3
Primary Analysis ................................................................................................................34
19.4
Secondary Analyses............................................................................................................35
19.5
Safety Analysis ...................................................................................................................35
19.6
Interim Analysis..................................................................................................................35
20
Provisions to Monitor the Data to Ensure the Safety of Subjects..........................................36
21
Vulnerable Populations..........................................................................................................36
22
Community-Based Participatory Research............................................................................36
23
Sharing of Results with Subjects ...........................................................................................36
24
Setting....................................................................................................................................36
25
Provisions to Protect the Privacy Interests of Subjects .........................................................36
26
Resources Available ..............................................................................................................36
27
Prior Approvals......................................................................................................................36
28
Compensation for Research-Related Injury...........................................................................36
29
Economic Burden to Subjects................................................................................................37
30
Consent Process.....................................................................................................................37
31
Process to Document Consent in Writing..............................................................................37
32
Drugs or Devices ...................................................................................................................38
32.1
Nanoliposomal Irinotecan...................................................................................................38
32.1.1
Active Substance and Source..........................................................................................38
32.1.2
Drug Shipment ................................................................................................................38
32.1.3
Preparation ......................................................................................................................38
32.1.4
Storage and Stability .......................................................................................................38
32.2
Fluorouracil and Leucovorin ..............................................................................................38
33
References..............................................................................................................................39
34
Appendices/ Supplements......................................................................................................41
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1
OBJECTIVES
1.1
Primary Objective

To determine the objective response rate of nanoliposomal irinotecan (Nal-
IRI) + fluorouracil (5-FU) and leucovorin in patients with refractory advanced high-grade 
neuroendocrine cancer of GI, unknown, or pancreatic origin.
1.2
Secondary Objective

To determine overall survival, progression-free survival, time to treatment failure, safety, 
clinical response and, quality of life (QOL) changes resulting from the combination 
treatment of nanoliposomal irinotecan (Nal-IRI) + fluorouracil (5-FU) and leucovorin.
1.3
Exploratory Objective

