A Phase II Trial of Irinotecan Liposome and Bevacizumab in Women With Platinum Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Phase: PHASE2
Conditions: Platinum-Resistant Fallopian Tube Carcinoma, Platinum-Resistant Ovarian Carcinoma, Platinum-Resistant Primary Peritoneal Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Refractory Fallopian Tube Carcinoma, Refractory Ovarian Carcinoma, Refractory Primary Peritoneal Carcinoma
Sponsor: Northwestern University

CONFIDENTIAL
This material is the property of
The Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Do not disclose or use except as authorized in writing by the study sponsor (PI).
NU Study Number: NU 20G02
Ipsen Study Number: A-US-60010-011
A Phase II Trial of Irinotecan Liposome and Bevacizumab in 
Women with Platinum Resistant Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer
Principal Investigator:
Daniela Matei, MD
Northwestern University Feinberg School of Medicine
303 E. Superior St., Suite 04-107
Chicago, IL 60611
Phone: 312-472-4684
Email: daniela.matei@northwestern.edu
Biostatistician:
Masha Kocherginsky, PhD
Northwestern University Feinberg School of Medicine
Email: mkocherg@northwestern.edu
Study Intervention(s):
Irinotecan liposome injection (ONIVYDE®) and bevacizumab (Avastin®)
IND Number:
153324
IND Holder:
Daniela Matei, MD
Funding Source: 
Ipsen Biopharmaceuticals
Version Date:
January 20, 2022 (Amendment 3)
Coordinating Center:
Clinical Trials Office
The Robert H. Lurie Comprehensive Cancer Center (RHLCC)
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
https://www.cancer.northwestern.edu/research/clinical-trials-office/index.html
IRB #: STU00213582 Approved by NU IRB for use on or after 9/26/2022 through 9/25/2023.

NU Study Number: NU 20G02
Ipsen Study Number: A-US-60010-011
Protocol Amendment 3 – Version Date: January 20, 2022
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................5
STUDY SCHEMA ............................................................................................................................7
STUDY SUMMARY .........................................................................................................................7
1.0
INTRODUCTION—BACKGROUND & RATIONALE........................................................12
1.1
Disease Background .....................................................................................................12
1.2
Rationale for the Current Study.....................................................................................12
1.3
Intervention Background & Overview ............................................................................13
1.3.1
Bevacizumab .................................................................................................................13
1.3.2
Irinotecan Liposome ......................................................................................................15
1.4
Exploratory Studies .......................................................................................................16
2.0
OBJECTIVES ....................................................................................................................16
2.1
Primary Objective ..........................................................................................................16
2.2
Secondary Efficacy Objectives......................................................................................16
2.3
Secondary Safety Objective ..........................................................................................17
2.4
Exploratory Objective ....................................................................................................17
3.0
SUBJECT ELIGIBILITY.....................................................................................................17
3.1
Inclusion Criteria............................................................................................................18
3.2
Exclusion Criteria...........................................................................................................22
4.0
TREATMENT PLAN ..........................................................................................................25
4.1
Treatment Overview ......................................................................................................25
4.2
Treatment Administration ..............................................................................................26
4.2.1
Bevacizumab .................................................................................................................27
4.2.2
Irinotecan Liposome ......................................................................................................28
4.2.3
Safety Lead-In Cohort ...................................................................................................28
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NU Study Number: NU 20G02
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4.2.4
Definition of Dose Limiting Toxicity (DLT) .....................................................................30
4.3
Toxicity Management & Dose Modifications/Interruptions.............................................31
4.4
Concomitant Medications/Treatments ...........................................................................38
4.5
Duration of Therapy.......................................................................................................41
4.6
Duration of Follow Up....................................................................................................42
4.6.1
Short Term (Safety) Follow Up Phase...........................................................................42
4.6.2
Long Term Follow Up Phase.........................................................................................43
4.7
Removal of Subjects from the Study as a Whole/Off-Study Criteria .............................43
5.0
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS.....................................45
6.0
CORRELATIVES/SPECIAL STUDIES..............................................................................49
7.0
ENDPOINT ASSESSMENTS AND EVALUABILITY ........................................................49
7.1
Primary Endpoint and Evaluability.................................................................................49
7.2
Secondary Efficacy Endpoints and Evaluability.............................................................49
7.3
Secondary Safety Endpoints and Evaluability...............................................................52
7.4
Exploratory Endpoints and Evaluability .........................................................................53
7.5
Definitions......................................................................................................................54
8.0
STATISTICAL CONSIDERATIONS ..................................................................................57
8.1
Study Design .................................................................................................................57
8.2
Sample Size ..................................................................................................................57
8.3
Power Analysis ..............................................................................................................57
8.4
Criteria for Stopping the Study Early .............................................................................58
8.4.1
Safety Criteria................................................................................................................58
8.4.2
Efficacy Criteria .............................................................................................................58
8.5
Accrual and Feasibility...................................................................................................58
8.6
Data Analysis Plans.......................................................................................................59
9.0
DRUG INFORMATION ......................................................................................................59
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9.1
Bevacizumab .................................................................................................................59
9.2
Irinotecan Liposome ......................................................................................................61
10.0
ADVERSE EVENTS ..........................................................................................................64
10.1
Adverse Event Monitoring .............................................................................................64
10.2
Definitions & Descriptions..............................................................................................64
10.3
Event Reporting.............................................................................................................67
11.0
STUDY MANAGEMENT....................................................................................................69
11.1
Institutional Review Board (IRB) Approval and Consent...............................................69
11.1.1 Consenting Subjects with Limited Proficiency in English ..............................................70
11.2
Amendments .................................................................................................................70
11.3
Registration Procedures................................................................................................70
11.4
Data Submission ...........................................................................................................71
11.5
Instructions for External Participating Sites...................................................................71
11.6
Data Management and Monitoring/Auditing ..................................................................71
11.7
Adherence to the Protocol.............................................................................................72
11.8
Investigator Obligations.................................................................................................73
11.9
Publication Policy ..........................................................................................................73
APPENDICES................................................................................................................................74
Appendix A
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ......74
Appendix B
New York Heart Association (NYHA) Classification of Cardiac Failure .............75
Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1...............76
Appendix D
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ....................79
Appendix E
Cockcroft-Gault Equation for Creatinine Clearance ...........................................80
Appendix F
Summary of Changes ........................................................................................81
REFERENCES ..............................................................................................................................89
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LIST OF ABBREVIATIONS
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase
CA-125
Cancer antigen 125
CBC
Complete blood count
CBR
Clinical Benefit Rate
CMP
Comprehensive metabolic panel
CR
Complete response
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTO
Clinical Trials Office
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of response
DSMC
Data and Safety Monitoring Committee 
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
GCIG 
Gynecological Cancer Intergroup 
GCP
Good clinical practice
H&PE
History & physical exam
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
INR
International normalized ratio
IRB
Institutional Review Board
IV (or iv)
Intravenously
LLN
Lower limit of normal
mAb
Monoclonal antibody
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PARP
Poly (ADP-ribose) polymerase
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PD
Progressive disease
PFS
Progression-free survival
PFS-16
16 week progression-free survival
PI
Principal Investigator
PR
Partial response
PT
Prothrombin time
QAM
Quality Assurance Monitor
RECIST
Response Evaluation Criteria in Solid Tumors
RNI
Reportable new information
SAE
Serious adverse event
SD
Stable disease
TKI
Tyrosine kinase inhibitor
TTR
Time to response
ULN
Upper limit of normal
VEGF
Vascular Endothelial Growth Factor
WBC
White blood cells
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STUDY SCHEMA
Follow Up
After discontinuing treatment, follow q3m x 1 year, then q6m x 2 years, until progression or start of 
subsequent anti-cancer therapy.
Phase II Trial
Single center, Single arm, Open label
*The study will suspend enrollment twice for interim analysis: 1) after ≥2 of 6 subjects experience DLT or at n=6 for safety lead-in and 2) at n=10 for stage 1.
HPT=hypertension, ORR=objective response rate; CBR=clinical benefit rate; DOR=duration of response; SD=Stable Disease; TTR=time to response; PFS= 
progression free survival; PFS-16=16 week PFS. Refer to Section 7 for definitions, endpoints and evaluability and to Section 8 for statistical plans. 
Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer 
n=30 subjects (may enroll up to 33 to obtain at least 30 who are evaluable)
Platinum resistant disease
Epithelial histology
ECOG performance status 0-2
Adequate organ function
RECIST 1.1 measurable disease
Multiple prior therapies permitted; refer to full eligibility criteria (Section 3.0) for details.
                                                                      1 Cycle = 28 Days                            
                  Irinotecan Liposome                    +                        Bevacizumab
                              70 mg/m2 IV                                                                   10 mg/kg
                           Every 2 weeks                                                                Every 2 weeks
      Reductions to 50 and 43 mg/m2 permitted      Reductions to 5 mg/kg permitted for HPT & proteinuria
Toxicity Assessment: 
Every cycle (q4w)
Imaging Response Assessment (RECIST 1.1): 
Every 2 cycles for the first 5 cycles; Every 3 cycles thereafter.
Continue treatment until disease progression or unacceptable toxicity.
Stage 1 with Safety Lead-In
(n=10, including the lead-in)*
First 6 subjects = Safety lead-in
If ≤ 1/6 subjects with DLTs, continue enrollment.
First 10 evaluable subjects = Stage 1
If ≥ 2/10 responses, continue to Stage 2.
Stage 2
(n=20)
Primary endpoint: ORR
Secondary & Exploratory endpoints: Best 
Response, CBR, DOR, Duration of SD, TTR, PFS, 
PFS-16, Toxicity, and CA-125 Levels
Simon’s Optimal Two Stage Design with Safety Lead-In during Stage 1
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NU Study Number: NU 20G02
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STUDY SUMMARY
Title
A Phase II Trial of Irinotecan Liposome and Bevacizumab in Women with 
Platinum Resistant Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer
Version
Protocol version January 20, 2022 (Amendment 3)
Study Center(s)
Single center trial at Northwestern University
Study Design
This is a single center, single arm, open label, phase II trial with a 
Simon’s optimal two-stage design. A safety run-lead cohort has been 
designed, wherein the first 6 subjects who receive at least 1 dose of 
combination trial therapy will be observed for at least 42 days for dose 
limiting toxicity, in order to ensure the safety of the experimental 
combination of irinotecan liposome and bevacizumab. Study endpoints 
are defined in Section 7.0. Criteria for stopping the study early are 
described in Section 8.4.
Study Population & 
Diagnosis
Platinum-resistant ovarian cancer, fallopian cancer, and primary 
peritoneal cancer
Treatment Plan
This is a single center, single arm, open label, phase II trial of 
bevacizumab in combination with irinotecan liposome in women with 
recurrent, platinum-resistant ovarian, fallopian tube, or primary peritoneal 
cancer.  
Each cycle of combination trial therapy will be 28 days. Bevacizumab will 
be administered at a starting dose of 10 mg/kg IV every two weeks (i.e., 
on days 1 and 15 of each 28 day cycle), with dose reduction to 5 mg/kg 
permitted for toxicity.  Irinotecan liposome will be administered at a 
starting dose of 70 mg/m2 IV every two weeks (i.e., on days 1 and 15 of 
each 28 day cycle), with dose reductions to 50 mg/m2 and 43 mg/m2 
permitted for toxicity. Trial therapy will continue until disease 
progression, unacceptable toxicity, withdrawal, or death (whichever 
occurs first). 
To exclude prohibitive toxicity, a safety lead-in cohort of the initial 6 
subjects will be conducted. If unacceptable dose limiting toxicity (DLT) is 
observed, a protocol amendment to explore alternate dosing schemes 
will be considered. 
Refer to Section 4.0 for the full treatment plan and DLT criteria.
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NU Study Number: NU 20G02
Ipsen Study Number: A-US-60010-011
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Key Eligibility Criteria
Key Inclusion Criteria:

Histologically or cytologically confirmed epithelial ovarian cancer, 
fallopian tube cancer, or primary peritoneal cancer

Recurrent, platinum resistant disease, defined as progression    
< 6 months after completion of a platinum-based therapy 
regimen or as persistent disease that remains after completion 
of a platinum-based therapy

Measurable disease as assessed by RECIST 1.1 

Must have received at least 1 but no more than 3 prior platinum-
based chemotherapy regimens

Age ≥ 18 years 

ECOG performance status of 0-2

Adequate organ and bone marrow function
Key Exclusion Criteria:

Exclusions for receipt of prior systemic anti-cancer therapy:
o
No prior irinotecan-based therapies.
o
No more than 3 prior platinum-based chemotherapy 
regimens. 
o
No more than 2 prior non-platinum, cytotoxic chemotherapy 
regimens.

Exclusions for washout from prior systemic anti-cancer therapy:
o
No chemotherapy, immunotherapy, monoclonal antibody 
(mAb) therapy, hormonal therapy, or other targeted therapy 
within ≤ 14 days prior to registration.
o
No investigational agents or investigational devices within ≤ 
14 days prior to registration.
o
No VEGF-targeting agents, including bevacizumab, within ≤ 
3 months prior to registration
Refer to Section 3.0 for a full list of eligibility criteria.
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‘Objectives
Primary Objective

Objective Response Rate (ORR)
Secondary Efficacy Objectives

Best Overall Response 

Clinical Benefit Rate (CBR) 

Duration of Response (DOR) 

Duration of Stable Disease (Duration of SD)

Time to Response (TTR) 

Median Progression-Free Survival (PFS) 

16 Week Progression-Free Survival (PFS-16) 
Secondary Safety Objective

Toxicity profile of irinotecan liposome in combination with 
bevacizumab according to NCI-CTCAE v5.0
Exploratory Objective

