Clinical trial NCT02289950
Conditions: Platinum-Sensitive Ovarian Cancer in First Relapse
Keywords: Ovarian Cancer in in first relapse Platinum-Sensitive
Sponsor: Eisai Inc.
Start date: 2015-03-19; Completion date: 2020-08-13
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
MORAb-003-011 is a global, multicenter, double-blind, randomized placebo-controlled study to assess the safety and efficacy of farletuzumab in combination with standard chemotherapy in subjects with low cancer antigen 125 (CA125) platinum-sensitive ovarian cancer in first relapse.

Detailed description:
Participants will be enrolled into 1 of 2 chemotherapy treatment arms at the investigator's discretion: carboplatin plus paclitaxel or carboplatin plus Pegylated Liposomal Doxorubicin (PLD), and then randomized in a 2:1 ratio to receive weekly farletuzumab 5 mg/kg or placebo (ie, Test Article). All participants will receive a loading dose for the first 2 weeks of 10 mg/kg Test Article (farletuzumab or placebo). Participants will be stratified at randomization by individual chemotherapy treatment regimen (targeted 1:1 ratio) and platinum-free interval following first-line therapy (6 to 12 months vs greater than 12 to 36 months).

Arms: arm 1: All participants will receive a loading dose for the first 2 weeks of 10 milligram per kilogram (mg/kg) farletuzumab, followed by 5 mg/kg weekly farletuzumab administered intravenously (IV). arm 2: All subjects will receive placebo weekly, administered intravenously (IV).
Interventions: intervention 1: Farletuzumab intervention 2: Placebo
Intervention descriptions: intervention 1: Farletuzumab will be administered intravenously (IV) weekly intervention 2: Placebo will be administered intravenously (IV) weekly

Protocol documents:
Prot_000.pdf: 
 
Clinical Study Protocol 
incorporating Amendment 03  
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1 
TITLE PAGE 
 
 
 
Clinical Study  Protocol 
Study Protocol 
Number: 
MORAb-003-011 
Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess 
the Efficacy and Safety of Farletuzumab (MORAb-003) in Combination 
with Carboplatin plus Paclitaxel or Carboplatin plus Pegylated Liposomal 
Doxorubicin (PLD) in Subjects with Low CA125 Platinum-Sensitive 
Ovarian Cancer 
Sponsor:  
.Eisai Inc. 
155 Tice Boulevard 
Woodcliff 
Lake, 
NJ 
07677 
USA 
Eisai Co., Ltd.  
4-6-10 Koishikawa 
Bunkyo-Ku,  
Tokyo 112-8088 
Japan 
Eisai , Ltd  
European Knowledge 
Centre 
Mosquito Way 
Hatfield, 
Hertfordshire 
AL10 9SN UK 
 
Investigational 
Product Name: 
Farletuzumab (MORAb-003) 
Indication: 
Platinum-sensitive Ovarian Cancer 
Phase: 
2 
Approval Date(s): 
V1.0 
10 Nov 2014  
(Original Protocol) 
 
V2.0 
12 Feb 2015  
(Amendment 01) 
 
V3.0 
18 Dec 2017 
(Amendment 02) 
 
V4.0 
06 Nov 2018 
(Amendment 03) 
IND Number: 
BB12219 
EudraCT Number: 
2014-003812-36 
ENGOT Number 
ENGOT-ov27 
BGOG Number 
BGOG-ov18 
GCP Statement: 
This study is to be performed in full compliance with International Council 
for Harmonisation of Technical Requirements for  Pharmaceuticals for 
Human Use (ICH) and all applicable local Good Clinical Practice (GCP) 
and regulations.  All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study. 


 
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REVISION HISTORY 
Revisions to Version 4.0 (per Amendment 03) 
Date: 06 Nov 2018 
Change 
Rationale 
Affected Protocol 
Sections 
Replaced “Morphotek” with “Eisai” 
where noted. 
Update of study ownership 
Title page, Section 6, 
Section 9.1.3, Section 
9.5.8, Section 9.6.1, 
Protocol Signature 
page, Document 
footers 
 
 
Revisions to Version 3.0 (per Amendment 02) 
Date:  18 Dec 2017 
Change 
Rationale 
Affected Protocol 
Sections 
Removed the 1:1 target stratification ratio 
and the associated minimum enrollment 
of 105 subjects per stratum and the 
description of the required number 
progression-free survival (PFS) events 
 
 
 
 
The cap of the 105 subjects to reach the 
1:1 chemotherapy strata ratio has been 
removed.  This change allows 
investigator discretion of chemotherapy 
with no impact to original primary PFS 
analysis of the combined strata. 
 
Revised accrual period based on 
current estimate. 
 
Made the median PFS and median OS 
in-between the medians of the 2 
chemotherapy strata since 50-50% is no 
longer applicable. 
 
Since the 2 tests related to the 2 
chemotherapy strata are removed, the 
sequential testing of PFS first and OS 
second became feasible now. 
 
Synopsis 
 
Section 9.1 
 
Section 9.1.2 
 
Section 9.4.1 
 
Section 9.4.4 
Removed the milestone (b) that at least 68 
PFS events in each stratum were 
necessary for primary endpoint analysis 
 
Synopsis 
 
Section 9.7.1.6.1 
Sample size considerations are no longer 
based of the effect of farletuzumab on 
PFS in each of the 2 chemotherapy 
regimens. 
Removed the second comparison from the 
sample size rationale 
Accrual period changed to 38 months 
Changed assumption for median PFS to 
11 months in the control arm 
Changed assumption for median overall 
survival (OS) to 32 months 
Sequential testing will also be employed 
for OS analysis 
 
Synopsis 
 
Section 9.7.2 
Removed the description of the PFS 
analysis to be conducted in both strata 
 
Section 9.7.1.6.1 


 
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Removed the description of the secondary 
efficacy analyses to be conducted in both 
strata 
Removed milestone (b) that at least 60 
OS events in each strata were necessary 
for analysis; OS will be determined when 
there are at least 124 OS events 
 
Synopsis 
 
Section 9.7.1.6.2 
Added that the primary and secondary 
analyses (PFS, OS, objective response 
[OR], duration of response [DR]) in each 
strata were to be considered as 
exploratory analyses 
 
Section 9.7.1.6.3 
Revised Figure 1 to remove target 
enrollments in each arm 
 
Section 9.1 
Revised inclusion criteria 6 and 7 
Clarification of intended eligibility to 
make consistent with other protocol 
sections. 
 
Synopsis 
 
Section 9.3.1 
Revised exclusion criteria 8 and 14 
 
Synopsis 
 
Section 9.3.2 
Added that the alpha allocation between 
the interim and final OS analyses will be 
determined based on the Lan-DeMets 
spending function with O’Brien-Fleming 
boundary 
Because OS is in the sequential 
procedure, this is applicable now. 
 
Section 9.7.3 


 
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Revisions to Version 2.0 (per Amendment 01) 
Date:  12 Feb 2015 
Change 
Rationale 
Affected Protocol 
Sections 
Provided method of randomization 
(central stratified block) 
In order to provide additional clarity on 
protocol design. 
 
Synopsis 
 
Section 9.1 
 
Section 9.1.2 
 
Section 9.4.4 
Updated Inclusion Criteria #8 and 
Exclusion Criteria #13 to clarify that no 
medical contraindications may be present 
as outlined in the chemotherapy product 
labels for the selected regimen to be used 
in this study 
In order to ensure consistency with 
chemotherapy prescribing information  
 
Synopsis 
 
Section 9.3.1 
 
Section 9.3.2 
Updated Inclusion Criteria #14 to state 
that subjects must continue to use a 
medically acceptable method of 
contraception throughout the entire study 
period and for 6 months after the last 
dose of Test Article is administered, 
rather than 5 months, which was the 
timeframe initially required. 
In order to ensure consistency with 
chemotherapy prescribing information 
 
Synopsis 
 
Section 9.3.1 
 
Section 9.5.4.2 
Updated Exclusion Criteria #8 to state 
that subjects may not have had a known 
allergic reaction to the concomitant 
chemotherapies selected by the 
investigator for planned treatment in this 
study. 
In order to ensure consistency with 
chemotherapy prescribing information 
 
Synopsis 
 
Section 9.3.2 
Clarified stopping rules for the study 
In order to provide additional clarity on 
protocol conduct. 
 
Section 9.3.3 
Added urine pregnancy testing (to be 
conducted locally) at Cycle 1 Day 1, 
Week 1 of every cycle in Combination 
and Maintenance Treatment periods, End 
of Treatment, and at the 30- and 60-Day 
Follow-up visits. 
In order to ensure consistency with 
chemotherapy prescribing information, 
and provide additional guidance 
regarding contraception and pregnancy 
testing. 
 
Table 5 
 
Section 9.5.1.4.3 
 
Table 6 
 
Table 7 
Specified that the censoring and handling 
rules on missing values will be detailed in 
the Statistical Analysis Plan (SAP), as 
well as potential sensitivity analyses with 
regard to missing values. 
In order to provide additional clarity on 
statistical handling of data. 
 
Section 9.7.1 


 
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Updated quantities of blood to be drawn 
for bioanalytical sampling 
In order to more closely align with 
central laboratory blood sample 
handling practices 
 
Synopsis 
 
Section 9.5.1.3.2 
 
Appendix 1 
 
Appendix 2 
The statement instructing sites to send 
images to Central Imaging Laboratory for 
rapid reads in the case of suspected 
disease progression was removed.  In 
addition, text was corrected to note that 
the Central Imaging Laboratory will no 
longer contact sites directly with results 
but will contact sponsor instead.  
Because it is anticipated that a limited 
number of sites will use the rapid read 
service, the statement was removed in 
order to eliminate the potential for bias 
that could be introduced by using a 
rapid read service.   
 
Section 9.5.1.2.1 
Inserted a statement indicating that the 
dose of farletuzumab will be recalculated 
based on the weight taken at each 
protocol specified time point 
To provide clarification that the dose 
should be adjusted according to 
changes in body weight throughout the 
treatment period and not based on 
weight at study baseline only 
 
Section 9.4.2.1 
Removal of reference to subject initials on 
the IP accountability log as only subject 
number will be captured.    
Subject initials will not be collected on 
the IP accountability logs. 
 
Section 11.8 
Other editorial changes have been made 
throughout 
To correct obvious errors and ensure 
accuracy of content 
 
Throughout 
 


 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  Farletuzumab (MORAb-003) 
Name of Active Ingredient:  MORAb-003 
Study Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess 
the Efficacy and Safety of Farletuzumab (MORAb-003) in Combination with Carboplatin plus 
Paclitaxel or Carboplatin plus Pegylated Liposomal Doxorubicin (PLD) in Subjects with Low CA125 
Platinum-Sensitive Ovarian Cancer 
Investigators 
List of investigators to be maintained separately by the sponsor 
Sites 
List of investigative sites to be maintained separately by the sponsor 
Study Period and Phase of Development 
Phase 2 
Objectives 
Primary: 
The primary objective of the study is to demonstrate that farletuzumab has superior efficacy 
compared to placebo in improving progression-free survival (PFS) as determined by Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1 when added to 1 of 2 standard chemotherapy 
regimens (carboplatin plus paclitaxel or carboplatin plus PLD) in subjects with platinum-sensitive 
ovarian cancer in first relapse who have a cancer antigen 125 (CA125) ≤ 3x the upper limit of normal 
(ULN) (105 U/mL) at study entry. 
Secondary: 
 
To assess the effect of farletuzumab on overall survival (OS) in this population 
 
To assess the effect of farletuzumab in prolonging second platinum-free interval longer than first 
platinum-free interval 
 
To assess the effect of farletuzumab on best objective response (OR) rate, time to response (TTR) 
and duration of response (DR) by RECIST 1.1 criteria  
 
To assess the safety and tolerability of farletuzumab 
 
To assess the pharmacokinetics and exposure-response relationships between farletuzumab and 
PFS and OS 
Exploratory: 
 
To explore blood CA125 change pattern during study 
 
To explore biomarkers that may correlate with the efficacy-related endpoints and farletuzumab 
mechanism of action 
 
To explore expression of CA125 and folate receptor alpha in blood, urine, and tissue to correlate 
to disease characteristics, exposure, efficacy-related endpoints, farletuzumab mechanism of 
action, and other biomarkers 


 
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Study Design 
MORAb-003-011 is a global, multicenter, double-blind, randomized placebo-controlled study. 
Subjects will be enrolled into 1 of 2 chemotherapy treatment arms at the investigator’s discretion:  
carboplatin plus paclitaxel or carboplatin plus PLD, and then randomized in a 2:1 ratio to receive 
weekly farletuzumab 5 mg/kg or placebo (ie, Test Article) using a central stratified block 
randomization scheme.  All subjects will receive a loading dose for the first 2  weeks of 
10 mg/kg Test Article (farletuzumab or placebo).  Subjects will be stratified at randomization by 
individual chemotherapy treatment regimen and platinum-free interval following first-line therapy (6-
12 months vs >12-36 months).   
All subjects must have CA125 ≤ 3 x ULN (105 U/mL) confirmed at Screening for study entry using a 
central laboratory designated by the sponsor to assure a standardized assay is used (Architect CA125 
II assay).  An archival tumor tissue sample taken at the time of initial diagnosis of ovarian cancer will 
be provided at Screening for analysis.  In addition, blood and urine samples will be collected at time 
points throughout the study for other supporting exploratory analyses.   
The study will consist of 4 phases:  Screening, Combination Treatment, Maintenance Treatment, and 
Follow-up.  At the end of the Combination Treatment Phase, subjects who have not experienced 
disease progression will enter the Maintenance Treatment Phase until disease progression.  Subjects 
who discontinue Test Article for reasons other than disease progression will be followed 
radiographically until documentation of disease progression or start of any new anticancer therapy 
and should still be followed for OS. 
An independent data monitoring committee (DMC) will be utilized to monitor the safety profile, and 
to enhance safety oversight.   
Number of Subjects 
A total of 210 subjects are planned for enrollment, including 140 subjects in the farletuzumab arm, 
and 70 subjects in the placebo arm. 
Inclusion Criteria 
1. Female subjects who are at least 18 years of age at the time of informed consent 
2. CA125 ≤ 3 x ULN (105 U/mL) confirmed within 2 weeks of randomization using a centralized 
laboratory assay 
3. A histologically confirmed diagnosis of high-grade serous epithelial ovarian cancer including 
primary peritoneal and fallopian tube malignancies; all other histologies, including mixed 
histology, are excluded 
4. Have been treated with debulking surgery and a first–line platinum based chemotherapy regimen 
5. Maintenance therapy during the first platinum-free interval is allowed; however, the last dose 
must have been at least 21 days prior to Randomization.   
6. Must be in a first relapse and have evaluable disease by computed tomography (CT) or magnetic 
resonance imaging (MRI) scan, according to RECIST 1.1 (subjects with measurable disease per 
RECIST 1.1 or radiographically visible and evaluable disease).  Subjects with only ascites or 
pleural effusion are excluded.    
7. Must have relapsed radiographically within ≥6 months and ≤36 months of completion of first-line 
platinum chemotherapy 
8. Must be a candidate for treatment with either carboplatin plus paclitaxel or carboplatin plus PLD 
with no medical contraindications present as outlined in the product labels for the selected 
regimen to be used in this study 
9. Have a life expectancy of at least 6 months, as estimated by the investigator 