Genetic profiling for mutations will be conducted on pre-study tumor samples and 
correlated with response. This prospective assessment may help identify response 
biomarkers that could serve as a guide in determining what treatment options may be best 
for a patient based on pretreatment tumor from biopsy or liquid profiling mutations.
2
BACKGROUND
Each year, an estimated 300,000 people are diagnosed with GI cancers, with over 150,000 people 
dying annually [1]. Almost 145,000 cases of colorectal cancer (CRC) are projected to be diagnosed 
in the US in 2019; with more than 51,000 deaths from the disease [1]. CRC and pancreatic cancers 
are the second and fourth leading causes of cancer death in both sexes the US [1]. Therefore, GI 
cancers are a major area of need for new drug development.
Encapsulation of irinotecan in a liposomal nanoparticle allows for a longer circulation time for 
irinotecan leading to an increase in irinotecan and its major metabolite, SN-38 levels in the tumor. 
In tumor xenografts nanoliposomal irinotecan (MM-398) achieves higher intra-tumor 
concentrations of both irinotecan (142-fold) and SN38 (9-fold) when compared to free Irinotecan 
[2]. Nanoliposomal irinotecan (MM-398) has been evaluated in clinical trials. In colorectal cancer, 
5-FU plus nanoliposomal irinotecan had activity in patients with progression on FOLFOX [3]. 
Promising activity was also reported in patients with gastric and gastro-esophageal junction tumors 
(GEJ) [4]. In pancreatic cancer, nanoliposomal irinotecan plus 5-FU demonstrated significant 
clinical activity in second line setting [5]. Nanoliposomal irinotecan is well tolerated. Commonly 
observed side effects (≥ 20%) are diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, 
stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were 
lymphopenia and neutropenia.
2.1
Nanoliposomal Irinotecan (Nal-IRI): Pharmaceutical and Therapeutic Background
Nal-IRI is irinotecan (also known as CPT-11) encapsulated in a liposome drug delivery system 
(liposomal irinotecan; Nal-IRI). The active ingredient of the Nal-IRI injection, irinotecan, is a 
member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water-soluble 
analog of the naturally-occurring alkaloid, camptothecin. Topoisomerase I inhibitors work to arrest 
uncontrolled cell growth by preventing the unwinding of DNA and therefore preventing 
replication. The pharmacology of irinotecan is complex, with extensive metabolic conversions 
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involved in the activation, inactivation, and elimination of the drug [6-8]. Irinotecan is a prodrug 
that is converted by nonspecific carboxylesterases into a 100-1000 fold more active metabolite, 
SN-38 [9]. SN-38 is cleared via glucuronidation, for which major pharmacogenetic differences 
have been shown, and biliary excretion. These drug properties contribute to the marked differences 
in efficacy and toxicity observed in clinical studies with irinotecan [10 11].
Drug carrier technologies represent a rational strategy to improve the PK and bio-distribution of 
irinotecan while protecting it from premature metabolism. Nal-IRI employs a novel intra-
liposomal drug stabilization technology for encapsulation of irinotecan into long-circulating 
liposome-based nanoparticles with high drug load and high in vivo stability. The stable nano-
liposome formulation of irinotecan has several attributes that may provide an improved therapeutic 
index. The controlled and sustained release should improve activity of this schedule-dependent 
drug by increasing duration of exposure of tumor tissue to drug, an attribute that allows it to be 
present in a higher proportion of cells during the more sensitive S-phase of the cell cycle.
The improved PK, high intravascular drug retention in the liposomes, and EPR effect may 
potentially result in site-specific drug delivery to solid tumors. Stromal targeting results from the 
subsequent depot effect, where liposomes accumulating in tumor associated macrophages release 
the active drug and convert it locally to the substantially more cytotoxic SN-38. The preferentially 
local bio-activation should result in reduced exposure to potential sites of toxicity and increased 
exposure to neighboring cancer cells within the tumor.
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of Nal-
IRI can be found in the Investigator’s Brochure.
2.1.1
Nal-IRI Preclinical Experience
Nal-IRI has been shown in preclinical settings to have a broad spectrum of activity in a wide range 
of solid tumors including colon, pancreatic, gastric, cervical, non-small cell lung, small cell lung, 
ovarian, thyroid, and breast cancers, as well as glioma, Ewing’s sarcoma, and neuroblastoma, often 
with a high degree of anti-tumor activity against resistant or difficult to treat cancer models [2 12]. 
Nal-IRI has also shown potent antitumor activity, including durable tumor regressions, and was 
markedly superior to the equivalent dose of free drug in a bioluminescent-based orthotopic 
xenograft pancreatic model [13].
2.1.2
Nal-IRI Preclinical Pharmacokinetics
The PK properties of Nal-IRI were evaluated in an HT-29 colon cancer subcutaneous xenograft 
model [2]. Both irinotecan and SN-38 were cleared very rapidly (within 8 hours) from the plasma 
following non-liposomal irinotecan administration; however, Nal-IRI clearance was demonstrated 
to be considerably slower and remained in circulation for over 50 hours. SN-38 plasma exposure 
was also greater though Cmax levels were reduced following Nal-IRI administration, suggesting 
the advantage of the irinotecan liposomal formulation in prolonging exposure and half-life via the 
ability of the lipid bilayer to protect the conversion of prodrug CPT-11 to SN-38. Further, both 
irinotecan and SN-38 accumulated in tissues for extended time (at least 1 week after Nal-IRI 
administration), yet there were relatively higher levels of prolonged accumulation in the tumor 
compared to normal tissue, where the metabolites are at very low levels after 48 hours (Figure 1). 
Activation of irinotecan to SN-38 by the liver is the primary path for SN-38 tumoral accumulation 
when non-liposomal irinotecan is administered. In contrast, these data suggest that accumulation 
of Nal-IRI in the tumor and subsequent liposome breakdown and local conversion of irinotecan to 
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SN-38 is responsible for the enhanced tumor exposure of SN-38 when Nal-IRI is administered. 
These preclinical data demonstrating longer retention time in tumor lesions with Nal-IRI 
administration compared to non-liposomal irinotecan administration formed the basis for clinical 
development.
Figure 1
Tissue Distribution of Nal-IRI in an HT-296 Xenograft Study
Figure 1: Levels of SN-38 in various tissues following a single Nal-IRI (20 mg/kg) dose are shown. Prolonged 
accumulation of SN-38 (~168 h) seen in tumor compared to other organs (~48 h).
2.1.3
Nal-IRI Pharmacokinetics in Humans
The PK profile of single agent Nal-IRI has been investigated in several studies, in which plasma 
levels of total irinotecan, SN-38 and encapsulated irinotecan were measured. In a single Phase II 
clinical study [4] direct comparison of the PK of irinotecan and SN-38 in patients administered 
Nal-IRI or conventional (i.e., free) irinotecan (Camptosar®) was evaluated. Compared to the 
administration of conventional irinotecan 300 mg/m2 Q3W, administration of Nal-IRI 120 mg/m2 
Q3W resulted in higher exposure of total irinotecan (Cmax: 13.4-fold, AUC0-∞: 46.2-fold, t1/2: 
2.0-fold), and higher SN-38 t1/2 (3-fold) and marginally higher AUC0-∞ (1.4-fold), however, SN-
38 Cmax was reduced by 5.3-fold (Figure 2).
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Figure 2
Mean Plasma Concentrations of Total Irinotecan and SN-38 Following the 
Administration of Either MM-398 (120 mg/m2) or Camptosar® (300 mg/m2) in Study 
PEP0206
Gastric cancer patients received either Nal-IRI (MM-398) at a dose of 120 mg/m2 (blue line) or, non-liposomal 
irinotecan (Camptosar®) at a dose of 300 mg/m2 (red line) every 3 weeks. Total irinotecan (top) and its active 
metabolite, SN-38 (bottom) were measured during Cycle 1. Error bars indicate 95% confidence interval. Dotted 
lines indicate lower limit of quantification (LLOQ); total irinotecan measurements consist of two LLOQ values 
because of two different irinotecan assays were used to measure low and high range of concentrations. The 
concentrations less than LLOQ values were set to the corresponding LLOQ [Data on file, Merrimack 
Pharmaceuticals; Ma 2015].
In other PK studies of single agent Nal-IRI, similar findings were observed when compared to 
standard doses of conventional irinotecan. Based on population PK analysis, no significant 
association was observed between the PK parameters of total irinotecan and SN-38 following Nal-
IRI monotherapy and when co-administered with 5-FU/LV. This result is consistent with the lack 
of drug interaction noted between irinotecan and 5-FU (Camptosar® US label). A summary table 
of PK parameters from 95 patients who received 60-180 mg/m2 Nal-IRI is found below (see Table 
1).
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Table 1
Summary Statistics of Nal-IRI PK Parameters across Multiple PK Studies
PK Parameters
Dose, 
mg/m2
Analytes
Total Irinotecan
SN-38
N
Median
%IQR
N
Median
%IQR
Cmax, μg/mL or 
ng/mL
60
4
28.8
86
4
3.8
226
80
25
38.0
36
25
4.7
89
90
6
53.6
37
6
7.5
89
100
11
41.9
41
11
6.2
79
120
45
59.4
32
45
7.2
57
180
4
102.4
87
4
11.8
89
T1/2
60
4
22.0
87
3†
145.1
233
80
23†
26.85
110
13†
49.3
103
90
6
14.8
97
6
35.7
53
100
11
21.6
192
10†
62.3
37
120
45
15.6
198
40†
57.4
67
180
4
22.8
86
4
50.2
122
AUC0-∞, h·μg/mL 
or h·ng/mL
60
4
352
489
3†
813
249
80
23†
1030
169
13†
587
69
90
6
1481
1123
6
506
102
100
11
919
256
10†
453
99
120
45
1258
192
40†
574
64
180
4
2076
90
4
1069
183
Vd, L/m2
60
4
3.0
87
NA
80
23†
2.2
55
90
6
1.5
40
100
11
2.2
24
120
45
1.9
52
180
4
2.1
30
†T1/2 and AUC0-∞were not calculated for a subset of patients due to insufficient number of samples in the terminal 
phase. NA= not available. Cmax are in μg/ml for total irinotecan and ng/ml for SN-38; AUC are in h μg/ml for total 
irinotecan and h ng/ml for SN-38 [Data on File, Merrimack Pharmaceuticals, Inc.].
The above PK results obtained from patients treated with either Nal-IRI or non-liposomal 
irinotecan confirmed the preclinical observation that Nal-IRI extended plasma PK of both CPT-11 
and SN-38 compared to treatment with non-liposomal irinotecan. Further, a Phase I clinical study 
of Nal-IRI monotherapy [14] investigated tumor levels of both CPT-11 and SN-38 following 
treatment with Nal-IRI using post-treatment biopsies. Based on model predictions, SN-38 levels 
in tumor were expected to be higher than in plasma, suggesting local conversion of CPT-11 to SN-
38 in the tumor microenvironment with Nal-IRI (Figure 3A). Predictions were confirmed by 
measuring levels of CPT-11 and SN-38 in tumor biopsy samples collected from patients 72 hours 
post-dose, demonstrating 5-fold higher levels of SN-38 in the tumor than the plasma (Figure 3 B-
C). Collectively the evidence suggests that the prolonged systemic exposure to CPT-11 and SN-
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38 leads to prolonged levels of SN-38 in tumor tissue, which in turn leads to prolonged DNA 
damage to tumor cells, suggesting an advantage of Nal-IRI compared to conventional irinotecan.
Figure 3
Clinical Evidence for Local Activation and Accumulation of SN-38 in Tumor 
Tissue
2.1.4
Nal-IRI Safety in Humans
It has been shown in animal and human PK studies that once irinotecan is released from the Nal-
IRI liposomes, the conversion of irinotecan to SN-38 is similar to that of the un-encapsulated 
irinotecan. The safety of Nal-IRI, therefore, may be indirectly compared with the safety of 
irinotecan, primarily based on a qualitative comparison of adverse reactions, as reported in the 
Camptosar® US label for irinotecan [Camptosar®, Pfizer]. The comparison is qualitative, as both 
irinotecan and Nal-IRI have been used in different doses and schedules as monotherapy and 
combination therapy with other chemotherapeutic agents; therefore, quantitative comparisons are 
difficult. The most common adverse reactions of irinotecan and Nal-IRI are similar and are mainly 
gastrointestinal events and myelosuppression. The common adverse reactions (>30%) observed in 
clinical studies with irinotecan in combination with other agents are: nausea, vomiting, abdominal 
pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including 
lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, 
and alopecia. The common adverse reactions (>30%) observed in single agent irinotecan therapy 
in clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, 
neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight 
decreasing, and alopecia (Camptosar® US label). With respect to liposomal irinotecan, Nal-IRI, 
when used in combination with 5-FU and leucovorin, the most common adverse reactions (≥20%) 
observed in clinical trials considered to be related are: diarrhea, nausea, vomiting, decreased 
A) The mechanistic tumor PK model of Nal-IRI predicted higher SN-38 levels in tumor compared 
to plasma. The range of actual data, collected from a Phase I study of patients (n=12) with 
advanced solid tumors, is indicated by the gray (tumor) or green (plasma) vertical bars.
B) CPT-11 levels
C) SN-38 levels, as measured from patient tumor (black) and plasma (green) samples collected 
72h post-Nal-IRI infusion [14]. 
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appetite, neutropenia, fatigue, anemia, stomatitis and pyrexia. The overall safety profile of Nal-
IRI is presented in detail in the related Investigator Brochure. Additionally, Table 2 (refer to 
ONIVYDE® package insert, revised: 06/2017 ) summarizes the most common ≥Grade 3 adverse 
events with ≥2% incidence compared with the control arm from the NAPOLI-1 trial comparing 
Nal-IRI + 5-FU/LV (at a dose of 80 mg/m2 given on an every-2-week schedule), or Nal-IRI 
monotherapy (at a dose of 120 mg/m2 given on an every-3-week schedule), with 5-FU/LV alone 
(given weekly for 4 weeks followed by 2 weeks of rest) in the same population of patients who 
had received prior gemcitabine therapy.
Table 2
Summary of Grade 3 or Higher Adverse Events in NAPOLI-1 Study
2.2
Fluorouracil and Leucovorin (5-FU/ LV)
5-Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. The 
deoxyribonucleotide of the drug inhibits thymidylate synthase, thus inhibiting the formation of 
thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA. It also interferes 
with RNA synthesis and is used in the treatment of carcinoma of the colon, rectum, breast, stomach 
and pancreas.
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of 
purines and pyrimidines. Leucovorin does not require the enzyme dihydrofolate reductase (DHFR) 
for conversion to tetrahydrofolic acid. The effects of methotrexate and other DHFR-antagonists 
are inhibited by leucovorin. Leucovorin can potentiate the cytotoxic effects of fluorinated 
pyrimidines (i.e., fluorouracil and floxuridine). After 5-FU is activated within the cell, it is 
accompanied by a folate cofactor, and inhibits the enzyme thymidylate synthase, thus inhibiting 
pyrimidine synthesis. Leucovorin increases the folate pool, thereby increasing the binding of folate 
cofactor and active 5-FU with thymidylate synthase.
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2.3
Rationale for Combination Therapy
Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide–
platinum combination is considered the standard chemotherapy, but duration of benefit is short 
and survival ~ one year or less, and currently no standard second line therapy exists. Irinotecan 
alone or in combination has shown some efficacy in patients treated for small cell lung cancer 
which had pathological similarities with neuroendocrine tumors and temozolomide and 
capecitabine has shown efficacy but with limited response rates in non-pancreatic NETs. The 
Nordic study evaluated survival in patients who received either platinum or temozolomide based 
regimens first line and reported survival of ~11-13 months in both groups. Currently the ECOG –
ACRIN Cancer research group is studying the optimal first line regimen in NCT 02595424.
In a retrospective study to determine safety and efficacy of the FOLFIRI regimen in patients with 
NECs grade 3 after failure of etoposide–platinum combination, efficacy was seen in patients with 
high grade NECs. Among 39 patients who failed etoposide–platinum combination, 19 (49%; 12 
women, median age 53 (29–78) years) received the FOLFIRI regimen with a median number of 6 
(1–16) courses. Six patients (31%) had at least one episode of grades 3–4 toxicity (neutropenia, 
n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable 
disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 
months. Overall survival was 18 vs 6.8 months in ineligible patients. The authors concluded that 
FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients 
with NECs grade 3 who remain in good condition and with reasonable LFTs after failure of 
etoposide–platinum combination, however to our knowledge this has not yet been studied 
prospectively. Others have shown FOLFOX has activity in NETs of all grades, as well as 
Temodar® and capecitabine is a commonly used regimen confirming the role of both irinotecan 
and 5-FU in this disease. [17, 18, 19]
The NAPOLI trial in second line advanced pancreatic adenocarcinoma showed the safety and 
tolerability and success of nanoliposomal irinotecan in this setting and was recently approved for 
use. The regimen is well-tolerated and most frequent toxicities seen are neutropenia, diarrhea, 
vomiting, and fatigue. The most recent SEER database publication updating survival of all Nets 
shows that grade 3 and 4 Nets have a median survival of 10 months, with no new therapies under 
development for these patients clearly represent an area of unmet need.
5-FU based therapy is the current practice although it is not standard and we hypothesize that 
Nal-IRI+ 5-FU would offer significant response, with maintenance of QOL, and be a viable second 
line option for these patients.
3
INCLUSION AND EXCLUSION CRITERIA
3.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years.
2. Participant 
must 
have 
a 
locally 
advanced 
and 
unresectable 
or 
metastatic 
gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal (GI) tract, 
pancreas, or of other known or unknown primary site where 5FU based therapy would be 
considered reasonable by the treating MD, lung primary is excluded. Patients may have 
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either progressed on therapy or within 6 months of completing therapy or be intolerant of 
therapy to be considered eligible.
3. Participant must have tissue available for central pathology review and, must have 
pathologically/histologically confirmed high grade neuro endocrine defined as Ki-67 
proliferative index of 20-100% or, must have evidence of at least 10 mitotic figures per 10 
high powered fields. 
4. Comprehensive Genomic Profiling must be ordered per institutional guidelines prior to 
enrollment using archival tissue, fresh tissue, or blood sample as part of standard of care. 
If no archival tissue is available, then patient must have fresh biopsy prior to treatment 
administration if clinically indicated.  If fresh biopsy is not required as part of standard of 
care, then a blood sample will be collected and used instead. 
5. Have an ECOG Performance Status of 0 - 2. Appendix H
6. Have the following clinical laboratory values:

Leukocytes ≥ 3,000/mm3

Absolute neutrophil count ≥ 1,500/mm3

Hemoglobin ≥ 9 g/dL

Platelets ≥ 100,000/mm3

Total bilirubin ≤ institutional upper limit of normal (ULN) or ≤ 1.5 X institutional 
ULN (if the patient has liver metastases)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase 
[SGPT]) ≤ 2.5 X institutional ULN or (≤ 5 X institutional ULN if the patient has 
liver metastases)

Serum or plasma creatinine ≤ 1.5 X institutional ULN or
Measured or calculated creatinine clearance by Cockcroft Gault Equation ≥ 50 
mL/min for subjects with creatinine levels > 1.5 X ULN (refer to Appendix F).
7. Have measurable disease per RECIST 1.1 criteria present.
8. Participant must have a life expectancy of ≥ 12 weeks as determined clinically by the 
treating physician.
9. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., barrier or hormonal plus barrier method of birth control; abstinence) prior to study 
entry. Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately.