To measure serum CA-125 levels
Refer to Section 2.0 and Section 7.0 for additional information.
Sample Size
In this phase II design, we anticipate enrolling 30 subjects who are 
evaluable for the primary endpoint; up to 33 subjects may be enrolled to 
yield at least 30 evaluable subjects. Refer to Section 8.0 for additional 
details. 
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Statistical Methodology
Thirty evaluable subjects will be analyzed in this phase II study. The 
study is designed to achieve 80% power with 5% one-sided type 1 error 
rate (alpha) to test the primary hypothesis of 20% improvement in 
objective response rate (ORR) per RECIST 1.1 vs. the null hypothesis of 
11.8% ORR in the historic controls.1  The proportion of evaluable 
subjects experiencing an objective response will be estimated with a 
95% exact binomial confidence interval. The confidence interval will be 
adjusted for the sequential nature of the two-stage procedure.
As this trial uses an optimum two-stage design, an interim analysis is 
planned after 10 evaluable subjects have been accrued and evaluated 
for ORR. Additionally, the first 6 evaluable subjects who receive at least 
1 dose of combination trial therapy will be observed for at least 42 days 
as part of an initial safety lead-in.
Refer to Section 8.0 for the full statistical analysis plan and early 
stopping criteria. 
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1.0
INTRODUCTION—BACKGROUND & RATIONALE
1.1
Disease Background
Ovarian cancer causes more deaths than any other female reproductive tract cancer.2,3 
Standard management includes cytoreductive surgery and neoadjuvant/adjuvant platinum-
based chemotherapy. However, the majority of women diagnosed with advanced-stage 
epithelial ovarian cancer experience tumor recurrence and subsequent resistance to 
platinum-based therapies. Platinum resistant ovarian cancer is uniformly fatal.4 The 
development of novel therapies for this deadly cancer is critically needed. 
Recent investigation in the platinum-resistant ovarian cancer setting demonstrates that U.S. 
Food and Drug Administration (FDA)-approved cytotoxic monotherapies are more 
efficacious when combined with the vascular endothelial growth factor (VEGF) receptor-
targeted therapy bevacizumab.1 While these combinations are tolerable, toxicity 
management remains challenging. As such, the development of novel drug delivery 
systems (such as liposomal formulations) and targeted therapies for ovarian cancer are of 
interest to reduce toxicity and improve efficacy. The current trial seeks to study the 
combination of irinotecan liposome and bevacizumab in women with recurrent, platinum 
resistant ovarian cancer. 
1.2
Rationale for the Current Study
Platinum resistant ovarian cancer has limited therapeutic options.5 FDA-approved single 
agent treatment strategies include topotecan, liposomal doxorubicin, paclitaxel, etoposide, 
gemcitabine, and bevacizumab.6  Following the AURELIA trial, the FDA-approved the use 
of bevacizumab in combination with any one of the following cytotoxic agents: topotecan, 
liposomal doxorubicin, or paclitaxel. The AURELIA trial demonstrated that combining single 
agent FDA-approved chemotherapy (topotecan, liposomal doxorubicin or paclitaxel) with 
anti-angiogenic bevacizumab improved response rates and induced longer progression-
free survival (PFS), when compared to single agent chemotherapy alone, in women with 
recurrent, platinum-resistant ovarian cancer who had received no more than 2 prior lines of 
systemic therapy. The RECIST objective response rate in this trial was 27% for the 
combination regimen, as compared to 11.8% for single agent chemotherapy. Median PFS 
also increased from 3.4 months to 6.7 months when the anti-angiogenic agent was added 
to single agent chemotherapy.1 Based on the findings from this trial, we propose that  
combining bevacizumab with novel cytotoxic agents, such as irinotecan liposome, would be 
of significant clinical interest in women with recurrent platinum-resistant ovarian cancer for 
whom response rates to traditional cytotoxic agents remain low (e.g., 11.8% ORR in 
AURELIA).1 
Limited evaluation of irinotecan with bevacizumab in ovarian cancer has been undertaken 
to date.  Irinotecan is a camptothecin derivative whose active metabolite, SN-38, inhibits 
the action of topoisomerase I. In a prior study, irinotecan in combination with bevacizumab 
induced an ORR of approximately 27% in subjects with recurrent platinum sensitive and 
resistant ovarian cancer.7  In another study, low dose bevacizumab and weekly irinotecan 
induced an ORR of approximately 40% in bevacizumab-naïve ovarian cancer subjects.8 
Additionally, no clinically meaningful effects on the pharmacokinetics of irinotecan or its 
active metabolite, SN-38, were observed when bevacizumab was administered in 
combination with irinotecan. These prior results provide a strong rationale to further study 
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NU Study Number: NU 20G02
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irinotecan and bevacizumab combination treatment strategies in this setting. Liposomal 
irinotecan drug formulations have not yet been evaluated for the treatment of ovarian 
cancer.  We hypothesize that the liposomal encapsulation will enhance drug delivery and 
bioavailability, thereby improving efficacy and reducing toxicity. 
The goal of this trial is to test the combination of bevacizumab and irinotecan liposome for 
the first time in platinum resistant ovarian cancer, aiming to demonstrate activity in the 
range (or better) of that observed in the AURELIA trial,1 which targeted a population of 
subjects who received either fewer or a similar number of prior lines of therapy than the 
present trial design. 
The present trial will study bevacizumab at a standard starting dosing regimen of 10 mg/kg 
IV every 2 weeks (per the AURELIA trial),1 in combination with investigational irinotecan 
liposome. Prior experience with irinotecan liposome in a phase I dose finding trial for solid 
tumors demonstrated a maximum tolerated dose (MTD) of 80 mg/m2 when dosed IV every 
2 weeks as monotherapy.9 The subsequent NAPOLI-1 trial of irinotecan liposome used in 
combination with other agents for pancreatic adenocarcinoma demonstrated a reasonable 
safety profile for the 80 mg/m2 dose.10,11 The FDA-recommended dose for the same patient 
population as NAPOLI-1 is 70mg/m2 with dose reductions to 50 mg/m2 and 43 mg/m2. In 
light of this prior experience, the current trial has been designed with a safety lead-in cohort 
to test a starting dose of irinotecan liposome of 70 mg/m2 IV in combination with a starting 
dose of bevacizumab of 10 mg/kg IV, every two weeks. If unacceptable dose limiting 
toxicity (DLT) is observed during the safety lead-in, the protocol will be suspended, and 
additional dosing strategies (such as a reduced starting dose of 50 mg/m2 for irinotecan 
liposome) will be explored in a protocol amendment. Dose reductions for toxicity will be 
permitted to 5 mg/kg IV every 2 weeks for bevacizumab, and to 50 mg/m2 and 43 mg/m2 IV 
every 2 weeks for irinotecan liposome.
1.3
Intervention Background & Overview
1.3.1
Bevacizumab
1.3.1.1   Bevacizumab—Mechanism of Action
Bevacizumab (sold under the trade name Avastin® and marketed by 
Genentech/Roche) is a recombinant humanized monoclonal IgG1 
antibody (mAb) that specifically binds to and inhibits vascular endothelial 
growth factor A (VEGF-A). VEGF regulates angiogenesis, vascular 
permeability, and endothelial cell growth and migration. Because 
sustained angiogenesis is a hallmark of many cancers, including ovarian 
cancer, inhibiting the VEGF pathway is an attractive approach for cancer 
therapy. Anti-VEGF agents, such as bevacizumab, prevent tumor growth 
and cause tumor regression by inhibiting neovascularization and 
normalizing tumor vasculature. Due to its mechanism of action as a 
targeted therapy, there has been recent interest to combine bevacizumab 
with standard cytotoxic chemotherapeutic regimens that have non-
overlapping toxicity profiles. 
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NU Study Number: NU 20G02
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1.3.1.2   Bevacizumab—Clinical Experience and Toxicity Profile
Bevacizumab is U.S. FDA-approved for the treatment of recurrent 
epithelial ovarian, fallopian tube, or primary peritoneal cancer in 
combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan 
at a dose of 10 mg/kg every 2 weeks (with paclitaxel, pegylated liposomal 
doxorubicin, or topotecan given every week) or 15 mg/kg every 3 weeks 
(with topotecan given every 3 weeks). 
Leading to its FDA-approval, bevacizumab was investigated in a 
multicenter, open-label, randomized study (AURELIA trial / MO22224 / 
NCT00976911)1 of 361 patients with recurrent, platinum-resistant, 
epithelial ovarian, fallopian tube, or primary peritoneal cancer who 
recurred within < 6 months of their most recently received platinum-based 
therapy. This two-arm study compared chemotherapy alone to the 
combination of bevacizumab + chemotherapy. Chemotherapy options 
were at the discretion of the investigator and included paclitaxel (80 
mg/m2 on days 1, 8, 15 and 22 every 4 weeks), pegylated liposomal 
doxorubicin (40 mg/m2 on day 1 every 4 weeks), and topotecan (4 mg/m2 
on days 1, 8 and 15 every 4 weeks or 1.25 mg/m2 on days 1-5 every 3 
weeks). In the bevacizumab arm, patients received bevacizumab at a 
dose of 10 mg/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks. 
Patients were treated until disease progression, unacceptable toxicity, or 
withdrawal. The addition of bevacizumab to cytotoxic chemotherapy 
demonstrated a statistically significant improvement (p-value < 0.0001) in 
progression-free survival (PFS), where the combination regimens that 
included bevacizumab had a median PFS of 6.8 months, compared to 3.4 
months for the single agent chemotherapy regimens [HR 0.38 (95% CI: 
0.30-0.49)].  These data support the use of bevacizumab in combination 
with cytotoxic drugs for the treatment of platinum-resistant, recurrent 
epithelial ovarian, fallopian tube, and primary peritoneal cancer.1 
The toxicity profile of bevacizumab is manageable and expected for 
agents of its class. Common adverse reactions may include (but are not 
limited to) epistaxis, headache, hypertension, rhinitis, proteinuria, taste 
alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, 
exfoliative dermatitis, fatigue, poor appetite, diarrhea, dizziness, weight 
loss, arthralgia and myalgia. Serious adverse reactions include 
gastrointestinal perforation, fistula, surgery and wound healing 
complications, hemorrhage, arterial and venous thromboembolic events, 
hypertensive crisis, posterior reversible encephalopathy syndrome, 
nephrotic syndrome, proteinuria, infusion-related reactions, ovarian 
failure, and congestive heart failure. 
Refer to the full FDA prescribing information and current U.S. Package 
Insert for additional details, including a full toxicity profile. 
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NU Study Number: NU 20G02
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1.3.2
Irinotecan Liposome
1.3.2.1   Irinotecan Liposome—Mechanism of Action
Irinotecan liposome (sold under the trade name ONIVYDETM and 
marketed by Ipsen) is a lipid-encapsulated form of the drug irinotecan.  
Irinotecan is a camptothecin derivative whose active metabolite, SN-38, 
inhibits the action of topoisomerase I. By binding to the topoisomerase I-
DNA complex, SN-38 prevents re-ligation of DNA single-strand breaks, 
which ultimately leads to exposure time-dependent DNA double strand 
breaks and cell death. 
 Irinotecan liposome consists of a lipid bilayer vesicle that encapsulates 
irinotecan in an aqueous space. The liposome is designed to protect 
irinotecan from early conversion to SN-38. As such, the liposomal 
formulation has therapeutic advantages over the free form of the drug 
(irinotecan), including improved drug delivery in tumor tissue and 
sustained levels of bioavailable active drug. Ninety-five percent of 
irinotecan remains contained within the liposome during circulation, 
protecting healthy tissues from exposure. Additionally, in mice bearing 
human tumor xenografts, liposomal irinotecan achieved similar 
intratumoral exposure of SN-38 as irinotecan when administered at a 5-
fold lower dose than the irinotecan-equivalent dose.12,13  
1.3.2.1   Irinotecan Liposome—Clinical Experience and Toxicity Profile
Irinotecan liposome is U.S. FDA-approved in combination with fluorouracil 
and leucovorin for the treatment of patients with recurrent, metastatic 
pancreatic adenocarcinoma, following prior treatment with gemcitabine. 
The indicated dose of irinotecan liposome in this combination regimen is 
70 mg/m2 IV every 2 weeks, with recommended dose reductions to 50 
and 43 mg/m2 IV every 2 weeks for toxicity management. 
Leading to its FDA-approval, irinotecan liposome was investigated in a 
global, multicenter, open-label, randomized phase III trial (NAPOLI-1 trial / 
NCT01494506)10,11 of 417 patients with metastatic pancreatic ductal 
adenocarcinoma who had progressed following prior treatment with 
gemcitabine-based therapy. Patients were randomized to receive either 
irinotecan liposome monotherapy (120 mg/m2 every 3 weeks) or 
fluorouracil + folinic acid. A third arm consisting of irinotecan liposome (80 
mg/m2) with fluorouracil + folinic acid every 2 weeks was added later 
(1:1:1), in a protocol amendment. Patients were treated until disease 
progression, unacceptable toxicity, or withdrawal. In this trial, the 
combination of irinotecan liposome + fluorouracil + folinic acid significantly 
prolonged median overall survival (OS) and progression-free survival 
(PFS) compared with fluorouracil + folinic acid control therapy. The 
median OS for irinotecan liposome + fluorouracil + folinic acid was 6.2 
months, compared to 4.2 months for the control therapy fluorouracil + 
folinic acid [p-value=0.039, HR 0.75 (95% CI: 0.57-0.99)]. The median 
PFS for irinotecan liposome + fluorouracil + folinic acid was 3.1 months, 
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Protocol Amendment 3 – Version Date: January 20, 2022
     16
compared to 1.5 months for the control therapy fluorouracil + folinic acid 
[p-value < 0.001, HR 0.57 (95% CI: 0.43-0.76)]. Irinotecan liposome-
based combination therapy had a manageable safety profile; the most 
common toxicities were hematologic or gastrointestinal. The grade 3 or 4 
adverse events that occurred most frequently were neutropenia, diarrhea, 
vomiting, and fatigue.10-13  Additional serious toxicities of the drug include 
interstitial lung disease, hypersensitivity reactions, and sepsis. 
Refer to the full FDA prescribing information, current U.S. Package Insert, 
and Investigator’s brochure for additional details, including a full toxicity 
profile.
Collectively, these data support the development of future oncology 
clinical trials to investigate irinotecan liposome in combination regimens. 
Its use in the platinum-resistant, recurrent ovarian cancer setting in 
combination with bevacizumab is a novel opportunity that remains to be 
explored.  
1.4
Exploratory Studies
Evaluation of the serum biomarker CA-125 is frequently used as a standard of care 
assessment in the management of recurrent ovarian cancer. However, its use as a reliable 
endpoint for tumor response in the setting of recurrent disease has remained understudied, 
until recently.14 The criteria for defining progression according to CA-125 response have 
been validated in the recurrent setting,14 and the Gynecological Cancer Intergroup (GCIG) 
requests that data from all clinical trials using these definitions be made available, so that 
continual validation and improvement can be accomplished.15 Towards this goal, the 
current study will perform an exploratory analysis of serum CA-125 levels as a surrogate 
marker of tumor response and progression. 
2.0
OBJECTIVES
2.1
Primary Objective
2.1.1
To assess the antineoplastic efficacy of irinotecan liposome in combination with 
bevacizumab in women with recurrent, platinum resistant ovarian cancer, as 
measured by the Objective Response Rate (ORR). 
2.2
Secondary Efficacy Objectives
2.2.1
To determine the Overall Best Response per RECIST 1.1 in women with recurrent, 
platinum resistant ovarian cancer who have received treatment with irinotecan 
liposome in combination with bevacizumab.
2.2.2
To determine the Clinical Benefit Rate (CBR) for irinotecan liposome in combination 
with bevacizumab in women with recurrent, platinum resistant ovarian cancer.
2.2.3
To calculate the Duration of Response (DOR) for irinotecan liposome in combination 
with bevacizumab in women with recurrent, platinum resistant ovarian cancer.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     17
2.2.4
To calculate the Duration of Stable Disease (Duration of SD) for irinotecan liposome 
in combination with bevacizumab in women with recurrent, platinum resistant 
ovarian cancer.
2.2.5
To calculate the Time to Response (TTR) for irinotecan liposome in combination 
with bevacizumab in women with recurrent, platinum resistant ovarian cancer.
2.2.6
To measure Median Progression-Free Survival (PFS) in women with recurrent, 
platinum resistant ovarian cancer who have received treatment with irinotecan 
liposome in combination with bevacizumab.
2.2.7
To measure 16 Week Progression-Free Survival (PFS-16) in women with recurrent, 
platinum resistant ovarian cancer who have received treatment with irinotecan 
liposome in combination with bevacizumab.
2.3
Secondary Safety Objective
2.3.1
To assess the Toxicity Profile of irinotecan liposome in combination with 
bevacizumab in women with recurrent, platinum resistant ovarian cancer according 
to NCI-CTCAE v5.0.
2.4
Exploratory Objective
2.4.1
To measure Serum CA-125 Levels in women with recurrent, platinum resistant 
ovarian cancer who have received treatment with irinotecan liposome in 
combination with bevacizumab. 
3.0
SUBJECT ELIGIBILITY
The target population for this study is subjects with recurrent, platinum resistant ovarian, fallopian 
tube, or primary peritoneal cancer. This will be a single center trial conducted at the Robert H. 
Lurie Comprehensive Cancer Center of Northwestern University (RHLCCC), which will serve as 
the coordinating center for this study. Potential subjects may be referred to the Principal 
Investigator (PI).
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Any questions regarding eligibility should be directed to the lead PI and 
the assigned quality assurance monitor (QAM; croqualityassurance@northwestern.edu). Study 
treatment may not begin until after a subject has been registered. Refer to Section 11 for 
complete instructions regarding registration procedures.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     18
3.1
Inclusion Criteria
3.1.1
Subjects must have histologically or cytologically confirmed epithelial ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer. 
NOTE: Subjects with carcinosarcoma histology and/or mixed epithelial histology 
are not eligible. 
3.1.2
Subjects must have recurrent, platinum resistant or refractory disease, defined as 
progression < 6 months after completion of a platinum-based chemotherapy 
regimen or as persistent disease that remains after completion of a platinum-based 
therapy.
3.1.3
Subjects must have measurable disease as assessed by RECIST 1.1.16 See 
Section 7.5.1 and Appendix C for the evaluation of measurable disease.
3.1.4
Subjects must have received at least 1 but no more than 3 prior platinum-based 
chemotherapy regimens.
3.1.5
Subjects must have adequately recovered (in the opinion of the treating 
investigator) from adverse events due to prior anti-cancer therapy, with the 
exceptions of any grade alopecia and ≤ grade 2 peripheral neuropathy per NCI-
CTCAE version 5.0.
3.1.6
Subjects must be age ≥ 18 years.
3.1.7
Subjects must exhibit an ECOG performance status of 0-2. 
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     19
3.1.8
Subjects must have adequate organ and bone marrow function as defined below:
System
Laboratory  Value
HEMATOLOGIC
Hemoglobin
≥ 9.0 g/dL*
White blood cell (WBC) count
≥ 3.0 x 109/L*
Absolute neutrophil count (ANC)
≥ 1.5 x 109/L*
Platelet count
≥ 75 x 109/L*
*See exclusion criterion 3.2.5 for exclusions regarding receipt of 
growth factor support and/or blood products within ≤14 days prior to 
registration.
HEPATIC
Serum total bilirubin
≤ 1.5 x ULN  or direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 x  ULN
AST(SGOT) and ALT(SPGT)
≤ 2.5 x ULN or ≤ 5.0 x ULN for subjects with liver metastases.
Serum albumin
≥ 3.0 g/dL
RENAL
Creatinine clearance
≥ 60 mL/min
Creatinine clearance should be calculated using the Cockcroft-Gault 
formula (Appendix E).
Urine protein
< 2+ (urine dipstick)
or
< 100 mg/dL (random protein urinalysis)
or
< 1 g/24h (24 hour urine collection)
COAGULATION
International Normalized Ratio 
(INR) 
≤ 1.5 x ULN 
or
For subjects receiving anticoagulant therapy, INR must be within 
the therapeutic range of intended use of anticoagulants, as 
determined by the treating investigator.
Activated Partial Thromboplastin 
Time (aPTT) 
≤ 1.5 x ULN 
or
For subjects receiving anticoagulant therapy, aPTT must be within 
the therapeutic range of intended use of anticoagulants, as 
determined by the treating investigator.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     20
3.1.9
For subjects with a known history of human immunodeficiency virus (HIV), the HIV 
viral load must be undetectable for ≥ 6 months prior to registration, and subjects 
must be receiving effective anti-retroviral HIV therapy, if indicated. 
NOTE: HIV testing is not required for subjects without a known history of HIV, 
unless mandated by a local health authority.
NOTE: Use of strong CYP3A4 inhibitors/inducers is prohibited (refer to Section 
4.4.3 and Exclusion Criterion 3.2.7). Subjects who are using concurrent strong 
CYP3A4 inhibitors/inducers (e.g., ritonavir, cobicistat) as part of their anti-retroviral 
therapy (ART) regimen may be switched to an alternative ART regimen (with 
minimal drug-drug interaction profile) before study participation; however, they are 
excluded from the study if their regimen cannot be altered.
3.1.10
For subjects with a known history of hepatitis B virus (HBV) infection or hepatitis C 
virus (HCV) infection, the HBV/HCV viral load must be undetectable, and subjects 
must be receiving effective suppressive HBV/HCV therapy, if indicated.
NOTE: HBV and HCV testing is not required for subjects without a known history of 
HBV or HCV, unless mandated by a local health authority.
3.1.11
Subjects with previously treated brain metastases are eligible if follow-up brain 
imaging after central nervous system (CNS)-directed therapy shows no evidence of 
progression for ≥ 28 days prior to registration, and any neurologic symptoms have 
returned to baseline.
3.1.12
Subjects with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy assessment of 
the investigational regimen for this trial are eligible.
3.1.13
Subjects with a known history severe cardiac disease, current symptoms of cardiac 
disease (e.g., unstable angina pectoris or cardiac arrhythmia), or a history of 
treatment with cardiotoxic agents should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification (Appendix 
B). To be eligible for this trial, these subjects must be class 2B or better. 
3.1.14
For subjects with hypertension, hypertension must be well controlled on 
medication. 
NOTE: For the purposes of determining eligibility only, uncontrolled hypertension at 
baseline is defined as a consistent baseline bp of ≥ 140 mmHg systolic and/or ≥ 90 
mmHg diastolic, on initial and repeat checks. (A repeat check is only required if the 
initial check is ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic.)
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     21
3.1.15
Females of reproductive potential must agree to undergo a urine or serum 
pregnancy test, and the results must be negative in order to initiate treatment. 
NOTE:    A female of reproductive potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria:
•
Has not undergone a hysterectomy or bilateral oophorectomy
•
Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 
months)
3.1.16
Females of reproductive potential must agree to use adequate contraception 
(abstinence or two methods of birth control, such as a barrier method in 
combination with hormonal contraception) while receiving trial therapy and for 7 
months following completion of trial therapy. Should a woman become pregnant or 
suspect she is pregnant while is participating in this study, she should inform her 
treating physician immediately.
NOTE:    A female of reproductive potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria:
•
Has not undergone a hysterectomy or bilateral oophorectomy
•
Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 
months)
3.1.17
Subjects must agree to not nurse/breastfeed while receiving trial therapy and for 6 
months after the last dose of trial therapy.
Note: These subjects are excluded because there is an unknown but potential risk 
for adverse events to the nursing infant. 
3.1.18
Surgical wounds (including wounds from tooth extractions and jaw-invasive dental 
procedures) must be fully healed and subjects must have adequately recovered (in 
the opinion of the treating investigator) from adverse events due to prior surgical 
procedures.
NOTE: Refer to exclusion criterion 3.2.3 for additional information regarding prior 
surgeries.
3.1.19
Subjects (or their legally authorized representative if subject has impaired decision-
making capacity) must have the ability to understand and the willingness to sign a 
written informed consent document.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     22
3.2
Exclusion Criteria
3.2.1
Exclusions for receipt of prior systemic anti-cancer therapy:

Subjects must not have received any prior irinotecan-based therapies.

Subjects must not have received more than 3 prior platinum-based 
chemotherapy regimens. 

Subjects must not have received more than 2 prior non-platinum, cytotoxic 
chemotherapy regimens.
Note: Prior receipt of biological therapies is permitted. These may include but are 
not limited to hormonal therapies, immunotherapies, monoclonal antibodies 
(mAbs), tyrosine kinase inhibitors (TKIs), poly (ADP-ribose) polymerase (PARP) 
inhibitors, or other targeted agents. Refer to the below exclusion criterion for 
washout rules.
3.2.2
Exclusions for washout from prior systemic anti-cancer therapy:

Subjects must not have received chemotherapy, immunotherapy, monoclonal 
antibody (mAb) therapy, hormonal therapy, or other targeted therapy within ≤ 
14 days prior to registration.

Subjects must not have received investigational agents or investigational 
devices within ≤ 14 days prior to registration.