 
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10. Other significant medical conditions must be well-controlled and stable in the opinion of the 
investigator for at least 30 days prior to Randomization 
11. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 
12. Subjects being enrolled to receive paclitaxel plus carboplatin treatment must have neuropathic 
function (sensory and motor) ≤ Grade 2 according to the National Cancer Institute’s (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
13. Laboratory results within the 2 weeks prior to Randomization must be as follows: 
- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3  
- Platelet count ≥ 100,000 cells/mm3  
- Hemoglobin ≥ 9 g/dL 
- Creatinine < 1.5 x ULN (CTCAE Grade 1) 
- Bilirubin < 1.5 x ULN (CTCAE Grade 1) 
- Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 3 x ULN 
(CTCAE Grade 1) 
- Alkaline Phosphatase < 2.5 x ULN (CTCAE Grade 1) 
- Baseline albumin ≥ Lower Limit of Normal 
14. Subjects of childbearing potential must be surgically sterile or consent to use a medically 
acceptable method of contraception throughout the study period.  All females will be considered 
to be of childbearing potential unless they are postmenopausal (eg, amenorrheic for at least 
12 consecutive months, in the appropriate age group, and without other known or suspected 
cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing).  If a patient of 
childbearing potential is neither surgically sterile nor postmenopausal, a highly-effective 
contraceptive method (ie, a method that can achieve a failure rate of less than 1% per year when 
used consistently and correctly) must start either before or at Screening and continue throughout 
the entire study period and for 6 months after the last dose of Test Article is administered.  
Pregnant and/or lactating females are excluded 
15. Subjects must provide written informed consent and be willing and able to comply with all 
aspects of the protocol  
Exclusion Criteria 
1. Known central nervous system (CNS) tumor involvement 
2. Evidence of other active invasive malignancy requiring treatment other than surgery in the past 
3 years 
3. Clinically significant heart disease (eg, congestive heart failure of New York Heart Association 
Class 3 or 4, angina not well controlled by medication, or myocardial infarction within 6 months) 
4. Electrocardiogram (ECG) demonstrating clinically significant arrhythmias that are not adequately 
medically managed (Note:  subjects with chronic atrial arrhythmia, ie, atrial fibrillation or 
paroxysmal supraventricular tachycardia [SVT], are eligible) 
5. Active serious systemic disease, including active bacterial or fungal infection 
6. Active viral hepatitis or active human immunodeficiency virus (HIV) infection.  Asymptomatic 
positive serology is not exclusionary 
7. Other concurrent immunotherapy (eg, immunosuppressants or chronic use of systemic 
corticosteroids with the exception that low-dose corticosteroids [50 mg/day prednisone or 
equivalent corticosteroid] are allowed; these should be discussed with the Medical Monitor) 
8. Known allergic reaction to a prior monoclonal antibody therapy or have any documented 
Anti-Drug Antibody (ADA) response; additionally known allergic reaction to the concomitant 


 
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chemotherapies selected by the investigator for planned treatment in this study unless 
desensitization is planned. 
9. Previous treatment with farletuzumab or other folate receptor targeting agents 
10. Previous treatment with cancer vaccine therapy 
11. For subjects being enrolled to receive PLD plus carboplatin, prior treatment with anthracyclines 
or anthracenodiones 
12. Breast-feeding, pregnant, or likely to become pregnant during the study 
13. Any medical or other condition that, in the opinion of the investigator, would preclude the 
subject’s participation in a clinical study including medical contraindications as outlined in the 
product labels for the chemotherapies selected by the investigator for planned treatment in this 
study 
14. Patients who have had secondary debulking surgery or any second line therapy 
15. Currently enrolled in another clinical study or used any investigational drug or device within 
30 days (or 5 x half-life for investigational drugs where the half-life is known) preceding 
informed consent 
Study Treatments 
The Test Article (farletuzumab or placebo) will be administered intravenously (IV) weekly.  All 
subjects will receive a loading dose for the first 2 weeks of 10 mg/kg farletuzumab (or placebo), 
followed by 5 mg/kg weekly.  
Duration of Treatment 
The duration of participation for individual subjects is expected to be approximately 46 months.  This 
includes a maximum screening period of 30 days, an estimated median Test Article treatment period 
of 15 months, and an additional estimated survival follow-up period of 30 months.  Subjects may 
discontinue for intolerable toxicity or may withdraw consent for any other reason at any time.  
Subjects who choose to discontinue Test Article but agree to continue in the study should still be 
followed for disease progression and OS. 
Concomitant Drug/Therapy 
In addition to Test Article, all subjects will receive 6 cycles of chemotherapy:  either carboplatin 
(area under the curve [AUC] 5) plus paclitaxel (175 mg/m2 IV every 3 weeks), or carboplatin 
(AUC 5) plus PLD (30 mg/m2 IV every 4 weeks).   
Assessments 
Primary Efficacy: 


 
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 
PFS based on radiographic assessments utilizing RECIST 1.1 criteria 
Secondary Efficacy: 
 
Overall Survival 
 
Length of first versus second platinum-free interval  
 
Tumor Response (OR, TTR, DR per RECIST 1.1) 
 
Biomarkers: 
 
CA125 levels in blood and tissue 
 
Folate receptor alpha levels in blood, tissue, and urine 
 
Other exploratory biomarkers 
 
Pharmacokinetics/Pharmacodynamics: 
 
Determination of farletuzumab serum concentration 
 
Exposure-response  
Safety: 
 
Adverse Events (AEs) (including drug hypersensitivity AEs) 
 
Clinical laboratory tests (serum chemistry and hematology)  
 
Tolerability (discontinuations, treatment delays, dose reductions) 
 
ECGs 
 
Physical examinations  
 
ECOG Performance Status 
 
ADA 
Standard safety monitoring and grading will be assessed using the NCI CTCAE.   
Bioanalytical Methods 
Serum samples will be analyzed to measure circulating farletuzumab concentrations using a validated 
quantitative assay.  Similarly, a tiered analysis approach will be used to identify, confirm, and titer 
potential ADA responses in serum samples using validated assays.  A blood sample (5.0 mL) will be 
collected for each test at Screening and at various time points throughout the study.  Complete 
instructions for processing and shipping samples will be located in the laboratory manual, and 
bioanalytical method descriptions for serum farletuzumab and ADA are included as appendices to the 
protocol. 
Statistical Methods 
Analysis Populations: 
 
Intent-to-Treat Population (ITT), defined as all randomized subjects according to the treatment 
assigned by interactive response technology (IRT).  This is the primary analysis population for all 
efficacy endpoints. 
 
Safety Analysis Set (SAS), defined as all randomized subjects who received at least 1 dose of 
Test Article and who had at least 1 safety assessment following the first dose of Test Article, 
analyzed by the treatment received.  All safety endpoints will be analyzed using this set of 
subjects. 
 
Evaluable Populations, defined as all randomized subjects who received at least 1 dose of Test 
Article and who had a baseline and at least 1 on-treatment assessment performed.  They will be 


 
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used to evaluate tumor response, farletuzumab serum drug levels, and other biomarker defined 
populations.  
Primary Efficacy Endpoint Evaluation: 
PFS is defined as the time (in months) from the date of randomization to the date of the first 
observation of progression based on the investigator’s radiographic assessment (RECIST 1.1), or date 
of death, whatever the cause.  The cut-off date for PFS will be based on the following milestone:  
a) at least a total number of 143 PFS events, or b) a minimum of 6 months PFS follow-up from last 
subject enrolled, whichever occurs later.  The cut-off date for PFS will be used for secondary efficacy 
variables, as well as survival data supporting the interim survival analysis. 
The stratified log rank test will be utilized to compare PFS between farletuzumab and placebo at the 
1-sided 10% level of significance.  Both one-sided and two-sided P values of the stratified log rank 
test will be calculated.  The stratification factors are:  (1) chemotherapy (carboplatin plus paclitaxel 
vs. carboplatin plus PLD), and (2) length of platinum-free interval following first line therapy 
(6-12 months vs. >12-36 months).  The hazard ratio (HR) will be estimated based on Cox’s 
proportional hazards model stratified by the same two factors.   
Key Secondary Efficacy Endpoint Evaluation: 
OS is defined as the time from the date of randomization to the date of death, due to all causes.  An 
additional cut-off date for final OS analysis will be determined based on the time when there are at 
least a total number of 124 OS events.  OS will be analyzed using methods similar to the PFS 
analyses. 
Interim Analyses 
The first DMC review of safety data will occur when the 15th subject completes Cycle 1 of the 
Combination Treatment Phase to assure that the tolerability of the modified farletuzumab dosing and 
chemotherapy combinations are acceptable. 
An interim analysis for OS will be performed to accompany the primary PFS analysis of the study.  
Survival status reported up to the primary analysis cut-off date will be included in this analysis.  
Study follow-up for survival will continue after the interim OS analysis. 
Sample Size Rationale 
Sample size considerations are based on the primary PFS endpoint to compare the effect of 
farletuzumab versus placebo on PFS irrespective of the chemotherapy (the 2 strata combined).  
The study is designed to detect with approximately 85% power a PFS HR of 0.667 (33.3% risk 
reduction) in the farletuzumab arm compared with the placebo arm with a 1-sided type I error of 0.10, 
which translates into a 50% increase in median PFS from 11 months in the placebo arm (10 months 
for carboplatin plus paclitaxel, and 11.3 months for carboplatin plus PLD) to approximately 16 
months in the farletuzumab arm.  A variable accrual period of approximately 38  months and a 20% 
loss to imaging follow-up rate has been assumed.  Using a treatment allocation of 2:1 
(farletuzumab:placebo), 210 patients will be enrolled in the study and a target of at least 143 PFS 
events in the combined chemotherapy strata will be required for the primary analysis. 
  


 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................6 
3 
TABLE OF CONTENTS .................................................................................................12 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................17 
5 
ETHICS............................................................................................................................21 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................21 
5.2 
Ethical Conduct of the Study .................................................................................22 
5.3 
Subject Information and Informed Consent ...........................................................22 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................23 
7 
INTRODUCTION ...........................................................................................................23 
7.1 
Indication ...............................................................................................................23 
7.1.1 
Current Therapeutic Options ........................................................................23 
7.1.2 
MORAb-003 (Farletuzumab).......................................................................24 
7.1.2.1 
Mechanism of Action ...........................................................................24 
7.1.2.2 
Clinical Experience With Farletuzumab ..............................................24 
7.1.2.3 
Common Serious Adverse Events Expected to Occur in the Study 
Population Even in the Absence of Study Drug Exposure ..................25 
7.2 
Study Rationale ......................................................................................................25 
8 
STUDY OBJECTIVES ....................................................................................................27 
8.1 
Primary Objective ..................................................................................................27 
8.2 
Secondary Objectives .............................................................................................27 
8.3 
Exploratory Objectives ..........................................................................................27 
9 
INVESTIGATIONAL PLAN ..........................................................................................28 
9.1 
Overall Study Design and Plan ..............................................................................28 
9.1.1 
Screening Phase ...........................................................................................29 
9.1.2 
Randomization .............................................................................................30 
9.1.3 
Combination Treatment Phase .....................................................................30 
9.1.4 
Maintenance Treatment Phase .....................................................................30 
9.1.5 
End of Treatment .........................................................................................31 
9.1.6 
Follow-Up Phase ..........................................................................................31 
9.1.7 
End of Study ................................................................................................31 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................31 
9.3 
Selection of Study Population ................................................................................31 
9.3.1 
Inclusion Criteria .........................................................................................31 
9.3.2 
Exclusion Criteria ........................................................................................33 


 
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9.3.3 
Removal of Subjects From Therapy or Assessment ....................................34 
9.4 
Treatments..............................................................................................................35 
9.4.1 
Treatments Administered .............................................................................35 
9.4.1.1 
Farletuzumab........................................................................................35 
9.4.1.2 
Placebo .................................................................................................35 
9.4.1.3 
Administration of Test Article .............................................................36 
9.4.2 
Dose Modification .......................................................................................37 
9.4.2.1 
Test Article (Farletuzumab or Placebo) ...............................................37 
9.4.2.2 
Chemotherapy ......................................................................................38 
9.4.2.2.1 
Paclitaxel ........................................................................................38 
9.4.2.2.2 
Pegylated Liposomal Doxorubicin (PLD) .....................................39 
9.4.2.2.3 
Carboplatin .....................................................................................41 
9.4.3 
Identity of Investigational Products .............................................................41 
9.4.3.1 
Farletuzumab........................................................................................41 
9.4.3.2 
Placebo .................................................................................................42 
9.4.3.3 
Chemotherapies ....................................................................................42 
9.4.3.4 
Chemical Name, Structural Formula of Investigational Product .........42 
9.4.3.5 
Comparator Drug .................................................................................42 
9.4.3.6 
Labeling for Test Article ......................................................................42 
9.4.3.7 
Storage Conditions ...............................................................................43 
9.4.4 
Method of Assigning Subjects to Treatment Groups ...................................43 
9.4.5 
Selection of Doses in the Study ...................................................................43 
9.4.6 
Selection and Timing of Dose for Each Subject ..........................................44 
9.4.7 
Blinding........................................................................................................44 
9.4.8 
Prior and Concomitant Therapy ...................................................................45 
9.4.8.1 
Premedications .....................................................................................45 
9.4.8.1.1 
Premedications for Test Article .....................................................45 
9.4.8.1.2 
Premedications for Chemotherapy .................................................46 
9.4.8.2 
Drug-Drug Interactions ........................................................................46 
9.4.8.3 
Prohibited Concomitant Therapies and Drugs .....................................46 
9.4.9 
Treatment Compliance .................................................................................47 
9.4.10 
Drug Supplies and Accountability ...............................................................47 
9.5 
Study Assessments .................................................................................................48 
9.5.1 
Assessments .................................................................................................48 
9.5.1.1 
Screening Assessments ........................................................................48 
9.5.1.1.1 
Demography ...................................................................................48 
9.5.1.1.2 
Medical History and Physical Examinations .................................48 


 
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9.5.1.1.3 
Body Weight, Height, and Body Surface Area ..............................49 
9.5.1.1.4 
Prior Cancer History ......................................................................49 
9.5.1.1.5 
Performance Status (ECOG) ..........................................................49 
9.5.1.1.6 
Assessment of Cardiac Function ....................................................49 
9.5.1.2 
Efficacy Assessments ...........................................................................49 
9.5.1.2.1 
RECIST 1.1 (CT or MRI) ..............................................................49 
9.5.1.2.2 
CA125 Assessment ........................................................................51 
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................51 
9.5.1.3.1 
Pharmacokinetic Assessments .......................................................51 
9.5.1.3.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................51 
9.5.1.4 
Safety Assessments ..............................................................................53 
9.5.1.4.1 
Adverse Events ..............................................................................53 
9.5.1.4.2 
Serious Adverse Events and Other Events of Interest ...................54 
9.5.1.4.3 
Laboratory Measurements .............................................................55 
9.5.1.4.4 
Physical Examinations ...................................................................57 
9.5.1.4.5 
Electrocardiograms ........................................................................57 
9.5.1.4.6 
ECOG Performance Status ............................................................57 
9.5.1.4.7 
Adverse Events of Interest .............................................................57 
9.5.2 
Schedule of Procedures/Assessments ..........................................................59 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................59 
9.5.2.2 
Description of Procedures/Assessments Schedule ...............................67 
9.5.3 
Appropriateness of Measurements ...............................................................67 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest..........................................................................................................67 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................67 
9.5.4.2 
Reporting of Pregnancy and Exposure to Test Article Through 
Breastfeeding .......................................................................................68 
9.5.4.3 
Reporting of Other Events of Interest ..................................................69 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................69 
9.5.4.3.2 
Reporting of Study-Specific Events ...............................................69 
9.5.4.4 
Expedited Reporting ............................................................................69 
9.5.4.5 
Breaking the Blind ...............................................................................70 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................70 
9.5.5 
Completion/Discontinuation of Subjects from Study (EOS) .......................70 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................71 