A female of childbearing potential is any woman, regardless of sexual orientation or 
whether they have undergone tubal ligation, who meets the following criteria: 1) has 
not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months)

Women of childbearing potential and sexually active males must be strongly advised 
to use an accepted and effective method of contraception or to abstain from sexual 
intercourse for the duration of their participation in the study
10. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
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Refer to Appendix A for the ELIGIBILITY VERIFICATION FORM: INCLUSION CRITERIA 
checklist.
3.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. 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 trial treatment. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability.
2. Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency.
3. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
4. Known hypersensitivity to any of the components of Nal-IRI, other liposomal products, 
fluoropyrimidines, or leucovorin.
5. Investigational therapy administered within 4 weeks, or within a time interval less than at 
least 5 half-lives of the investigational agent, whichever is longer, prior to the first 
scheduled day of dosing in this study.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or nursing female participants.
8. Unwilling or unable to follow protocol requirements.
9. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
Refer to Appendix B for the ELIGIBILITY VERIFICATION FORM: EXCLUSION 
CRITERIA checklist.
3.3
Special Populations
The following special populations will be excluded:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Pregnant women

Prisoners
3.4
Inclusion of Women and Minorities
Men, women, and members of all races and ethnic groups are eligible for this study.
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 37 evaluable participants at multiple sites, including Roswell Park, are required. 
To account for non-evaluable patients, a total of 41 patients may be accrued.
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5
LOCAL AND STUDY-WIDE RECRUITMENT METHODS
Participants will be identified/recruited/screened from patients at the Gastrointestinal Center at 
Roswell Park and from GI clinics at participating sites, from multi-disciplinary conference 
discussion and from community referral.
6
MULTI-SITE RESEARCH
It is the responsibility of the principal Investigator to ensure that:

All sites have the most current version of the protocol, consent document, and HIPAA 
authorization.

All required approvals (initial, continuing review and modifications) have been obtained 
at each site (including approval by the site’s IRB of record).

All modifications have been communicated to sites and approved (including approval by 
the site’s IRB of record) before the modification is implemented.

All engaged participating sites will safeguard data, including secure transmission of data, 
as required by local information security policies.

All local site investigators will conduct the study in accordance with applicable federal 
regulations and local laws.

All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy.
Refer to Appendix C: Instructions for Multiple Site Studies.
7
STUDY TIMELINES
A maximum of 37 evaluable participants at multiple sites, including Roswell Park, will be enrolled. 
Accrual is expected to take approximately 6 years.
8
STUDY ENDPOINTS
8.1
Primary Endpoint

Objective Response Rate as determined by RECIST 1.1
8.2
Secondary Endpoints
To determine overall survival, progression-free survival, time to treatment failure, safety, clinical 
response and, quality of life (QOL)

Overall Survival: Determined from time of first dosing of study treatment combination to 
time of death or initiation of a new therapy, whichever occurs first

PFS: Determined from time of first dosing of study treatment combination to documented 
disease progression by RECIST 1.1.

Time-to Treatment Failure (TTF): Defined as the time from study enrollment to 
discontinuation of treatment for any reason, including disease progression, treatment 
toxicity, and death.
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
The proportion of patients achieving an objective response based on prior response to 
platinum etoposide

Clinical benefit response (i.e., either achievement of pronounced and sustained [≥4 weeks 
contiguous] improvement in pain intensity, analgesic consumption, or performance status, 
or a combination of these, without any worsening in any of the other factors, or stability in 
pain intensity, analgesic consumption, and performance status with pronounced and 
sustained [≥4 weeks contiguous] weight gain)

QOL: EORTC-QLQ-C30

Safety 
8.3
Exploratory Endpoint

 Comprehensive molecular profiling for mutations, immune-oncology biomarkers (Tumor 
Mutational Burden and Microsatellite Instability) and for select protein expression 
biomarkers (ERCC1, MGMT, PD-L1, TOP2A, TS) will be conducted on all pre-study 
tumor samples (tissue or liquid biopsy) and will be correlated with patient treatment 
outcome. 
9
DESIGN
This is an open-label, single-arm, multi-center Phase 2 study of Nal-IRI + 5-FU/LV in patients 
with refractory advanced high-grade neuroendocrine cancer of GI, unknown or pancreatic origin.
10 TREATMENT
10.1 Dosing and Administration
Nal-IRI + 5-FU/LV: Day 1 and Day 15 of each 28-day cycle

Nal-IRI 70 mg/m2 (equivalent to 80 mg/m2 irinotecan HCl trihydrate salt) IV infusion over 
90 minutes ( -10 min/+ 15 min) followed by, 

Leucovorin (l + d racemic form) 400 mg/m2, IV over 30 min (± 5 minutes) then, 

5-FU 2400 mg/m2 IV over 46 hours (±60 minutes), on Days 1 and 15 of each 28-day cycle.
According to the Prescribing Information, the recommended starting dose of Nal-IRI in patients 
known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous 
infusion over 90 minutes. The dose may be increased to 70 mg/m2 after the first cycle in the 
absence of drug-related toxic effects.
Investigators are advised to counsel subjects assigned to receive 5-FU about risk of 
photosensitivity and to take sun protection measures accordingly.
10.1.1 Premedication
A corticosteroid and an antiemetic should be administered 30 minutes prior to Nal-IRI infusion.
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10.1.2 Administration of Nal-IRI
Prior to administration, the appropriate dose of Nal-IRI must be diluted in 5% Dextrose Injection 
(D5W) or 0.9% Sodium Chloride Injection to a final volume of 500 mL. Care should be taken not 
to use any diluents other than D5W or 0.9% sodium chloride.
The actual dose of Nal-IRI to be administered will be determined by calculating the patient’s body 
surface area at the beginning of each cycle. A ± 5% variance in the calculated total dose will be 
allowed for ease of dose administration. Since Nal-IRI vials are single-use vials, site staff must not 
store any unused portion of a vial for future use and they must discard unused portions of the 
product.

Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard 
unused portion.

Nal-IRI will be administered on Days 1 and 15 of each 28-day cycle. Given the variability 
of infusion pumps, a window of -10 minutes and +15 minutes is permitted (i.e., infusion 
time is 90 minutes: -10 min/+15 min).
Treatment will continue until disease progression or intolerable toxic effects arise.
Reported adverse events (AEs) and potential risks are described in Section 13. Appropriate dose 
modifications are described in Section 10.2.
Treatment is intended for an outpatient setting. However, at the investigator’s/physician’s 
discretion, the participant may receive treatment as an inpatient, if deemed necessary.
10.2 Dose Modifications and Treatment Delays
Nal-IRI and 5-FU/LV have class specific safety profiles based on their mechanism of action but 
may also cause AEs that overlap. For management of AEs which can be clearly attributed to Nal-
IRI or 5-FU/LV, or AEs without clear attribution to either study treatment, management of toxicity 
should include temporary hold or permanent discontinuation of both agents.
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Table 3
Recommended Dose Modifications for Nal-IRI
Toxicity
NCI CTCAE v5.0
Occurrence
Nal-IRI adjustment in 
participants receiving 
70 mg/m2
Participants 
homozygous for 
UGT1A1*28 without 
previous increase to 
70 mg/m2
Withhold Nal-IRI.
Initiate loperamide for late onset diarrhea of any severity.
Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless 
clinically contraindicated) for early onset diarrhea of any severity.
Upon recovery to ≤ Grade 1, resume Nal-IRI at:
First
50 mg/m2
43 mg/m2
Second
43 mg/m2
35 mg/m2
Grade 3 or 4 adverse 
reactions
Diarrhea 
Third
Discontinue Nal-IRI
Discontinue Nal-IRI
Interstitial Lung Disease
First
Discontinue Nal-IRI
Discontinue Nal-IRI
Anaphylactic Reaction
First
Discontinue Nal-IRI
Discontinue Nal-IRI
10.2.1 Diarrhea
Irinotecan can induce both early and late forms of diarrhea that appear to be mediated by different 
mechanisms. Early diarrhea (occurring during or shortly after infusion of irinotecan) is cholinergic 
in nature. It is usually transient and only infrequently severe. It may be accompanied by symptoms 
of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyper-
peristalsis that can cause abdominal cramping. For patients who experienced early cholinergic 
symptoms during the previous cycle of Nal-IRI, prophylactic administration of atropine will be 
given at the discretion of the investigator. Late diarrhea (generally occurring more than 24 hours 
after administration of irinotecan) can be life threatening since it may be prolonged and may lead 
to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with 
Loperamide, and octreotide should be considered if diarrhea persists after Loperamide, as 
described below (Therapy for Diarrhea). Loss of fluids and electrolytes associated with persistent 
or severe diarrhea can result in life threatening dehydration, renal insufficiency, and electrolyte 
imbalances, and may contribute to cardiovascular morbidity. The risk of infectious complications 
is increased, which can lead to sepsis in patients with chemotherapy-induced neutropenia. Patients 
with diarrhea should be carefully monitored, given fluid and electrolyte replacement if they 
become dehydrated, and given antibiotic support if they develop ileus, fever, or severe neutropenia.
Therapy for Diarrhea
Acute diarrhea and abdominal cramps, developing during or within 24 hours after Nal-IRI 
administration, may occur as part of a cholinergic syndrome. The syndrome can be treated with 
atropine. Prophylactic or therapeutic administration of atropine, according to institutional 
standards, should be considered in patients experiencing cholinergic symptoms during the study. 
Diarrhea can be debilitating and on rare occasions is potentially life-threatening. Diarrhea should 
be managed according to institutional guidelines. In general, for grade 3 or 4 diarrhea, Nal-IRI 
should be withheld. Loperamide should be initiated for late-onset diarrhea of any severity. 
Intravenous or subcutaneous atropine 0.25 to 1 mg should be administered (unless clinically 
contraindicated) for early-onset diarrhea of any severity.
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QTc prolongation that occurs in the setting of diarrhea induced electrolyte imbalance should be 
treated with appropriate electrolyte repletion. Once the underlying abnormality is corrected and 
the ECG abnormalities have reversed, treatment may continue under careful monitoring and with 
appropriate dose modification for diarrhea as described above.
10.2.2 Neutropenia
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
irinotecan and Nal-IRI. Neutropenic complications should be managed promptly with antibiotic 
support. G-CSF may be used to manage neutropenia at the investigator’s discretion.