Subjects must not have received VEGF-targeting agents, including 
bevacizumab, within ≤ 3 months prior to registration.
3.2.3
Subjects must not have received prior radiotherapy to the pelvis or abdomen within 
≤ 3 months prior to registration. Subjects must not have received prior radiotherapy 
to other areas within ≤ 14 days prior to registration. 
3.2.4
Subjects must not have undergone a surgical procedure or jaw-invasive dental 
procedure (including tooth extraction) within ≤ 28 days prior to registration. 
NOTE: Refer to inclusion criterion 3.1.18 for additional information regarding prior 
surgeries.
3.2.5
Subjects must not have a known history of hypersensitivity reactions attributed to 
compounds of similar chemical or biologic composition to bevacizumab, irinotecan 
liposome, or any of their excipients. 
3.2.6
Subjects must not have received hematologic growth factors and/or blood products 
(transfusions) within ≤ 14 days prior to registration.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     23
3.2.7
Subjects must not be taking any of the medications listed in Section 4.4.3. Subjects 
receiving any medications or substances that are known strong CYP3A4 inducers, 
known strong CYP3A4 inhibitors, and/or known strong UGT1A1 inhibitors are 
ineligible. 

Known strong CYP3A4 inducers must be discontinued at least 2 weeks prior 
to initiation of irinotecan liposome to be eligible. 
-
Strong CYP3A4 inducers include, but are not limited to, the following: 
phenytoin, phenobarbital, primidone, carbamazepine, rifampin, rifabutin 
and rifapentine.

Known strong CYP3A4 and UGT1A1 inhibitors must be discontinued at least 
1 week prior to initiation of irinotecan liposome to be eligible.
-
Strong CYP3A4 inhibitors include, but are not limited to, the following: 
ketoconazole, clarithromycin, indinavir, itraconazole, lopinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole. 
(Note: fosaprepitant is permitted).
-
Strong UGT1A1 inhibitors include, but are not limited to, the following: 
atazanavir, gemfibrozil, indinavir and ketoconazole. 
NOTE: Sites should refer to a current pharmacy reference manual for a full list of 
strong CYP3A4 inducers/inhibitors and strong UGTA1 inhibitors.
3.2.8
Subjects must not have active peptic ulcer disease, active inflammatory bowel 
disease, active ulcerative colitis, or other active gastrointestinal condition with 
increased risk of perforation. Subjects must not have a history of abdominal fistula, 
gastrointestinal perforation, or intra-abdominal abscess within ≤ 6 months prior to 
registration.
3.2.9
Subjects must not have current clinical symptoms of bowel obstruction or a history 
of bowel obstruction within ≤ 6 months prior to registration.
3.2.10
Subjects must not have a history of a significant thromboembolic or vascular 
disorders within ≤ 3 months prior to registration, including but not limited to:

Pulmonary embolism

Deep vein thrombosis

Other arterial or venous thromboembolic events

Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

Peripheral arterial ischemia ≥ Grade 3 (per NCI-CTCAE v5.0)
3.2.11
Subjects must not have a history of a significant bleeding disorder within ≤ 6 
months prior to registration, including but not limited to:

Hematemesis, hematochezia, melena or other gastrointestinal bleeding ≥ 
Grade 2 (per NCI-CTCAE v5.0)
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NU Study Number: NU 20G02
Ipsen Study Number: A-US-60010-011
Protocol Amendment 3 – Version Date: January 20, 2022
     24

Hemoptysis of ½ teaspoon (2.5 mL) or more of red blood, or other pulmonary 
bleeding ≥ Grade 2 (per NCI-CTCAE v5.0)

Hematuria or other genitourinary bleeding ≥ Grade 2 (per NCI-CTCAE v5.0)
3.2.12
Subjects must not have a current non-healing wound, bone fracture, skin ulcer, or 
osteonecrosis of the jaw. 
3.2.13
Subjects must not be pregnant or expecting to conceive from the time of informed 
consent through 6 months after the last dose of trial treatment. 
NOTE: These subjects are excluded because there is an unknown but potential 
risk for adverse events to the developing fetus. 
3.2.14
Subjects must not have a known UGT1A1* variant or Gilbert’s syndrome. 
3.2.15
Subjects must not have received a live vaccine within ≤ 30 days prior to 
registration. 
NOTE:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines and are not allowed. If a subject receives SARS-CoV-
2 vaccinations (COVID-19 vaccinations) during study participation, it is the 
responsibility of the investigator to determine the suitability of the vaccine being 
given with the information provided by the manufacturer.
3.2.16
Subjects must not have a condition or an uncontrolled intercurrent illness including, 
but not limited to any of the following: 
•
Ongoing or active infection requiring systemic treatment, except 
uncomplicated urinary tract infection (UTI) or uncomplicated upper respiratory 
tract infection (URI);
•
Psychiatric illness/social situation that would limit compliance with study 
requirements;
•
Any other illness or condition that the treating investigator feels would interfere 
with study compliance or would compromise the subject’s safety or study 
endpoints.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     25
4.0
TREATMENT PLAN
4.1
Treatment Overview
This is a single center, single arm, open label, phase II trial of bevacizumab in combination 
with irinotecan liposome in women with recurrent platinum-resistant ovarian, fallopian tube, 
or primary peritoneal cancer.  Women who meet all eligibility criteria will be candidates for 
participation. The trial uses a Simon’s optimal two-stage design17 with a safety lead-in 
cohort. Study endpoints are defined in Section 7.0. Statistical analysis plans and criteria for 
stopping the study early are described in Section 8.0. 
Subjects must initiate trial therapy within ≤ 14 days of registration, or they will be removed 
from the study. Re-screening is permitted.
Each cycle of combination trial therapy will be 28 days. Bevacizumab will be administered 
at a starting dose of 10 mg/kg IV every two weeks (i.e., on days 1 and 15 of each 28 day 
cycle), with dose reduction to 5 mg/kg IV every two weeks permitted for toxicities of 
hypertension and proteinuria, as described in Table 4.3.1.  Irinotecan liposome will be 
administered at a starting dose of 70 mg/m2 IV every two weeks (i.e., on days 1 and 15 of 
each 28 day cycle), with dose reductions to 50 mg/m2 and 43 mg/m2 IV every two weeks 
permitted for toxicity, as described in Table 4.3.2. Trial therapy will continue until disease 
progression, unacceptable toxicity, withdrawal, or death (whichever occurs first), or as 
otherwise described in Section 4.5. The trial is designed as a combination regimen 
consisting of bevacizumab and irinotecan liposome; however, if one agent is discontinued 
due to toxicity or other reasons, subjects may continue receiving treatment with the second 
agent as a monotherapy (Refer to Section 4.2 for details).
To exclude prohibitive toxicity, a safety lead-in cohort of the initial 6 subjects will be 
conducted. All subjects in the lead-in cohort will be observed for at least 42 days after 
receipt of the first dose of combination trial therapy (i.e., for 2 weeks after C1D28, which is 
two weeks after completion of cycle 1) for dose limiting toxicity (DLT) as described in 
Section 4.2.3 and Section 4.2.4. If unacceptable dose limiting toxicity is observed, a 
protocol amendment to explore alternate dosing schemes will be considered. 
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     26
4.2
Treatment Administration
Table 4.1: Treatment Administration Summary
Schedule
Premedication
Agent
Dose/Route
Schedule
Supportive 
Therapies
Premedications 
are not required 
for bevacizumab, 
but they are permitted, 
if indicated, per 
treating investigator 
discretion and/or 
institutional 
standards.***
Bevacizumab
IV
10 mg/kg * 
every two 
weeks
BEFORE
irinotecan 
liposome 
Bevacizumab 
infusion rate is per 
institutional 
standards.
Supportive 
therapies are 
not required for 
bevacizumab, 
but they are 
but permitted, 
if indicated, per 
treating 
investigator 
discretion 
and/or 
institutional 
standards. ***
D1 and 
D15 of 
each
28-Day 
Cycle
Administer a 
corticosteroid and 
an anti-emetic 
approx. 30 min prior 
to infusing irinotecan 
liposome. *** 
Choice of 
corticosteroid and anti-
emetic is per treating 
investigator discretion 
and/or according to 
Institutional standards.  
Additional 
premedications may 
be used per treating 
investigator discretion 
and/or Institutional 
standards.
Irinotecan 
liposome
IV
70 mg/m2 **
AFTER 
Bevacizumab
Administer infusion 
over 90 minutes (± 
10 minutes)
The infusion rate will 
not be modified in 
the case of dose 
reduction.**
Supportive 
therapies are 
not required for 
irinotecan, but 
they are but 
permitted, if 
indicated, per 
treating 
investigation 
discretion 
and/or 
institutional 
standards. ***
*  The starting dose for bevacizumab is 10 mg/kg. Refer to Table 4.3.1 for permitted dose reductions.
** The starting dose for irinotecan liposome is 70 mg/m2.  Refer to Table 4.3.2 for permitted dose 
reductions. 
***Refer to Section 4.4 regarding prohibited medications.
Monotherapy allowances:
The trial is designed as a combination regimen consisting of bevacizumab and irinotecan 
liposome; however, if irinotecan liposome is withheld or discontinued, subjects may continue 
receiving bevacizumab as a monotherapy, as long as any toxicity warranting the 
interruption/discontinuation is only related to irinotecan liposome and not related to 
bevacizumab. The converse is also permitted. If bevacizumab is withheld or discontinued, 
subjects may continue receiving irinotecan liposome as a monotherapy, as long as any toxicity 
warranting the interruption/discontinuation is only related to bevacizumab and not related to 
irinotecan liposome. If a single agent is withheld while the second agent is continued as a 
monotherapy, missed doses of the withheld agent should not be made up when the withheld 
agent is later resumed. 
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NU Study Number: NU 20G02
Ipsen Study Number: A-US-60010-011
Protocol Amendment 3 – Version Date: January 20, 2022
     27
4.2.1
Bevacizumab

Dose/Route: 
Bevacizumab will be administered IV at a starting dose of 10 mg/kg, with dose 
reduction to 5 mg/kg permitted for hypertension and proteinuria according to 
Table 4.2.1 and Section 4.3.1.
Table 4.2.1—Bevacizumab Dose Levels
Dose Level
Bevacizumab Dose
 0 (Starting Dose)
10 mg/kg, IV, q2w
-1 (Dose Reduction) ¥,*
5 mg/kg, IV, q2w¥,*
¥  Dose re-escalation is not permitted following a dose reduction. 
* Dose reduction to 5 mg/kg bevacizumab is permitted only under certain circumstances, as 
described in Section 4.3.1. Dose reduction to less than 5 mg/kg is not permitted. Should a 
subject require a further dose reduction, the subject should discontinue bevacizumab.

Schedule:
Administer bevacizumab on day 1 and day 15 of each 28-day cycle (i.e., every 
2 weeks). Bevacizumab infusion rate is per institutional standards. 
Administer bevacizumab prior to administering irinotecan liposome. 
DO NOT ADMINISTER OR MIX BEVACIZUMAB WITH DEXTROSE 
SOLUTION.

Drug Preparation:
Refer to Section 9.1 for bevacizumab preparation instructions.

Premedications and Supportive Care:
Refer to Table 4-1 and Section 4.4.

Monotherapy Allowances:
Refer to Section 4.2.

Dose Interruptions and Modifications
Refer to Section 4.3.1. 
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4.2.2
Irinotecan Liposome

Dose/Route: 
Irinotecan liposome will be administered IV at a starting dose of 70 mg/m2, 
with dose reductions to 50 mg/m2 and 43 mg/m2 permitted for toxicity 
according to Table 4.2.2 and Section 4.3.2. 
Table 4.2.2—Irinotecan Liposome Dose Levels
Dose Level
Irinotecan Liposome Dose
0 (Starting Dose)
70 mg/m2, IV, q2w
-1 (First Dose Reduction) ¥
50 mg/m2, IV, q2w¥
-2 (Second Dose Reduction)*
43 mg/m2, IV, q2w¥,*
¥  Dose re-escalation is not permitted following a dose reduction. 
* Dose reduction to less than 43 mg/m2 is not permitted. Should a subject require a further dose 
reduction, the subject should discontinue irinotecan liposome.

Schedule:
Irinotecan liposome will be infused over 90 minutes (± 10 minutes) on day 1 
and day 15 of each 28-day cycle (i.e., every 2 weeks). The infusion rate will 
not be modified in the case of dose reduction.
Administer irinotecan liposome after administering bevacizumab.

Drug Preparation:
Refer to Section 9.2 for irinotecan liposome preparation instructions.

Premedications and Supportive Care:
Refer to Table 4-1 and Section 4.4.

Monotherapy Allowances:
Refer to Section 4.2.

Dose Interruptions and Modifications:
Refer to Section 4.3.2. 
4.2.3
Safety Lead-In Cohort
Drug interaction and increased toxicity is not anticipated; however, there is no 
clinical experience with the combination of bevacizumab and irinotecan liposome. 
To exclude prohibitive toxicity, the initial 6 subjects will constitute a safety lead-in 
cohort. All subjects in the lead-in cohort will be treated with combination therapy, 
as outlined in Table 4.1, and observed for dose limiting toxicity (DLT), as defined 
in Table 4.2.4. 
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Accrual will be suspended for interim safety analysis (Section 8.4) after the first 6 
evaluable subjects have been enrolled. All subjects in the lead-in cohort will be 
observed for at least 42 days after receipt of the first dose of combination trial 
therapy (i.e., for two weeks after C1D28, which is two weeks after completion of 
cycle 1) for dose limiting toxicity (DLT) as defined in Table 4.2.4 below. Accrual 
will re-commence if ≤ 1 of 6 evaluable subjects in the safety lead-in cohort 
experiences a DLT (as defined in Section 4.2.4). If ≥ 2 of 6 evaluable subjects in 
the safety lead-in cohort experience a DLT, the study will remain suspended, and 
an amendment to explore alternate dosing schemes will be considered. If 1 of the 
initial 6 subjects discontinues combination therapy before completing the DLT 
observation period for reasons other than having experienced a DLT, then this 
subject will not be evaluable for the DLT analysis, and an additional subject will 
be added to the safety lead-in cohort.
All study teams are expected to notify the Principal Investigator and assigned 
QAM (croqualityassurance@northwestern.edu) when a DLT has occurred.
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4.2.4
Definition of Dose Limiting Toxicity (DLT)
Table 4.2.4: Definition of DLT
Toxicity Category
Criteria Defining a DLT¥
≥ Grade 4 hematologic toxicity [with the exception of uncomplicated Grade 4 
leukopenia/neutropenia persisting for < 7 days]
≥ Grade 4 leukopenia persisting for ≥ 7 days
≥ Grade 4 non-febrile neutropenia persisting for ≥ 7 days
≥ Grade 3 febrile neutropenia 
≥ Grade 3 thrombocytopenia associated with bleeding
Any Grade hematologic toxicity that is treatment-related* and which results in a >14 
day delay in Cycle 2 Day 1 dosing
Hematologic£
Any hematologic event that requires the use of growth factors for clinical 
management
An elevated alanine or aspartate aminotransferase (ALT or AST) lab value that is ≥ 
3X the ULN, and at the same time, an elevated serum total bilirubin lab value that is 
≥ 2X the ULN, and at the same time, an alkaline phosphatase (ALP) lab value that 
is < 2X the ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.
≥ Grade 3 treatment-related* non-hematologic toxicity despite the use of 
adequate/maximal medical interventions and/or prophylaxis as dictated by local 
institutional clinical practices or the judgment of the treating Investigator,
EXCEPT: 
those that are clearly and incontrovertibly due to disease progression or 
extraneous causes
≥ Grade 3 fatigue lasting < 7 days
Non-hematologic£
Any Grade non-hematologic toxicity that is treatment-related* and which results in a 
>14 day delay in Cycle 2 Day 1 dosing
Grade 5 Events£
Any death that is not clearly due to the underlying disease, comorbidity, or 
extraneous causes
¥  All toxicities are to be assessed according to NCI CTCAE version 5.0.
* Treatment-related is defined as any toxicity that is possibly, probably or definitely related to either bevacizumab 
or irinotecan liposome.
£ All study teams are expected to notify the Principal Investigator and assigned QAM 
(croqualityassurance@northwestern.edu) when a DLT has occurred.
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4.3
Toxicity Management & Dose Modifications/Interruptions
Routine dosing on D1 and D15 of each cycle has a window of ±3 calendar days. 
Additionally, dose interruptions of ≤ 14 days to accommodate scheduling constraints 
(holidays, subject vacations, etc.) are permitted.
Dose interruptions of ≤ 28 days are permitted for the management of toxicity/adverse 
events.
Refer to Section 4.4.4 for guidelines on dose interruptions for bevacizumab for 28 days 
before and 28 days after surgical procedures.
4.3.1
Bevacizumab Dose Modifications/Interruptions 
Table 4.3.1 describes dose modifications for bevacizumab for toxicity 
management. A dose reduction to dose level -1 (bevacizumab 5 mg/kg IV every 
two weeks) is allowed per treating Investigator discretion for the management of 
hypertension and proteinuria that do not meet the criteria for discontinuation, per 
Table 4.3.1. Dose re-escalation is not permitted following a dose reduction.
In addition to what is described in Table 4.3.1, bevacizumab dose interruptions of 
≤28 days and/or dose reductions to dose level -1 (bevacizumab 5 mg/kg IV every 
two weeks) may be implemented at any time for any grade toxicity considered 
intolerable by the subject, or if thought to be in the best interest of the subject, if the 
event does not meet treatment discontinuation criteria as defined in Table 4.3.1.
Monotherapy allowances:
The trial is designed as a combination regimen consisting of bevacizumab and 
irinotecan liposome; however, if irinotecan liposome is withheld or discontinued, 
subjects may continue receiving bevacizumab as a monotherapy, as long as any 
toxicity warranting the interruption/discontinuation is only related to irinotecan 
liposome and not related to bevacizumab. The converse is also permitted. If 
bevacizumab is withheld or discontinued, subjects may continue receiving 
irinotecan liposome as a monotherapy, as long as any toxicity warranting the 
interruption/discontinuation is only related to bevacizumab and not related to 
irinotecan liposome. If a single agent is withheld while the second agent is 
continued as a monotherapy, missed doses of the withheld agent should not be 
made up when the withheld agent is later resumed.
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Table 4.3.1 – Bevacizumab Dose Modifications for Toxicity Management
Adverse Reaction
Severity (NCI CTCAE v5.0)**
Dose Modification*
Gastrointestinal 
Perforations and 
Fistulae

Gastrointestinal perforation, 
any grade

Tracheoesophageal fistula, 
any grade

Fistula, Grade 4

Fistula formation involving 
any internal organ
Discontinue bevacizumab.
Wound Healing 
Complications

Wound healing 
complications requiring 
medical intervention

Necrotizing fasciitis
Discontinue bevacizumab.

Grade 3 or 4
Discontinue bevacizumab.
Hemorrhage

Hemoptysis of ½ teaspoon 
(2.5 mL) or more
Hold bevacizumab (for a maximum of 4 
weeks) until bleeding has improved to ≤Grade 
1; resume bevacizumab at the same dose* 
once bleeding has improved to ≤Grade 1; 
discontinue bevacizumab if unable to resume 
within 4 weeks.