 
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9.5.7 
Confirmation of Medical Care by Another Physician .................................71 
9.5.8 
Data Monitoring Committee ........................................................................71 
9.6 
Data Quality Assurance .........................................................................................72 
9.6.1 
Data Collection ............................................................................................73 
9.6.2 
Clinical Data Management ..........................................................................74 
9.7 
Statistical Methods .................................................................................................75 
9.7.1 
Statistical and Analytical Plans ....................................................................75 
9.7.1.1 
Study Endpoints ...................................................................................75 
9.7.1.1.1 
Primary Endpoint ...........................................................................75 
9.7.1.1.2 
Secondary Endpoints .....................................................................76 
9.7.1.1.3 
Exploratory Endpoints ...................................................................76 
9.7.1.2 
Definitions of Analysis Sets.................................................................76 
9.7.1.3 
Subject Disposition ..............................................................................77 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................77 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................77 
9.7.1.6 
Efficacy Analyses ................................................................................77 
9.7.1.6.1 
Primary Efficacy Analysis .............................................................77 
9.7.1.6.2 
Secondary Efficacy Analyses ........................................................78 
9.7.1.6.3 
Exploratory Efficacy Analyses ......................................................78 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................79 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................79 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................79 
9.7.1.8 
Safety Analyses ....................................................................................79 
9.7.1.8.1 
Extent of Exposure .........................................................................80 
9.7.1.8.2 
Adverse Events ..............................................................................80 
9.7.1.8.3 
Laboratory Values ..........................................................................81 
9.7.1.8.4 
Cardiac Safety evaluation ..............................................................81 
9.7.1.8.5 
Other Safety Analyses ....................................................................81 
9.7.2 
Determination of Sample Size .....................................................................82 
9.7.3 
Interim Analysis ...........................................................................................82 
9.7.4 
Other Statistical/Analytical Issues ...............................................................83 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................83 
10 REFERENCE LIST .........................................................................................................84 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......86 
11.1 
Changes to the Protocol .........................................................................................86 


 
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11.2 
Adherence to the Protocol ......................................................................................86 
11.3 
Monitoring Procedures...........................................................................................87 
11.4 
Recording of Data ..................................................................................................88 
11.5 
Identification of Source Data .................................................................................88 
11.6 
Retention of Records ..............................................................................................88 
11.7 
Auditing Procedures and Inspection ......................................................................89 
11.8 
Handling of Test Article ........................................................................................89 
11.9 
Publication of Results ............................................................................................90 
11.10 Disclosure and Confidentiality ..............................................................................90 
11.11 Discontinuation of Study .......................................................................................91 
11.12 Subject Insurance and Indemnity ...........................................................................91 
12 APPENDICES .................................................................................................................92 
 
LIST OF IN-TEXT TABLES 
Table 1 
Treatments Administered ...........................................................................37 
Table 2 
PLD Toxicity—Hematological (ANC or Platelets) ...................................39 
Table 3 
PLD Toxicity—Palmar-Plantar Erythrodysesthesia ..................................40 
Table 4 
PLD Toxicity—Stomatitis .........................................................................40 
Table 5 
Clinical Laboratory Tests ...........................................................................56 
Table 6 
Schedule of Procedures/Assessments for PLD/Carboplatin 
Chemotherapy Arm ....................................................................................60 
Table 7 
Schedule of Procedures/Assessments for Paclitaxel/Carboplatin 
Chemotherapy Arm ....................................................................................64 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
MORAb-003-011 Study Schema ...............................................................29 
 
LIST OF APPENDICES 
Appendix 1 
Sample Collection Procedures and Bioanalytical Methods for Serum 
Farletuzumab levels and ADA ...................................................................93 
Appendix 2 
Quantity of Fluid and Tissue to be Collected ............................................94 
Appendix 3 
Eastern Cooperative Oncology Group Performance Status .......................95 
Appendix 4 
Protocol-Specific Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Quick Reference .................................................................96 
 


 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
1st Cmin 
trough concentration at Cycle 2 Day 1 
ADA 
Anti-drug Antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase (SGOT) 
ATC4 
Anatomical Therapeutic Chemical Class 4 
AUC 
area under the curve 
BGOG 
Belgian Gynecological Oncology Group 
BLQ 
below limit of quantitation 
BSA 
body surface area 
CA 
Competent Authority 
CA125 
cancer antigen 125 
CALYPSO 
Caelyx in Platinum Sensitive Ovarian patients 
Carbo 
carboplatin 
CDR 
complementarity determining region 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
Cmin 
minimum or “trough” concentration 
Cmin,av 
average trough concentration from the final 3 visits 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response 
CRA 
clinical research associate 
CRO 
contract research organization 
CSR 
clinical study report 


 
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Abbreviation 
Term 
CT 
computed tomography 
CTCAE 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events 
DHAE 
drug hypersensitivity adverse event 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ENGOT 
European Network of Gynecological Oncology Trials groups 
EOS 
end of study 
EOT 
end of treatment 
EU 
European Union 
FAR 
farletuzumab 
FDA 
United States Food and Drug Administration 
FRA 
folate receptor alpha 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IC 
informed consent 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IRT 
interactive response technology (web or voice randomization 
system) 
ITT 
intent-to-treat 


 
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Abbreviation 
Term 
IV 
intravenous  
LV 
left ventricular 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
microRNA 
MRI 
magnetic resonance imaging 
NE 
not evaluable 
OR 
objective response 
OS 
overall survival 
Pacli 
paclitaxel 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PE 
physical examination 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PLD 
pegylated liposomal doxorubicin 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
RBC 
red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RR 
response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SOC 
system organ class 


 
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Abbreviation 
Term 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SVT 
supraventricular tachycardia 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
TRAE 
Treatment-related adverse event 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
WHO DD 
World Health Organization Drug Dictionary 
 


 
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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
(Good Clinical Practice), Section 3, and any local regulations.  Any protocol amendment or 
revision to the ICF will be resubmitted to the IRB/IEC for review and approval, except for 
changes involving only logistical or administrative aspects of the study (eg, change in clinical 
research associate [CRA], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor. 
Documentation of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) (or if regionally required, the head of the medical institution) with a copy to 
the sponsor before study start and the release of any study drug to the site by the sponsor or 
its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigators (or the sponsor) will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) per local requirements.  The sponsor should also provide the IRB/IEC with a summary 
of the study’s outcome, where required. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given. 
The definition for end of the study, as required by certain regulatory agencies, is the time of 
data cut-off for the final analysis or the time of last subject/last treatment, whichever occurs 
later.  The estimated study end date is July 2019. 


 
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5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following: 
 
Principles of the World Medical Association Declaration of Helsinki October, 2013 
 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
 
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
 
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union (EU) country.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, 
to the Competent Authorities of all involved EU member states.  
 
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law 
No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP 
 
Other applicable regulatory authorities’ requirements or directives 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that she may withdraw from the study at any time, and 
that withdrawal of consent will not affect her subsequent medical treatment or relationship 
with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before her informed consent has been obtained. 


 
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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations.  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site. 
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai  (the 
sponsor) at approximately 90 investigational sites in North America, Europe and Japan. 
The name, telephone, fax number, and email address of the medical monitor and other 
contact personnel at the sponsor and of the contract research organization (CRO) will be 
provided on the Study Contact Sheet within the Regulatory Binder provided to each site. 
7 
INTRODUCTION 
7.1 
Indication 
The indication under study is platinum-sensitive ovarian cancer in first relapse with a cancer 
antigen 125 (CA125) level ≤ 3x the upper limit of normal (ULN).  
7.1.1 
Current Therapeutic Options 
The standard first-line therapy for advanced ovarian cancer, following maximal 
cytoreductive surgery, is platinum-based chemotherapy.  In 2004 the Ovarian Cancer 
Consensus Conference statements indicated carboplatin–paclitaxel as standard first-line 
therapy, and this regimen has been adopted as the control arm in the next generation studies 
(Guarneri, et al., 2010; Ledermann and Kristeleit, 2010).  According to DeVita, et al., in 
women treated with platinum and taxane combinations as first-line therapy, the response rate 
(RR) ranges from 70% to over 80% (2011).  Even if chemotherapy results in a complete 
clinical response (ie, normal physical examination [PE], normal serum CA125, and negative 
computed tomography [CT] scan of the abdomen and pelvis), about 50% of patients with 
Stage III or IV cancer have residual tumor.  Most patients (≈75%) respond to initial treatment 
for ovarian cancer, although most will eventually experience relapse (Morgan, et al., 2012).  
Of patients with persistent elevation of CA125, 90 to 95% have residual tumor, and the 
recurrence rate in patients with a clinical complete response after initial chemotherapy 
(6 courses of carboplatin and paclitaxel) is 60 to 70% (Gershenson and Ramirez, 2013).  The 
majority of patients eventually die of disease persistence or recurrence; long-term survival 
remains low, with a 5-year US relative survival rate of 44% across all stages (American 
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Results of the randomized, multicenter, Phase 3 study CALYPSO (Caelyx in Platinum 
Sensitive Ovarian patients), which enrolled 976 patients in relapsed/recurrent ovarian cancer, 
were published by Pujade-Lauraine, et al., in 2010.  Patients with histologically proven 
ovarian cancer with recurrence more than 6 months after first- or second-line platinum and 
taxane-based therapies were randomly assigned by stratified blocks to either 
carboplatin/pegylated liposomal doxorubicin (PLD) (carboplatin area under the curve 
[AUC] 5 plus PLD 30 mg/m2) (Carbo/PLD) every 4 weeks or carboplatin/paclitaxel 
(carboplatin AUC 5 plus paclitaxel 175 mg/m2) (Carbo/Pacli) every 3 weeks for at least 
6 cycles.  With median follow-up of 22 months, progression-free survival (PFS) for the 
Carbo/PLD arm was statistically superior to the Carbo/Pacli arm (hazard ratio [HR], 0.821; 
95% confidence interval [CI], 0.72 to 0.94; P=0.005); median PFS was 11.3 versus 
9.4 months, respectively. 
In light of the CALYPSO trial data, PLD has been proven to be a highly active partnering 
agent for carboplatin in platinum-sensitive ovarian cancer; therefore, both chemotherapy 
combinations are deemed suitable standard of care options for use as study controls in 
ovarian cancer.   
7.1.2 
MORAb-003 (Farletuzumab) 
7.1.2.1 
Mechanism of Action 
Farletuzumab is a humanized monoclonal antibody that binds to the folate receptor alpha 
(FRA).  The expression of FRA is known to relate to the malignant potential of the cancer.  
Farletuzumab’s mechanism of action is thought to be mediated via both complement-
dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) (MORAb-003 
Global Investigator’s Brochure, 2014).   
7.1.2.2 
Clinical Experience With Farletuzumab 
Farletuzumab has been studied in the treatment of ovarian cancer (epithelial, platinum 
sensitive, platinum resistant, first relapse, and refractory relapsed), non-small cell lung 
cancer, and solid tumors.  Farletuzumab is delivered by intravenous (IV) infusion.  
Eight clinical studies have been conducted to-date:  3 Phase 1 studies (MORAb-003-001, 
MORAb-003-005, MORAb-003-J081-102), 4 Phase 2 studies (MORAb-003-003, 
MORAb-003-009, MORAb-003-002, and long-term follow-up study MORAb-003-002A), 
and 1 Phase 3 study (MORAb-003-004).  Across all studies, a total of 1192 subjects have 
been exposed to farletuzumab:  56 subjects in Phase 1 studies, 397 subjects in Phase 2 
studies, and 739 subjects in Phase 3 studies (MORAb-003 Global Investigator’s Brochure, 
2014).   
In study MORAb-003-001, 25 subjects received different dose levels of farletuzumab.  
Among them, 3 subjects were treated at a dose level of 200 mg/m2, and 7 subjects were 
treated at a dose level of 400 mg/m2, which are approximately equivalent to 5 mg/kg and 
10 mg/kg, respectively.  There were no drug-related AEs of Grade 3, 4, or 5. 


 
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Fifteen ovarian cancer patients received farletuzumab plus Carbo/PLD in study 
MORAb-003-005.  Farletuzumab in combination with Carbo/PLD appears to be generally 
well-tolerated, and the safety profile of farletuzumab in combination with Carbo/PLD was 
consistent with that seen previously for the Carbo/PLD regimen.  The clinical studies are 
summarized in the MORAb-003 Global Investigator Brochure (2014). 
7.1.2.3 
Common Serious Adverse Events Expected to Occur in the Study Population 
Even in the Absence of Study Drug Exposure 
Since most patients with advanced ovarian cancer are treated as soon as possible, it can be 
very difficult to distinguish the symptoms related to the underlying disease from those related 
to the chemotherapy being administered.  Generally, symptoms and serious adverse events 
(SAEs) associated with the natural course of disease can include ascites, abdominal pain, 
nausea, vomiting, diarrhea, gastrointestinal obstruction, back pain, urinary dysfunction, liver 
abnormalities due to metastatic disease, and thromboembolic complications.  Those related to 
chemotherapy may include thrombocytopenia and neutropenia, nausea and vomiting and 
alopecia with most agents; and additionally those related to the specific chemotherapy being 
administered, such as cardiac toxicity and hand foot syndrome with PLD (DeVita and 
Rosenberg, 2006; DeVita, et al., 2011; Janssen, 2013). 
7.2 
Study Rationale 
A Phase 3 study (MORAb-003-004) was performed to examine the efficacy, safety, and 
pharmacokinetics (PK) of farletuzumab (FAR) when added to carboplatin/taxane 
chemotherapy in subjects with platinum-sensitive ovarian cancer in first relapse.  A total of 
1100 subjects were randomized, and of these, 1091 received at least one dose of study drug 
(361 in the placebo + carboplatin/taxane group, 367 in the FAR 1.25 mg/kg + 
carboplatin/taxane group, and 363 in the FAR 2.5 mg/kg + carboplatin/taxane group).  The 
primary analysis indicated that the study did not meet its primary endpoint for PFS (Data on 
file).  Median PFS based on independent review in the intent to treat (ITT) population was 
9.0, 9.5, and 9.7 months in the placebo, FAR 1.25 mg/kg, and FAR 2.5 mg/kg groups, 
respectively.  Neither FAR group was different statistically from the placebo group for either 
PFS or overall survival (OS), however subgroup analysis on CA125 and farletuzumab 
exposure indicated positive results for PFS and OS that warrant further investigation 
(MORAb-003 Global Investigator’s Brochure, 2014).   
MORAb-003-004 Subgroup Analysis 
CA125 has been used extensively as a serum biomarker to assess prognosis and recurrence in 
epithelial ovarian cancer.  In the Phase 3 study (MORAb-003-004), CA125 serum levels 
were collected for subjects at screening, baseline, and at on-going intervals throughout the 
study.  Due to the potential utility of CA125 as a biomarker of disease volume to supplement 
radiographic and clinical assessments, CA125 was pre-specified in the primary statistical 
analysis plan (SAP) as a covariate applied to subgroup efficacy analysis.  A threshold of 
3 x ULN was prespecified for these efficacy analyses.  Previous literature has demonstrated 
that lower CA125 levels may be indicative of a less advanced state of disease and that rising 