Withhold Nal-IRI for absolute neutrophil count below 1500/mm3 or neutropenic fever: 
monitor blood cell counts periodically during treatment.
10.2.3 Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been 
observed with irinotecan, however, have not been observed with Nal-IRI to date. This could be 
due to the limited cumulative patient exposure to date of Nal-IRI, or the use of appropriate 
premedication and early recognition and treatment of expected adverse events. There is insufficient 
evidence to know whether these known adverse reactions of irinotecan are also associated with 
Nal-IRI. Suspected drugs should be withheld immediately and aggressive therapy should be given 
if hypersensitivity reactions occur.

Nal-IRI can cause severe hypersensitivity reactions, including anaphylactic reactions. 
Permanently discontinue Nal-IRI in patients who experience a severe hypersensitivity 
reaction.
10.2.4 Interstitial Lung Disease (ILD)
Nal-IRI can cause severe and fatal ILD.

Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, 
pending diagnostic evaluation.

Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
10.2.5 Colitis/ Ileus
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. 
Patients experiencing ileus should receive prompt antibiotic support.
10.2.6 Thromboembolism
Thromboembolic events have been observed in patients receiving irinotecan-containing regimens; 
the specific cause of these events has not been determined.
10.2.7 Patients at Particular Risk
In clinical trials of the weekly schedule of irinotecan, it has been noted that patients with modestly 
elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a significantly greater 
likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that 
were less than 1.0 mg/dL (50.0% [19/38] versus 17.7% [47/226]; p<0.001). Patients with abnormal 
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glucuronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk of 
myelosuppression when receiving therapy with irinotecan.
10.2.8 Acute Infusion Associated Reactions
Acute infusion-associated reactions characterized by flushing, shortness of breath, facial swelling, 
headache, chills, back pain, tightness of chest or throat, and hypotension have been reported in a 
small number of patients treated with liposome drugs. In most patients, these reactions generally 
resolve within 24 hours after the infusion is terminated. In some patients, the reaction resolves by 
slowing the rate of infusion. Most patients who experienced acute infusion reactions to liposome 
drugs can tolerate further infusions without complications. See Section 10.3.3 for guidelines on 
the management of infusion reactions.
10.2.9 Other Potential Toxicities
Nal-IRI, the liposomal formulation of irinotecan is different from irinotecan in un-encapsulated 
formulation, so there is a potential for toxicities other than those caused by irinotecan. All patients 
should be monitored closely for signs and symptoms indicative of drug toxicity, particularly during 
the initial administration of treatment.
10.2.10  Pregnancy
The pregnancy category of irinotecan is D. Women of childbearing potential should be advised to 
avoid becoming pregnant while receiving treatment with irinotecan. If a pregnancy is reported, 
treatment should be discontinued. The patient should be withdrawn from the study, and the 
pregnancy should be followed until the outcome becomes known.
10.3 General Concomitant Medication and Supportive Care
10.3.1 Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
10.3.2 Care of Intravenous Site
Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of 
inflammation. Should extravasation occur, flushing the site with sterile saline and applications of 
ice are recommended, or as per institutional standard of care.
10.3.3 Management of Infusion Reactions
Infusion reactions will be defined according to the National Cancer Institute CTCAE (Version 5.0) 
definitions of an allergic reaction or anaphylaxis as defined below:
Allergic reaction (i.e., a disorder characterized by an adverse local or general response from 
exposure to an allergen):

Grade 1: Transient flushing or rash, drug fever <38° C (<100.4°F); intervention not 
indicated
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
Grade 2: Intervention or infusion interruption indicated; responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated 
for ≤ 24 hrs.

Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary 
infiltrates)

Grade 4: Life-threatening consequences; urgent intervention indicated
Anaphylaxis (i.e., a disorder characterized by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing hypersensitivity 
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis 
and loss of consciousness and may lead to death):

Grade 1: Not applicable

Grade 2: Not applicable

Grade 3: Symptomatic bronchospasm, with or without urticaria; parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension

Grade 4: Life-threatening consequences; urgent intervention indicated
Institutional policies or the following treatment guidelines shall be used for the management of 
infusion reactions.
Grade 1

Slow infusion rate by 50%

Monitor patient every 15 minutes for worsening of condition

Future infusions may be administered at a reduced rate (e.g. over 120 minutes for Nal- 
IRI), at the discretion of the Investigator
Grade 2

Stop infusion

Administer diphenhydramine hydrochloride 50 mg IV, acetaminophen 650 mg orally, and 
oxygen

Resume infusion at 50% of the prior rate once infusion reaction has resolved

Monitor patient every 15 minutes for worsening of condition

For all subsequent infusions, pre-medicate with diphenhydramine hydrochloride 50 mg IV, 
dexamethasone 10 mg IV and acetaminophen 650 mg orally.

Future infusions may be administered at a reduced rate (e.g., over 120 minutes for Nal- 
IRI), at the discretion of the Investigator
Grade 3

Stop infusion and disconnect infusion tubing from patient
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
Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
necessary

No further treatment will be permitted 
 Grade 4

Stop the infusion and disconnect infusion tubing from patient

Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm

Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV and other 
medications as medically necessary

Consider hospital admission for observation

No further treatment will be permitted
For patients who experience a second grade 1 infusion reaction, administer dexamethasone 10 mg 
IV. All subsequent infusions should be pre-medicated with diphenhydramine hydrochloride 50 mg 
IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally or as per institutional guidelines.
10.4 Prohibited Therapy
The following drugs are noted in the irinotecan prescribing information as interacting with 
irinotecan: St. John’s Wort, CYP3A4 inducing anticonvulsants (phenytoin, phenobarbital, and 
carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and 
verapamil. Treatment with these agents and any others that interact with irinotecan or 5-FU or 
leucovorin should be avoided wherever possible. Because 5-FU interacts with warfarin, caution 
should be exercised if concomitant use is necessary. No live attenuated vaccines should be given 
to participants. Refer to package inserts of 5-FU and leucovorin for any other drug interactions.
The following therapies are not permitted during the study treatment phase:
a) Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy or 
antibodies
b) Potentially curative radiotherapy: palliative radiotherapy is permitted
c) Any other investigational therapy
10.5 Other Considerations
10.5.1 Contraception
Nal-IRI and 5-FU/LV may have adverse effects on a fetus in utero. Furthermore, it is not known 
if Nal-IRI and 5-FU/LV have transient adverse effects on the composition of sperm.
Female and male participants of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for six (6) months after the 
last dose of study drug by complying with one of the following:
1
Practice abstinence from heterosexual activity; OR
2
Use (or have their partner use) acceptable contraception during heterosexual activity.
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Acceptable methods of contraception are:

Single method (one of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female subject’s male partner 
o
Contraceptive rod implanted into the skin

Combination method (requires use of two of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)  
o
Contraceptive sponge (nulliparous women only) 
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection.
Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study participants of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to six (6) months after the 
last dose of trial therapy. If there is any question that a subject of childbearing potential will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study.
10.5.2 Use in Pregnancy
If a participant inadvertently becomes pregnant while on treatment with Nal-IRI and Nal-IRI, the 
subject will immediately be removed from the study. The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor and to Ipsen without 
delay and within 24 hours to the Sponsor and within 2 working days to Ipsen if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Ipsen and followed as described in Section 17.2.2.
10.6 Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of disease 
progression, unacceptable toxicity or withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
oral medication regime, and participant withdraws from study.
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11 PROCEDURES INVOLVED
11.1 Participant Registration:
Eligibility of each participant will be established prior to registration.
Informed consent MUST be completed prior to receiving any study related procedures.
11.2 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Appendix D.
11.2.1 Baseline/ Screening Visit
The screening phase will begin once the patient signs the informed consent form. All procedures 
for screening and baseline are outlined in Appendix D: Schedule of Procedures and Observations. 
For further descriptions of the clinical and laboratory assessments required, please refer to Sections 
11.3 and 11.4 respectively.
11.2.2 On-Study Visits
Patients who are confirmed to meet all inclusion and exclusion criteria will be enrolled into the 
study. The first dose (Cycle 1 Day 1) must be given within 7 days of enrollment. All study 
procedures and assessments are outlined in Sections 11.3, 11.4, and Appendix D. 
During the treatment period, a window of ±2 days will apply to all visits, unless otherwise stated.
11.2.3 End of Treatment Visit
All patients must complete an End of Treatment (EOT) assessment at the time the Investigator 
removes the patient from treatment. This assessment should occur approximately 30 days 
(± 14 days) after the last dose of study treatment. All procedures and assessments are outlined in 
Appendix D.
11.2.4 Long-term Follow-up
After the End of Treatment visit, patients should continue to be followed for survival status once 
every 8 weeks (± 7 days) via telephone, email, clinic visit, or medical record review until death, 
lost to follow-up, withdrawal of consent, or study closure, whichever occurs first. 
Additionally, data on subsequent anti-cancer treatments should be collected during these contacts 
and documented in the eCRF. In the case of patients who are discontinued for reasons other than 
progressive disease per RECIST v1.1, disease evaluations (including imaging studies) should 
continue into the follow-up period, as described in Section 11.3.6below.
Participants who are unavailable for follow-up evaluations should be classified as lost to follow-
up for 1 of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator must 
make two separate attempts to re-establish contact with the participant. The attempts to re-
establish participant contact must be documented (e.g., certified letter).