Arterial thromboembolism, 
severe
Discontinue bevacizumab.
Thromboembolic 
Events

Venous thromboembolism, 
Grade 4
Discontinue bevacizumab.
Hypertension
Hypertension, 
Continued

Hypertensive crisis

Hypertensive 
encephalopathy
Discontinue bevacizumab.
Continue to monitor blood pressure at regular 
intervals in subjects with bevacizumab-
induced or -exacerbated hypertension after 
discontinuing bevacizumab.
Table continues on the following page.
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Table 4.3.1 – Bevacizumab Dose Modifications for Toxicity Management
Adverse Reaction
Severity (NCI CTCAE v5.0)**
Dose Modification*

Hypertension, severe
Monitor blood pressure regularly and treat 
hypertension with appropriate anti-
hypertensive therapy. 
Hold bevacizumab (for a maximum of 4 
weeks) if blood pressure is not controlled with 
medical management. (Uncontrolled is 
defined as a consistent bp of ≥160 mmHg 
systolic or ≥ 100 mmHg diastolic, on initial 
and repeat checks); resume bevacizumab at 
the same dose¥,* once controlled; discontinue 
bevacizumab if unable to control or if 
bevacizumab cannot be resumed within 4 
weeks.
Continue to monitor blood pressure at regular 
intervals in subjects with bevacizumab-
induced or -exacerbated hypertension after 
discontinuing bevacizumab.
¥A dose reduction to bevacizumab 5 mg/kg IV 
every two weeks is allowed per treating 
physician discretion for the management of 
hypertension that does not meet the criteria 
for discontinuation.
Posterior 
Reversible 
Encephalopathy 
Syndrome (PRES)

Any
Discontinue bevacizumab.
Renal Injury and 
Proteinuria
Renal Injury and 
Proteinuria, 
Continued

≥ 2+ (urine dipstick)

≥ 100 mg/dL (random 
protein urinalysis)
Undergo further assessment with a 24-hour 
urine collection.
           Table continues on the following page.
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Table 4.3.1 – Bevacizumab Dose Modifications for Toxicity Management
Adverse Reaction
Severity (NCI CTCAE v5.0)**
Dose Modification*

Proteinuria ≥ 2 grams per 
24 hours in absence of 
nephrotic syndrome
Monitor urine protein at regular intervals; hold 
bevacizumab (for a maximum of 4 weeks) 
until proteinuria < 2 grams per 24 hours; 
resume bevacizumab at the same dose¥,* 
once proteinuria improves to < 2 grams per 24 
hours; discontinue bevacizumab if unable to 
resume within 4 weeks.
¥A dose reduction to bevacizumab 5 mg/kg IV 
every two weeks is allowed per treating 
physician discretion for the management of 
proteinuria that does not meet the criteria for 
discontinuation.

Nephrotic syndrome
Discontinue bevacizumab.

Severe
Discontinue bevacizumab and administer 
medical therapy (e.g., epinephrine, 
corticosteroids, intravenous antihistamines, 
bronchodilators and/or oxygen).

Moderate
Interrupt infusion; resume at a decreased rate 
of infusion after symptoms resolve.
Infusion-Related 
Reactions

Mild
Decrease infusion rate.
Congestive Heart 
Failure

Any
Discontinue bevacizumab.

Grade 3 or Grade 4
Hold bevacizumab (for a maximum of 4 
weeks); resume bevacizumab at the same 
dose* once event improves to ≤ Grade 2; 
discontinue bevacizumab if unable to resume 
within 4 weeks.
Other 
Bevacizumab-
Related*** Event 
that is Not 
Described 
Elsewhere in this 
Table

Grade 1 or Grade 2
No dose modification required.*
*   Bevacizumab dose interruptions of ≤28 days and/or dose reductions to bevacizumab dose level -1 (5 mg/kg IV 
every two weeks) may be implemented at any time for any grade toxicity considered intolerable by the subject, or 
if thought to be in the best interest of the subject, if the event does not meet treatment discontinuation criteria as 
defined in Table 4.3.1. Refer to Table 4.2.1 for permitted dose levels. If a dose reduction to less than dose level -1 
is required, the subject should discontinue bevacizumab.
** Event Grade according to NCI-CTCAE v5.0 = National Cancer Institute Common Toxicity Criteria for Adverse 
Events Version 5.0.
*** Bevacizumab-related event is defined as an event that is definitely, probably, or possibly related to bevacizumab.
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4.3.2
Irinotecan Liposome Dose Modifications/Interruptions 
Table 4.3.2 describes dose modifications for irinotecan liposome for toxicity 
management. A dose reduction to dose level -1 and -2 (irinotecan liposome 50 
mg/m2 and 43 mg/m2 IV every two weeks, respectively) is allowed for the 
management of toxicity that does not meet the criteria for discontinuation, per 
Table 4.3.2. Dose re-escalation is not permitted following a dose reduction.
In addition to what is described in Table 4.3.2, irinotecan liposome dose 
interruptions of ≤ 28 days and/or dose reductions to dose levels -1 and -2 may be 
implemented at any time for any grade toxicity considered intolerable by the 
subject, or if thought to be in the best interest of the subject, if the event does not 
meet treatment discontinuation criteria as defined in Table 4.3.2.
Monotherapy allowances:
The trial is designed as a combination regimen consisting of bevacizumab and 
irinotecan liposome; however, if irinotecan liposome is withheld or discontinued, 
subjects may continue receiving bevacizumab as a monotherapy, as long as any 
toxicity warranting the interruption/discontinuation is only related to irinotecan 
liposome and not related to bevacizumab. The converse is also permitted. If 
bevacizumab is withheld or discontinued, subjects may continue receiving 
irinotecan liposome as a monotherapy, as long as any toxicity warranting the 
interruption/discontinuation is only related to bevacizumab and not related to 
irinotecan liposome. If a single agent is withheld while the second agent is 
continued as a monotherapy, missed doses of the withheld agent should not be 
made up when the withheld agent is later resumed.
Table 4.3.2 –Irinotecan Liposome Dose Modifications for Toxicity Management
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Adverse 
Reaction
Severity (NCI CTCAE v5.0)**
Dose Modification*
Interstitial Lung 
Disease
Any Grade/Severity
Discontinue irinotecan liposome.
Anaphylactic 
Reaction
Any Grade/Severity
Discontinue irinotecan liposome.
Grade 3 or 4                      
Late Onset Diarrhea       

Hold irinotecan liposome (for a maximum of 4 
weeks);

Initiate loperamide; recommended 
loperamide regimen is 4 mg after the first 
loose bowel movement followed by 2 mg 
every 2 hours thereafter (4 mg every 4 hours 
at night), until 12 hours have passed without 
a bowel movement. 

Resume irinotecan liposome at a reduced 
dose level*** once event improves to              
≤ Grade 1;

Discontinue irinotecan liposome if unable to 
resume within 4 weeks.
Diarrhea
Grade 2                             
Late Onset Diarrhea

Hold irinotecan liposome (for a maximum of 4 
weeks);

Initiate loperamide; recommended 
loperamide regimen is 4 mg after the first 
loose bowel movement followed by 2 mg 
every 2 hours thereafter (4 mg every 4 hours 
at night), until 12 hours have passed without 
a bowel movement. 

Resume irinotecan liposome at the same 
dose level or a reduced dose level*** per 
Treating Investigator discretion, once event 
improves to ≤ Grade 1;

Discontinue irinotecan liposome if unable to 
resume within 4 weeks.
Table continues on the following page.
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Grade 3 or 4                     
Early Onset Diarrhea

Hold irinotecan liposome (for a maximum of 4 
weeks);

Administer intravenous or subcutaneous 
atropine 0.25 to 1 mg (unless clinically 
contraindicated);

Resume irinotecan liposome at a reduced 
dose level*** once event improves to ≤ Grade 
1;

Discontinue irinotecan liposome if unable to 
resume within 4 weeks.
Diarrhea, 
continued
Grade 2                            
Early Onset Diarrhea

Hold irinotecan liposome (for a maximum of 4 
weeks);

Administer intravenous or subcutaneous 
atropine 0.25 to 1 mg (unless clinically 
contraindicated);

Resume irinotecan liposome at the same 
dose level or a reduced dose level*** per 
Treating Investigator discretion once event 
improves to ≤ Grade 1;

Discontinue irinotecan liposome if unable to 
resume within 4 weeks.
Grade 3 or Grade 4

Hold irinotecan liposome (for a maximum of 4 
weeks);

Resume irinotecan liposome at a reduced 
dose level*** once event improves to ≤ Grade 
1;

Discontinue irinotecan liposome if unable to 
resume within 4 weeks.

Maximum supportive care/prophylaxis is 
permitted, as described in Section 4.4.
Other Irinotecan 
Liposome-
Related**** Event 
that is Not 
Described 
Elsewhere in this 
Table
Grade 1 or Grade 2

No dose modification required.*
*    Irinotecan liposome dose interruptions of ≤28 days and/or dose reductions to dose level -1 or -2 (refer to Table 4.2.2 for dose 
levels) may be implemented at any time for any grade toxicity considered intolerable by the subject, or if thought to be in the 
best interest of the subject, if the event does not meet treatment discontinuation criteria as defined in Table 4.3.2.
 Footnotes continue on the following page.
**   Event Grade according to NCI-CTCAE v5.0= National Cancer Institute Common Toxicity Criteria for Adverse Events Version 5.0.
***  Refer to Table 4.2.2 for permitted dose levels. If a dose reduction to less than dose level -2 (43 mg/m2) is required, the subject 
should discontinue irinotecan liposome. 
**** Irinotecan liposome-related event is defined as an event that is definitely, probably, or possibly related to bevacizumab.
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4.4
Concomitant Medications/Treatments
4.4.1
Concomitant Medication Reporting
All medications taken from the time of informed consent through the time of the 
safety follow-up visit must be reported in the eCRF.
4.4.2
Pre-Medications 

Premedications for Irinotecan Liposome:
Administer a corticosteroid and an anti-emetic approx. 30 min prior to 
infusing irinotecan liposome. Choice of corticosteroid and anti-emetic is per 
treating investigator discretion and/or local Institutional standards. 

Premedications for Bevacizumab:
Bevacizumab does not require pre-medications, but they are permitted, 
if indicated, per treating investigator discretion and/or local institutional 
standards.
Refer to Section 4.2 for additional information.
Local institutional practices should be followed in case of a reaction to trial 
therapy. 
Additional oral and IV premedications and supportive care/prophylaxis measures 
may be used per Treating Investigation discretion and/or local Institutional 
standards as clinically indicated. (Examples may include but are not limited to 
dexamethasone, ondansetron, atropine, loperamide, palonosetron, fosaprepitant, 
aprepitant, and/or corticosteroid on day 1, 2 and 3, etc.) Refer to Table 4.4.3 for 
prohibited Medications and Therapies. 
4.4.3
Prohibited Medications and Therapies
While subjects are receiving trial therapy, all medications and medical therapy 
required for supportive care and/or the health of the subject are permitted (e.g., 
antibiotics, analgesics, and antiemetics), except for the prohibited medications 
listed in Table 4.4.3. Local institutional practices for supportive care should be 
followed in case of a reaction to trial therapy and for management of AEs.  
Table 4.4.3 – Prohibited Medications & Therapies
Concurrent anti-cancer 
therapies not specified in 
Not permitted within ≤ 14 days prior to registration or while 
receiving trial therapy. These include but are not limited to: 
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Table 4.4.3 – Prohibited Medications & Therapies
this protocol 

Hormonal therapy

Chemotherapy

Radiation therapy

Immunotherapy

Biologics

Anti-cancer radionuclides
NOTE: Refer to Section 4.4.4 for restrictions regarding when surgery is 
permitted.
Concurrent investigational 
agents not specified in this 
protocol
Not permitted within ≤ 14 days prior to registration or while 
receiving trial therapy.
Hematologic growth factors 
and blood products 
(transfusions)
Not permitted within ≤ 14 days prior to registration for all subjects.  
Not permitted while receiving trial therapy for subjects participating 
in the safety lead-in portion of the study. Should a subject who is 
participating in the safety lead-in portion of the study require the 
use of these agents while receiving trial therapy, trial therapy must 
be discontinued. (Note: These agents are permitted for subjects 
who are not participating in the safety lead-in.)
Live vaccines
Not permitted within ≤ 30 days prior to registration or while 
receiving trial therapy. Should a subject require the use of these 
agents while receiving trial therapy, trial therapy must be 
discontinued.
NOTE:  Seasonal influenza vaccines for injection are generally inactivated 
flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
Flu-Mist®) are live attenuated vaccines and are not allowed. If a subject 
receives SARS-CoV-2 vaccinations (COVID-19 vaccinations) during study 
participation, it is the responsibility of the investigator to determine the 
suitability of the vaccine being given with the information provided by the 
manufacturer.
Select herbal supplements
The following herbal supplements are not permitted while 
receiving irinotecan liposome:  

Curcumin supplements

Licorice supplements (all species are prohibited)

Panax/Asian ginseng supplements (American ginseng is permitted.)

St. John’s wort supplements

Turmeric supplements
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Table 4.4.3 – Prohibited Medications & Therapies
Known strong CYP3A4 
inducers (medications or 
substances)*
Not permitted within ≤ 2 weeks prior to initiation of irinotecan 
liposome or while receiving irinotecan liposome. These include, 
but are not limited to: 

Phenytoin

Phenobarbital

Primidone

Carbamazepine

Rifampin

Rifabutin

Rifapentine
Known strong CYP3A4 
inhibitors (medications or 
substances)*
Not permitted within ≤ 1 week prior to initiation of irinotecan 
liposome or while receiving irinotecan liposome. These include, 
but are not limited to:

Ketoconazole      (Note: The antiemetic fosaprepitant is permitted.)

Clarithromycin

Indinavir

Itraconazole

Lopinavir

Nefazodone

Nelfinavir

Ritonavir

Saquinavir

Telaprevir

Voriconazole
Known strong UGT1A1 
inhibitors (medications or 
substances)*
Not permitted within ≤ 1 week prior to initiation of irinotecan 
liposome or while receiving irinotecan liposome. These include, 
but are not limited to:

Atazanavir

Gemfibrozil

Indinavir

Ketoconazole 
*Sites should refer to a current pharmacy reference manual for a full list of strong CYP3A4 
inducers/inhibitors and strong UGTA1 inhibitors.
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4.4.4
Surgery
Hold bevacizumab for at least 28 days prior to elective surgery, including jaw-
invasive dental procedures. Do not administer bevacizumab for at least 28 days 
after surgery, and until the wound is fully healed. Discontinue bevacizumab in 
subjects who develop wound healing complications that require medical 
intervention or necrotizing fasciitis.
Subjects must not have undergone a surgical procedure within ≤ 28 days prior to 
registration. Refer to exclusion criterion 3.2.3 for additional information. 
4.5
Duration of Therapy
Subjects will continue to receive trial therapy until disease progression, unacceptable 
toxicity, withdrawal, or death; whichever occurs first.  
Subjects also can be taken off study medication treatment at any time per their own 
request, or per the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation of study medication must be clearly 
documented on the appropriate eCRF and may include (but are not limited to) the 
following:

Subject completes the recommended course of study medication treatment;

Subject experiences disease progression while receiving study medication;
NOTE: Serological progression (i.e., a rise in CA-125 alone) in the absence of 
clinical or radiographical signs of progression does not meet the definition of 
progressive disease.  
NOTE: For equivocal findings of progression per RECIST 1.1 (e.g., very small and 
uncertain new lesions; cystic changes or necrosis in existing lesions), treatment 
may continue until the next scheduled assessment. If at the next scheduled 
assessment, progression is confirmed, trial therapy should be discontinued, and 
the date of progression should be the earlier date when progression was 
suspected.

Subject experiences unacceptable toxicity related to study medication;

Subject voluntarily withdraws from study medication treatment;

Subject develops an inter-current illness, second malignancy, or other 
circumstance that prevents further administration of study medication;

Subject requires a treatment that is not permitted while on study or would interfere 
with study endpoints (See Section 4.4.3);

Subject becomes pregnant;

Subject’s study therapy is delayed/interrupted beyond the allowed period (See 
Section 4.3).

Treating investigator determines that the subject should discontinue study 
medication treatment for any reason (i.e. changes in condition, inability to comply 
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with protocol requirements, treatment is no longer in the subject’s best interest, 
etc.).  

Drug manufacturer can no longer provide study medication;

Death.
The reason(s) for protocol therapy discontinuation and the corresponding date(s) of 
discontinuation must be documented in the eCRF. 
Following the last dose of protocol therapy, subjects will be considered off treatment. Off-
treatment subjects will proceed to follow up per Section 4.6.  Subjects who are off 
protocol therapy are to be followed until they meet the criteria for Off Study (see Section 
4.7). Follow-up data will be required unless consent was withdrawn.
4.6
Duration of Follow Up
Refer to Section 4.4 and Section 10.0 regarding the duration for reporting concomitant 
medications, AEs, and SAEs during the follow-up period.
NOTE: For subjects with bevacizumab-induced or -exacerbated hypertension, continue to 
monitor blood pressure at regular intervals after discontinuing bevacizumab, until blood 
pressure returns to baseline or stabilizes and is well controlled. Refer to Section 4.3 for 
details.
NOTE: Collection of RECIST 1.1 and CA-125 data is critical for study endpoints. Refer to 
Section 5.0 regarding the timing of when these assessments should be performed in 
subjects who discontinue protocol therapy and enter the follow up phase of the study.
4.6.1
Short Term (Safety) Follow Up Phase
End of Treatment (EOT) Visit
Refer to Section 5.0 for details on the assessments that are to be conducted at 
the EOT visit. Subjects who have received at least 1 dose of either irinotecan 
liposome or bevacizumab will have an end of treatment (EOT) visit ≤14 days 
after the decision to permanently discontinue trial therapy. If feasible, it is 
recommended that the EOT visit occur prior to the initiation of subsequent 
therapy. 
EXCEPTION: The EOT visit is not required if it would fall within ≤ 14 days of the 
safety follow up visit; in these cases, the EOT visit may be skipped, and instead 
the patient may proceed to the safety follow up visit. See the following paragraph 
for details regarding the safety follow up visit.  
Safety Follow Up Visit
Refer to Section 5.0 for details on the assessments that are to be conducted at 
the safety follow up visit. All subjects who have received at least 1 dose of either 
irinotecan liposome or bevacizumab will have a safety follow up visit 
approximately 30 days (± 7 days) after the last dose of study medication. 
Subjects will be followed for toxicity and concomitant medication use through this 
visit. In addition, subjects who are removed from treatment for unacceptable 
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adverse events will be followed clinically (per standard of care) until resolution or 
stabilization of the adverse event, or as indicated. 
After completion of the Safety Follow Up Visit, patients who have discontinued 
trial therapy for reasons other than disease progression will proceed to the Long 
Term Follow Up Phase of the study (Section 4.6.2).  Patients who have 
discontinued trial therapy due to disease progression will discontinue study 
participation upon completion of the Safety Follow Up Visit (i.e., Long Term 
Follow Up Phase is not required). 
NOTE: Subjects experiencing ongoing drug-related toxicity at the time of the 
Safety Follow Up Visit may continue to be followed clinically (per standard of 
care) until resolution or stabilization of the adverse event, or as indicated.
4.6.2
Long Term Follow Up Phase
Following the last dose of trial therapy, subjects who have not yet progressed will 
be followed for up to 3 years, or until progression, initiation of subsequent anti-
cancer therapy, withdrawal, or death; whichever occurs first.  As outlined in 
Section 5.0, follow every 3 months (± 14 days) for 1 year post-last dose, then 
every 6 months (± 30 days) thereafter, for up to a total of 3 years.
Information to be collected at each long term follow up time point:
1.
Survival status
2.
Disease status (i.e., has the subject progressed?)
3.
Subsequent anti-cancer therapies received
NOTE: Collection of RECIST 1.1 and CA-125 data is critical for study endpoints. 
Refer to Section 5.0 regarding the timing of when these assessments should be 
performed in subjects who discontinued protocol therapy for reasons other than 
disease progression.
Upon completion of follow-up, subjects will be considered off study, per Section 
4.7.
4.7
Removal of Subjects from the Study as a Whole/Off-Study Criteria
This section describes reasons that a subject would discontinue study participation (i.e. 
“off study”). Refer to Section 4.7 for reasons that a subject would discontinue trial therapy 
(i.e., “off treatment”). 
Subjects can be removed from the study at any time per their own request, or at the 
discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation must be clearly documented on the appropriate eCRF and 
may include (but are not limited to) the following:

Subject completes the study follow-up period, (Refer to Section 4.6);

Subject withdraws consent for further data submissions, (No follow-up permitted);
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
Treating investigator determines that the subject should discontinue study 
participation for any reason, (i.e., inability to comply with study procedures, study 
participation is no longer in the subject’s best interest, etc.);

Termination of the study by the study Sponsor;

Subject becomes lost to follow-up (LTF) per institutional standard; 

Death.
The reason(s) for discontinuation of study participation and the corresponding date(s) of 
participation/discontinuation must be documented in the eCRF. 
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5.0
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS
Trial Period:
Screening 
Treatment1, 19
Post-Treatment
Cycles/Visits:
Screening/Baseline
D1 of each 
Cycle1
D15 of each 
Cycle
End of Treatment 
Visit
Safety Follow Up Visit
Long Term Follow Up
Scheduling Window (Calendar Days), 
Unless Otherwise Indicated:
≤28 days 
prior to 
registration
≤28 days 
prior to 
treatment 
initiation
≤14 days 
prior to 
treatment 
initiation
≤3 days 
prior to 
treatment 
initiation
≤ 3 days 
prior to D1 
≤ 3 days 
prior to D15
≤14 days after the 
decision to 
discontinue trial 
therapy 20
30 days (± 7) after the 
last dose of trial 
therapy
Follow q3m (± 14 days)   
after the last dose of 
trial therapy x 1 year 
then q6m (± 30 days)  
thereafter x 2 years
Administrative Procedures
Informed Consent & Eligibility Criteria
X
Demographics and Medical History
X
Review Concomitant Medications 2
X
X
X
Cardiac Function Risk Assessment 3
X
Contraception and Breastfeeding 
Counseling 4
X
Survival Status and Follow Up 5,6
X5
X6
Clinical Procedures/Assessments
Review AEs or Baseline Symptoms 7
X
X
X
Physical Examination
X
X
X20
X
ECOG Performance Status 8
X
X
X
Blood Pressure 9
X
X
X
X20
X
Other Vitals 10
X
X
X
X20
X
Laboratory Procedures/Assessments
CBC w/ Differential and Platelets 11
X
X
X
X
CMP 12
X
X
X
X
Coagulation Tests 13
X
Urine Protein Analysis 14
X
X
X
X20
X
CA-125 15
X15
  X15
                                                    X15
Urine or Serum Pregnancy Test 16 
X16
X
X
HIV, HBV, and HCV Testing 17
X
Efficacy Measurements
Tumor imaging/assessment18
X
X
X
Study Treatment
Irinotecan Liposome19
D1
D15
Bevacizumab19
D1
D15
Refer to footnotes on the following pages.