 
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levels may correlate with disease progression (Markman, 1997; Markman, et al., 2006).  This 
CA125 biomarker defined population of ≤3 x ULN includes subjects with normal CA125 
levels and subjects with marginally elevated levels, therefore a patient population that may be 
associated with a lower overall disease burden or potentially less residual disease that may 
not be adequately captured radiographically.  It is postulated that this disease environment 
characterized by less overall disease burden and less rapidly proliferating disease may be 
better suited to antibody treatment with farletuzumab, because farletuzumab exposure levels 
and tumor localization may take time to adequately accumulate based on the long half-life 
and to generate an associated immune response.  It has also been suggested that CA125 (also 
known as MUC16) is implicated in the inhibition of target cell killing via ADCC by 
suppressing natural killer cell function, thereby reducing the efficacy of immunotherapeutic 
antibodies (Felder, et al., 2014). 
The MORAb-003-004 subgroup analyses of primary data showed that subjects with 
baseline CA125 ≤ 3 x ULN (n=186) in the ITT population receiving high dose 
(2.5 mg/kg) farletuzumab versus those with baseline CA125 > 3 x ULN had a difference in 
median PFS of 13.6 months compared to 8.8 months in placebo (HR=0.49; P=0.0014).  
Subjects in the high dose >3 x ULN group had no difference in PFS (HR=0.97).  The PFS 
clinical benefit was observed in further post-hoc analyses at several baseline and screening 
CA125 cut points with favorable HR at lower CA125 cut point levels but diminishing 
potential clinical effect as CA125 rises.  An optimized CA125 cut point analysis was done as 
a supporting analysis of the CA125 subgroup efficacy analyses, and ≤ 3 x ULN was 
identified as the optimal cut point level.  In addition, data from the final analysis indicated a 
positive benefit for OS (key secondary endpoint) for subjects with CA125 ≤ 3 x ULN in the 
2.5 mg/kg FAR dose with a HR of 0.44 (P=0.0054).  
In study MORAb-003-004, 77% of subjects were classified as serous histopathologic type 
and generally had better outcome across PFS and OS than other histology types including 
specifically clear cell.  In the MORAb-003-004 study primary data subgroup of serous 
ovarian cancer subjects with screening CA125 ≤ 3 x ULN, the observed PFS difference was 
14.3 months in 2.5 mg/kg farletuzumab versus 9.9 months in placebo (HR=0.52; P=0.0021).  
Serous tumors are associated with high target expression (94.4% expression of folate 
receptor alpha) and a more well-defined pattern of CA125 expression; therefore, subjects 
with serous tumors have been identified as an appropriate target population for the proposed 
proof-of-concept study (Data on file).  
An exposure-response analysis of MORAb-003-004 found that PFS and OS in subjects with 
higher farletuzumab serum exposure levels was significantly longer compared with subjects 
with below-median farletuzumab levels and subjects receiving placebo treatment.  Analyses 
were performed across various PK parameters including Cmin,av, 1st Cmin, AUC, and 
steady-state Cmin with similar results of potential observed benefit for higher exposure 
subjects.  
Exposure-response analyses and PK simulation suggested that improved clinical benefit 
could potentially be obtained by increasing exposure of farletuzumab.  PK concentration 


 
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simulations were performed based on the PK model to predict an optimal dosage regimen to 
achieve the target farletuzumab exposures.  The results indicated that target 1st Cmin (above 
54 μg/mL) and steady-state Cmin (above 120 µg/mL) can be reached and sustained in almost 
all patients following weekly dosing at 5 mg/kg. In addition, the 10-mg/kg loading dose 
given at the first and second treatments could bring the serum farletuzumab level to the 
targeted steady-state serum concentration within 2 weeks of start of treatment.  (MORAb-003 
Global Investigator’s Brochure, 2014).  
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to demonstrate that farletuzumab has superior efficacy 
compared with placebo in improving PFS, as determined by Response Evaluation Criteria In 
Solid Tumors (RECIST) 1.1 (Eisenhauer, et al., 2009), when added to the standard 
chemotherapy regimens of carboplatin plus paclitaxel or carboplatin plus PLD, in subjects 
with platinum-sensitive ovarian cancer in first relapse who have a CA125 ≤ 3 x ULN 
(105 U/mL) at study entry. 
8.2 
Secondary Objectives 
The secondary objectives of the study are: 
 
To assess the effect of farletuzumab on OS in this population 
 
To assess the effect of farletuzumab in prolonging second platinum-free interval longer 
than first platinum-free interval 
 
To assess the effect of farletuzumab on best objective response (OR) rate, time to 
response (TTR) and duration of response (DR) by RECIST 1.1 criteria (Appendix 4) 
 
To assess the safety and tolerability of farletuzumab 
 
To assess the PK and exposure-response relationships between farletuzumab and PFS and 
OS 
8.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
 
To explore blood CA125 change pattern during study 
 
To explore biomarkers that may correlate with the efficacy-related endpoints and 
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 
To explore expression of CA125 and folate receptor alpha in blood, urine, and tissue to 
correlate to disease characteristics, exposure, efficacy-related endpoints, farletuzumab 
mechanism of action, and other biomarkers 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
MORAb-003-011 is a global, multicenter, double-blind, randomized placebo-controlled 
study in subjects with platinum-sensitive ovarian cancer in first relapse who have low CA125 
(≤ 3 x ULN, or 105 U/mL). 
Approximately 210 subjects will be enrolled into 1 of 2 chemotherapy treatment arms at the 
investigator’s discretion:  either carboplatin (AUC 5) plus paclitaxel (175 mg/m2 IV every 3 
weeks) or carboplatin (AUC 5) plus PLD (30 mg/m2 IV every 4 weeks).  Subjects will then 
be randomized in a 2:1 ratio to receive farletuzumab or placebo using a central stratified 
block randomization scheme.  All subjects will receive a loading dose for the first 2 weeks of 
10 mg/kg farletuzumab (or placebo), followed by 5 mg/kg weekly.  Subjects will be stratified 
at randomization by individual chemotherapy treatment regimen and platinum-free interval 
following first-line therapy (6-12 months vs >12-36 months).  The randomization block will 
be defined in the IRT system.   
All subjects must have CA125 ≤ 3 x ULN (105 U/mL) confirmed for study entry at 
Screening using a central laboratory designated by the sponsor to assure the use of a 
standardized assay (Architect CA 125 II assay).  An archival tumor tissue sample taken at the 
time of initial diagnosis of ovarian cancer will be provided at Screening for analysis.  In 
addition, blood and urine samples will be collected at time points throughout the study for 
other supporting exploratory analyses.   
An independent, unblinded data monitoring committee (DMC) will be utilized to monitor the 
safety profile of the study, and to enhance safety oversight.  The first DMC review of safety 
data will occur when the 15th subject completes Cycle 1 of the Combination Treatment 
Phase to assure that the tolerability of the modified farletuzumab dosing and chemotherapy 
combinations are acceptable.  Please refer to Section 9.5.8 for additional details on the DMC. 
The study will consist of 4 phases:  Screening, Combination Treatment, Maintenance, and 
Follow-up.  At the end of the Combination Treatment Phase, subjects who have not 
experienced disease progression will enter the Maintenance Phase until disease progression. 
Subjects who discontinue Test Article for reasons other than disease progression will be 
followed radiographically until documentation of disease progression or start of any new 
anticancer therapy.  All subjects who discontinue Test Article for any reason, except for 
withdrawal of consent from the study, will be followed for survival.  Subjects may choose to 
discontinue Test Article therapy and continue to be followed for disease progression and 
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An overview of the study design is presented in Figure 1. 
Subject
Enrollment
(N‐210)
Investigator’s Choice: Carbo/PLD + 
Randomized Test Article 
Investigator's Choice: Carbo/Pacli + 
Randomized Test Article
Carbo/Pacli + 
Placebo
Carbo/PLD + 
Placebo
Carbo/PLD + 
Farletuzumab
Carbo/Pacli + 
Farletuzumab
Weekly Maintenance
(Single‐Agent Farletuzumab or Placebo)
Disease Progression
(Primary Endpoint: PFS)
Overall Survival Follow‐Up
 
Figure 1 
MORAb-003-011 Study Schema 
9.1.1 
Screening Phase 
All Screening procedures must be completed within 30 days prior to and including the date 
of Randomization unless otherwise specified.  The purpose of the Screening Phase is to 
obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any Screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3. 
For specific details on the Screening Phase, refer to the Schedule of Procedures/Assessments 
(Table 6 and Table 7). 


 
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9.1.2 
Randomization 
Subjects who are eligible for this study will be enrolled into 1 of 2 chemotherapy treatment 
options at the investigator’s discretion:  either carboplatin (AUC 5) plus paclitaxel (175 
mg/m2 IV every 3 weeks) or carboplatin (AUC 5) plus PLD (30 mg/m2 IV every 4 weeks).  
Subjects will then be randomized in a 2:1 ratio to receive farletuzumab or placebo using a 
central stratified block randomization scheme and stratified by platinum-free interval 
following first-line therapy (6-12 months vs >12-36 months).  The randomization block will 
be defined in the IRT system.   
9.1.3 
Combination Treatment Phase 
The Combination Treatment Phase will extend from the start of Test Article administration 
until either disease progression is confirmed by radiographic assessment, or 6 cycles of 
chemotherapy are completed, whichever occurs first.  Subjects are expected to initiate 
treatment with Test Article as close to the day of Randomization as possible but no later than 
7 days following Randomization.  If a delay in the start of Test Article beyond that timeframe 
is expected, the Eisai Medical Monitor must be contacted. 
Subjects will receive the following treatments during the Combination Treatment Phase:  
6 cycles of open-label treatment with either carboplatin (AUC 5) plus paclitaxel (175 mg/m2 
IV every 3 weeks) or carboplatin (AUC 5) plus PLD (30 mg/m2 IV every 4 weeks) in 
combination with Test Article (either farletuzumab or placebo).  All subjects will receive a 
loading dose for the first 2 weeks of 10 mg/kg farletuzumab (or placebo), followed by 
5 mg/kg weekly thereafter.   
Up to 2 additional cycles of Combination Treatment (to a maximum of 8 cycles) may be 
administered at the investigator’s discretion.   
Subjects who experience intolerable toxicity to chemotherapy and cannot complete 6 cycles 
of treatment should continue on to Maintenance Treatment with farletuzumab or placebo.   
During the Combination Treatment Phase, computed tomography (CT) or magnetic 
resonance imaging (MRI) scans will be conducted every 6 weeks until documentation of 
disease progression. 
For specific details on the Combination Treatment Phase, refer to the Schedule of 
Procedures/Assessments (Table 6 and Table 7). 
9.1.4 
Maintenance Treatment Phase 
All subjects who complete the Combination Treatment Phase (as outlined in Section 9.1.3) 
will be eligible to receive Maintenance Treatment with farletuzumab (or placebo) 5 mg/kg 
weekly.  The assessments to be completed during this phase are detailed in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  Maintenance treatment will continue until 
disease progression is confirmed by radiographic assessment, or until the subject 


 
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discontinues treatment with Test Article for any other reason.  During this phase, CTs or 
MRIs (see Section 9.5.1.2.1) will be conducted every 9 weeks (3 cycles) until documentation 
of disease progression. 
9.1.5 
End of Treatment 
All subjects who discontinue treatment with Test Article at any time and for any reason will 
have an End of Treatment (EOT) Visit conducted.  The assessments to be conducted at this 
visit are detailed in the Schedule of Procedures/Assessments (Table 6 and Table 7).   
All EOT visit procedures should be conducted within 1 week following the last infusion of 
Test Article, unless the subject’s medical management warrants otherwise. 
9.1.6 
Follow-Up Phase 
The Follow-Up Phase for each subject will begin immediately after the EOT assessments 
have been completed and will continue as long as the study subject is alive or until the study 
subject withdraws consent or the sponsor chooses to discontinue the study.  The assessments 
to be conducted during this phase are detailed in the Schedule of Procedures/Assessments 
(Table 6 and Table 7).  Subjects who discontinue treatment with Test Article before disease 
progression will continue to undergo tumor response assessment by CT or MRI every 
9 weeks until documentation of disease progression or start of another anticancer therapy.  
New anticancer therapies initiated during the Follow-up Phase will also be collected for these 
subjects.   
9.1.7 
End of Study 
Following completion of all study-related assessments (eg, as a result of completion of 
survival follow-up), the End of Study (EOS) electronic case report form (eCRF) page should 
be completed.  Refer to Section 9.5.5 for the definition of End of Study.  
9.2 
Discussion of Study Design, Including Choice of Control Groups 
See Section 7.2 for a discussion of the study design. 
9.3 
Selection of Study Population 
Approximately 210 subjects with low CA125 (≤3 x ULN or 105 U/mL) platinum-sensitive 
ovarian cancer in first relapse will be randomized at approximately 90 sites in regions that 
include North America, Europe, and Japan.  Subjects who do not meet all of the inclusion 
criteria or who meet any of the exclusion criteria will not be enrolled into the study. 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 


 
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1. Female subjects who are at least 18 years of age at the time of informed consent 
2. CA125 ≤3 x ULN (105 U/mL) confirmed within 2 weeks of randomization using a 
centralized laboratory assay 
3. A histologically confirmed diagnosis of high-grade serous epithelial ovarian cancer 
including primary peritoneal and fallopian tube malignancies; all other histologies, 
including mixed histology, are excluded 
4. Have been treated with debulking surgery and a first-line platinum-based chemotherapy 
regimen 
5. Maintenance therapy during the first platinum-free interval is allowed; however, the last 
dose must have been at least 21 days prior to Randomization.   
6. Must be in a first relapse and have evaluable disease by CT or MRI scan, according to 
RECIST 1.1 (subjects with measurable disease per RECIST 1.1 or radiographically 
visible and evaluable disease).  Subjects with only ascites or pleural effusion are 
excluded.  See Appendix 4.   
7. Must have relapsed radiographically within ≥6 months and ≤36 months of completion of 
first-line platinum chemotherapy  
8. Must be a candidate for treatment with either carboplatin plus paclitaxel or carboplatin 
plus PLD with no medical contraindications present as outlined in the product labels for 
the selected regimen to be used in this study 
9. Have a life expectancy of at least 6 months, as estimated by the investigator 
10. Other significant medical conditions must be well-controlled and stable in the opinion of 
the investigator for at least 30 days prior to Randomization 
11. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 
12. Subjects being enrolled to receive paclitaxel plus carboplatin treatment must have 
neuropathic function (sensory and motor) ≤ Grade 2 according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (National 
Cancer Institute, 2010) 
13. Laboratory results within the 2 weeks prior to Randomization must be as follows: 
-Absolute neutrophil count (ANC) ≥1,500 cells/mm3 
-Platelet count ≥100,000 cells/mm3 
-Hemoglobin ≥9 g/dL 
-Creatinine <1.5 x ULN (CTCAE Grade 1) 
-Bilirubin <1.5 x ULN (CTCAE Grade 1) 
-Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ˂3 x ULN 
(CTCAE Grade 1) 
-Alkaline Phosphatase <2.5 x ULN (CTCAE Grade 1) 
-Baseline albumin ≥ Lower Limit of Normal 
14. Subjects of childbearing potential must be surgically sterile or consent to use a medically 
acceptable method of contraception throughout the study period.  All females will be 
considered to be of childbearing potential unless they are postmenopausal (eg, 


 
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amenorrheic for at least 12 consecutive months, in the appropriate age group, and without 
other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month 
before dosing).  If a patient of childbearing potential is neither surgically sterile nor 
postmenopausal, a highly-effective contraceptive method (ie, a method that can achieve a 
failure rate of less than 1% per year when used consistently and correctly) must start 
either prior to or at Screening and continue throughout the entire study period and for 
6 months after the last dose of Test Article is administered.  Pregnant and/or lactating 
females are excluded 
15. Subject must provide written informed consent and be willing and able to comply with all 
aspects of the protocol 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Known central nervous system (CNS) tumor involvement 
2. Evidence of other active invasive malignancy requiring treatment other than surgery in 
the past 3 years 
3. Clinically significant heart disease (eg, congestive heart failure of New York Heart 
Association Class 3 or 4, angina not well controlled by medication, or myocardial 
infarction within 6 months) 
4. Electrocardiogram (ECG) demonstrating clinically significant arrhythmias that are not 
adequately medically managed (Note:  subjects with chronic atrial arrhythmia, ie, atrial 
fibrillation or paroxysmal supraventricular tachycardia [SVT], are eligible) 
5. Active serious systemic disease, including active bacterial or fungal infection 
6. Active viral hepatitis or active human immunodeficiency virus (HIV) infection.  
Asymptomatic positive serology is not exclusionary. 
7. Other concurrent immunotherapy (eg, immunosuppressants or chronic use of systemic 
corticosteroids, with the exception that low-dose corticosteroids [50 mg/day prednisone 
or equivalent corticosteroid] are allowed; these should be discussed with the Medical 
Monitor) 
8. Known allergic reaction to a prior monoclonal antibody therapy or have any documented 
Anti-Drug Antibody (ADA) response; additionally known allergic reaction to the 
concomitant chemotherapies selected by the investigator for planned treatment in this 
study unless desensitization is planned 
9. Previous treatment with farletuzumab or other folate receptor targeting agents 
10. Previous treatment with cancer vaccine therapy 
11. For subjects being enrolled to receive carboplatin plus PLD, prior treatment with 
anthracyclines or anthracenodiones 
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13. Any medical or other condition that, in the opinion of the investigator, would preclude 
the subject’s participation in a clinical study including medical contraindications as 
outlined in the product labels for the chemotherapies selected by the investigator for 
planned treatment in this study 
14.  Patients who have had secondary debulking surgery or any second line therapy 
15. Currently enrolled in another clinical study or used any investigational drug or device 
within 30 days (or 5 x half-life for investigational drugs where the half-life is known) 
preceding informed consent 
9.3.3 
Removal of Subjects From Therapy or Assessment 
The investigator will discontinue a subject’s study treatment (chemotherapies and/or Test 
Article) or withdraw the subject from the study if any of the following circumstances occur at 
any time during the subject’s study participation:  
 