Death: Date and cause of death will be recorded for those participants who die within 
30 days after last dose of study drug (telephone verification is acceptable).
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11.3 Clinical Procedures
11.3.1 Medical History and Pre-existing Conditions
A medical history will include all pertinent prior medical conditions, surgeries or other medical 
procedures, along with demographic information, as applicable.
11.3.2 Physical Examination and Vital Signs
Vital signs will include height (at baseline/screening only), weight, resting blood pressure, pulse, 
respiratory rate and temperature.
11.3.3 Performance Status
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be obtained at 
Screening and within 72 hours of enrollment by the Investigator or his/her designee via questioning 
of the patient about their functional capabilities (Appendix A).
11.3.4 Electrocardiogram (ECG)
A 12 lead ECG will include a description of the cardiac rate, rhythm, interval durations and an 
overall clinical interpretation. If the ECG is abnormal, clinical significance or non-significance 
should be indicated.
11.3.5 Adverse Event Assessment
The Investigator should complete all routine and standard of care assessments to evaluate for 
toxicity and symptoms of drug-induced adverse events. This may include, but is not limited to, 
verbal reports from the patient and/or caregiver, physical examination and laboratory findings.
The period for treatment-emergent adverse events and safety findings will be from the time of first 
study drug administration to 30 days after the date of last study drug administration. For detailed 
information on adverse event reporting, see Section 17. In addition, information on patient 
hospitalizations and/or hospital visits should also be collected, whether or not associated with an 
adverse event.
11.3.6 Disease Evaluation
Tumor response will be evaluated according to the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 [12], to establish disease progression by CT or MRI. In addition, other 
imaging procedures, as deemed appropriate by the Investigator, will be performed to assess sites 
of neoplastic involvement. The same method of assessment for each lesion must be used 
throughout the study. Investigators should select target and non-target lesions in accordance with 
RECIST v1.1 guidelines. Follow up measurements and overall response should also be in 
accordance with these guidelines.
Tumor assessments should be completed until it has been determined that the patient has 
progressive disease (in accordance with RECIST v1.1). 
For patients who do not have documented disease progression per RECIST v. 1.1 at the time of 
treatment termination, imaging studies should continue to be performed into the follow-up period 
every 8 weeks until radiological disease progression is documented.
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11.3.7 EORTC-QLQ-C30
Health-related quality of life (HRQL) will be assessed by the EORTC-QLQ-C30. The EORTC-
QLQ-C30 is a reliable and widely used measure of the quality of life of cancer patients in 
multicultural clinical research settings. It incorporates nine multi-item scales: five functional scales 
(physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea 
and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures 
are also included (Appendix E).
Patients will be required to complete the EORTC-QLQ-C30 at the time points outlined in the 
Schedule of Procedures and Observations (Appendix D). On days that the patient is to receive 
study drug, assessments should be completed prior to study drug administration.
11.4 Laboratory Procedures
Whole blood samples will be collected and assessed locally at baseline, Day 1 of every treatment 
cycle and at the End of Treatment follow-up visit.
Note: Blood and urine samples will be processed and analyzed in accordance with each 
participating sites’ institutional guidelines and standard operating procedures.
11.4.1 Hematology
Complete blood count (CBC) with automated differentials: Must include a white blood count 
(WBC) and differential, hemoglobin, hematocrit and platelet count.
11.4.2 Chemistry
Comprehensive metabolic panel (CMP): chloride, CO2, potassium, sodium, BUN, glucose, 
calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G 
ratio, BUN/creatinine ratio, osmol (Calc), anion gap. In addition:

Magnesium

Phosphate
11.4.3 UGT1A1*28
A whole blood sample will be collected and assessed locally at baseline to test for UGT1A1*28 
allele status. The result is not needed prior to the initial dose of Nal-IRI.
11.4.4 Urine or Serum Pregnancy Test
A urine or serum pregnancy test will be obtained for all females of childbearing potential at 
screening, at the start of each cycle during study treatment, and at the End of Treatment visit. 
Exempt female patients will include those who have undergone a bilateral oophorectomy or 
hysterectomy or who are menopausal (defined as absence of a menstrual cycle for at least 24 
consecutive months).
11.4.5 Comprehensive Genomic Profiling
Archival tissue (if available) or fresh tissue (if archival not available, and if clinically indicated to 
re-biopsy) or blood sample should be submitted for Comprehensive Genomic Profiling (using any 
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NGS laboratory per institutional guidelines) or data collection of prior results, as per standard of 
care, in order to meet inclusion criteria. Archival or fresh tissue, blood, or data collection of prior 
results must be obtained for genomic profiling at baseline and prior to treatment initiation.
If a site is utilizing a commercial vendor for NGS, they will fill the appropriate forms to conduct 
standard of care comprehensive genomic profiling and send the tumor biopsy samples or blood 
sample for comprehensive genomic profiling.
NETWORK SITES: Data collection of results of comprehensive genetic profiling conducted 
prior to enrollment, as part of standard of care, will meet baseline inclusion criteria for 
comprehensive genetic profiling. 
For patients that have not had prior comprehensive genetic profiling performed prior to enrollment, 
tissue, archival or fresh, or a blood sample for profiling can be performed at a NGS Laboratory, 
per institutional guidelines of the participating sites as part of standard of care at baseline. 
Blood sample collection for FoundationOne®, processing and shipping information at the two 
other timepoints, see the FoundationOne® Appendix I. 
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
11.4.6  Central Pathology Review
Patient eligibility must be confirmed by central pathology review of existing histology specimens. 
The preference is for primary diagnostic tumor, rather than post-treatment tumor tissue.
The following slides of neuroendocrine tumor of GI tract (or unknown primary) and the 
corresponding surgical pathology report are required for this review:

Representative H&E 

Ki-67 stained slide

Pathology Report
FOR EXTERNAL (NETWORK) SITES: The slides and report should be labeled with the 
Clinical Study number (I-64518), Subject’s Study ID number and initials, and the Surgical 
Accession number. Network sites should use their own preferred shipping method to send the 
materials 
for 
Central 
Pathology 
review 
to 
the 
address 
below. 
Email 
CRSLabPathTeam@RoswellPark.org at time of submission with shipment information (e.g. 
courier tracking #) and slide return instructions.
Roswell Park Cancer Institute
c/o CSPO - Study I-64518
GBSB Room S-636
Elm and Carlton Streets
Buffalo, NY 14263
CRSLabPathTeam@RoswellPark.org
Ph: 716-845-1678
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Fax: 716-845-3216 
12 WITHDRAWAL OF SUBJECTS
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity: treatment related or unrelated

Investigator judgment

The Investigator may discontinue a participant if, in his/her judgment, it is in the best 
interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain 
information regarding the reason for withdrawal