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1.
Initiate trial treatment within ≤ 14 days after registration. 
2.
All medications taken from the time of informed consent through the time of the safety follow-up visit must be reported in the eCRF. Refer to Section 4.4 and Exclusion 
Criterion 3.2.6 for information regarding permitted and prohibited medications.
3.
Subjects with a known history severe cardiac disease, current symptoms of cardiac disease (e.g., unstable angina pectoris or cardiac arrhythmia), or a history of 
treatment with cardiotoxic agents should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (Appendix 
B) within ≤ 28 days prior to registration. To be eligible for this trial, subjects must be class 2B or better. Refer to Inclusion Criterion 3.1.13 for details.
4.
Prior to registration, females of reproductive potential must agree to use adequate contraception (abstinence or two methods of birth control, such as a barrier 
method in combination with hormonal contraception) while receiving trial therapy and for 7 months following completion of trial therapy. Refer to Inclusion Criterion 
3.1.16 for details. Prior to registration, subjects must also agree to not nurse /breastfeed while receiving trial therapy and through 6 months after the last dose of 
trial therapy. Refer to Inclusion Criterion 3.1.17 for details.
5.
All subjects who have received at least 1 dose of trial therapy will have a safety follow up visit approximately 30 days (± 7) after the last dose. Subjects will be 
followed for toxicity and concomitant medication use through this visit. In addition, subjects who discontinue treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. Refer to Section 4.6 for details.
6.
Following the last dose of trial therapy, subjects will be followed for up to 3 years, or until disease progression, initiation of subsequent anti-cancer therapy, withdrawal, 
or death; whichever occurs first.  Follow every 3 months (± 14 days) for 1 year post-last dose, then every 6 months (± 30 days) thereafter, for up to a total of 3 years. 
Collect subject survival status, disease status (i.e., has the subject progressed?), and subsequent anti-cancer therapies received. Additionally, subjects who 
discontinue treatment due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event. Refer to Section 4.6 for details.
7.
All routine AEs, regardless of attribution or clinical significance, occurring from the time of subject registration, through 30 days after the last administration of trial 
therapy, must be recorded. Any event that occurs more than 30 days after the last dose of trial therapy and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported as an adverse event or expedited adverse event, as applicable. All SAEs, regardless of attribution, occurring from time of signed 
informed consent, through 30 days after the last administration of study drug, must be reported upon discovery or occurrence. Refer to Section 10.0 for details.
8.
Refer to Appendix A  for ECOG performance status criteria.
9.
For subjects with hypertension at baseline, hypertension must be well controlled [uncontrolled at baseline is defined as a baseline bp of ≥ 140 mmHg systolic 
and/or ≥ 90 mmHg diastolic on initial and repeat checks (A repeat check is only required if the initial check is ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic)] on 
medication within ≤ 28 days prior to registration. Refer to Inclusion Criterion 3.1.14 for details.  For all subjects who are receiving bevacizumab, monitor blood 
pressure prior to each cycle or at regular intervals, approximately every 2-4 weeks.  After discontinuing bevacizumab, continue to monitor blood pressure at regular 
intervals in subjects with bevacizumab-induced or -exacerbated hypertension, until blood pressure returns to baseline or stabilizes and is well controlled. Refer to 
Section 4.3 for details.
10. Other vitals are to include weight, and height (height is required at baseline only). 
11. Complete blood cell count (CBC) is to include a full differential and platelets.
12. Serum comprehensive metabolic panel (CMP) is to include sodium, potassium, chloride, CO2, creatinine, glucose (fasting is not required), BUN, total protein, albumin, 
calcium, alkaline phosphatase, ALT, AST, and total bilirubin.
13. Coagulation tests are to include PT/INR (prothrombin time/international normalized ratio) and aPTT (activated partial thromboplastin time).
Footnotes continue on the following page. 

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14. Conduct dipstick urinalysis (or random protein urinalysis) at the indicated times to monitor for the development or worsening of proteinuria. Subjects with a ≥ 2+ urine 
dipstick reading (or ≥ 100 mg/dL random protein urinalysis) should undergo further assessment with a 24-hour urine collection. Refer to Inclusion Criterion 3.1.8 and 
Section 4.3.1 for details.
15. Conduct the serum CA-125 test on D1 (≤14 days) of each cycle and at the time of disease progression (or as soon as is feasible after progression is documented). 
Subjects who discontinue trial therapy for reasons other than disease progression should continue to have their serum CA-125 drawn every 4 weeks (± 7 days) 
during follow-up until disease progression, initiation of subsequent anti-cancer therapy, end of study, withdrawal, or death (whichever occurs first). If the subject 
experiences a CA-125 response (Section 7.4), conduct a confirmatory CA-125 test ≥ 28 days later. If the subject experiences a CA-125 progression (Section 7.4), 
conduct a confirmatory CA-125 test ≥ 7 days later. 
NOTE: Serological progression (i.e., a rise in CA-125 alone) in the absence of clinical or radiographical signs of progression does not meet the definition of 
progressive disease.
16. Pregnancy test at the indicated times is only required for females of reproductive potential. During screening, females of reproductive potential must agree to undergo 
a urine or serum pregnancy test within ≤ 3 days prior to initiating trial therapy. The result must be negative in order to initiate trial therapy. Refer to Inclusion Criterion 
3.1.15 for details.
17. HIV, HBV, and HCV testing within ≤ 28 days prior to registration is only required for subjects with a known HIV, HBV, or HCV infection, respectively.  Note that for 
subjects with a known history of HIV, the subject’s medical history must indicate that the HIV viral load has been undetectable for ≥ 6 months prior to registration. 
Refer to Inclusion Criteria 3.1.9 and 3.1.10 for details.
18. Imaging results will be assessed according to RECIST 1.1 criteria. Tumor imaging is to consist of CT scan of chest abdomen and pelvis. CT scan with contrast is 
the preferred imaging assessment; CT scan without contrast is permitted if contrast is not clinically indicated/feasible. Chest X-ray and MRI are permitted in lieu of 
CT scan only as described in the published RECIST 1.1 criteria.16  
During screening/baseline, conduct imaging:
-
Within ≤ 28 days prior to registration. 
While receiving trial therapy, conduct imaging:
-
Every 2 cycles for the first 5 cycles [i.e. prior to initiation of C3D1 and C5D1 (-7 day window).]
-
Every 3 cycles thereafter [i.e., prior to initiation of C8D1, C11D1, C14D1, etc. (-7 day window).]
-
At the time of disease progression (or as soon as is feasible). 
NOTE: Serological progression (i.e., a rise in CA-125 alone) in the absence of clinical or radiographical signs of progression does not meet the definition of 
progressive disease. For equivocal findings of progression per RECIST 1.1 (e.g., very small and uncertain new lesions; cystic changes or necrosis in 
existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, trial therapy 
should be discontinued, and the date of progression should be the earlier date when progression was suspected.
A complete response (CR) or partial response (PR) per RECIST 1.1 must be confirmed via repeat imaging ≥ 28 days after the response was first observed. 
During follow up, conduct imaging:
Subjects who discontinue trial therapy for reasons other than disease progression should continue to be imaged every 12 weeks (± 7 days) or as clinically 
indicated per standard of care until disease progression, initiation of subsequent anti-cancer therapy, end of study, withdrawal, or death (whichever occurs first). 
19. Routine dosing on D1 and D15 of each cycle has a window of ±3 calendar days. Refer to Section 4.0 for the treatment plan. Refer to Section 4.3 for permitted dose 
modifications/interruptions. Refer to Section 4.5 for details on the duration of trial therapy and reasons why subjects should discontinue trial therapy.
NOTE: Serological progression (i.e., a rise in CA-125 alone) in the absence of clinical or radiographical signs of progression does not meet the definition of 
progressive disease. For equivocal findings of progression per RECIST 1.1 (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), 
treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, trial therapy should be discontinued, 
and the date of progression should be the earlier date when progression was suspected.
Footnotes continue on the following page. 

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20. Subjects who have received at least 1 dose of either irinotecan liposome or bevacizumab will have an end of treatment (EOT) visit ≤14 days after the decision to 
permanently discontinue trial therapy. If feasible, it is recommended that the EOT visit occur prior to the initiation of subsequent therapy. See Section 4.6  for 
additional detail.
EXCEPTION: The EOT visit is not required if it would fall within ≤ 14 days of the safety follow up visit; in these cases, the EOT visit may be 
skipped, and instead the patient may proceed to the safety follow up visit. See footnote 5 and Section 4.6 for additional detail. 

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6.0
CORRELATIVES/SPECIAL STUDIES
This trial does not have any correlative/special studies. There is no correlative specimen 
collection.
7.0
ENDPOINT ASSESSMENTS AND EVALUABILITY
In this phase II design, we anticipate enrolling 30 subjects who are evaluable for the primary 
endpoint. In anticipation of some subjects not being evaluable, up to 33 subjects may be enrolled 
to yield at least 30 evaluable subjects. Refer to Section 8.2 for details. 
7.1
Primary Endpoint and Evaluability
7.1.1
Objective Response Rate (ORR)
The primary objective is to assess the antineoplastic efficacy of irinotecan 
liposome in combination with bevacizumab in women with recurrent, platinum 
resistant ovarian cancer, as measured by the Objective Response Rate (ORR).
The primary endpoint of ORR is defined as the proportion of treated subjects 
who experience an objective response [confirmed complete response (CR) or 
confirmed partial response (PR) per RECIST 1.116]. Confirmation of response 
should be conducted via imaging ≥ 28 days after the response was first 
documented. The date of first response for either CR or PR will be used for the 
calculation of ORR.
ORR data will be collected from baseline until the response has been confirmed, 
the subject experiences disease progression, the subject initiates subsequent 
anti-cancer therapy, or the subject completes study participation (whichever 
occurs first).
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for the primary endpoint.
7.2
Secondary Efficacy Endpoints and Evaluability
7.2.1
Overall Best Response
To determine the Overall Best Response per RECIST 1.1, this endpoint will 
tabulate the proportion of subjects who experience each the following as their 
best response to trial therapy: CR, PR, SD, PD or not evaluable (NE) per 
RECIST 1.1.16 
Overall Best Response data will be collected from baseline until the subject 
experiences disease progression, the subject initiates subsequent anti-cancer 
therapy, or the subject completes study participation (whichever occurs first).
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Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.2
Clinical Benefit Rate (CBR)
To determine the CBR, this endpoint will calculate the proportion of treated, 
evaluable subjects who experience clinical benefit from trial therapy. 
Clinical benefit is defined as confirmed complete response (CR); confirmed 
partial response (PR); or stable disease (SD) for ≥ 4 months (calculated from the 
initiation of trial therapy on C1D1) per RECIST 1.1.16 
CBR data will be collected from baseline until the subject experiences disease 
progression, initiates subsequent anti-cancer therapy, or completes study 
participation (whichever occurs first).
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.3
Duration of Response (DOR) 
To calculate the DOR for the combination of irinotecan liposome and 
bevacizumab, this endpoint will be calculated as the time that elapsed between 
the day of first documented response to trial therapy (CR or PR, whichever is first 
recorded) and subsequent disease progression (taking as reference for 
progressive disease the smallest tumor measurements recorded on study). 
For DOR analysis, response is defined as complete response (CR) or partial 
response (PR) per RECIST 1.1; and disease progression is defined as 
progressive disease (PD) per RECIST 1.1.16 
DOR data will be collected from the time of first response to trial therapy until the 
subject experiences disease progression, initiates subsequent anti-cancer 
therapy, or completes study participation (whichever occurs first). If disease 
progression is not observed prior to initiating subsequent anti-cancer therapy or 
completing study participation, the DOR will be censored as the last available 
disease assessment.
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.4
Duration of Stable Disease (Duration of SD) 
To calculate the Duration of SD (CR, PR, and SD) for the combination of 
irinotecan liposome and bevacizumab, this endpoint will be calculated as the time 
that elapsed between the day of initiation of trial therapy and subsequent disease 
progression (taking as reference for progressive disease the smallest 
measurements recorded on study). 
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Duration of SD analysis will capture subjects who achieve a best response of 
CR, PR, or SD, as defined per RECIST 1.1. For Duration of SD analysis, disease 
progression is defined as progressive disease (PD) per RECIST 1.1.16
Duration of SD data will be collected from baseline until the subject experiences 
disease progression, initiates subsequent anti-cancer therapy, or completes 
study participation. If disease progression is not observed prior to initiating 
subsequent anti-cancer therapy or completing study participation, the Duration of 
SD will be censored as the last available disease assessment.
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.5
Time to Response (TTR)
To calculate the Time to Response (TTR) for the combination of irinotecan 
liposome and bevacizumab, this endpoint will be calculated as the time that 
elapsed between the initiation of trial therapy (C1D1) and the day of first 
documented response to therapy. 
For TTR analysis, a response to therapy is defined as a confirmed complete 
response (CR) or confirmed partial response (PR) per RECIST 1.1.16 The first 
date of response will be used for the calculation.
TTR data will be collected from baseline until the subject experiences response, 
initiates subsequent anti-cancer therapy, or completes study participation. If 
response is not observed prior to initiating subsequent anti-cancer therapy or 
completing of study participation, the TTR will be censored as the last available 
disease assessment.
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.6
Median Progression-Free Survival (PFS)
To measure Median Progression-Free Survival (PFS) for the combination of 
irinotecan liposome and bevacizumab, this endpoint will calculate the 
progression-free survival time as the time that elapsed between the initiation of 
trial therapy (C1D1) and the day of first documented disease progression or 
death from any cause for all evaluable subjects. Median PFS will be calculated 
based on the Kaplan-Meier estimates of PFS. Refer to Section 8.0 for the full 
statistical plan. 
For PFS analysis, disease progression is defined as progressive disease (PD) 
per RECIST 1.1,16 other documented clinical or radiographical progression per 
physician judgement, or death due to disease. NOTE: Serological progression 
(i.e., a rise in CA-125 alone) in the absence of clinical or radiographical signs of 
progression does not meet the definition of progressive disease.  
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PFS data will be collected from baseline until the subject experiences disease 
progression, initiates subsequent anti-cancer therapy, completes study 
participation, or experiences death from any cause (whichever is sooner). If 
disease progression or death from any cause is not observed prior to initiating 
subsequent anti-cancer therapy or completing study participation, the PFS will be 
censored as the last available disease assessment. 
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.2.7
16 Week Progression-Free Survival (PFS-16)
To measure 16 Week Progression-Free Survival (PFS-16) for the combination of 
irinotecan liposome and bevacizumab, this endpoint will be calculated based on 
the Kaplan-Meier estimates of PFS as the proportion of subjects who are alive 
and progression-free at 16 weeks after initiating trial therapy. Refer to Section 8.0 
for the full statistical plan. 
For PFS analysis, disease progression is defined as progressive disease (PD) 
per RECIST 1.1,16 other documented clinical or radiographical progression per 
physician judgement, or death due to disease. 
NOTE: Serological progression (i.e., a rise in CA-125 alone) in the absence of 
clinical or radiographical signs of progression does not meet the definition of 
progressive disease.  
PFS data will be collected from baseline until the subject experiences disease 
progression, initiates subsequent anti-cancer therapy, completes 16 weeks of 
study participation, or experiences death from any cause (whichever is sooner). If 
disease progression or death from any cause is not observed prior to initiating 
subsequent anti-cancer therapy or completing 16 weeks of study participation, 
the PFS will be censored as the last available disease assessment. 
Evaluability: All eligible subjects who receive at least 1 dose of trial combination 
therapy will evaluable for this endpoint.
7.3
Secondary Safety Endpoints and Evaluability
7.3.1
Toxicity Profile
To assess the Toxicity Profile of irinotecan liposome in combination with 
bevacizumab, this secondary endpoint will collect and report the frequency of 
adverse events by type, severity (grade), timing, and attribution to irinotecan 
liposome and bevacizumab according the NCI-CTCAE version 5.0 (Appendix D). 
Evaluability: All subjects who receive at least 1 dose of trial therapy (combination 
therapy or monotherapy) will evaluable for this endpoint.
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Note that this study will include a safety lead-in of the first 6 subjects in stage 1. If 
a subject who is enrolled in the safety lead-in cohort discontinues combination 
trial therapy for reasons other than DLT before completing the DLT observation 
period, an additional subject will be added to the safety run-in cohort. Refer to 
Section 8.4 and Section 4.2.3 for details. 
7.4
Exploratory Endpoints and Evaluability
7.4.1
Serum CA-125 Levels
To measure serum CA-125 levels in women with recurrent, platinum resistant 
ovarian cancer who have received treatment with irinotecan liposome in 
combination with bevacizumab, this endpoint will tabulate serum CA-125 levels 
and determine the following, according to the Gynecological Cancer Intergroup 
(GCIG) criteria:15

CA-125 Response Rate

CA-125 Complete Response Rate

CA-125 Progression Rate
The CA-125 Response Rate is defined as the proportion of evaluable subjects 
who experience a CA-125 Response. A CA-125 Response is defined as a ≥50% 
reduction in CA-125 levels from a pre-treatment sample. The response must be 
confirmed and maintained for at least 28 days. The date when the CA-125 level 
is first reduced by 50% is the date of the CA-125 response. 
The CA-125 Complete Response Rate is defined as the proportion of evaluable 
subjects who are CA-125 Complete Responders. A CA-125 Complete 
Responder is defined as a subject who has a CA-125 Response and whose CA-
125 level falls to within the reference range. Subjects who have a fall/decrease in 
CA-125 to within the reference range but whose initial CA-125 was less than 
twice the upper limit of the reference range have not had a CA-125 Response 
and cannot be classified as a CA-125 Complete Responder.
The CA-125 Progression Rate is defined as the proportion of evaluable subjects 
who experience a CA-125 Progression Event. A CA-125 Progression Event is 
defined as a subject who meets any of the following:

Subject with elevated CA-125 pretreatment, followed by normalization of 
CA-125, followed by a subsequent increase in CA-125, where the 
increase demonstrates a CA-125 ≥ 2X ULN, with confirmation ≥ 1 week 
later; the date when the CA-125 first increases to ≥ 2X ULN is the date of 
the CA-125 Progression Event; death will also count as a Progression 
Event.