The subject’s continued participation, in the investigator’s judgment, would be 
detrimental to her health 
 
The subject withdraws consent for continued participation or refuses further treatment 
with the study agent(s) 
 
The subject experiences an intolerable toxicity to chemotherapy not ameliorable by 
symptomatic treatment or dose schedule modification  
 
The subject has objective evidence of disease progression  
 
The Test Article is held for more than 28 days 
 
The subject experiences a hypersensitivity AE to Test Article of CTCAE Grade 3 that 
cannot be medically managed to a level of Grade 2 or a reaction of Grade 4 (see 
Section 9.5.1.4.7)  
 
The subject receives other anticancer therapy (eg, chemotherapy or radiotherapy) during 
the Combination Treatment Phase or Maintenance Treatment Phase 
 
The subject becomes pregnant 
The investigator should confirm whether a subject will discontinue Test Article but agree to 
continue protocol-specified, off-treatment study visits, procedures, and survival follow-up, or 
whether the subject will withdraw consent.  If a subject withdraws consent, the date will be 
documented. 
The reason for discontinuation will be documented.  If a subject discontinues treatment with 
Test Article and agrees to continue in the study, the subject will enter the Follow-Up Phase 
and complete protocol-specified EOT visits, procedures, and survival follow-up.  Subjects 
who discontinue treatment for reasons other than disease progression (radiographic) will be 
followed radiographically until disease progression or initiation of another anticancer 
therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), 
where possible. 


 
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All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to discontinue the study. 
At the time of the completion of the study by the sponsor, provisions will be made to allow 
for continued treatment of subjects who have not yet experienced disease progression and are 
receiving Test Article as long as the efficacy endpoints of the trial have been met.  In the 
event the study is terminated and the efficacy endpoints have not been met, all subjects will 
be required to discontinue Test Article administration. 
9.4 
Treatments 
“Test Article” refers to the experimental drug being tested.  The Test Article in this study is 
farletuzumab (or placebo).  “Study Drug” refers to any drug(s) or formulations under 
evaluation in the study, including the Test Article and background chemotherapies.  The 
Study Drugs in this study are farletuzumab, placebo, carboplatin, paclitaxel and PLD. 
9.4.1 
Treatments Administered 
At the end of the Screening Phase, all eligible subjects will be enrolled into 1 of 2 
chemotherapy treatment arms at the investigator’s discretion:  either carboplatin (AUC 5) 
plus paclitaxel (175 mg/m2 IV every 3 weeks) or carboplatin (AUC 5) plus PLD (30 mg/m2 
IV every 4 weeks).   
Subjects will then be randomized in a 2:1 ratio to receive Test Article (farletuzumab or 
placebo).  Subjects will receive a 10 mg/kg loading dose of Test Article for 2 weeks, 
followed by 5 mg/kg weekly.  Combination Treatment will be administered by qualified 
personnel in the clinic for 6 cycles.  Up to 2 additional cycles of Combination Treatment (to a 
maximum of 8 cycles) may be administered at the investigator’s discretion.  Subjects who 
experience intolerable toxicity to chemotherapy and cannot complete 6 cycles of treatment 
should continue on to Maintenance Treatment with farletuzumab or placebo.   
On Day 1 of each cycle, the Test Article will be administered prior to chemotherapy 
(carboplatin plus paclitaxel or carboplatin plus PLD).   
9.4.1.1 
Farletuzumab 
For subjects assigned to receive farletuzumab, the unblinded pharmacist or other 
appropriately qualified unblinded investigational site personnel (hereafter referred to as 
“unblinded pharmacist”) will prepare the required volume of farletuzumab in an infusion 
bag.  The remaining farletuzumab left in a vial after withdrawing the subject's assigned dose 
is not to be used for subsequent doses. 
9.4.1.2 
Placebo 
For subjects assigned to receive placebo, the unblinded pharmacist will prepare an infusion 
bag identical to that used for farletuzumab administration.  For the placebo infusion, the 


 
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amount of 0.9% sodium chloride administered should equal the volume which would be used 
if the subject was randomized to farletuzumab. 
9.4.1.3 
Administration of Test Article 
The unblinded pharmacist (or designee) will document the time of drug preparation and then 
provide the prepared Test Article to blinded site personnel in a blinded manner for 
administration.  Only appropriately trained blinded investigational site personnel are 
permitted to administer Test Article to study subjects.   
Dilution of farletuzumab in normal saline is not necessary, however if institutional guidelines 
require dilution of monoclonal antibodies, farletuzumab may be diluted in a 1:1 ratio with 
normal saline.   
For subjects randomized to receive placebo, the unblinded pharmacist should calculate the 
volume of farletuzumab that would have be given if the subject had been randomized to 
farletuzumab and then prepare saline equal to that volume in order to maintain the blind. 
Test Article will be administered IV using an in-line 0.20 or 0.22 micron filter.  The initial 
infusion will be delivered at 1 mL/min and the rate progressed as tolerated to 10 mL/min.  If 
10 mL/min is well-tolerated, subsequent infusions may begin at that rate.  If infusion-related 
adverse effects are encountered, the infusion rate should be decreased by at least 50%, and 
then advanced back to the highest rate that was well-tolerated.  (See Section 9.5.1.4.7 for the 
assessment and treatment of infusion-related adverse effects).   
If an indwelling venous access device is used, Test Article will be administered via a 
different lumen than that used for blood collections whenever possible.  Test Article should 
be administered via the most distal lumen of a multi-lumen catheter to reduce the possibility 
of confounding drug level analyses. 
To ensure that the subject receives the full dose of Test Article, the tubing should be flushed 
with a volume of normal saline sufficient to deliver the Test Article remaining in the tubing. 
Additional details on procedures for preparation of Test Article for administration are 
outlined in the Pharmacy Manual. 
The following treatments will be administered to subjects in this study (Table 1). 


 
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Table 1 
Treatments Administered 
Drug Name 
Dose 
Dose Form/Route of 
Administration 
Dose Schedule 
Farletuzumab 
(MORAb-003) 
10 mg/kg 
(Loading Dose) 
Solution, delivered by 
IV infusion 
Once weekly for the first 
2 weeks of treatment 
Farletuzumab 
(MORAb-003) 
5 mg/kg 
Solution, delivered by 
IV infusion 
Once weekly, starting at Cycle 
1/Week 3 and continuing until 
disease progression 
-Or- 
 
 
 
Placebo 
 Same volume as 
farletuzumab 
Farletuzumab-matched solution 
(normal saline), delivered by IV 
infusion 
Same as above for 
farletuzumab 
-And- 
 
 
 
Carboplatin 
AUC 5 
Solution, delivered by 
IV infusion 
Every 3 weeks for 6 Cycles 
Paclitaxel 
175 mg/m2 
Solution, delivered by 
IV infusion 
Every 3 weeks for 6 Cycles 
-Or- 
 
 
 
Carboplatin 
AUC 5 
Solution, delivered by 
IV infusion 
Every 4 weeks for 6 Cycles 
PLD 
30 mg/m2 
Solution, delivered by 
IV infusion 
Every 4 weeks for 6 Cycles 
AUC = area under the curve; IV = intravenous; PLD = pegylated liposomal doxorubicin 
 
9.4.2 
Dose Modification 
9.4.2.1 
Test Article (Farletuzumab or Placebo) 
The dose of Farletuzumab will be calculated based on the weight taken at each protocol 
specified time point. 
If Test Article is delayed more than 28 days, the subject must be discontinued from Test 
Article and should complete EOT procedures and continue to the Follow-Up Phase of the 
study. 
Reasonable efforts will be taken to maintain a weekly dosing schedule of the Test Article.  In 
the event of a delay in dosing with chemotherapy (carboplatin plus paclitaxel or carboplatin 
plus PLD), the dose of Test Article will be administered as planned.  These will be 
considered “Test Article Administration Only” visits, as noted in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  If chemotherapy must be held longer than 
4 weeks within a given cycle, the subject should discontinue the Combination Treatment 
Phase and may move to the Maintenance Treatment Phase of the study.   


 
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9.4.2.2 
Chemotherapy 
The chosen regimen of chemotherapy (carboplatin plus paclitaxel or carboplatin plus PLD) 
must not change after randomization.   
If there is toxicity due to chemotherapy (carboplatin plus paclitaxel or carboplatin plus PLD) 
during the first 6 cycles, doses may be reduced.  Dose reductions of paclitaxel, PLD, or 
carboplatin should be made according to the schedules provided in Section 9.4.2.2.1, 
Section 9.4.2.2.2, and Section 9.4.2.2.3, respectively.  Dose reductions for toxicities not 
listed in these sections can be made per package insert.  In case the chemotherapy is 
discontinued due to intolerable toxicity, the subject will move into the Maintenance 
Treatment Phase and continue treatment with Test Article (farletuzumab or placebo) until 
confirmation of disease progression. 
If there is a change of >10% of body weight, or as per study site guidelines, doses of 
carboplatin, paclitaxel, and PLD should be recalculated.  Detailed instructions on dose 
modifications will be provided in the Pharmacy Manual. 
The sponsor’s Medical Monitor may be consulted for any issues related to dose 
modifications. 
If there is a delay in dosing with chemotherapy, a “Test Article Administration Only” visit 
will be conducted (see Table 6 and Table 7).  At the time of resuming chemotherapy 
administration, the administration cycle will reset.  For example, the first day of carboplatin 
plus paclitaxel or carboplatin plus PLD administration will be on Week 1 Day 1 of the 
appropriate cycle.  The protocol schedule of evaluations will be driven by the day and 
number of chemotherapy cycles (carboplatin plus paclitaxel or carboplatin plus PLD). 
9.4.2.2.1 
PACLITAXEL 
Neutropenia or thrombocytopenia  
 
Paclitaxel should not be administered until:  
- 
the neutrophil count is at least 1,500 cells/mm3, and  
- 
the platelet count is at least 100,000 cells/mm3 
 
Subjects who experience severe neutropenia (neutrophil < 500 cells/mm3 for a week or 
longer) during paclitaxel therapy should have the dose reduced by 20% for subsequent 
courses of paclitaxel.   
Peripheral neuropathy 
Grade 2 peripheral neuropathy during paclitaxel therapy should have the dose reduced by 
20% for subsequent courses of paclitaxel. 


 
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9.4.2.2.2 
PEGYLATED LIPOSOMAL DOXORUBICIN (PLD)  
If the subject experiences early symptoms or signs of infusion reaction, immediately 
discontinue the infusion, give appropriate premedications (antihistamine and/or short acting 
corticosteroid) and restart at a slower rate. 
To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or 
hematological toxicity, the dose may be reduced or delayed.  Guidelines for dose 
modification secondary to these adverse effects (as detailed in the CAELYX® Product 
Information sheet [2013]) are provided below (Table 2, Table 3, and Table 4).  The toxicity 
grading in these tables is based on the CTCAE criteria. 
The tables for PPE and stomatitis provide the schedule followed for dose modification in 
clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 
4 week treatment cycle). 
Table 2 
PLD Toxicity—Hematological (ANC or Platelets) 
GRADE 
ANC 
(cells/mm3) 
PLATELETS 
(cells/mm3) 
MODIFICATION 
Grade 1  
1,500 – 1,900  
75,000 – 150,000  
Resume treatment with no dose reduction  
Grade 2  
1,000 - <1,500  
50,000 - <75,000  
Wait until ANC ≥1,500 cells/mm3 and platelets 
≥75,000 cells/mm3; redose with no dose reduction  
Grade 3  
500 - <1,000  
25,000- <50,000  
Wait until ANC ≥1,500 cells/mm3 and platelets 
≥75,000 cells/mm3; redose with no dose reduction  
Grade 4  
<500  
<25,000  
Wait until ANC ≥1,500 cells/mm3 and platelets 
≥75,000 cells/mm3; decrease dose by 25% or continue 
full dose with growth factor support.  
ANC = absolute neutrophil count; PLD = pegylated liposomal doxorubicin 
 


 
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Table 3 
PLD Toxicity—Palmar-Plantar Erythrodysesthesia 
Toxicity Grade at Current 
Assessment  
Week After Prior Dose  
Week 4 
Week 5  
Week 6  
Grade 1:  mild erythema, swelling, or 
desquamation not interfering with daily 
activities 
Redose unless  
subject has 
experienced a 
previous Grade 3 or 
4 skin toxicity, in 
which case wait an 
additional week  
Redose unless  
subject has 
experienced a 
previous Grade 3 or 
4 skin toxicity, in 
which case wait an 
additional week  
Decrease dose by 
25%; return to 
4 week interval  
Grade 2:  erythema, desquamation, or 
swelling interfering with, but not 
precluding normal physical activities; 
small blisters or ulcerations less than 
2 cm in diameter 
Wait an additional 
week  
Wait an additional 
week  
Decrease dose by 
25%; return to 
4 week interval  
Grade 3:  blistering, ulceration, or 
swelling interfering with walking or 
normal daily activities; cannot wear 
regular clothing 
Wait an additional 
week  
Wait an additional 
week  
Withdraw subject  
Grade 4:  diffuse or local process 
causing infectious complications, or a 
bedridden state or hospitalization 
Wait an additional 
week  
Wait an additional 
week  
Withdraw subject  
 
Table 4 
PLD Toxicity—Stomatitis 
Toxicity Grade at 
Current Assessment  
Week After Prior Dose  
Week 4 
Week 5  
Week 6  
Grade 1:  painless ulcers, 
erythema, or mild 
soreness 
Redose unless  
subject has experienced a 
previous Grade 3 or 4 
stomatitis in which case 
wait an additional week  
Redose unless  
subject has experienced a 
previous Grade 3 or 4 
stomatitis in which case 
wait an additional week  
Decrease dose by 25%; 
return to 4 week 
interval  
or withdraw subject per 
physician’s assessment  
Grade 2:  painful 
erythema, oedema, or 
ulcers, but can eat 
Wait an additional 
week  
Wait an additional 
week  
Decrease dose by 25%; 
return to 4 week 
interval  
or withdraw subject per 
physician’s assessment  
Grade 3:  painful 
erythema, oedema, or 
ulcers, but cannot eat 
Wait an additional 
week  
Wait an additional 
week  
Withdraw subject  
Grade 4:  requires 
parenteral or enteral 
support 
Wait an additional 
week  
Wait an additional 
week  
Withdraw subject 
 


 
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Subjects on this study will typically receive a cumulative anthracycline dose significantly 
below 450 mg/m2, and thus will not require routine monitoring of left ventricular (LV) 
cardiac function.  Should the above dose be exceeded in a rare subject, or should there be 
clinical evidence of deterioration of LV function at any dose, monitoring of LV function 
(typically by echocardiogram or multigated acquisition scan) should be instituted and no 
further anthracycline should be administered if there is evidence of impaired LV function. 
9.4.2.2.3 
CARBOPLATIN 
Neutropenia or thrombocytopenia 
Carboplatin should not be repeated until the neutrophil count is at least 1500 cells/mm3 and 
the platelet count is at least 100, 000 cells/mm3.   
For renal toxicity of carboplatin the dose in mg will be modified per institutional procedures 
to maintain AUC 5. 
In the event of an allergic reaction to carboplatin, the subject may undergo a desensitization 
procedure at the discretion of the investigator.  The standard protocol in use at the 
investigative site should be used.  The subject may remain on the study if, after completion of 
the desensitization procedure, they are a candidate to remain on carboplatin plus paclitaxel or 
carboplatin plus PLD therapy at the planned dose and schedule.  
9.4.3 
Identity of Investigational Products 
Farletuzumab will be supplied to the clinical site by a third-party drug distribution vendor. 
Farletuzumab is packaged in single-use vials.  The dose of farletuzumab required for a 
subject is to be taken from as many vials as required.  Any farletuzumab remaining in a vial 
after withdrawing the subject's assigned dose is not to be used for subsequent doses.   
Saline for placebo will be provided by the site and delivered to the blinded study team in a 
manner that will preserve the blind. 
9.4.3.1 
Farletuzumab 
Farletuzumab (Chemical Name:  MORAb-003) is a humanized IgG1/κ monoclonal antibody 
that binds to the human FRA.  The MORAb-003 antibody is produced by a transfected 
Chinese hamster ovary K1 cell line and has been constructed by grafting murine 
complementarity-determining (humanized) regions into a human IgG1/κ backbone.  
Farletuzumab is formulated as 5.0 mg/mL (± 0.5 mg/mL) in phosphate buffered 
physiological saline (pH 7.2) (MORAb-003 Global Investigator’s Brochure, 2014).  No 
animal-derived materials, except production cells, are used in any step of the cultivation and 
purification processes for MORAb-003 production.   