Sponsor decision.
13 RISKS TO SUBJECTS
The most common adverse events (≥20 %) that were observed with Nal- IRI in combination with 
5-FU/LV in clinical trials considered to be related were: diarrhea, fatigue/asthenia, vomiting, 
nausea, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 
10% Grade 3 or 4) were lymphopenia and neutropenia (see package insert).
14 POTENTIAL BENEFITS TO SUBJECTS
Tolerability of multi-drug regimens is important in advanced cancer. The longer the duration of 
manageable treatment should translate into improved outcome due to longer drug exposure. Triplet 
drug regimens such as FOLFIRINOX are known to have significant toxicity, and use is limited to 
patients with better performance status (i.e. ECOG performance score of 0 or 1). With prolonged 
FOLFIRINOX treatment, oxaliplatin is often discontinued from the regimen due to toxicity. 
Therefore, if equally effective doublet regimens can be identified, patients may be able to tolerate 
prolonged treatment better, and even poor performance status patients may receive benefit.
In addition, results from the NAPOLI-1 Phase 3 trial show statistically significant improvement 
of OS of the Nal-IRI + 5-FU/LV doublet in patients with metastatic pancreatic cancer previously 
treated with gemcitabine [15 16].
15 DATA AND SPECIMEN BANKING
Not Applicable: All tissue samples will be sent directly to the NGS lab that the institute chooses 
for analysis. 
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16 MEASUREMENT OF EFFECT
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [12]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria (refer to Appendix G for summary of RECIST 1.1 criteria).
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 8weeks (± 1 week) 
following initial documentation of objective response.
16.1 Response Parameters
Clinical assessments including QOL forms using EORTC QLQ 30 will occur at baseline and 
monthly while on study.
17 SAFETY EVALUATION
17.1 Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
17.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
17.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF. 
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
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17.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
17.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
17.2 Grading and Reporting Adverse Events
17.2.1 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 5.0 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology and documented according to the grading scales provided in the CTCAE Version 5.0.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.
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
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
17.2.2 Reporting and Follow-Up of Pregnancy
Patients who become pregnant while on study must immediately discontinue study treatment, and 
the pregnancy must be immediately reported to the medical monitor. Pregnancies occurring up to 
six (6) months after the completion of the study medication must also be reported to the Sponsor.
The Investigator should inform the patient of the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy.
In the event of a pregnancy occurring in the partner of a male patient participating in the study, the 
pregnant partner should be requested to report the pregnancy to the Sponsor. The partner should 
also be informed of the risks of continuing with the pregnancy, the possible effects on the fetus, 
and be followed until conclusion of the pregnancy.
17.3 Reporting Adverse Events:
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
Guidelines for Routine Adverse Event Reporting for Pilot, Phase 2, and Phase 3 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.4 Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.
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
A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
17.4.1 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
Roswell Park SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer to 
Section 17.7for details on reporting Unanticipated Problems.
17.5 Investigator Reporting: Notifying the Study Sponsor
Investigators MUST report within 1 business day upon becoming aware, to Ipsen ANY Serious 
Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention.
FAX: 866-681-1063 or
Email to: drugsafety.USA@ipsen.com
17.6 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
17.7 Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
a.
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data.
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b. The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 17.4.
17.7.1 Reporting Unanticipated Problems:
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CRS QA Office will submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
18 DATA MANAGEMENT AND CONFIDENTIALITY
18.1 Data Collection
Full build studies are managed by Roswell Park CRS Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs.
The genomic profiling results will be sent to the requesting Investigator at each site. The study 
coordinator will be responsible for entering results into the study database. 
18.2 Maintenance of Study Documents
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park.
18.3 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation.
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18.4 Termination of the Study
It is agreed that, for reasonable cause, either the Roswell Park Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, Roswell Park may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of participants enrolled in 
the study.
18.5 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
19 STATISTICAL PLAN
This is an open-label, single-arm, multi-center Phase 2 study of Nal-IRI + 5-FU/LV in patients 
with refractory advanced high-grade neuroendocrine cancer of GI, unknown or pancreatic origin. 
19.1 Sample Size Determination
A maximum of 37 participants evaluable for the primary outcome will be enrolled in this study. 
We expect to enroll approximately 6-7 patients per year; therefore accrual is expected to take 
6 years. The budget will allow for including of 10-15% more patients in case some are unevaluable 
for primary endpoint.
The sample size calculations are based on the primary analysis, using the Simon two-stage design 
based on the minimax criterion to evaluate the following hypotheses: H0: π≤π0 versus HA: π>π0. 
Historically, the objective response rate of this patient population is π0=0.15. We expect the true 
response rate (π) of the proposed treatment to be π=0.30; as such, the study design (n1=18 n2=19) 
achieves 80% power at a significance level of α = 0.1.
To account for patients that may be non-evaluable for response and are replaced, a total of 41 
patients may be accrued.
19.2 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
19.3 Primary Analysis
The primary objective of this study is to evaluate the objective response rate (ORR) of 
nanoliposomal irinotecan with fluorouracil (5-FU) and leucovorin in advanced high-grade 
neuroendocrine cancer of GI, unknown or pancreatic origin. The primary outcome is objective 
response (based on best overall response (CR+PR), as defined by the RECIST 1.1 criteria, within 
6 months of treatment initiation. Objective response will be treated as binary data and will be 
summarized using frequencies and relative frequencies; with the ORR estimated using an 80% 
confidence interval obtained using Jeffrey’s prior method.
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Historically, the ORR in this patient population is approximately 0.15. As such, a treatment with 
an ORR less than or equal to 0.15, it will not be considered promising, while a treatment with an 
ORR above 0.15 will be considered promising. Therefore, the primary analysis will utilize the 
Simon two-stage design (based on the minimax criterion) to test the following hypotheses:
H0: π=0.15 versus HA: π>0.15, 
where π is the true response rate of the proposed treatment combination. 
In stage 1, n1=18 will be enrolled and response evaluated. If T1=3 or fewer responses are observed, 
then the study will terminate and the treatment will not be considered promising; otherwise, an 
additional n2=19 patients will be enrolled in stage 2. If T=8 or fewer of the total n=n1+n2=37 
patients have a response the treatment will not be considered promising; otherwise the treatment 
will be considered promising for further study.
Subject replacement: Patients that drop-out of the study prior to evaluation of response due to 
clinical progression, toxicity, or other disease/treatment-related reasons will be treated as non-
responses. Patients who do not complete a response assessment prior to study drop-out due to non-
disease and non-treatment related reasons will be considered ‘non-evaluable for the primary 
outcome’ and will be replaced.
19.4 Secondary Analyses
The secondary objectives are to determine overall survival, progression-free survival, time to 
treatment failure, safety, clinical response and, quality of life (QOL).
Overall survival, progression-free survival, and time to treatment failure are treated as bivariate 
time-to-event data and will be summarized using standard Kaplan-Meier methods, where estimates 
of the median time will be obtained with 90% confidence intervals. The definition of the start- and 
end-dates for these variables is provided in Section 8.2.
Clinical benefit response (defined in Section 8.2) will be treated as binary data and summarized 
using frequencies and relative frequencies. The clinical benefit response rate will be estimated 
using a 90% confidence interval obtained by Jeffrey’s prior method.
The quality of life (QOL) measures based on the EORTC-QLQ-C30 will be treated as quantitative 
data and summarized by time-point using the mean and standard deviation. The QOL scores at 
each follow-up time may be compared with base-line levels using the paired t-test or sign test.
19.5 Safety Analysis
Toxicities and adverse events will be summarized by attribution and grade using frequencies and 
relative frequencies. High grade (3+) toxicity and adverse event rates may be estimated using 90% 
confidence intervals obtained by Jeffrey’s prior method. DSMB monitoring will also occur 
periodically to ensure safety of study subjects.
19.6 Interim Analysis
The primary efficacy analysis utilizes a Simon two-stage design based on the minimax criterion. 
In stage 1, n1=18 will be enrolled and response evaluated. If T1=3 or fewer responses are observed, 
then the study will terminate and the treatment will not be considered promising; otherwise, an 
additional n2=19 patients will be enrolled in stage 2.
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20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS
All Roswell Park studies will be reviewed at the scheduled Early Phase Clinical Trial Committee 
meetings and the minutes are forwarded to the IRB for review.
The Roswell Park Data and Safety Monitoring Committee (DSMC) will assess the progress of the 
study, the safety data, and critical efficacy endpoints. The DSMC will review the study and will 
make recommendations that include but not limited to; (a) continuation of the study, (b) 
modifications to the design (c) suspension of, or (d)termination of the study. 
21 VULNERABLE POPULATIONS
Not Applicable.
22 COMMUNITY-BASED PARTICIPATORY RESEARCH
Not Applicable.
23 SHARING OF RESULTS WITH SUBJECTS
Individual response data is shared with the participant as a part of their clinical care.
24 SETTING
All treatment will be conducted on an outpatient basis at the Gastrointestinal Center within 
Roswell Park and at the participating sites. Potential study participants will be identified and 
recruited from current GI Center patients and from community referral.
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26 RESOURCES AVAILABLE
Not Applicable.
27 PRIOR APPROVALS
Not Applicable.
28 COMPENSATION FOR RESEARCH-RELATED INJURY
If the subject believes they have been injured as a direct result of their participation in this research 
study, they will be advised to notify the Roswell Park Patient Advocate at (716) 845-1365 or the 
Study Doctor at (716) 845-8195.
Medical diagnosis and treatment for the injury will be offered, and a determination will be made 
regarding appropriate billing for the diagnosis and treatment of the injury. A financial counselor 
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(716-845-3161) will be able to provide an explanation of coverage and to answer questions the 
subject may have regarding study related billing.
The subject is not prevented from seeking to collect compensation for injury related to malpractice, 
fault, or blame on the part of those involved in the research.
29 ECONOMIC BURDEN TO SUBJECTS
The participants will not be subject to any economic burden.
30 CONSENT PROCESS
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
31 PROCESS TO DOCUMENT CONSENT IN WRITING
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed.
The Investigator or designee shall provide a copy of the signed consent form to the participant and 
the signed original shall be maintained in the Investigator File. A copy of the signed consent form 
must be filed in the participant file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options.
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32 DRUGS OR DEVICES
32.1 Nanoliposomal Irinotecan 
Nal-IRI (ONIVYDE®), in combination with fluorouracil and leucovorin, is approved by the FDA 
for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease 
progression following gemcitabine-based therapy.
Nal-IRI- will be provided by the study sponsor at no cost to the participant.
32.1.1 Active Substance and Source
Nanoliposomal irinotecan is a sterile, white to slightly yellow opaque isotonic liposomal 
dispersion. Each 10 mL single-dose vial contains 43 mg irinotecan free base at a concentration of 
4.3 mg/mL. The liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, 
which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the 
sucrose octasulfate salt. The vesicle is composed of 1, 2-distearoyl-sn-glycero-3-phosphocholine 
(DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, and methoxy-terminated polyethylene glycol (MW 
2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL. Each mL also 
contains 2-[4-(2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid (HEPES) as a buffer 
4.05 mg/mL and sodium chloride as an isotonicity reagent 8.42 mg/mL.
32.1.2 Drug Shipment
Nanoliposomal irinotecan will be provided by Ipsen and shipped to each participating site.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.1.3 Preparation
Refer to package insert.
32.1.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility and, in accordance with the applicable 
regulatory requirements.

Store Nal-IRI at 2ºC to 8ºC (36°F to 46°F).

Do NOT freeze.

Protect from light.
Drug storage temperature will be maintained and recorded, as applicable.
32.2 Fluorouracil and Leucovorin
Fluorouracil and Leucovorin costs will be covered by the participant or the participant’s medical 
insurance provider as standard of care treatment.
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33 REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67(1):7-30 
doi: 10.3322/caac.21387[published Online First: Epub Date]|.
2. Kalra AV, Kim J, Klinz SG, et al. Preclinical activity of nanoliposomal irinotecan is governed 
by tumor deposition and intratumor prodrug conversion. Cancer Res 2014;74(23):7003-
13 doi: 10.1158/0008-5472.CAN-14-0572[published Online First: Epub Date]|.
3. Chibaudel B, Maindrault-Goebel F, Bachet JB, et al. PEPCOL: a GERCOR randomized phase 
II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-
fluorouracil as second-line therapy in metastatic colorectal cancer. Cancer medicine 
2016;5(4):676-83 doi: 10.1002/cam4.635[published Online First: Epub Date]|.
4. Roy AC, Park SR, Cunningham D, et al. A randomized phase II study of PEP02 (MM-398), 
irinotecan or docetaxel as a second-line therapy in patients with locally advanced or 
metastatic gastric or gastro-oesophageal junction adenocarcinoma. Annals of oncology : 
official journal of the European Society for Medical Oncology / ESMO 2013;24(6):1567-
73 doi: 10.1093/annonc/mdt002[published Online First: Epub Date]|.
5. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy 
(NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 
2016;387(10018):545-57 doi: 10.1016/S0140-6736(15)00986-1[published Online First: 
Epub Date]|.
6. Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, 
pharmacology, and continued development of the camptothecins. Clin Cancer Res 
2002;8(3):641-61 
7. Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K. Intracellular roles of SN-38, a metabolite 
of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 
1991;51(16):4187-91 
8. Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S, Rustum YM. Irinotecan in the 
treatment of colorectal cancer: clinical overview. J Clin Oncol 2001;19(5):1501-18 doi: 
10.1200/JCO.2001.19.5.1501[published Online First: Epub Date]|.
9. Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly 
active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. 
Cancer Res 2006;66(6):3271-7 doi: 10.1158/0008-5472.CAN-05-4007[published Online 
First: Epub Date]|.
10. Kang MH, Wang J, Makena MR, et al. Activity of MM-398, nanoliposomal irinotecan (nal-
IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to 
drug and high SLFN11 expression. Clin Cancer Res 2015;21(5):1139-50 doi: 
10.1158/1078-0432.CCR-14-1882[published Online First: Epub Date]|.
11. Tsai CS, Park JW, Chen LT. Nanovector-based therapies in advanced pancreatic cancer. J 
Gastrointest Oncol 2011;2(3):185-94 doi: 10.3978/j.issn.2078-6891.2011.034[published 
Online First: Epub Date]|.
12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 
2009;45(2):228-47 doi: http://dx.doi.org/10.1016/j.ejca.2008.10.026[published Online 
First: Epub Date]|.
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13. Kang MH, Wang J, Makena MR, et al. Activity of MM-398, Nanoliposomal Irinotecan (nal-
IRI), in Ewing's Family Tumor Xenografts Is Associated with High Exposure of Tumor 
to Drug and High <em>SLFN11</em> Expression. Clinical Cancer Research 
2015;21(5):1139-50 doi: 10.1158/1078-0432.Ccr-14-1882[published Online First: Epub 
Date]|.
14. Ramanathan RK, Korn RL, Sachdev JC, et al. 261 Lesion characterization with ferumoxytol 
MRI in patients with advanced solid tumors and correlation with treatment response to 
MM-398, nanoliposomal irinotecan (nal-IRI). European Journal of Cancer 2014;50:87 
doi: 10.1016/S0959-8049(14)70387-9[published Online First: Epub Date]|.
15. Von Hoff D, Li CP, Wang-Gillam A, et al. O-0003NAPOLI-1: RANDOMIZED PHASE 3 
STUDY OF MM-398 (NAL-IRI), WITH OR WITHOUT 5-FLUOROURACIL AND 
LEUCOVORIN, VERSUS 5-FLUOROURACIL AND LEUCOVORIN, IN 
METASTATIC PANCREATIC CANCER PROGRESSED ON OR FOLLOWING 
GEMCITABINE-BASED THERAPY. Annals of Oncology 2014;25(suppl_2):ii105-ii06 
doi: 10.1093/annonc/mdu193.3[published Online First: Epub Date]|.
16. Chen LT, Wang-Gillam A, Li CP, et al. Final results of NAPOLI-1: A phase 3 study of nal-
IRI (MM-398) ± 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV in metastatic 
pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Annals of 
Oncology 2016;27(suppl_6):622PD-22PD doi: 10.1093/annonc/mdw371.14[published 
Online First: Epub Date]|.
17. Hadoux J et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine 
carcinoma. Endocr Relat Cancer. 2015 Jun;22(3):289-98.
18.  Faure M et al. Systemic chemotherapy with FOLFOX in metastatic grade 1/2 
neuroendocrine cancer. Mol Clin Oncol. 2017 Jan;6(1):44-48. 
19. Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014) 179-179.
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34 APPENDICES/ SUPPLEMENTS
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Appendix A
Inclusion Criteria Checklist
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM:
INCLUSION CRITERIA
Participant Name: (Multi-site: use participant initials): ___________________________
Medical Record No.: (Multi-site: use participant ID): _____________________________
Title: Phase 2 Single-Arm Study of Nanoliposomal Irinotecan with Fluorouracil and Leucovorin 
in Refractory Advanced High-Grade Neuroendocrine Cancer of GI, Unknown, or Pancreatic 
Origin 
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years.
2.
Participant must have a locally advanced and unresectable or metastatic 
gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal 
(GI) tract, pancreas, or of other known or unknown primary site where 
5FU based therapy would be considered reasonable by the treating MD, 
lung primary is excluded. Patients may have either progressed on 
therapy or within 6 months of completing therapy or be intolerant of 
therapy to be considered eligible.
3.
Participant must have tissue available for central pathology review and, 
must have pathologically/histologically confirmed high grade neuro 
endocrine defined as Ki-67 proliferative index of 20-100% or, must 
have evidence of at least 10 mitotic figures per 10 high powered fields.
4.
Comprehensive Genomic Profiling must be ordered per institutional 
guidelines prior to enrollment using archival tissue, fresh tissue, or 
blood sample as part of standard of care. If no archival tissue is 
available, then patient must have fresh biopsy prior to treatment 
administration if clinically indicated.  If fresh biopsy is not required as 
part of standard of care, then a blood sample will be collected and used 
instead.
5.
Have an ECOG Performance Status of 0 - 2. Refer to Appendix H.
6.
Have the following clinical laboratory values:

Leukocytes ≥ 3,000/mm3

Absolute neutrophil count ≥ 1,500/mm3

Hemoglobin ≥ 9 g/dL

Platelets ≥ 100,000/mm3

Total bilirubin ≤ institutional upper limit of normal (ULN) or ≤ 1.5 
X institutional ULN (if the patient has liver metastases)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic 
transaminase [SGOT])/alanine aminotransferase (ALT) (serum 
glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X institutional 
ULN or (≤ 5 X institutional ULN if the patient has liver 
metastases)

Serum or plasma creatinine ≤ 1.5 X institutional ULN OR,
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
Calculated creatinine clearance ≥ 50 mL/min for subjects with 
creatinine levels > 1.5 X ULN using Cockcroft-Gault equation 
(refer to Appendix F).
7.
Have measurable disease per RECIST 1.1 criteria present.
8.
Participant must have a life expectancy of ≥ 12 weeks as determined 
clinically by the treating physician.
9.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., barrier or hormonal plus barrier method of 
birth control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.

A female of childbearing potential is any woman, regardless of 
sexual orientation or whether they have undergone tubal ligation, 
who meets the following criteria: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive 
months)

Women of childbearing potential and sexually active males must 
be strongly advised to use an accepted and effective method of 
contraception or to abstain from sexual intercourse for the duration 
of their participation in the study
10. Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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Appendix B
Exclusion Criteria Checklist
Participant Name: (Multi-site: use participant initials): ___________________________
Medical Record No.: (Multi-site: use participant ID): _____________________________
Title: Phase 2 Single-Arm Study of Nanoliposomal Irinotecan with Fluorouracil and Leucovorin 
in Refractory Advanced High-Grade Neuroendocrine Cancer of GI, Unknown, or Pancreatic 
Origin 
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
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 trial treatment. This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.
2.
Participants with known dihydropyrimidine dehydrogenase (DPD) 
deficiency.
3.
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).
4.
Known hypersensitivity to any of the components of Nal-IRI, other 
liposomal products, fluoropyrimidines, or leucovorin.
5.
Investigational therapy administered within 4 weeks, or within a time 
interval less than at least 5 half-lives of the investigational agent, 
whichever is longer, prior to the first scheduled day of dosing in this 
study.
6.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
7.
Pregnant or nursing female participants.
8.
Unwilling or unable to follow protocol requirements.
9.
Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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Appendix C
Instructions for Multi-Site Studies 
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Comprehensive Cancer Center
CRS Quality Assurance (QA) Network Office
CRSNetworkCoordinators@RoswellPark.org
Elm and Carlton Streets
Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-8084
After hours, weekends, and holidays request the Roswell Park Investigator
716-845-2300
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by Roswell Park and can be amended to 
reflect institutional requirements.

All consent changes must be reviewed by Roswell Park QA Network Office prior to 
submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being 
used.

Within 5 business days, notify the Roswell Park QA Network Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
Roswell Park does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The 
Subject 
Screening 
and 
Enrollment 
Log 
must 
be 
emailed 
(CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park QA Network Office within 
1 business day of the date the participant is consented. Once the Investigator has determined that 
eligibility has been met, complete the eligibility check list and email it to the Roswell Park 
Network Coordinator at CRSNetworkCoordinators@RoswellPark.org.
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4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the Roswell Park 
Network, site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.

If an entry has been documented in error put a single line through the entry and initial 
and date the change. The Roswell Park Network QA Coordinator must be able to read 
what has been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of Roswell Park to inform the Investigator/ institution as to when 
these documents no longer need to be retained. If, for any reason, the Investigator 
desires to no longer maintain the study records, they may be transferred to another 
institution, another investigator, or to Roswell Park upon written agreement between 
the Investigator and Roswell Park.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug 
received, dispensed to participants and wasted, lot number, date dispensed, participant 
ID number and initials, quantity returned, balance remaining, manufacturer, expiration 
date, and the initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific; they are study source 
documents and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall 
be documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have 
its own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
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7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network Monitor within 1 business day of being 
made aware of the SAE to SafetyEventReporting@roswellpark.org. A preliminary written report 
must follow within 1 business day of the first notification using the following forms:

MedWatch 3500A
A complete follow-up report must be sent to the Roswell Park Network QA Coordinator when 
new information becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.7.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network Monitor within 1 business day of being made 
aware of the Unanticipated Problem by completing the Roswell Park Unanticipated Problem 
Report Form and emailing it to the Roswell Park Network QA Coordinator.
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Appendix D
Schedule of Procedures and Observations
Baseline/ 
Screening
Treatment Phase
Follow-Up Phase
Every 
Treatment 
Cycle3
Evaluation
-28 days
Day 1
Day 
15
Every 8 
weeks after 
1st dose of 
study drug 
treatment
End of 
Treatment 
Follow-up 
Visit4
Long Term 
Follow-Up5
Medical History
X1
Pre-Existing Conditions
X1
Physical Examination6, 
including vital signs7
X2
X
X
X
Comprehensive Genomic 
Profiling11
X 
Foundation liquid testing22
X (one time see 
Appendix I)
X22
Central Pathology Review23
X
ECOG Performance Status
X2, 12
X
X
EORTC-QLQ-C30
X2
X
12-lead electrocardiogram 
(ECG)8
X1, 13
X
Hematology9
X2, 14
X
X
X
Chemistry10
X2, 14
X
X
X
UGT1A1*28 testing
X2, 15
Pregnancy Test (Urine or 
Serum)
X2
X
X
Disease Assessment (CT/ 
MRI: chest, abdomen, 
pelvis)17 
X1a
X21
X
Study Drugs: Nal-IRI + 5-
FU/LV18
X
X
Concomitant Medications
X16
X
X
X
X
Adverse Events
X19
X
X
X
X
Survival Status20
X
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1
Procedures to be completed within 28 days prior to 1st dose of study drug.  
1a.  CT/MRI scan (of chest, abdomen, and pelvis) should be completed within 28 days or at the 
Sponsor’s (Principal Investigator) discretion prior to 1st dose of study drug.
2
Procedures to be completed within 7 days prior to 1st dose of study drug 
3
All cycles are 28-day cycles, unless modified due to toxicity.
4
The End of Treatment (EOT) Follow-Up visit should occur 30 days (± 14 days) after last dose of study 
drug.
5
Long-tern follow-up: Follow-up contact should be made every 8 weeks (± 7 days) until death or study 
completion; data collected should include overall survival status as well as subsequent treatment 
information.
6
Standard of care physical exam may be used if performed within 2 weeks prior to signed consent.
7
Vital signs will include height (at baseline/screening only), weight, resting blood pressure, pulse, 
respiratory rate and temperature.
8
To be repeated as clinically indicated during the study.
9
Hematology (CBC) with automated differentials: WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, absolute 
eosinophils, % basophils, absolute basophils, % lymphocyte, absolute lymphocyte, platelet confirmation 
(as clinically indicated), and differential confirmation (as clinically indicated
10
Chemistry (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), 
anion gap. In addition: magnesium, phosphate.
11
Comprehensive Genomic Profiling results are required for eligibility. Sites should use their preferred 
clinical lab for standard of care NGS testing on tissue or blood. Note: Prior genomic profiling results 
from any clinical laboratory, at any time prior to enrollment, can be used to meet this baseline criteria. 
12
ECOG to be performed at Screening and within 72 hours of enrollment.
13
Two independent readings at least 1 minute apart.
14
After screening, samples should be obtained within 2 days from scheduled date of collection.
15
Result not required prior to enrollment in the study or prior to receiving the initial dose of Nal-IRI.
16
Medications ongoing, or discontinued, within 1 week prior to first dose of study drug.
17
Disease evaluation according to RECIST v. 1.1 (see Section 16).
18
Administered on Day 1 and Day 15 of each 28-day Cycle. Refer to Section 10.1for dosing and 
administration. Study drug administration should occur ±2 days from scheduled date of administration.
19
Adverse events that occur during baseline/screening should be documented as pre-existing conditions; 
only SAEs that are felt by the Investigator to be directly related to a study procedure should be reported 
during baseline/screening.
20
Data collected should include overall survival status as well as subsequent treatment information.
21
Disease evaluations should be done every 8 weeks (± 7 days) after 1st dose.
22
Two 8.5 mL tubes of blood will be collected from each patient at two different time points: during the 
first follow-up scan (around 8 weeks) and at disease progression. Please see Appendix I at all sites.
23
High grade neuroendocrine tumor must be confirmed by Central Pathology Review at Roswell Park. 
Refer to Section 11.4.6 for specimen submission instructions.
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Appendix E
EORTC QLQ-C30 (version 3)
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Appendix F
Calculation for Serum or plasma Creatinine Clearance
Serum or Plasma Creatinine Clearance =
Serum or Plasma Creatinine Clearance =
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Appendix G
RECIST 1.1 Summary
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-approved 
facility using protocol-defined parameters. The same method of assessment and the same technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. RECIST 1.1 
will be used to assess objective tumor response.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, will be identified as target lesions and recorded and measured at baseline. Target lesions 
will be selected on the basis of their size. Lesions with the longest diameter (short axis for lymph nodes) 
and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and are for accurate repetitive 
measurements (either by imaging techniques or clinically) will be chosen. A sum of the longest diameter 
(short axis for lymph nodes) of all target lesions will be calculated and reported as the baseline sum 
diameters. This will be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease.
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have a reduction 
in short axis to < 10 mm. Changes in tumor measurements must be confirmed by repeat studies 
performed no less than 6 weeks after the criteria for response are first met.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. Changes in tumor measurements must be confirmed by repeat 
studies performed no less than 6 weeks after the criteria for response are first met.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
references 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. The appearance of one or more new lesions is also considered progression.
Stable Disease (SD): Neither a sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameter while on study. Participants having a 
documented response with no confirmation of the response will be listed with stable disease.
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short axis) and 
non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, blastic bone lesions, or abdominal masses / 
abdominal organomegaly identified by physical exam that is not measurable by imaging) should be 
identified as non-target lesions and indicated as present in the source documents at baseline. The general 
location will also be documented on the images drawing a regularly-shaped Region of Interest. 
Measurements of the non-target lesions will not be performed, but the presence or absence of each should 
be noted throughout follow-up and evaluation.
Complete Response: Disappearance of all non-target lesions and normalization of tumor marker level, 
if applicable. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target lesion(s) 
and/or maintenance of tumor marker level above the upper limits of normal.
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Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression of existing 
non-target lesions. Although a clear progression of non-target lesions is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status should 
be confirmed at a later time.
Evaluation of Response
Time point response assessments will be performed every 8 weeks. To determine time point response, refer 
to Table 4 and Table 5 below.
Table 4
Time Point Response Criteria: target (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 5
Time Point Response Criteria: non-target disease only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of efficacy in 
trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until disease 
progression/recurrence, taking into account any requirement for confirmation. In general, the participant’s 
best response assignment will depend on the achievement of both measurement and confirmation criteria 
and will be determined by combining the participant’s status of target lesions, non-target lesions, and new 
lesions.

Residual Disease: In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm 
the complete response status.

Symptomatic Deterioration: Participants with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, and 
not related to study treatment or other medical conditions should be reported as progressive 
disease due to “symptomatic deterioration.” Every effort should be made to document objective 
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progression even after discontinuation of treatment due to symptomatic deterioration. 
Symptomatic deterioration that may lead to discontinuation of treatment include, but is not 
limited to, symptoms such as:

Weight loss of > 10% of body weight.

Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing pain/increasing 
requirement for narcotic analgesics).

Decline in performance status of > 1 level on ECOG scale.
Confirmation Measurement
A confirmatory assessment is required no less than 6 weeks after a PR or CR is deemed.
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and never more than 4 weeks before the 
beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam.
Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an 
MRI is performed, the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the same pulse 
sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should 
be performed with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site 
can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there 
is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint.
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a participant to be considered in complete clinical 
response.
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG PET imaging can 
be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-
up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will be the date of 
the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET 
in this circumstance should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image.
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Appendix H
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix I
FoundationOne® Liquid testing (for all sites)
Background and Significance:  
Over the past few years, circulating tumor DNA (ctDNA) has emerged as an important diagnostic and 
predictive tool in different solid tumors. A recent study performed in non-small cell lung cancer showed 
that a comprehensive ctDNA analysis identified biomarkers more rapidly and completely than tissue-
based genotyping. Another study in melanoma patients showed that ctDNA levels correlate with treatment 
response and predict disease relapse before radiologic progression. A pilot study performed in 10 
pancreatic NET patients (including 1 high grade) detected tumor specific mutations and copy number 
variations in the ctDNA, however, there is very limited data on the molecular concordance between tissue 
and ctDNA in high-grade GEP-NETs. The long-term goal of our project is to identify if ctDNA can be 
used as an alternative to tissue-based genotyping in high-grade GEP-NETs. Besides we also aim to 
identify if ctDNA level can predict response to treatment in this population. Finally, using ctDNA, we 
want to assess if there is a genomic evolution of high-grade NETS during treatment. 
Methods: Patient samples from the proposed non-randomized, open-label, single-arm, Phase 2 study 
evaluating the efficacy of nanoliposomal irinotecan with fluorouracil and folinic acid in refractory 
advanced high-grade neuroendocrine cancer of GI, unknown or pancreatic origin (NCT03736720) will be 
used. Two 8.5 mL tubes provided by Foundation Medicine in their standard liquid biopsy kit and a 
custom requisition/manifest form with an FMI study ID on it will be provided to ensure each sample is 
processed as part of the clinical trial. 
For External Sites: For the research on treatment and follow-up samples, please obtain the 
FoundationOne® kit directly from FoundationOne® for use for this study.  Please use the special 
customized study requisition form when submitting the research FoundationOne® samples.  
Two 8.5 mL tubes of blood will be collected from each patient at two different time points: during the 
first follow up scan (around 8 weeks) and at disease progression. (If a patient shows progression at 8 
weeks or prior, only one sample will be collected). Collected blood will be sent for FoundationOne® 
Liquid assay which uses a hybrid-capture, next-generation sequencing test method combined with 
computational algorithms that enable accurate variant calls by discriminating sequencing artifacts from 
bona fide mutations. The liquid assay identifies base substitutions, indels, CNAs, and rearrangements in 
70 commonly altered oncogenes. ctDNA will be measured by quantification of Mutant Allele Fraction 
(MAF). To compare MAF pre and post therapy, a paired t-test will be used. A multivariate Cox 
proportional hazards regression analysis will be performed to correlate changes in MAF with progression-
free survival and overall survival. All tests are two-sided and will be performed at a nominal significance 
level of 0.05. 
Please see FoundationOne® liquid specimen instructions on the following page.
Shipping address:
Specimens will be sent to the address below:
Attn: Prospective Clinical Trial Specimen
Foundation Medicine
150 Second Street
Cambridge, MA 02141
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Specimen Instructions
Peripheral Whole Blood
Use only tubes provided inside the FoundationOne®Liquid Specimen 
Collection and Shipping Kit. Other tubes will not be accepted.
      Instructions For Use
Accurate analysis of cell-free DNA requires proper collection technique and handling of 
the sample. Failure to adhere to these instructions can compromise results by diluting 
cell-free DNA with DNA from white blood cell lysis.
Shipping Instructions
1. Place the samples, FoundationOne Liquid 
requisition form, insurance information, and 
any other attachments into the FoundationOne 
Liquid Specimen Collection and Shipping  Kit.
2. Place the specimen kit (including samples 
and paperwork) into the provided FedEx 
shipping pack, first ensuring that primary 
specimen containers (e.g. tubes) are labeled 
with two patient-specific identifiers. Seal the 
shipping pack.
3. Complete the pre-printed shipping labels 
(if necessary) and apply to shipping pack.
4. Call 800.463.3339 to request a 
pick-up or drop the package at 
your site’s designated FedEx pick-
up location and ship sealed shipping 
pack to:
Foundation Medicine, Inc.
150 Second St
Cambridge,  MA 02141
Phone: 888
ReferenceClinical and Laboratory Standards Institute. H3-A6, Procedures for the collection of diagnostic blood specimens by venipuncture; approved 
standard-sixth edition.
© 2018 Foundation Medicine, Inc. | Foundation Medicine® and FoundationOne® are registered trademarks of Foundation Medicine, Inc. 
www.foundationmedicine.com   |  Tel.  888.988.3639   |  Fax 617.418.229  MKT-0060-02
1
Check special tubes provided in FoundationOne Liquid kits to confirm 
liquid is clear and without cloudiness or crystals.
2
Label tubes with date of collection and two patient identifiers.
3
Collect two tubes of whole blood (8.5mL per   tube).
• Prevent backflow: tubes contain chemical additives and it is 
important to avoid backflow into patient.
• Collect specimen by venipuncture according to CLSI H3-A6.¹
• Fill tubes completely (8.5mL per tube).
4
Remove the tube from adapter and immediately mix by gentle 
inversion 8 to 10  times.  Inadequate or delayed mixing may result 
in inaccurate test results. One inversion is a complete turn of the 
wrist, 180°, and back per the figure below.
5
Place specimen, completed requisition form (TRF) (remember to 
include patient’s diagnosis), insurance information, available 
reports, and accompanying documents into the FoundationOne 
Liquid Specimen Collection and Shipping Kit (copies of pathology 
reports and/or other clinical documentation).
• Confirm each tube is labeled with the supplied labels indicating 
the date of collection and two unique patient identifiers (label 
included in kit).
6
Preferably on the same day of collection, ship via FedEx priority 
overnight delivery at ambient temperature. Do not freeze or 
refrigerate blood samples.
Temperature is important. Keep at room 
temperature (43-99° F, 6-37° C).
DO NOT FREEZE.
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