Subject with elevated CA-125 pretreatment, which never normalizes, 
followed by subsequent increase in CA-125, where the increase 
demonstrates a CA-125 ≥ 2X the nadir, with confirmation ≥ 1 week later; 
the nadir is the lowest CA-125 value recorded while on study prior to the 
increase; the date when the CA-125 first increases to ≥ 2X the nadir is 
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the date of the CA-125 Progression Event; death will also count as a 
Progression Event.

Subject with CA-125 in the reference range before treatment, followed by 
subsequent increase in CA-125, where the increase demonstrates a CA-
125 ≥ 2X ULN, with confirmation ≥ 1 week later; the date when the CA-
125 first increases to ≥ 2X ULN is the date of the CA-125 Progression 
event. Death will also count as a Progression Event.
Serum CA-125 data will be collected from ≤ 14 days prior to treatment initiation 
until the EOT visit, or until the time of confirmation, whichever is later. 
 
Evaluability: Eligible subjects who meet all of the following will be evaluable for 
this endpoint:

Completion of a pre-treatment serum CA-125 test. (For the endpoints of CA-
125 Response Rate and CA-125 Complete Response Rate, the pre-
treatment CA-125 value must be ≥ 2X ULN within 2 weeks before starting 
treatment.)

Receipt of ≥1 dose of trial combination therapy, followed by completion of 
an interim CA-125 test. 
7.5
Definitions
7.5.1
RECIST 1.1 Response Criteria
RECIST 1.1 response criteria16 (Appendix C) will be used to assess tumor 
response for the primary endpoint. RECIST 1.1 uses the following categories of 
response: Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), and Progressive Disease (PD).
At each scheduled imaging response assessment (refer to Section 5.0 for the 
schedule), a radiologic response will be determined, based on the RECIST 1.1 
response criteria.  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 should always be done rather 
than clinical examination unless the lesion(s) being followed cannot be imaged 
but are assessable by clinical exam.
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 should always be done rather than clinical 
examination, unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.
For equivocal findings of progression (e.g. very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the 
next scheduled assessment. If at the next scheduled assessment, progression is 
confirmed, the date of progression should be the earlier date when progression 
was suspected.
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For subjects who achieve a CR or PR, responses should be confirmed ≥ 28 days 
after the initial response was observed. The date of first response will be used in 
the calculation for ORR. 
CT scan with contrast is the preferred imaging assessment; CT scan without 
contrast is permitted if contrast is not clinically indicated/feasible. Chest X-ray 
and MRI are permitted in lieu of CT scan only as described in the published 
criteria by Eisenhower et. al.16  Refer to the published criteria for more 
information. Questions regarding the criteria should be directed to the lead PI. 
7.5.2
NCI-CTCAE v5.0 
The National Institutes of Health Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 5.0 will be used to assess adverse events for this 
trial and is available here. Refer to Section 10.0 for additional details on adverse 
events assessment and reporting. 
7.5.3
Objective Response Rate (ORR) 
The ORR is defined as the proportion of treated subjects who experience an 
objective response [confirmed complete response (CR) or confirmed partial 
response (PR) per RECIST 1.1 criteria]. Refer to Section 7.1 for additional 
details. 
7.5.4
Clinical Benefit Rate (CBR) 
The CBR is defined as the proportion of treated subjects who experience clinical 
benefit [confirmed complete response (CR); confirmed partial response (PR); or 
stable disease (SD) for ≥ 4 months per RECIST 1.1 criteria]. Refer to Section 
7.2.2 for additional details.
7.5.5
Duration of Response (DOR)
DOR is defined as the time that elapses between the first day of documented 
response to trial therapy and subsequent disease progression. For DOR 
analysis, response is defined as complete response (CR) or partial response 
(PR) per RECIST 1.1 criteria; and disease progression is defined as progressive 
disease (PD) per RECIST 1.1 criteria.  Refer to Section 7.2.3 for additional 
details. 
7.5.6
Duration of Stable Disease (SD)
Duration of SD is defined as the time that elapses between the day of initiation of 
trial therapy and subsequent disease progression (taking as reference for 
progressive disease the smallest measurements recorded on study). Duration of 
SD analysis will capture subjects who achieve a best response of CR, PR, or SD, 
as defined per RECIST 1.1 criteria. For Duration of SD analysis, disease 
progression is defined as progressive disease (PD) per RECIST 1.1 criteria. 
Refer to Section 7.2.4 for additional details. 
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7.5.7
Time to Response (TTR)
TTR is defined as the time that elapses between the initiation of trial therapy 
(C1D1) and the day of first documented response to therapy. For TTR analysis, a 
response to therapy is defined as a confirmed complete response (CR) or 
confirmed partial response (PR) per RECIST 1.1 criteria. Refer to Section 7.2.5 
for additional details. 
7.5.8
Progression-Free Survival (PFS)
PFS is defined as the amount of time that elapses between the initiation of trial 
therapy (C1D1) and the day of first documented disease progression. Refer to 
Section 7.2.6 and Section 7.278 for additional details. 
7.5.9
CA-125 Response
CA-125 Response is defined as a ≥50% reduction in CA-125 levels from a pre-
treatment sample. The response must be confirmed and maintained for at least 
28 days. The date when the CA-125 level is first reduced by 50% is the date of 
the CA-125 response. Refer to Section 7.4.1 for additional details. 
7.5.10
CA-125 Complete Responder
A CA-125 Complete Responder is defined as a subject who has a CA-125 
Response and whose CA-125 level falls to within the reference range. The date 
when the CA-125 first falls to within the reference range is the date of the CA-125 
Complete Response. Subjects who have a fall of CA-125 to within the reference 
range but whose initial CA-125 was less than twice the upper limit of the 
reference range have not had a CA-125 Response and cannot be classified as a 
CA-125 Complete Responder. Refer to Section 7.4.1 for additional details. 
7.5.11
CA-125 Progression
A CA-125 Progression event is defined as a subject who meets any of the 
following:

Subject with elevated CA-125 pretreatment, followed by normalization of 
CA-125, followed by a subsequent increase in CA-125, where the 
increase demonstrates a CA-125 ≥ 2X ULN, with confirmation ≥ 1 week 
later; the date when the CA-125 first increases to ≥ 2X ULN is the date of 
the CA-125 Progression event.

Subject with elevated CA-125 pretreatment, which never normalizes, 
followed by subsequent increase in CA-125, where the increase 
demonstrates a CA-125 ≥ 2X the nadir, with confirmation ≥ 1 week later; 
the nadir is the lowest CA-125 value recorded while on study prior to the 
increase; the date when the CA-125 first increases to ≥ 2X the nadir is 
the date of the CA-125 Progression event.

Subject with CA-125 in the reference range before treatment, followed by 
subsequent increase in CA-125, where the increase demonstrates a CA-
125 ≥ 2X ULN, with confirmation ≥ 1 week later; the date when the CA-
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125 first increases to ≥ 2X ULN is the date of the CA-125 Progression 
event.
Refer to Section 7.4.1 for additional details. 
8.0
STATISTICAL CONSIDERATIONS
8.1
Study Design
This is a single center, single arm, open label, phase II trial with a Simon’s optimal two-
stage design.17 A safety lead-in cohort has been designed for the first 6 subjects who 
complete at least 1 cycle of treatment, in order to ensure the safety of the experimental 
combination of irinotecan liposome and bevacizumab. Study endpoints are defined in 
Section 7.0. Criteria for stopping the study early are described in Section 8.3. 
8.2
Sample Size 
In this phase II design, we anticipate enrolling 30 subjects who are evaluable for the 
primary endpoint. In anticipation of some subjects not being evaluable, up to 33 subjects 
may be enrolled to yield at least 30 evaluable subjects.
If a subject who is enrolled in the safety lead-in cohort discontinues combination trial 
therapy for reasons other than a DLT before completing the DLT observation period, an 
additional subject should be added to the safety lead-in cohort. Refer to Section 4.2.3 for 
details on the safety lead-in design and to Section 4.2.4 for the definition of a DLT. 
8.3
Power Analysis
The primary endpoint of the study is the objective response rate (ORR), defined as the 
proportion of evaluable subjects experiencing a confirmed CR or PR per RECIST 1.1 
Criteria. The ORR for single agent chemotherapy was 11.8% in the AURELIA trial.1  The 
current study is designed to test a 20% improvement in ORR (goal ORR of ≥31.8%), as 
compared to the AURELIA historical control. 
Specifically, the study is designed with 80% power and 5% one-sided type 1 error rate 
(alpha) to test the null hypothesis (H0) that the proportion of evaluable subjects 
responding to the drug combination (P) is ≤0.118 versus the alternate hypothesis (H1) 
that P is ≥0.318. With 30 evaluable subjects, if the number of objective responses is 7 or 
more, the null hypothesis (H0:P≤0.118) is rejected with an error rate of 0.045 (target 
alpha was 0.050).  If the number of objective responses is less than or equal to 6, the 
alternate hypothesis (H1:P≥0.318) is rejected with an error rate of 0.190 (target beta was 
0.200). 
The statistical software program PASS was used to calculate the sample size. Refer to 
Section 7.0 for details on evaluability. 
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8.4
Criteria for Stopping the Study Early
8.4.1
Safety Criteria
The first six evaluable subjects who complete at least 1 cycle of combination trial 
therapy will be part of an initial safety lead-in cohort. A safety analysis will be 
conducted after all six subjects have been observed for at least 42 days after 
receipt of the first dose of combination trial therapy (i.e., for two weeks after 
C1D28, which is two weeks after completion of cycle 1) for dose limiting toxicity 
(DLT). All toxicities will be tabulated. The study will re-commence enrollment if ≤ 
1 of 6 evaluable subjects in the safety lead-in cohort experience(s) a DLT (as 
defined in Section 4.2.4). If ≥ 2 of 6 evaluable subjects in the safety lead-in 
cohort experience a DLT, the study will remain suspended, and an amendment 
to explore alternate dosing schemes will be considered. This decision rule is 
based on the traditional “3+3” Phase I design decision rule for the maximum 
tolerated dose (MTD) cohort. Toxicity counts, toxicity rates, and the results of the 
analysis will be reviewed by the DSMC.
If a subject who is enrolled in the safety lead-in cohort discontinues combination 
trial therapy for reasons other than DLT before completing the DLT observation 
period, an additional subject will be added to the safety run-in cohort.
Refer to Section 4.2.3 for details on the safety lead-in design and to Section 4.2.4 
for the definition of a DLT.
8.4.2
Efficacy Criteria
As this trial uses an optimum two-stage design,17 an interim analysis is planned 
after 10 evaluable subjects have been accrued. Specifically, after testing the drug 
combination on 10 subjects in the first stage, the two stage design considerations 
indicate that the trial should be terminated if 1 or fewer subjects experiences an 
objective response (confirmed CR or PR per RECIST1.1 criteria). If two or more 
of the 10 subjects respond, the study will continue to the second stage. If the trial 
continues to the second stage following completion of the first stage analysis, a 
total of 30 anticipated evaluable subjects (from both stages combined) will be 
studied.  All evaluable subjects, including those enrolled in the first stage and the 
safety run-in cohort, will be included in endpoint analyses. 
The target is 30 evaluable subjects. In anticipation of some subjects not being 
evaluable, up to 33 subjects may be enrolled to yield at least 30 evaluable 
subjects.
8.5
Accrual and Feasibility
It is anticipated that accrual will be completed in approximately 2.5 years. Approximately 
1-3 subjects will be possible candidates and will screened for participation each month, 
and approximately 1 subject will be enrolled each month.
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8.6
Data Analysis Plans
8.6.1
Analysis Plan for the Primary Objective
The primary endpoint is the objective response rate (ORR) per RECIST 1.1. The 
proportion of evaluable subjects experiencing an objective response will be 
estimated with a 95% exact binomial confidence interval. The confidence interval 
will be adjusted for the sequential nature of the two-stage procedure.18 
8.6.2
Analysis Plans for Secondary Objectives
Safety and tolerability will be summarized by providing a frequency of adverse 
events by severity, type, timing and attribution. Overall best response rate and 
Clinical benefit rate (CBR) will be estimated with a proportion and confidence 
interval. Duration of response (DOR) and Duration of stable disease will be 
estimated as median and interquartile range (IQR) or mean and a confidence 
interval depending on the distribution.  Descriptive statistics (e.g., mean, median, 
SD, IQR, min and max) will be used to summarize data for continuous variables, 
and counts and corresponding percentages will be used to summarize data for 
discrete variables. Progression-free survival (PFS) and time to response (TTR) 
will be analyzed using the Kaplan-Meier method. Median PFS and 16-week PFS 
estimates will be reported along with the confidence intervals. 
8.6.3
Analysis Plans for the Exploratory Objective
Serum CA-125 levels will be summarized using descriptive statistics for the time 
points of interest, and CA-125 response rate and CA-125 complete response rate 
will be summarized as counts and percentages.  Time to CA-125 progression or 
death will be estimated using the method of Kaplan-Meier, and CA-125 
progression rate at time points of interest will be estimated based on these 
Kaplan-Meier estimates.
9.0
DRUG INFORMATION
9.1
Bevacizumab
9.1.1
Other names 
AVASTIN® (Marketed by Genentech, Inc.)
MVASITM/bevacizumab-awwb (Marketed by Amgen, Inc.)
NOTE: The preferred drug of choice is AVASTIN, whenever feasible. Biosimilars 
are only permitted in cases where AVASTIN is not covered by health insurance.
9.1.2
Classification - type of agent
Bevacizumab is a vascular endothelial growth factor inhibitor. Bevacizumab is a 
recombinant humanized monoclonal IgG1 antibody that contains human 
framework regions and murine complementarity-determining regions. 
Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) 
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expression system. Refer to the current Package Insert / FDA prescribing 
information for additional information.
9.1.3
Mode of action
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors 
on the surface of cells. The interaction of VEGF with its receptors leads to 
endothelial cell proliferation and new blood vessel formation in in vitro models of 
angiogenesis. Refer to the current Package Insert / FDA prescribing information 
for additional information.
9.1.4
Storage and stability
Refer to the current Package Insert / FDA prescribing information for storage and 
stability information.
9.1.5
Protocol dose specifics
Commercial supply of bevacizumab will be administered IV on day 1 and day 15 
of each 28-day cycle at a starting dose of 10 mg/kg, with dose reduction to 5 
mg/kg permitted according to Table 4.3.1.
Bevacizumab dosing is based on subject baseline weight on C1D1; however, 
doses will be adjusted for subjects who experience a ≥10% change in weight 
from baseline. Actual weight will be used. Rounding is permissible within 5% of 
the nominal dose.
Administer bevacizumab prior to administering irinotecan liposome.
9.1.6
Preparation
Refer to the current U.S. Package Insert / FDA prescribing information for 
preparation instructions.
9.1.7
Route of administration for this study
Administer bevacizumab as an intravenous (IV) infusion on day 1 and day 15 of 
each 28-day cycle. Bevacizumab infusion rates are per institutional standards.  
9.1.8
Incompatibilities
DO NOT ADMINISTER OR MIX BEVACIZUMAB WITH DEXTROSE SOLUTION.
9.1.9
Side Effects
Refer to the current Package Insert / FDA prescribing information for a complete 
listing of all toxicities.
9.1.10
Availability & Supply 
Bevacizumab is commercially available and will not be supplied by the study. 
9.1.11
Return and Retention of Study Drug
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All unused and/or partially used and/or expired drug may be destroyed at the site 
per Institutional policy for commercially supplied agents. 
9.1.12
Accountability
The site Investigator, or a responsible party designated by the Investigator, is 
responsible for keeping accurate records of the amount administered to subjects 
per Institutional policy for commercially supplied agents. 
9.2
Irinotecan Liposome
9.2.1
Other names 
ONIVYDETM (marketed by Ipsen)
Irinotecan liposome injection
9.2.2
Classification - type of agent
Irinotecan liposome is formulated with irinotecan hydrochloride trihydrate, a 
topoisomerase I inhibitor, into a liposomal dispersion for intravenous use.
9.2.3
Mode of action
Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a 
lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in 
DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 
bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of 
the single-strand breaks, leading to exposure time-dependent double-strand DNA 
damage and cell death. In mice bearing human tumor xenografts, irinotecan 
liposome administered at irinotecan HCl-equivalent doses 5-fold lower than 
irinotecan HCl achieved similar intratumoral exposure of SN-38. 12,13  
9.2.4
Storage and stability
Store irinotecan liposome vials refrigerated at 2ºC to 8ºC (36°F to 46°F). Do not 
freeze. Protect from light. See Section 9.1.6 (Preparation) for storage conditions 
for the diluted product prior to admiration to subjects. 
9.2.5
Protocol dose specifics
Irinotecan liposome will be administered at a starting dose of 70 mg/m2, IV, q2w, 
with dose reductions permitted to 50 mg/m2 and 43 mg/m2 as described in 
Section 4.0. Doses are expressed as free base. 
Irinotecan liposome dosing is based on subject baseline BSA on C1D1; however, 
doses will be adjusted for subjects who experience a ≥5% change in BSA from 
baseline. Actual weight will be used when calculating BSA. Rounding is 
permissible within 5% of the nominal dose.
[NOTE: The drug strength of irinotecan liposome injection in the United States is 
expressed on the basis of irinotecan free base.  Should a dose need to be 
converted from a dose based on irinotecan hydrochloride trihydrate salt (“salt”) to 
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a dose based on irinotecan free base, this can be is accomplished by substituting 
the molecular weight of irinotecan hydrochloride trihydrate salt (677.19 g/mole) 
with the molecular weight of irinotecan free base (586.68 g/mole), which results 
in a conversion factor of 0.866. Therefore, the 80 mg/m2 salt dose is equivalent to 
a 69.3 mg/m2 irinotecan free base dose (rounded to 70 mg/m2.)]
9.2.6
Preparation
Irinotecan liposome is a cytotoxic drug. Follow applicable Institutional special 
handling and disposal procedures.  
Prior to administration, irinotecan liposome injection must be diluted in 5% 
Dextrose or Normal Saline (0.9% Sodium Chloride) to a suitable volume for 
infusion. The solution for infusion (irinotecan liposome injection and its 
admixtures) must not be frozen. Freezing will disrupt the liposome structure and 
result in the release of free irinotecan. 
Preparation Instructions 

Withdraw the calculated volume of irinotecan liposome from the vial.