 
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The formulations to be used in this clinical study are presented below: 
Study product: 
Farletuzumab 
Formulation: 
Phosphate buffered saline with 0.01% Tween 80 
Strength: 
5 mg/mL 
Route of 
administration: 
IV infusion 
 
Farletuzumab as an investigational product is available for IV administration in single-use 
vials (5 mL and 20 mL) of sterile drug product (5 mg/mL farletuzumab in 
phosphate-buffered saline with 0.01% Tween 80). 
Additional details of the farletuzumab drug substance and drug product are provided in the 
MORAb-003 Global Investigator’s Brochure (2014). 
9.4.3.2 
Placebo 
Normal saline will be used as placebo and will be supplied by the investigational site unless 
prohibited by local regulations or institutional policy. 
9.4.3.3 
Chemotherapies 
The chemotherapies administered during the study (carboplatin, paclitaxel, and PLD) will be 
supplied by the investigational site unless prohibited by local regulations or institutional 
policy.  All chemotherapeutic agents used in this clinical trial will meet the applicable US 
Food and Drug Administration (FDA), European Medicines Agency, or local regulatory 
standards. 
9.4.3.4 
Chemical Name, Structural Formula of Investigational Product 
MORAb-003 
9.4.3.5 
Comparator Drug 
Placebo is used as a comparator in this randomized, double blind study.  (Refer to 
Section 9.4.3.2 for details.) 
9.4.3.6 
Labeling for Test Article 
Farletuzumab will be labeled as investigational product per local regulations, and supplied to 
the clinical site by a third-party drug distribution vendor. 


 
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9.4.3.7 
Storage Conditions 
The chemotherapies (carboplatin, paclitaxel, and PLD) must be stored as instructed on their 
associated labels.   
Farletuzumab must be kept in a secure location at the study site, stored at 2°C to 8°C in its 
original container, and protected from light.  Note that all relevant site-specific guidelines 
and country-specific labeling requirements must be followed.  The investigator or designee 
(or if regionally required, the head of the medical institution) is responsible for ensuring that 
the temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 
Additional details on the storage, handling, and inventory of farletuzumab will be provided in 
the study Pharmacy Manual and MORAb-003 Global Investigator’s Brochure (2014). 
9.4.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.  All investigational sites will receive training during their 
initiation visits regarding procedures to enroll subjects.   
After the Screening Phase, subjects who qualify for the study will be randomized in a 
2:1 ratio to the following treatment groups:  either farletuzumab or placebo weekly. 
Central stratified block randomization will be used, which will be performed by interactive 
response technology (IRT).  The IRT system will generate the randomized identification 
numbers.   
Randomization will be stratified as follows: 
1. Carboplatin/paclitaxel versus carboplatin/PLD  
2. By platinum-free interval following first-line therapy (6-12 months vs >12-36 months) 
9.4.5 
Selection of Doses in the Study 
The results of the exposure-response analysis of MORAb-003-004 and subsequent PK 
modeling suggests that target exposure levels can be reached and sustained in almost all 
subjects following weekly dosing at 5 mg/kg, with 2 loading doses of 10 mg/kg for the first 
2 weeks of treatment to facilitate rapid serum farletuzumab concentration levels (Data on 
file; MORAb-003 Global Investigator’s Brochure, 2014). 


 
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9.4.6 
Selection and Timing of Dose for Each Subject 
Refer to Section 9.4.1 for details on selection and timing of doses for individual subjects. 
9.4.7 
Blinding 
This study is randomized and double-blinded.  A master list of all treatments and the subject 
numbers associated with them will be maintained by the IRT vendor.  In the event that 
emergency conditions require knowledge of the Test Article given, the blind may be broken 
through the IRT system.  Emergency procedures for revealing drug codes are given in 
Section 9.5.4.5.  If possible, before breaking the blind, the investigator should consult with 
the sponsor to ascertain the necessity of breaking the code. 
During the Randomization Phase, subjects and all personnel involved with the conduct and 
interpretation of the study will be blinded to the treatment codes, including investigators, site 
personnel, and sponsor staff, unless specifically designated as unblinded and independent 
from the study team.  Such independent, unblinded study personnel may include:  drug 
distribution, interactive web or voice response system (IRT) vendor staff, an independent site 
monitor for each site for drug accountability and pharmacy oversight, DMC members, and an 
independent statistician who generates outputs for DMC review.  Pharmacovigilance staff 
will be unblinded as necessary for reporting to regulatory authorities, with appropriate 
controls to assure that access to any unblinded information is restricted to the safety reporting 
staff.  The sponsor will maintain a list of any designated individuals at the investigative site, 
sponsor, and select vendors (where appropriate) that are designated as unblinded. 
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
with the sponsor or CRO and accessible only to authorized persons (eg, Eisai Global Safety, 
DMC) until the time of unblinding, per standard operating procedure. 
Best practices within the site should be exercised to maintain the blinding of investigators, 
subjects, study coordinators and all study staff.  Unblinded site personnel will include a 
pharmacist or designee, who will prepare the Test Article (farletuzumab or placebo) and 
dispense it in a blinded fashion.  All relevant site personnel will receive training during site 
initiation visits on blinding and unblinding procedures. 
The primary site monitor will be blinded; hence, a separate unblinded monitor will be 
assigned specifically for drug accountability and monitoring of pharmacy procedures.  Data 
collection and management staff will maintain blinding of data until a formal unblinding 
notification is provided by the sponsor for final analysis of the primary efficacy endpoint.  
All unblinded data maintained during the study until final unblinding authorized for analysis, 
including safety data required for the DMC or as requested by regulatory agencies, will be 
maintained in a secure, restricted-access data file system. 
The study will be unblinded for analysis purposes at the time of the primary PFS analysis; 
however, no subject-level unblinding information will be communicated to the sites until the 
final OS analysis has been completed.   


 
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Each investigator will ensure that the blind is broken only in accordance with the protocol 
conditions for unblinding due to medical necessity or for safety reasons.  Individual subject 
unblinding by the investigator should only be performed in the case of a medical emergency 
requiring knowledge of the treatment assignment.  Premature unblinding must be reported to 
the medical monitor immediately and must be documented with an explanation (eg, due to an 
SAE). 
Specific details for blinding and pharmacy procedures will be outlined in the site’s blinding 
plan and/or the Pharmacy Manual, and all pharmacy-related questions should be directed to 
the unblinded monitor.  All other study-related questions should be directed to the sponsor 
medical monitor or other sponsor personnel (or designee), as appropriate. 
9.4.8 
Prior and Concomitant Therapy 
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of Test Article and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 days after the final 
dose of Test Article will be recorded.   
Any medication that is considered necessary for the subject’s health and that is not expected 
to interfere with the evaluation of or interact with farletuzumab or other study treatments may 
be continued during the study. 
Aspirin, nonsteroidal antiinflammatory drugs, and low-molecular-weight heparin are 
permissible but should be used with caution.  Granulocyte colony-stimulating factor or 
equivalent may be used in accordance with American Society of Clinical Oncology (ASCO), 
institutional, or national guidelines.  Erythropoietin may be used according to ASCO, 
institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts. 
9.4.8.1 
Premedications 
All premedications for Test Article and chemotherapy must be reported in the eCRF. 
9.4.8.1.1 
PREMEDICATIONS FOR TEST ARTICLE 
All subjects must be premedicated within 4 hours prior to Test Article (farletuzumab or 
placebo) infusion with acetaminophen 650 mg by mouth or clinical equivalent per clinic 
routine and country availability.   
In the event of a hypersensitivity AE believed to be associated with Test Article 
(farletuzumab or placebo) infusion, subjects should be premedicated for subsequent infusions 
with antipyretic and histamine receptor blocking medications (eg, diphenhydramine, 
ranitidine, etc.), per the clinic routine, in order to reduce the incidence/severity of fluid 
retention and/or hypersensitivity reactions.  These medications will be reported in the eCRF. 


 
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Refer to Section 9.5.1.4.7 for additional details regarding the administration of secondary 
prophylaxis for treatment of hypersensitivity AEs. 
9.4.8.1.2 
PREMEDICATIONS FOR CHEMOTHERAPY 
Antiemetics may be given with chemotherapy at the discretion of the investigator.  
Premedications for carboplatin and paclitaxel should be given according to country-specific 
labeling.   
Carboplatin 
Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes 
of carboplatin administration.  Epinephrine, corticosteroids and antihistamines may be 
employed to alleviate symptoms. 
Paclitaxel 
All subjects must be premedicated with corticosteroids prior to paclitaxel administration in 
order to prevent severe hypersensitivity reactions.  A typical regimen is dexamethasone 
20 mg orally, administered approximately 12 and 6 hours before paclitaxel, diphenhydramine 
(or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or 
ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel administration. 
Pegylated Liposomal Doxorubicin (PLD)  
No premedication is required for use with PLD.  Serious and sometimes life-threatening 
infusion reactions to PLD, which are characterized by allergic-like or anaphylactoid-like 
reactions, may occur within minutes of starting the infusion.  Medications to treat these 
symptoms (eg, antihistamines, corticosteroids, adrenaline, and anticonvulsants), as well as 
emergency equipment, should be available for immediate use. 
9.4.8.2 
Drug-Drug Interactions 
There are no known drug-drug interactions between any of the therapeutic or concomitant 
medications used in the study.  
9.4.8.3 
Prohibited Concomitant Therapies and Drugs 
Subjects should not receive other anticancer therapies while on study.  If subjects receive 
additional non-study anticancer therapies, such as chemotherapy, hormone therapy, or 
immunotherapy, this will be judged to represent evidence of disease progression, and Test 
Article will be discontinued.  These subjects should complete all EOT assessments and 
continue to be followed for survival in the Follow-Up Phase. 


 
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9.4.9 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  Unblinded 
CRAs will review treatment compliance during site pharmacy visits and at the completion of 
the study.  Test Article is to be dispensed only to subjects enrolled in the clinical trial.  
Infusions of the study drugs are to be administered by appropriately trained and qualified 
personnel.  
9.4.10 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
unblinded pharmacist until the following documentation has been received by the sponsor or 
CRO personnel: 
 
A signed and dated confidentiality agreement 
 
A copy of the final protocol signature page, signed and dated by the investigator 
 
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted 
 
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
 
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number 
 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
 
An investigator-signed and dated Form FDA 1572, where applicable 
 
Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 
1572, where applicable 
 
A signed and dated curriculum vitae of the PI, and, where available, a copy of the PI’s 
current medical license or medical registration number (preferably included on the 
curriculum vitae) 
 
A signed and dated clinical studies agreement 
 
A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required) 
The unblinded pharmacist will be responsible for the accountability of all study drugs/study 
supplies (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to ICH GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.   
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, reconciliation of unused study drugs that are 


 
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shipped to site but not dispensed to subjects, and return of reconciled study drugs to the 
sponsor or (where applicable) destruction of reconciled study drugs at the site.  This includes, 
but may not be limited to:  (a) documentation of receipt of study drugs, (b) study drugs 
dispensing/return reconciliation log, (c) study drugs accountability log, (d) all shipping 
service receipts, (e) documentation of returns to the sponsor, and (f) certificates of 
destruction for any destruction of study drugs that occurs at the site, where available.  All 
forms will be provided by the sponsor.  Any comparable forms that the site wishes to use 
must be approved by the sponsor. 
The Test Article and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor (ie, unblinded CRA) or a representative of a 
health authority (eg, FDA, Medicines and Healthcare Products Regulatory Agency).   
Drug accountability will be reviewed during site pharmacy visits and at the completion of the 
study by the unblinded CRA. 
As permissible by site standards, all empty and partially used Test Article vials are to be 
destroyed by the site.  Destruction will occur following the site’s standard procedures and 
certificates of destruction will be maintained.  If destruction on site is not allowed, 
arrangements can be made to return used vials to the depot. 
At the conclusion of the study or by sponsor directive, and upon completion of drug 
accountability and reconciliation procedures by the site’s unblinded personnel and review by 
the unblinded CRA, any unused vials of Test Article that were shipped to the site but not 
administered to subjects must be destroyed by the site or boxed, sealed, and shipped back to 
the sponsor’s designated central or local depot, following all local regulatory requirements.  
In some regions, study drugs may be removed from the site and hand delivered to the central 
or local depot by sponsor representatives.   
9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Screening Assessments 
9.5.1.1.1 
DEMOGRAPHY 
Subject demography information will be collected during Screening.  Demography 
information includes date of birth (or age), gender, and race/ethnicity.  Subject initials will 
not be collected to protect subject confidentiality. 
9.5.1.1.2 
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  Relevant medical and surgical history must be noted in the eCRF. 


 
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PEs (comprehensive or abbreviated/symptom-directed) will be performed as designated in 
the Schedule of Procedures/Assessments (Table 6 and Table 7).  Comprehensive PEs will be 
performed at Screening and at the EOT visit, and will include evaluations of the following 
systems:  general appearance, HEENT, respiratory, cardiovascular, abdomen, 
musculoskeletal, neurological, extremities, lymph nodes, dermatologic, and vital signs.  
Abbreviated PEs will be conducted at all other time points, as indicated in Table 6 and Table 
7.  Abbreviated PEs will include follow-up of interval complaints and review of the 
cardiorespiratory system.   
Documentation of the PE will be included in the source documentation at the site.  
Significant findings at the Screening Visit will be recorded on the Medical History eCRF.  
Changes from Screening PE findings that meet the definition of an AE will be recorded on 
the Adverse Events eCRF.   
9.5.1.1.3 
BODY WEIGHT, HEIGHT, AND BODY SURFACE AREA 
Body weight will be measured at Screening, and at the time points listed in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  Body weight will always be collected prior 
to Test Article (farletuzumab or placebo) administration at the specified time points. 
Height will be measured on all subjects only at the Screening visit. 
9.5.1.1.4 
PRIOR CANCER HISTORY 
During Screening, disease stage and tumor histologic type at initial diagnosis for each 
subject’s ovarian cancer will be collected.  
Any prior cancer therapy will also be recorded. 
Historical CA125 results will also be collected.   
9.5.1.1.5 
PERFORMANCE STATUS (ECOG) 
All subjects will be assessed for ECOG Performance Status (Appendix 3) at Screening and at 
the time points listed in the Schedule of Procedures/Assessments (Table 6 and  Table 7). 
9.5.1.1.6 
ASSESSMENT OF CARDIAC FUNCTION 
All subjects enrolled will have a 12-lead ECG conducted at Screening and at the EOT Visit. 
9.5.1.2 
Efficacy Assessments 
9.5.1.2.1 
RECIST 1.1 (CT OR MRI) 
As part of the disease assessment by RECIST 1.1 criteria (Appendix 4), CT with IV and oral 
contrast of the chest, abdomen and pelvis will be performed.  Following baseline, subsequent 


 
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chest CT is only required if a lesion is identified in the chest or metastasis to the chest is 
suspected at any point during the study. 
In subjects who have been followed previously by MRI, those who are intolerant of CT 
contrast media, or where there is a preference for MRI, MRI is acceptable.  If MRI of the 
chest, abdomen, and pelvis is performed, CT of the chest without contrast must also be 
performed at baseline.  Following baseline, subsequent non-contrast CT of the chest is only 
required if a target lesion is identified in the chest or metastasis to the chest is suspected at 
any point during the study. 
Positron emission tomography (PET)/CT scans are generally not acceptable for study 
readings; however, if the CT portion meets criteria for an “optimized CT” as defined in the 
radiology charter, these CTs may be submitted.  The same methods of assessment and same 
techniques (eg, CT scan, spiral CT scan, or MRI) should be used throughout the study to 
characterize each identified and reported lesion.  Lossy compressed images should not be 
submitted as information is lost when image is compressed.  
Radiographic assessments (CT or MRI) will be performed according to the Schedule of 
Procedures/Assessments (Table 6 and Table 7). 
Subjects who discontinue treatment with Test Article for reason other than disease 
progression (eg, AE or intolerable toxicity) should be followed radiographically until 
documented progression or initiation of any new anticancer treatment.  Where feasible, 
follow-up scans should be obtained at the same schedule as Maintenance Treatment (ie, 
every 9 weeks) until disease progression is confirmed or at study completion. 
The investigators’ objective measures of disease (CT or MRI scan), graded according to the 
RECIST 1.1 criteria (Appendix 4), will be used to determine PFS, the primary efficacy 
endpoint of the study.  Subjects with measurable disease will be assigned to one of the 
categories of change in disease state, namely, “complete response (CR),” “partial response 
(PR),” “stable disease (SD),” “progressive disease (PD),” or “not evaluable (NE).”  Subjects 
with evaluable only disease will be assigned to one of the categories of change in disease 
state, namely, “complete response (CR),” “stable disease (SD),” “progressive disease (PD),” 
or “not evaluable (NE).”  The interpretation of the scan will be recorded on the eCRF. 
Secondary efficacy endpoints involving assessment dates, date of response, and date of 
disease progression will also be based on data from the investigators’ assessment of images 
using RECIST 1.1 criteria (eg, length of platinum-free interval, OR, TTR, and DR). 
All CT or MRI scans will be sent by the study sites to an independent central imaging 
laboratory for quality control purpose.  Refer to Section 9.6 for additional details.   


 
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9.5.1.2.2 
CA125 ASSESSMENT  
Assessment of CA125 levels will be used to determine eligibility and will be used for 
exploratory analysis, and will be measured at the time points specified in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).   
At Screening, CA125 levels will be analyzed by the Central Laboratory for confirmation of 
eligibility.  Samples for this analysis must be provided within 2 weeks prior to 
Randomization.   
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.3.1 
PHARMACOKINETIC ASSESSMENTS 
Blood samples for the assessment of serum levels of farletuzumab are to be drawn before and 
after the infusion (ie, within 1 hour after the completion of the infusion) of Test Article as 
specified in the Schedule of Procedures/Assessments (Table 6 and Table 7).  Quantities of 
blood to be drawn at each study time point are provided in Appendix 2.  See Laboratory 
Manual for a description of collection, handling, and shipping procedures for PK samples. 
Samples will be analyzed using a fluorescent immunoassay format that measures free forms 
of farletuzumab in human serum.  This assay was validated for regression model fit, 
selectivity, accuracy/precision, minimum required dilution, range of quantification, dilutional 
linearity/prozone, sample stability, and robustness.  See Appendix 1 for additional details on 
PK analyses.   
Blood samples for the assessment of serum levels of farletuzumab are to be collected via an 
indwelling catheter or via venipuncture into tubes for serum collection provided by the 
Central Laboratory.  If the samples are collected through a catheter, 1.0 mL of blood will be 
withdrawn and discarded to assure that the solution used to maintain catheter patency does 
not dilute the sample.  If a multilumen catheter is used, samples should be drawn “upstream” 
or proximal to the Test Article delivery lumen, never from the same lumen that was used for 
Test Article delivery.  If the Test Article is being administered by peripheral IV, do not 
withdraw the blood from the arm in which the Test Article is being given.  The anatomical 
sites from which the samples are drawn and through which Test Article is administered must 
be documented in the medical record. 
Logistical considerations may dictate a deviation from the protocol-specified sample 
collection time point.  In each case, the actual time of sampling and actual start/stop times of 
infusions must be documented.   
9.5.1.3.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Archived tumor tissue, blood, and urine samples will be collected from all consenting study 
subjects from both treatment groups for biomarker analyses.  The objective of these analyses 
is the potential identification of biomarkers that either predict or determine clinical response 


 
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to farletuzumab, or that may be used to understand the pharmacology of farletuzumab in a 
subject.  Samples will be collected at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  Instructions for the collection, processing, 
storage, and shipping of samples will be provided in a separate Laboratory Manual. 
An archival tumor tissue sample (formalin-fixed, paraffin embedded block) taken at the time 
of initial diagnosis of ovarian cancer will be collected during Screening in order to assess 
tumor histology and for assessment of biomarkers.  These analyses require either the original 
primary tumor block or 15-20 (4-5 micron) serial sections cut from the original primary 
tumor block.  If a minimum of 15 slides are not available, contact the CRA to discuss.   
Tissue biomarker samples from study subjects may be used to analyze deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), microRNA (miRNA), or proteins by any of a number of 
technologies including next generation sequencing, polymerase chain reaction (PCR), 
mutation analysis, immunohistochemistry, or other assays/methods. 
A urine sample will be collected at Screening, within 2 weeks of Randomization, for 
biomarker analysis.   
At Screening, within 2 weeks of Randomization, 22.0 mL of blood will be collected for 
biomarker and nucleic acid extraction and analysis (one 8.5-mL vial for DNA extraction, 
one 6.0-mL vial for plasma, one 5.0-mL vial for serum, and one 2.5-mL vial for RNA 
extraction). 
At subsequent time points throughout the study (Table 6 and Table 7), 11 mL of blood will 
be collected for biomarker assessment (one 5.0-mL vial for serum, and one 6.0-mL vial for 
plasma).  
Genomic (blood) DNA/RNA/miRNA extracted from whole blood from study subjects may 
be analyzed by any of a number of technologies including next generation sequencing, PCR, 
mutation analysis, or other assay/methods.  
Serum, urine, and plasma biomarker samples from study subjects may be analyzed using any 
of a number of technologies including genomic, proteomic, metabolomic, lipidomic, or other 
assays/methods.   
Samples (tissue, serum, plasma, urine, genomic nucleic acid) may be used for biomarker 
discovery and/or validation to identify biomarkers that may be useful to predict treatment 
response (efficacy, PD), and/or safety-related outcomes.  Samples may also be used for the 
development of potential diagnostics for farletuzumab.  The decision to perform exploratory 
biomarker analysis may be based on the clinical outcome of the study and/or the signals 
observed in other clinical studies. 


 
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9.5.1.4 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE 
grades (for both increasing and decreasing severity), and SAEs; regular monitoring of 
hematology, and blood chemistry values; periodic measurement of ECGs; performance of 
PEs; assessment of ECOG scores; and assessment of survival status, as detailed in the 
Schedule of Procedures/Assessments (Table 6 and Table 7). 
9.5.1.4.1 
ADVERSE EVENTS  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the study drug(s).   
The criteria for identifying AEs in this study are: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
 
Any new disease or exacerbation of an existing disease; however, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(ie, prior to the first administration of study drug) 
 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not. 
All AEs observed during the study will be reported on the eCRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit and for 30 days after the subject’s last dose 
of Test Article.   
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  The investigator is responsible 
for reviewing all laboratory findings in all subjects to determine if they constitute an AE.  
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.  
Any ECG abnormality that the investigator considers to be an AE should be reported as such.  
All AEs must be followed for 30 days after the subject’s last dose of Test Article, or until 
resolution, whichever comes first.  All SAEs must be followed to resolution or, if resolution 
is unlikely, to stabilization. 


 
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Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study drug(s). 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to the CTCAE v4.03 (National 
Cancer Institute, 2010).  Investigators will report CTCAE grades for all AEs. 
Assessing Relationship to Study Drug(s) 
Items to be considered when assessing the relationship of an AE to the study drug(s) are: 
 
Temporal relationship of the onset of the event to the initiation of the study drug 
 
The course of the event, especially the effect of discontinuation of study drug(s) or 
reintroduction of study drug(s), as applicable 
 
Whether the event is known to be associated with the study drug or with other similar 
treatments 
 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded in the eCRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
9.5.1.4.2 
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 


 
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 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
Other events of interest include pregnancy or exposure to study drug through breastfeeding; 
AEs associated with study drug overdose, misuse, abuse, or medication error.  These events 
of interest are to be captured using the SAE procedures but are to be considered as SAEs 
only if they meet one of the above criteria.  All AEs associated with events of interest are to 
be reported in the eCRF whether or not they meet the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
 
Hospitalizations due to disease progression  
 
Planned hospitalizations required by the protocol 
 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
Death due to disease progression is a study endpoint, and is therefore not considered an SAE 
in this study and does not need to be reported as such, unless required by local regulations.   
9.5.1.4.3 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed for safety assessment, including hematology, 
chemistry, and pregnancy testing are summarized in Table 5.  Subjects should be in a seated 
or supine position during blood collection.  The Schedule of Procedures/Assessments    
(Table 6 and Table 7) lists the visits and time points at which blood for clinical laboratory 
tests will be collected in the study. 


 
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Table 5 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and white blood cell count with 
differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
Chemistry 
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), bilirubin (total, 
direct, and indirect), blood urea nitrogen, calcium, bicarbonate, chloride, 
cholesterol, creatinine, globulin, glucose, lactate dehydrogenase, magnesium, 
phosphorous, potassium, sodium, total protein, triglycerides, uric acid 
Pregnancy Test (hCG) 
Serum, urine (highly-sensitive) 
ALT (SGPT) = alanine aminotransferase; AST (SGOT) = aspartate aminotransferase; hCG = human chorionic 
gonadotropin; RBC = red blood cell;  
 
Clinical laboratory tests during the study will be performed by ICON Laboratories (with the 
exception of urine pregnancy tests, which will be performed locally).  Eligibility will be 
determined by the central laboratory.  All protocol-required blood samples (as noted in the 
Schedule of Procedures/Assessments [Table 6 and Table 7]) will be collected and sent to the 
central laboratory as specified in the laboratory manual.   
In addition, local laboratories may be used for treatment decisions, safety evaluation, and for 
management of chemotherapy-related toxicity, as appropriate; however, local laboratory 
results will not be collected.  All local hematology and blood chemistry samples are to be 
obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle.  
A laboratory abnormality reported by either the central laboratory or local laboratory may 
meet the criteria to qualify as an AE as described in this protocol (see Section 9.5.1.4.1 and 
the eCRF Completion Guidelines).  In these instances, the AE corresponding to the 
laboratory abnormality will be recorded on the Adverse Event eCRF. 
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.4.2), the site 
must fax or email the SAE report including the laboratory report (as regionally required) to 
the sponsor using the SAE form (see Section 9.5.4.1). 
For women of childbearing potential (refer to Section 9.3.1 for details), pregnancy testing 
will be performed prior to and throughout the study period.  At Screening, a single sample of 
blood will be taken for a serum human chorionic gonadotropin (hCG) pregnancy test, which 
will be submitted to the central laboratory for analysis.  In addition, prior to Test Article 
administration, a highly-sensitive urine pregnancy test (hCG) will be administered locally at 
the timepoints specified in the Schedule of Procedures/Assessments (Table 6 and Table 7).  
Results of these tests will be entered into the eCRF.   
Refer to Appendix 2 for specific quantities of blood to be drawn during the study.  


 
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9.5.1.4.4 
PHYSICAL EXAMINATIONS 
PEs will be performed at the time points listed in the Schedule of Procedures/Assessments 
(Table 6 and Table 7).  Refer to Section 9.5.1.1.2 for additional details. 
9.5.1.4.5 
ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained at the time points listed in the Schedule of 
Procedures/Assessments (Table 6 and Table 7).  Complete, standardized, 12-lead ECG 
recordings that permit all 12-leads to be displayed on a single page with an accompanying 
lead II rhythm strip below the customary 3 × 4 lead format are to be used.  In addition to a 
rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously.  Subjects must be in the recumbent position for a period of 5 minutes prior to 
the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1) and the eCRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF. 
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.4.2) the site must fax or 
email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1). 
9.5.1.4.6 
ECOG PERFORMANCE STATUS 
All subjects will be assessed for ECOG Performance Status (Appendix 3) at Screening and at 
the time points listed in the Schedule of Procedures/Assessments (Table 6 and  Table 7). 
9.5.1.4.7 
ADVERSE EVENTS OF INTEREST 
Immunologic symptoms associated with hypersensitivity reactions are possible with 
administration of any monoclonal antibody and should be considered AEs and recorded in 
the eCRF.   
Hypersensitivity 
The following signs and symptoms are considered hypersensitivity AEs if they occur within 
24 hours of Test Article infusion:  
 
Cytokine release syndrome 
 
Flushing 
 
Fever 
 
Rigors/chills 
 
Sweating/diaphoresis 
 
Pruritus/itching 


 
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 
Urticaria 
 
Bronchospasm/wheezing 
 
Bronchial edema 
Hypersensitivity AEs are to be graded according to CTCAE v4.03 (National Cancer Institute, 
2010).  Hypersensitivity AEs are to be recorded in the eCRF and, if serious, should also be 
reported in an expedited manner using the SAE form as well in the same manner and 
timeframe as reporting of SAEs (Section 9.5.4.1).   
All subjects will be assessed for ADA responses.  Blood samples will be collected for this 
purpose at Screening and at various time points throughout the study, as described in the 
Schedule of Procedures/Assessments (Table 6 and  Table 7). 
Hypersensitivity AEs have been seen in the Phase 1 and 2 clinical trials of farletuzumab 
during and immediately following the administration of farletuzumab.  In general, 
hypersensitivity AEs to monoclonal antibodies are immediate, typically occurring during the 
first few minutes of the first infusion.  However, up to 30% of reactions to monoclonal 
antibodies are delayed and may occur in later infusions (Lenz, 2007).   
Treatment of Hypersensitivity AEs 
If a hypersensitivity AE occurs during infusion of Test Article, the rate of infusion should be 
decreased by at least 50% and then advanced back to the highest rate that was well-tolerated.  
Otherwise, the infusion should be terminated completely in accordance with standard 
practice at the investigational site or based on the CTCAE.   
In the event of a hypersensitivity AE, the subject may be treated with an additional 650 mg 
acetaminophen orally, either alone or in combination with diphenhydramine 25-50 mg orally 
(Grade 1 reaction) or IV (Grade 2 reaction).  At any point at which the investigator deems 
necessary, other therapeutic interventions should be initiated based on the signs and 
symptoms and the severity associated with the event. 
Secondary Prophylaxis of Hypersensitivity AEs 
For subjects who have experienced hypersensitivity AEs, secondary prophylaxis is 
recommended and given at the investigator’s discretion.  Details of secondary prophylaxis 
are outlined in Section 9.4.8.1.1 and below:  
 
Subjects experiencing hypersensitivity AEs consisting of Grade 1 events can be managed 
with secondary prophylaxis for subsequent infusions.  Along with an antipyretic of 
choice (acetaminophen to a dose of 1000 mg orally has been used) and concurrent use of 
diphenhydramine, an H2 receptor antagonist can be considered, such as ranitidine 
(50 mg IV).  Secondary prophylaxis should be administered approximately 30-60 minutes 
prior to dosing with Test Article.   