Dilute in 500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride 
Injection, USP and mix diluted solution by gentle inversion.

Protect diluted solution from light. 

The diluted solution for infusion should be administered immediately, but 
may be stored at room temperature (15º to 30ºC) for up to 4 hours prior 
to the start of the infusion. If necessary, the solution for infusion may be 
refrigerated [2ºC to 8ºC (36ºF to 46ºF)] for no more than 24 hours prior to 
use. Do not freeze.

Allow diluted solution to come to room temperature prior to 
administration.

Use Institutional standards on overfill. 
9.2.7
Route of administration for this study
The diluted solution of irinotecan liposome should be administered as a 90-
minute (± 10 minutes) intravenous infusion without the use of an in-line filter. The 
infusion rate will not be modified in the case of dose reduction.
9.2.8
Incompatibilities
None known. Irinotecan liposome injection has been tested for compatibility with 
a number of materials, and no compatibility issues have been identified.  Infusion 
sets without inline filters are recommended for use. However, an infusion set with 
an in-line filter that has a pore size of at least 0.2 μm is compatible for use.
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9.2.9
Side effects
Refer to the current Investigator’s Brochure (IB) for a complete listing of all 
toxicities.
9.2.10
Availability & Supply 
Irinotecan liposome will be provided by Ipsen in sterile single-dose vials, each 
containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL (which 
converts to 5.0 mg/mL irinotecan hydrochloride trihydrate salt). It will be provided 
directly to each participating site’s investigational pharmacy at no charge to 
subjects participating in the clinical trial. Drug ordering information is available in 
NOTIS as a stand-alone document.
The treating investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
9.2.11
Return and Retention of Study Drug
The site investigator or designee is responsible for taking an inventory of each 
shipment of irinotecan liposome received, and comparing it with the 
accompanying form. Accurate records will be kept in the source documentation 
of all irinotecan liposome administration (including dispensing and dosing), and 
the amount remaining at the conclusion of the trial. Upon completion or 
termination of the study (or at other times, as per local site institutional 
policy/norms), all unused and/or partially used investigational product will be 
destroyed at the site per local institutional policy. The manufacturer will provide 
memos with lot number and expiration dates, and expired drug may be destroyed 
per local policy. It is the site Investigator’s responsibility to arrange for disposal of 
all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are 
kept. Irinotecan liposome is a cytotoxic drug. Follow applicable Institutional 
special handling and disposal procedures.  
9.2.12   Accountability
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 
agents provided by the Study. Store and maintain a separate Drug Accountability 
Records (DARF) for each agent. Sites may use standard DARFs according to 
Institutional SOPs. 
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10.0
ADVERSE EVENTS
10.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. In addition, certain adverse events must 
be reported in an expedited manner to allow for optimal monitoring and subject safety 
and care. 
10.2
Definitions & Descriptions
10.2.1
Adverse Event (AE)
An adverse event (AE) is any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product or 
undergoing an experimental intervention, and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product or 
experimental intervention, whether or not related to the investigational product or 
intervention.
All routine AEs, regardless of attribution or clinical significance, occurring from 
time of subject registration, through 30 days after the last administration of trial 
therapy, must be recorded. Any event that occurs more than 30 days after the 
last dose of treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported accordingly as an adverse event or expedited 
adverse event, as applicable. See Section 10.3.1 for instructions on recording 
routine AEs.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms, referencing CTCAE when applicable. In general, AEs 
are not procedures or measurements, but should reflect the reason for the 
procedure or the diagnosis based on the abnormal measurement. Preexisting 
conditions that worsen in severity or frequency during the study should also be 
recorded (a preexisting condition that does not worsen is not an AE). Further, a 
procedure or surgery is not an AE; rather, the event leading to the procedure or 
surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations that led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e.g., thrombocytopenia, peripheral edema, QT prolongation).
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10.2.1.1     Adverse Event Assessment
This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the 
last dose of treatment and is attributed (possibly, probably, or 
definitely) to the agent(s) must also be reported accordingly as an 
adverse event or expedited adverse event, as applicable.
1.
Identify the type of adverse event using the NCI CTCAE v 5.0. 
(Appendix D)
2.
Grade the adverse event using the NCI CTCAE v 5.0.
3.
Determine whether the adverse event is related to the protocol 
therapy.  

Attribution categories are as follows:
o
Definite: AE is clearly related to the study treatment.
o
Probable: AE is likely related to the study treatment.
o
Possible: AE may be related to the study treatment.
o
Unlikely: AE not likely to be related to the study 
treatment.
o
Unrelated: AE is clearly NOT related to the study 
treatment.
4.
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified 
as resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not 
listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
10.2.1.2     Severity of Adverse Events
All non-hematologic adverse events will be graded according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. The CTCAE v5 is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/c
tc.htm
If no CTCAE grading is available, the severity of an AE is graded as 
follows:

Mild (grade 1): Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated.  
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
Moderate (grade 2): Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-appropriate instrumental 
ADL*. 
o
*Instrumental ADL refers to preparing meals, shopping for 
groceries or clothes, using the telephone, managing 
money, etc.  

Severe (grade 3): Severe or medically significant but not 
immediately life threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL**. 
o
**Self-care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden.

Life-threatening (grade 4): Life-threatening consequences; 
urgent intervention indicated. 

Fatal (grade 5): Death related to AE.
10.2.2
Serious Adverse Event (SAE)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence. See Section 10.3.2 for instructions on 
reporting SAE’s.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, should be reported as 
Grade 5 “disease progression” in the system class “General disorders 
and administration site conditions.” Evidence that the death was a 
manifestation of underlying disease (e.g. radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.

Is life threatening.
The subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.

Requires in-subject hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Any important medical event that does not meet the above criteria, but that in 
the judgment of the investigator jeopardizes the subject, may be considered 
for reporting as a serious adverse event. The event may require medical or 
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surgical intervention to prevent one of the outcomes listed in the definition of 
“Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
10.2.3
Unanticipated Problem Involving Risks to Subject or Others (UPIRSO)
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

is unexpected (in terms of nature, severity, or frequency) given the 
procedures described in the research protocol documents (e.g., the IRB-
approved research protocol and informed consent document) and the 
characteristics of the human subject population being studied

is 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); and 

suggests that the research places human subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized, even if no harm has actually occurred.
10.3
Event Reporting
10.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data and Safety Monitoring 
Committee (DSMC) according to the study’s phase and risk level, as outlined in 
the DSMP. 
10.3.2
Expedited Reporting
Although not an adverse event in and of itself, pregnancy as well as its outcome 
must be documented via expedited reporting via the NU CTO SAE Form. On the 
“Seriousness Criteria” drop down box of the SAE Form, select “Pregnancy.” Any 
pregnancy occurring in a subject or subject’s partner from the time of consent to 
90 days after the last dose of study drug must be reported and then followed for 
outcome. 
10.3.2.1  Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CTO SAE Form, 
provided as a separate document, is required.
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The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The subject’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)

Country of incidence 
All SAEs will be reported to, and reviewed by, the DSMC, per the 
DSMP.
All expedited events require both expedited reporting and routine 
reporting. 
10.3.2.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University) and to participating sites whom have 
reporting responsibilities to Northwestern University. Participating sites 
should follow their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly 
reported to the NU IRB within 24 hours of notification. 

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to 
Northwestern University and to the NU IRB within 5 working days 
of notification.

Information pertaining to an NU subject that fits into any of the 
categories listed on the Reportable New Information page will be 
reported to the NU IRB within 5 business days of knowledge or 
notification.
10.3.2.3  Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life 
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DSMC).
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All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
10.3.2.4  Reporting to Ipsen
All Serious Adverse Events (SAEs) and events of pregnancy occurring 
from the time of informed consent through 30 days following the last 
dose of trial therapy will be reported by the Coordinating Center to Ipsen 
using the CTO SAE form.  Any SAEs occurring more than 30 days 
following the last dose of the study treatment that are believed to be 
related to study drug will also be reported to Ipsen. 
The Coordinating Center will send the initial completed SAE form within 
24 hours of notification via email to Ipsen (drugsafety.USA@ipsen.com).  
If only limited information is initially available and new information later 
becomes available, or if an ongoing SAE changes in its intensity or 
relationship to the study drug, a follow-up report will be generated and 
sent to Ipsen as information becomes available. 
For questions regarding the reporting process, please contact Ipsen:

Pharmacovigilance Telephone Call Center (24 hours/7 days): 
855-463-5127

Pharmacovigilance Fax: 855-631-0644

General and Emergency email: drugsafety.USA@Ipsen.com

Affiliate general Pharmacovigilance mailbox: 
pharmacovigilance.USA@ipsen.com
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
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Prior to a subject’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.
11.1.1
Consenting Subjects with Limited Proficiency in English 
For potential study patients with limited proficiency in English, a short form 
consent document (written in the language understood by the patient) will be 
used during the initial consent process. In addition, the services of an interpreter 
who is fluent in both English and the language understood by the potential study 
patient will be used to explain the contents of the long form consent document 
(written in English). If the patient enrolls, they will be re-consented using an IRB-
approved long form consent document that has been translated to the language 
understood by the patient, when it is available. The process will be conducted in 
accordance with guidelines and policies of the IRB of record.
11.2
Amendments
Amendments to the protocol will be maintained by the assigned Medical Writer. Requests 
for revisions may come from multiple sources, including but not limited to the Principal 
Investigator, study team, drug company, or FDA. All amendments will be subject to the 
review and approval of the appropriate local, institutional, and governmental regulatory 
bodies, as well as by Ipsen. Amendments will be distributed by the lead institution 
(Northwestern) to all participating sites upon approval by the Northwestern University 
IRB.
11.3
Registration Procedures
11.3.1
Registering a Subject to the Safety Lead-In Cohort
For potential subjects for the safety lead-in portion, study teams are asked to 
inform the assigned QAM (croqualityassurance@northwestern.edu) of the date 
and time that the subject will need to be registered.  
BEFORE a subject can be treated on study, the following items must be 
completed and submitted to confirm eligibility and receive an identification 
number:

Subject’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)

Copy of the pathology report (upload to NOTIS)

Signed and dated Eligibility Checklist (upload to NOTIS and keep original 
hard copy in a secure location/study chart)
The assigned QAM will review all source documentation required to confirm 
eligibility that is readily available in the subject’s electronic medical record (EMR).  
Any information that is not available in the EMR must be de-identified and 
emailed to the QAM. Once the QAM confirms the subject is eligible, he or she will 
register the subject, assign a subject identification number, provide a cohort 
assignment (as applicable), and send a confirmation of registration to involved 
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personnel. Registration will then be complete and the subject may begin study 
treatment. 
11.3.2 Registering a Subject after the Safety Lead-In Cohort has been Filled
For potential subjects for phase II/III and select pilot studies, study teams are 
asked to inform the assigned QAM (croqualityassurance@northwestern.edu) of 
the date and time that the subject will need to be registered.  
BEFORE a subject can be treated on study, the following items must be 
completed and submitted to confirm eligibility and receive a subject identification 
number: 

Subject’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)

Copy of the pathology report (upload to NOTIS)

Signed and dated Eligibility Checklist (upload to NOTIS and keep original 
hard copy in a secure location/study chart)
The assigned QAM will review the registration documents. Once review is 
complete, he or she will register the subject, assign a subject identification 
number, provide a cohort assignment (as applicable) and send a confirmation of 
registration to involved personnel. Registration will then be complete and the 
subject may begin study treatment. 
11.4
Data Submission
Data collection for this study will be done through NOTIS. Access to the trial in NOTIS is 
granted to appropriate roles identified at the time of participating site activation, or upon 
request. Site users will not be able to access the study in NOTIS until all required and 
study specific trainings are completed. 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedures table.  Generally, all data for safety run-ins during the 
period subjects are evaluated for Dose Limiting Toxicities (DLTs) must be submitted on a 
weekly basis. Generally, for all other phase II subjects, data are due with 10 days of a 
visit or end of cycle.  A set amount of data may also be requested for any screen failures, 
as is defined by the study. In most instances, this will include collection of adverse events 
and baseline data from the time of registration to the date of screen failure. 
11.5
Instructions for External Participating Sites
Not applicable. 
11.6
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to the CTO website for additional information). The level of risk attributed to this 
study requires high intensity monitoring, as outlined in the DSMP. The assigned QAM, 
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with oversight from the Data and Safety Monitoring Committee, will monitor this study in 
accordance with the study phase and risk level. In addition, the study will abide by all 
safety reporting regulations, as set forth in the Code of Federal Regulations. 
11.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.7.1   Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, a modification must be 
submitted to the NU IRB within 5 business days of making the change, and the 
assigned QAM must be notified within 24 hours of such change. Such 
modifications also need to be reported to the FDA, as applicable, within the 
appropriate timelines. 
11.7.2   Other Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that is under the investigator's 
control and that has not been approved by the Institutional Review Board (IRB). 
Protocol deviations must be reported according to the policies and procedures of 
the IRB of record.
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study

Results from willful or knowing misconduct on the part of the 
investigator(s)

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies
All protocol deviations will be documented by the study team on a paper or 
electronic deviation tracking log (see NOTIS for copy of log) as they occur. The 
deviation tracking log must be made available upon request for review by the 
assigned QAM. The deviation tracking log must be reviewed, signed, and dated 
by the investigator prior to each monitoring visit, or otherwise in a timely manner, 
whichever occurs first. The PI signed and dated deviation tracking log will be 
uploaded to eCRFs prior to each scheduled monitoring visit or upon request. 
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Deviations will be reviewed per the DSMP.
11.8
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
subjects. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
11.9
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches its 
primary completion date, as defined by ClinicalTrials.gov. This is the date that the final 
subject was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three months 
after a study’s primary completion date, the PI must send a written request for data 
approval to the QAM which includes justification. Requests must be made a minimum of 
six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release 
will be provided to the PI. If the request is approved, the QAM will present the data set to 
the DSMC for approval. A final, DSMC-approved dataset, as applicable, will then be 
released 6-8 weeks after the request was made. The investigators are expected to use 
only DSMC-approved data and statistical analyses any time they are disseminating trial 
data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and 
statistical analyses are used appropriately. Once the biostatistician and QAM gives final 
approval, the publication may be submitted to external publisher.
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APPENDICES
Appendix A
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale
ECOG (Zubrod) Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work).
2
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours.
3
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair.
5
Dead.
Adapted from:
Oken, M.M., et. al. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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Appendix B
New York Heart Association (NYHA) Classification of Cardiac Failure
NYHA Functional Classification
Class
Symptoms
Those with cardiac disease and the following symptoms:
I
No limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain.
II
Slight limitation of physical activity. 
Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, 
or anginal pain.
III
Marked limitation of physical activity. 
Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain.
IV
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure or the angina syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Adapted from: 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of 
the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.
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Appendix C
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
RECIST version 1.1 will be used in this trial for assessment of tumor response. The information in this 
appendix has been adapted from the published criteria and is provided as a reference. Please refer to the 
published criteria for additional information. Questions regarding the criteria should be directed to the lead 
PI. The published criteria can be accessed at:
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
RECIST 1.1 RESPONSE EVALUATION
EVALUATION OF TARGET LESIONS
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression).
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study.
EVALUATION OF NON-TARGET LESIONS
Complete Response (CR)
Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits.
Progressive Disease (PD)
Unequivocal progression (refer to the published criteria for details) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
Equivocal Progression:
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date 
when progression was suspected. Refer to the published criteria for additional information regarding the 
determination of ‘unequivocal’ and ‘equivocal’ progression.
Method of Assessment:
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 should always 
be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.
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Selection of Target and Non-Target Lesions:
When more than one measurable lesion is present at baseline, all measurable lesions up to a maximum 
of five measurable lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement, in which circumstance, the next largest lesion that can be 
measured reproducibly should be selected. 
Pathological nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥15 mm by CT scan. All other pathological nodes (those with short axis 
≥10 mm but <15 mm) should be considered non-target lesions. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should be recorded at baseline. Measurements are not required and these lesions 
should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression.’ 
Measurable Tumor Lesions: 
Measurable disease per RECIST 1.1 is defined as the presence of at least one measurable lesion. 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II of the published 
criteria for information on imaging guidance). 
• 10 mm caliper measurement by clinical exam (lesions that cannot be accurately measured with 
calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).  
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated progression in the 
lesion.
Measurability of Malignant Lymph Nodes: 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis of these nodes will be measured and followed.  Nodes that 
have a short axis <10 mm are considered non-pathological and should not be recorded or followed. 
Non-Measurable Tumor Lesions: 
All lesions that do not meet the above definition of measurable lesions/nodes, including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis) as well as truly 
non-measurable lesions are considered non-measurable disease. Lesions considered truly non-
measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     78
Cystic Lesions:  
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same subject, these are preferred for selection as target lesions.
Adapted from:
E.A. Eisenhower, et al. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan; 45(2):228-47.
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Protocol Amendment 3 – Version Date: January 20, 2022
     79
Appendix D
Common Terminology Criteria for Adverse Events (CTCAE) v5.0
The descriptions and grading scales found in the revised National Cancer Institute’s Common 
Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) will be used to assess adverse 
events for this trial. NCI-CTCAE v5.0 is available at the following link: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_
8.5x11.pdf.
Refer to Section 10.0 for additional details on adverse events assessment and reporting. 
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Protocol Amendment 3 – Version Date: January 20, 2022
     80
Appendix E
Cockcroft-Gault Equation for Creatinine Clearance
The Cockcroft and Gault formula for creatinine clearance is recommended as an estimate of glomerular 
filtration rate (GFR) for assisting with drug dosing decisions in renal impairment.
For Females:
Creatinine Clearance = 0.85 x (140 - age in years) x (weight in kg)
                                               72 x (serum creatinine in mg/dL)
                                    
 OR
0.85 x (140 - age in years) x (weight in kg)
      0.814 x (serum creatinine in µmol/L)
Adapted from: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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Protocol Amendment 3 – Version Date: January 20, 2022
     81
Appendix F
Summary of Changes
Protocol Amendment 1—December 11, 2020
Section
Prior Version
Amendment 1 Revisions
Rationale
Cover page
IND number: TBD
IND number: 153324
Administrative update to add 
IND number
Cover page and throughout
Protocol version/date: August 
6, 2020 (Initial version) 
Protocol version/date: 
December 11, 2020 
(Amendment 1)
Administrative update
Table of Contents
N/A
Updates the Table of 
Contents
Administrative update
Inclusion Criterion 3.1.8
Appendix E (Cockcroft-
Gault Equation for 
Creatinine Clearance)
Inclusion criterion 3.1.8 
required serum creatinine ≤ 
1.5 x ULN at study entry
Inclusion criterion 3.1.8 has 
been revised to require 
creatinine clearance ≥ 60 
mL/min at study entry, as 
calculated per the Cockcroft-
Gault formula. Appendix E 
has been added to reference 
the formula.
Revision in response to the 
following FDA reviewer 
comment:
“Modify inclusion criteria to use 
creatinine clearance calculated 
using Cockcroft-Gault 
Equation rather than serum 
creatinine.”
Inclusion Criterion 3.1.9
For subjects with a known 
history of human 
immunodeficiency virus (HIV), 
the HIV viral load must be 
undetectable for ≥ 6 months 
prior to registration, and 
subjects must be receiving 
effective anti-retroviral HIV 
therapy, if indicated.
NOTE: HIV testing is not 
required for subjects without a 
known history of HIV, unless 
mandated by a local health 
authority.
For subjects with a known 
history of human 
immunodeficiency virus 
(HIV), the HIV viral load must 
be undetectable for ≥ 6 
months prior to registration, 
and subjects must be 
receiving effective anti-
retroviral HIV therapy, if 
indicated.
NOTE: HIV testing is not 
required for subjects without 
a known history of HIV, 
unless mandated by a local 
health authority.
NOTE: Use of strong 
CYP3A4 inhibitors/inducers is 
prohibited (refer to Section 
4.4.3 and Exclusion Criterion 
3.2.7). Subjects who are 
using concurrent strong 
CYP3A4 inhibitors/inducers 
(e.g., ritonavir, cobicistat) as 
part of their anti-retroviral 
therapy (ART) regimen may 
be switched to an alternative 
ART regimen (with minimal 
drug-drug interaction profile) 
before study participation; 
however, they are excluded 
from the study if their regimen 
Revision in response to the 
following FDA reviewer 
comment:
“Refer to the following 
guidance: 
https://www.fda.gov/regulatory-
information/search-fda-
guidance-documents/cancer-
clinical-trial-eligibility-criteria-
patients-hiv-hepatitis-b-virus-
or-hepatitis-c-virus.”
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Protocol Amendment 3 – Version Date: January 20, 2022
     82
Section
Prior Version
Amendment 1 Revisions
Rationale
cannot be altered.
Table 4.2.4 (Definition of 
DLT)
The DLT criteria for non-
hematologic toxicity were as 
follows:
• ≥ Grade 3 treatment-related* 
toxicity despite the use of 
adequate/maximal medical 
interventions and/or 
prophylaxis as dictated by 
local institutional clinical 
practices or the judgment of 
the treating Investigator, 
EXCEPT:

nausea, vomiting, or 
diarrhea (lasting <3 days 
or without supportive 
care measures)

alopecia

fatigue

hypersensitivity reaction
• Any Grade non-hematologic 
toxicity that is treatment-
related* and which results in a 
>14 day delay in Cycle 2 Day 
1 dosing
• Any Grade non-hematologic 
toxicity that is treatment-
related* and which results in a 
>14 day delay in Cycle 2 Day 
1 dosing
Footnote: * Treatment-related 
is defined as any toxicity that 
is possibly, probably or 
definitely related to either 
bevacizumab or irinotecan 
liposome.
The DLT criteria for non-
hematologic toxicity have 
been revised as follows:
• ≥ Grade 3 treatment-
related* non-hematologic 
toxicity despite the use of 
adequate/maximal medical 
interventions and/or 
prophylaxis as dictated by 
local institutional clinical 
practices or the judgment of 
the treating Investigator, 
EXCEPT: 

those that are clearly 
and incontrovertibly due 
to disease progression 
or extraneous causes

≥ Grade 3 fatigue lasting 
< 7 days
• Any Grade non-hematologic 
toxicity that is treatment-
related* and which results in 
a >14 day delay in Cycle 2 
Day 1 dosing
•  An elevated alanine or 
aspartate aminotransferase 
(ALT or AST) lab value that is 
≥ 3X the ULN, and at the 
same time, an elevated 
serum total bilirubin lab value 
that is ≥ 2X the ULN, and at 
the same time, an alkaline 
phosphatase (ALP) lab value 
that is < 2X the ULN, as 
determined by way of 
protocol-specified laboratory 
testing or unscheduled 
laboratory testing.
Footnote: * Treatment-related 
is defined as any toxicity that 
is possibly, probably or 
definitely related to either 
bevacizumab or irinotecan 
liposome.
Revision in response to the 
following FDA reviewer 
comment:
“Modify your DLT criteria to 
include:
a.
Hy's law
b.
Grade 3 or higher 
fatigue ≥ 7 days should 
be considered at DLT
c.
Any grade ≥3 treatment 
related non-hematologic 
toxicity despite the use 
of  adequate/ maximal 
medical interventions 
EXCEPT those that are 
clearly and 
incontrovertibly due to 
disease progression or 
extraneous causes.”
Section 5.0 (Study 
Procedures and Schedule 
of Assessments)
N/A
Adds a physical exam to the 
End of Treatment Visit.
Adds a comprehensive 
chemistry panel to the Safety 
Follow Up Visit
Addition of assessments for 
safety monitoring
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     83
Section
Prior Version
Amendment 1 Revisions
Rationale
Section 11.1.1
N/A
Adds Section 11.1.1 to 
describe provisions for 
consenting subjects with 
limited proficiency in English:
For potential study patients 
with limited proficiency in 
English, a short form consent 
document (written in the 
language understood by the 
patient) will be used during 
the initial consent process. In 
addition, the services of an 
interpreter who is fluent in 
both English and the 
language understood by the 
potential study patient will be 
used to explain the contents 
of the long form consent 
document (written in English). 
If the patient enrolls, they will 
be reconsented using an IRB-
approved long form consent 
document that has been 
translated to the language 
understood by the patient, 
when it is available. The 
process will be conducted in 
accordance with guidelines 
and policies of the IRB of 
record.
Revision in response to the 
following IRB reviewer 
comment:
“What are the provisions for 
non-English speakers?”
Appendix F (Summary of 
Changes)
N/A
Adds a ‘Summary of 
Changes’ to summarize 
protocol revisions
Administrative update
Throughout
N/A
Adjusts formatting and style 
to accommodate protocol 
revisions. 
Corrects typographical errors.
Administrative update.
Protocol Amendment 2—November 30, 2021
Section
Revision
Rationale
Cover page & throughout
Updates protocol version/date from December 11, 2020 
(Amendment 1) to November 30, 2021 (Amendment 2)
Administrative update
Table of Contents                     
&                                  
Throughout
Updates page numbers on the bottom of each page and in the 
Table of Contents
Administrative update
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NU Study Number: NU 20G02
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Protocol Amendment 3 – Version Date: January 20, 2022
     84
Section
Revision
Rationale
Inclusion criterion 3.1.14
Addition of bolded text:
For subjects with hypertension, hypertension must be well 
controlled on medication. 
NOTE: For the purposes of determining eligibility only, 
uncontrolled hypertension at baseline is defined as a 
consistent baseline bp of ≥ 140 mmHg systolic and/or ≥ 90 
mmHg diastolic, on initial and repeat checks. (A repeat check 
is only required if the initial check is ≥ 140 mmHg systolic 
or ≥ 90 mmHg diastolic.)
Revises language to clarify 
that baseline blood pressure 
checks only need to be 
repeated in cases where the 
bp is ≥ 140 mmHg systolic of ≥ 
90 mmHg diastolic.
Exclusion criterion 3.2.1
Deletion of strikethrough text:
Exclusions for receipt of prior systemic anti-cancer therapy:

Subjects must not have received any prior irinotecan-
based therapies.

Subjects must not have received more than 3 prior 
platinum-based chemotherapy regimens. 

Subjects must not have received more than 2 prior non-
platinum, cytotoxic chemotherapy regimens.
Note: Prior receipt of non-VEGF-targeting biological therapies 
is permitted. These may include but are not limited to 
hormonal therapies, immunotherapies, monoclonal antibodies 
(mAbs), tyrosine kinase inhibitors (TKIs), poly (ADP-ribose) 
polymerase (PARP) inhibitors, or other targeted agents. Refer 
to the below exclusion criterion for washout rules.
Administrative update to 
correct discrepancy. Revises 
language to align with 
exclusion criterion 3.2.2, where 
prior receipt of VEGF-targeting 
therapies is permitted, 
provided such agents are not 
administered within 3 months 
prior to registration
Exclusion criterion 3.2.2           
&                                      
Applicable repetitive 
sections throughout
Deletion of strikethrough text and addition of bolded text:
Exclusions for washout from prior systemic anti-cancer 
therapy:

Subjects must not have received chemotherapy, 
immunotherapy, monoclonal antibody (mAb) therapy, 
hormonal therapy, or other targeted therapy within ≤ 14 
days prior to registration.

Subjects must not have received investigational agents 
or investigational devices within ≤ 14 days prior to 
registration.

Subjects must not have received VEGF-targeting 
agents, including bevacizumab, within ≤ 6 months 3 
months prior to registration.
Revises washout from prior 
bevacizumab therapy from 6 
months to 3 months per PI 
request. Six months is 
unnecessarily long and is an 
accrual barrier.
Exclusion criterion 3.2.6         
&                                      
Applicable repetitive 
sections throughout
Deletion of strikethrough text and addition of bolded text:
Subjects must not have received hematologic growth factors 
and/or blood products (transfusions) within ≤ 28 days 14 days 
prior to registration.
Revises washout from prior 
hematologic growth factors 
and/or blood products from 28 
days to 14 days per PI 
request. Twenty eight days is 
unnecessarily long for this 
patient population and is an 
accrual barrier.
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Protocol Amendment 3 – Version Date: January 20, 2022
     85
Section
Revision
Rationale
Exclusion criterion 3.2.9
Deletion of strikethrough text and addition of bolded text:
Subjects must not have current clinical symptoms of bowel 
obstruction or a history of bowel obstruction within ≤ 6 
months prior to registration. Subjects also must not have:

Current evidence of tumor recto-sigmoid involvement by 
pelvic examination

Current tumor bowel involvement on CT scan 

Current clinical symptoms of bowel obstruction
Revises the exclusion criterion 
regarding tumor bowel 
involvement for clarity, per PI 
request.
Section 4.6.1                   
(Short Term Safety Follow 
Up Phase)                           
&                                              
Section 5.0                   
(Study Procedures and 
Schedule of Assessments)
Deletion of strikethrough text and addition of bolded text to 
Section 4.6.1. Addition of bolded text to footnote 20 of Section 
5.0.
All subjects who have received at least 1 dose of either 
irinotecan liposome or bevacizumab will have an EOT visit 0-7 
days after the last dose of trial therapy and prior to initiation of 
subsequent therapy. Subjects who have received at least 1 
dose of either irinotecan liposome or bevacizumab will 
have an end of treatment (EOT) visit ≤14 days after the 
decision to permanently discontinue trial therapy. If 
feasible, it is recommended that the EOT visit occur prior 
to the initiation of subsequent therapy. EXCEPTION: The 
EOT visit is not required if it would fall within ≤ 14 days of 
the safety follow up visit; in these cases, the EOT visit 
may be skipped, and instead the patient may proceed to 
the safety follow up visit. 
Extends the window for the 
end of treatment visit to 
accommodate flexibility in 
patient scheduling.
Section 5.0                   
(Study Procedures and 
Schedule of Assessments)
Deletion of strikethrough text and addition of bolded text:
Study Procedures and Schedule of Assessments Table, 
Footnote 9: 
For subjects with hypertension at baseline, hypertension must 
be well controlled (well controlled is defined as < 160 mmHg 
systolic and < 100 mmHg diastolic on initial and repeat checks) 
[uncontrolled at baseline is defined as a baseline bp of ≥ 
140 mmHg systolic and/or ≥ 90 mmHg diastolic on initial 
and repeat checks (A repeat check is only required if the 
initial check is ≥ 140 mmHg systolic or ≥ 90 mmHg 
diastolic)] on medication within ≤ 28 days prior to registration. 
Refer to Inclusion Criterion 3.1.14 for details.  
Corrects discrepancy. Revises 
the definition of ‘uncontrolled 
baseline hypertension’ in 
footnote 9 of Section 5.0 to 
align with the definition as it is 
written in Section 3.1.14.
Section 5.0                   
(Study Procedures and 
Schedule of Assessments)
Deletion of strikethrough text and addition of bolded text:
Study Procedures and Schedule of Assessments Table, 
Footnote 17: 
Abbreviation for hepatitis B virus = HBC HBV
Administrative update. 
Corrects typographical error.
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Protocol Amendment 3 – Version Date: January 20, 2022
     86
Section
Revision
Rationale
Table 4.3.3            
(Prohibited Medications and 
Therapies)
Addition of bolded text:
Hematologic growth factors and blood products (transfusions):  
Not permitted while receiving trial therapy for subjects 
participating in the safety lead-in portion of the study. 
Should a subject who is participating in the safety lead-in 
portion of the study require the use of these agents while 
receiving trial therapy, trial therapy must be discontinued. 
(Note: These agents are permitted for subjects who are 
not participating in the safety lead-in.)
Per PI request, removes 
hematologic growth factors 
and/or blood products from the 
list of prohibited medications 
for patients who are not 
participating in the safety lead-
in portion of the trial. Use of 
these agents is reasonable in 
this patient population after the 
safety lead-in has been 
completed.
Section 4.6.1 (Short Term 
Safety Follow Up Phase)
&
Section 4.6.2 (Long Term 
Follow Up Phase)
Addition of bolded text.
4.6.1—Safety Follow Up Visit: Refer to Section 5.0 for details 
on the assessments that are to be conducted at the safety 
follow up visit. All subjects who have received at least 1 dose 
of either irinotecan liposome or bevacizumab will have a safety 
follow up visit approximately 30 days (± 7 days) after the last 
dose of study medication. Subjects will be followed for toxicity 
and concomitant medication use through this visit. In addition, 
subjects who are removed from treatment for unacceptable 
adverse events will be followed clinically (per standard of 
care) until resolution or stabilization of the adverse event, or 
as indicated. 
After completion of the Safety Follow Up Visit, patients 
who have discontinued trial therapy for reasons other 
than disease progression will proceed to the Long Term 
Follow Up Phase of the study (Section 4.6.2).  Patients 
who have discontinued trial therapy due to disease 
progression will discontinue study participation upon 
completion of the Safety Follow Up Visit (i.e., Long Term 
Follow Up Phase is not required). 
NOTE: Subjects experiencing ongoing drug-related 
toxicity at the time of the Safety Follow Up Visit may 
continue to be followed clinically (per standard of care) 
until resolution or stabilization of the adverse event, or as 
indicated.
4.6.2—Long Term Follow Up Phase: Following the last dose of 
trial therapy, subjects who have not yet progressed will be 
followed for up to 3 years, or until progression, initiation of 
subsequent anti-cancer therapy, withdrawal, or death; 
whichever occurs first.  As outlined in Section 5.0, follow every 
3 months (± 14 days) for 1 year post-last dose, then every 6 
months (± 30 days) thereafter, for up to a total of 3 years.
Administrative revision to add 
clarifying language. Clarifies 
that the Long Term Follow Up 
Phase of the study is only for 
patients who have not yet 
progressed.
Section 7.5                        
(Definitions)
Deletion of strikethrough text and addition of bolded text:
DOR is defined as the time that elapses between the first day 
of documented response to trial therapy and subsequent 
disease progression. For DOR analysis, response is defined 
as complete response (CR) or partial response (PR) or stable 
disease (SD) per RECIST 1.1 criteria; and disease progression 
is defined as progressive disease (PD) per RECIST 1.1 
criteria.  Refer to Section 7.2.3 for additional details. 
Administrative update to 
correct discrepancy. Corrects 
error in definition of “duration 
of response” to align with 
Section 7.2.3.
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Protocol Amendment 3 – Version Date: January 20, 2022
     87
Section
Revision
Rationale
Section 10.3.2.4    
(Reporting to Ipsen)
Addition of bolded text:
The Coordinating Center will send the initial completed SAE 
form within 24 hours of notification via email to Ipsen 
(drugsafety.USA@ipsen.com)...  
…For questions regarding the reporting process, please 
contact Ipsen:

Pharmacovigilance Telephone Call Center (24 
hours/7 days): 855-463-5127

Pharmacovigilance Fax: 855-631-0644

General and Emergency email: 
drugsafety.USA@Ipsen.com

Affiliate general Pharmacovigilance mailbox: 
pharmacovigilance.USA@ipsen.com
Administrative update. Adds 
additional contact information 
for Ipsen’s Pharmacovigilance 
Team.
Throughout
Grammatical and formatting edits. 
Administrative update
Protocol Amendment 3—January 20, 2022
Section
Revision
Rationale
Cover page & throughout
Updates protocol version/date from November 30, 2021 
(Amendment 2) to January 20, 2022 (Amendment 3)
Administrative update
Table of Contents                     
&                                  
Throughout
Updates page numbers on the bottom of each page and 
in the Table of Contents
Administrative update
Inclusion criterion 3.1.16
Deletion of strikethrough text and addition of bolded text:
Females of reproductive potential must agree to use 
adequate contraception (abstinence or two methods of 
birth control, such as a barrier method in combination 
with hormonal contraception) while receiving trial 
therapy and for 6 months 7 months following 
completion of trial therapy.
Increases the required contraception 
timeframe for females from 6 months 
post-therapy to 7 months post-
therapy, to align with the current 
Invesgiator’s brochure (version 15, 
dated December 2021) for irinotecan 
liposome injection.
Section 5.0 (Study 
Procedures and Schedule of 
Assessments Table)
Deletion of strikethrough text and addition of bolded text:
Footnote 4: Prior to registration, females of reproductive 
potential must agree to use adequate contraception 
(abstinence or two methods of birth control, such as a 
barrier method in combination with hormonal 
contraception) while receiving trial therapy and for 6 
months 7 months following completion of trial therapy.
Increases the required contraception 
timeframe for females from 6 months 
post-therapy to 7 months post-
therapy, to align with the current 
Invesgiator’s brochure (version 15, 
dated December 2021) for irinotecan 
liposome injection.
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     88
Section
Revision
Rationale
Exclusion criterion 3.2.15
Addition of bolded text:
Subjects must not have received a live vaccine within ≤ 
30 days prior to registration. 
NOTE:  Seasonal influenza vaccines for injection are 
generally inactivated flu vaccines and are allowed; 
however, intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines and are not allowed. If a 
subject receives SARS-CoV-2 vaccinations (COVID-
19 vaccinations) during study participation, it is the 
responsibility of the investigator to determine the 
suitability of the vaccine being given with the 
information provided by the manufacturer.
Provides guidance for SARS-CoV-2 
(COVID-19) vaccinations, to align 
with the current Invesgiator’s 
brochure (version 15, dated 
December 2021) for irinotecan 
liposome injection.
Table 4.4.3 (Prohibited 
Medications and Therapies)
Live vaccines: Not permitted within ≤ 30 days prior to 
registration or while receiving trial therapy. Should a 
subject require the use of these agents while receiving 
trial therapy, trial therapy must be discontinued.
NOTE:  Seasonal influenza vaccines for injection are 
generally inactivated flu vaccines and are allowed; 
however, intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines and are not allowed. If a 
subject receives SARS-CoV-2 vaccinations (COVID-
19 vaccinations) during study participation, it is the 
responsibility of the investigator to determine the 
suitability of the vaccine being given with the 
information provided by the manufacturer.
Provides guidance for SARS-CoV-2 
(COVID-19) vaccinations, to align 
with the current Invesgiator’s 
brochure (version 15, dated 
December 2021) for irinotecan 
liposome injection.
Section 9.2.8 (Irinotecan 
Liposome Injection—
Incompatibilities)
Deletion of strikethrough text and addition of bolded text:
Incompatibilities—None known. Irinotecan liposome 
injection has been tested for compatibility with limited a 
number of materials, and no compatibility issues have 
been identified. Infusion sets without inline filters are 
recommended for use. However, an infusion set with 
an in-line filter that has a pore size of at least 0.2 μm 
is compatible for use.
The following materials were tested: 
• Infusion sets (without in-line filter) made of PVC or 
polyethylene lined  
• IV bags made of PVC or coextruded film of 
polyolefin/polyamide
Updates information regarding 
compatibility of irinotecan liposome 
injection with infusion sets, to align 
with the current Investigator’s 
brochure for irinotecan liposome 
injection.
Appendix F (Summary of 
Changes)
Adds a summary of revisions for protocol amendment 3
Administrative update
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Protocol Amendment 3 – Version Date: January 20, 2022
     89
REFERENCES
1.
Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for 
platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. 
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