 
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 
Subjects experiencing hypersensitivity AEs consisting of Grade 2 events can be managed 
with secondary prophylaxis for subsequent infusions, along with diphenhydramine 
50 mg IV, ranitidine 50 mg IV, and dexamethasone 20 mg IV.  Secondary prophylaxis 
should be administered approximately 30-60 minutes prior to dosing with Test Article.   
Prophylaxis regimens are given at the investigator’s discretion and should be recorded in the 
eCRF.  
If a Grade 3 hypersensitivity AE occurs, the subject may be continued at the discretion of the 
investigator, provided the reaction can be reduced to and maintained at Grade 2 or lower.  In 
the event that a Grade 4 hypersensitivity AE occurs, the subject will be discontinued from 
Test Article and moved to the Follow-Up Phase of the study.   
Interstitial Lung Disease 
Interstitial lung disease AEs are defined as AEs identified within the narrow-search 
Standardized Medical Dictionary for Regulatory Affairs Query (SMQ) for “interstitial lung 
disease,” including, but not limited to: 
 
Interstitial lung disease 
 
Pulmonary fibrosis 
 
Pneumonitis 
These events have been seen in clinical studies with other monoclonal antibodies; therefore, 
they will be monitored in this study and analyzed by CTCAE grade separately from other 
AEs.   
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments 
Table 6 and Table 7 present the Schedule of Procedures/Assessments for the study.  
 


 
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Table 6 
Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm  
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
IC, demography, eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor histology, disease staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Height/BSA/weighte 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
ECOG assessment 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
RECIST imaging—CT or MRIf 
X 
 
 
 
 
 
Xf 
 
Xf 
 
 
Xf 
 
X 
 
 
 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Archived tumor blockh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Chemistryi 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum CA125j 
X 
X 
 
 
 
X 
 
 
 
Xj 
 
 
 
X 
 
 
 
Pregnancy test (serum, urine)k 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Biomarker blood samplel 
X 
X 
 
 
 
X 
 
 
 
Xl 
 
 
 
X 
 
 
 
Biomarker urine samplel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum farletuzumab samplem 
 
X 
 
 
 
X 
 
 
 
Xm 
 
 
 
X 
X 
X 
 
Serum ADA samplen 
 
X 
 
 
 
X 
 
 
 
Xn 
 
 
 
X 
X 
X 
 
Premedication (required)o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Test Article administrationp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Carbo + PLD administration 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 61 of 101 
 
Table 6 
Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm  
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Survival contact, anticancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
ADA = human anti-drug antibody; AE = adverse event; BSA = body surface area; CA125 = cancer antigen 125; Carbo = carboplatin; CT =computerized tomography; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; hCG = human chorionic gonadotropin; IC = Informed Consent; IV = intravenous; 
MRI = magnetic resonance imaging; PE = physical examination; PLD = pegylated liposomal doxorubicin; Rand. = Randomization; RECIST = Response Evaluation Criteria In Solid 
Tumors. 
a: All Screening procedures are to be completed within 30 days prior to and including the date of Randomization unless otherwise specified.  Procedures for the Cycle 1 Week 1 
Visit do not need to be repeated if they were conducted within 14 days of Randomization. 
b: All visits should be scheduled to occur within ±2 days of the target visit date, unless otherwise specified.  The EOT Visit must be performed within 7 days of the last infusion of 
Test Article (farletuzumab or placebo), unless the subject’s medical management warrants otherwise.  Scans performed within 2 week of the last infusion of Test Article do not 
need to be repeated.  
c: Follow-up visits will be performed at 30 and 60 days (within ±7 days) after the date of last Test Article administration.  Thereafter, subjects will be contacted by phone monthly 
for the next 7 months and then every other month until death or the end of the study.  During these visits and calls, anticancer therapy treatments will be collected and recorded.  
Subjects who discontinue treatment for reasons other than disease progression (radiographic) will be followed radiographically until disease progression or initiation of another 
anticancer therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), where possible. 
d: Comprehensive PEs will be conducted during Screening and at the EOT Visit.  Abbreviated PEs (including follow-up of interval complaints and review of the cardiorespiratory 
system) will be conducted at Week 1 of each cycle during the Combination Treatment Phase and Week 1 of every third cycle during the Maintenance Treatment Phase 
(beginning with Maintenance Cycle 3). 
e: Height will be collected during Screening only.  Body weight will be measured during Screening, prior to Test Article administration on Week 1 of each cycle, and at the EOT 
Visit.  BSA should only be recalculated for the purpose of chemotherapy dose modification if the subject experiences a > 10% change in body weight.   
f: RECIST 1.1 will be used for this study.  CT or MRI scans may be obtained any time during the week prior to the next scheduled visit.  Scans will be performed during Screening; 
every 6 weeks during Combination Treatment Phase (eg, Cycle 2 Week 2, Cycle 3 Week 4, Cycle 5 Week 2, and Cycle 6 Week 4); every 9 weeks during the Maintenance 
Treatment Phase (Week 3 of every third cycle beginning with Maintenance Cycle 3), and at the EOT Visit.  Subjects who discontinue treatment for reasons other than disease 
progression (radiographic) will be followed radiographically until disease progression or initiation of another anticancer therapy, on the same schedule as the Maintenance 
Treatment Phase (ie, every 9 weeks), where possible.  Scans performed within 2 weeks of the last Test Article administration do not need to be repeated. 
g: 12-lead ECG will be performed during Screening and at the EOT Visit. 
 


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 62 of 101 
 
Table 6 
Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm  
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
h: At Screening, the archival tumor tissue sample (taken at the time of initial diagnosis of ovarian cancer) will be collected for central histology confirmation and exploratory 
analyses of potential biomarkers.  In the absence of the original primary tumor block, 15 to 20 unstained slides are required.  If a minimum of 15 slides are not available, contact 
the CRA to discuss.   
i: Hematology and Chemistry will be obtained during Screening, prior to Test Article infusion on Week 1 of every cycle during the Combination Treatment Phase, Week 1 of every 
third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.  Hematology and Chemistry for the Combination Treatment 
Phase Cycle 1 Week 1 visit do not need to be repeated if the Screening samples were obtained within 14 days of Cycle 1 Day 1 
j: Screening CA125 must be assessed by the central laboratory within 2 weeks prior to randomization.  On-study CA125 samples will be obtained at Week 1 of every cycle during 
the Combination Treatment Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.   
k: Only for female subjects of childbearing potential.  At Screening, a serum pregnancy test (hCG) is to be conducted, which will be analyzed by the central laboratory from the 
same vial of blood drawn for the chemistry panel.  Prior to Test Article administration at the following timepoints, a highly-sensitive urine pregnancy test (hCG) will be 
conducted locally at the site:  Cycle 1 Day 1, Week 1 of all Combination and Maintenance Treatment cycles, the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
l: Blood samples for biomarker analysis will be collected during Screening within 2 weeks prior to Randomization, at Week 1 of every cycle during the Combination Treatment 
Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT visit.  Urine samples will be collected at 
the Screening visit only, within 2 weeks prior to Randomization.  Details for sample collection and handling are provided in the laboratory manual. 
m: Serum farletuzumab samples are to be drawn pre- and postinfusion (within 1 hour after the completion of the infusion) of Test Article at Week 1 of each cycle during the 
Combination Treatment Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- 
and 60-Day Follow-up Phase visits.   
n: Serum ADA samples are to be drawn prior to infusion of Test Article at Week 1 of each cycle during the Combination Treatment Phase, at Week 1 of every sixth cycle during the 
Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
o: All subjects must be premedicated within 4 hours prior to each infusion of Test Article with acetaminophen 650 mg, or the local equivalent.  Premedications for carboplatin 
should be given according to country-specific labeling.  All premedications must be recorded on the Premedications eCRF page. 
p: The first dose of Test Article should be administered as close to the day of Randomization as possible but no more than 7 days following randomization; otherwise, medical 
monitor approval is required.  Test Article will be administered IV once weekly prior to chemotherapy during the Combination Treatment Phase and once weekly during the 
Maintenance Treatment Phase.  All subjects will receive a loading dose for the first 2 weeks (Cycle 1, Weeks 1 and 2) of farletuzumab (or placebo) 10 mg/kg, followed by 
5 mg/kg weekly until disease progression or discontinuation of Test Article.  
q: Concomitant medications are any new, discontinued, or ongoing medications (excluding protocol-required premedications) that have been taken within 30 days prior to the first 
dose of Test Article until 30 days after the last dose of Test Article (first follow-up visit).   


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 63 of 101 
 
Table 6 
Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm  
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
r: All AEs occurring after the subject signs the IC form and continuing through 30 days after the last infusion of Test Article should be recorded.  Serious AEs that are ongoing at 
the time of discontinuation of Test Article will be followed until resolution (or until stable if resolution is not expected). 
 


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 64 of 101 
 
Table 7 
Schedule of Procedures/Assessments for Paclitaxel/Carboplatin Chemotherapy Arm  
Evaluations 
Screen. 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
 
 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1-Xb 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-up 
Phone 
Call 
Day −30 
to Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day
15 
Day  
1 
Day  
8 
Day 
15 
IC, demography, eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor histology, disease staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Height/BSA/weighte 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
ECOG assessment 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
RECIST imaging—CT or MRIf 
X 
 
 
 
 
 
Xf 
 
 
Xf 
 
X 
 
 
 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Archived tumor blockh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Chemistryi 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Serum CA125j 
X 
X 
 
 
Xj 
 
 
Xj 
 
 
 
X 
 
 
 
Pregnancy test (serum, urine)k 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
Biomarker blood samplel 
X 
X 
 
 
X 
 
 
Xl 
 
 
 
X 
 
 
 
Biomarker urine samplel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum farletuzumab samplem 
 
X 
 
 
X 
 
 
Xm 
 
 
 
X 
X 
X 
 
Serum ADA samplen 
 
X 
 
 
X 
 
 
Xn 
 
 
 
X 
X 
X 
 
Premedication (required)o  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Test Article administrationp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Carbo + Pacli administration 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival contact, anticancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 65 of 101 
 
Table 7 
Schedule of Procedures/Assessments for Paclitaxel/Carboplatin Chemotherapy Arm  
Evaluations 
Screen. 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
 
 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1-Xb 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-up 
Phone 
Call 
Day −30 
to Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day
15 
Day  
1 
Day  
8 
Day 
15 
ADA = human anti-drug antibody; AE = adverse event; BSA = body surface area; CA125 = cancer antigen 125; Carbo = carboplatin; CT =computerized tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; hCG = human chorionic gonadotropin; IC = informed consent; 
IV = intravenous; MRI = magnetic resonance imaging; Pacli = paclitaxel; PE = physical examination; Rand. = Randomization; RECIST = Response Evaluation Criteria In Solid 
Tumors. 
a: All Screening procedures are to be completed within 30 days prior to and including Randomization unless otherwise specified.  Procedures for the Cycle 1 Week 1 Visit do not 
need to be repeated if they were conducted within 14 days of Randomization.   
b: All visits should be scheduled to occur within ±2 days of the target visit date, unless otherwise specified.  The EOT Visit must be performed within 7 days of the last infusion of 
Test Article (farletuzumab or placebo), unless the subject’s medical management warrants otherwise.  Scans performed within 2 week of the last infusion of Test Article do not 
need to be repeated. 
c: Follow-up visits will be performed at 30 and 60 days (within ±7 days) after the date of last Test Article administration.  Thereafter, subjects will be contacted by phone monthly 
for the next 7 months and then every other month until death or the end of the study.  During these visits and calls, anticancer therapy treatments will be collected and recorded.  
Subjects who discontinue treatment for reasons other than disease progression (radiographic) will be followed radiographically until disease progression or initiation of another 
anticancer therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), where possible. 
d: Comprehensive PEs will be conducted during Screening and at the EOT Visit.  Abbreviated PEs (including follow-up of interval complaints and review of the cardiorespiratory 
system) will be conducted at Week 1 of each cycle during the Combination Treatment Phase and at Week 1 of every third cycle during the Maintenance Treatment Phase 
(beginning with Maintenance Cycle 3). 
e: Height will be collected during Screening only.  Body weight will be measured during Screening, prior to Test Article administration on Week 1 of each cycle, and at the EOT 
Visit.  BSA should only be recalculated for the purpose of chemotherapy dose modification if the subject experiences a > 10% change in body weight.   
f: RECIST 1.1 will be used for this study.  CT or MRI scans may be obtained any time during the week prior to the next scheduled visit.  Scans will be performed during 
Screening; every 6 weeks during the Combination Treatment Phase (Week 3 of every second cycle); and then every 9 weeks (Week 3 of every third cycle beginning with 
Maintenance Cycle 3 ) thereafter during the Maintenance Treatment Phase, and at the EOT Visit.  Subjects who discontinue treatment for reasons other than disease progression 
(radiographic) will be followed radiographically until disease progression or initiation of another anticancer therapy, on the same schedule as the Maintenance Treatment Phase 
(ie, every 9 weeks), where possible.  Scans performed within 2 weeks of the last Test Article administration do not need to be repeated. 
g: 12-lead ECG will be performed during Screening and at the EOT Visit. 
h: At Screening, the archival tumor tissue sample (taken at the time of initial diagnosis of ovarian cancer) will be collected for central histology confirmation and exploratory 
analyses of potential biomarkers.  In the absence of the original primary tumor block, 15 to 20 unstained slides are required.  If a minimum of 15 slides are not available, contact 
the CRA to discuss.   
i: Hematology and Chemistry will be obtained during Screening, prior to Test Article infusion at Week 1 of every cycle during the Combination Treatment Phase, Week 1 of 
every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.  Hematology and Chemistry for the Combination 


 
Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 66 of 101 
 
Table 7 
Schedule of Procedures/Assessments for Paclitaxel/Carboplatin Chemotherapy Arm  
Evaluations 
Screen. 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
 
 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1-Xb 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-up 
Phone 
Call 
Day −30 
to Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day
15 
Day  
1 
Day  
8 
Day 
15 
Treatment Phase Cycle 1 Week 1 visit do not need to be repeated if the Screening samples were obtained within 14 days of Cycle 1 Day 1. 
j: Screening CA125 must be assessed by the central laboratory within 2 weeks prior to randomization.  On-study CA125 samples will be obtained at Week 1 of every cycle during 
the Combination Treatment Phase; at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.   
k: Only for female subjects of childbearing potential.  At Screening, a serum pregnancy test (hCG) is to be conducted, which will be analyzed by the central laboratory from the 
same vial of blood drawn for the chemistry panel.  Prior to Test Article administration at the following timepoints, a highly-sensitive urine pregnancy test (hCG) will be 
conducted locally at the site:  Cycle 1 Day 1, Week 1 of all Combination and Maintenance Treatment cycles, the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
l: Blood samples for biomarker analysis will be collected during Screening within 2 weeks prior to randomization, at Week 1 of every cycle during the Combination Treatment 
Phase; at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3);  and at the EOT visit.  Urine samples will be collected at 
the Screening visit only, within 2 weeks prior to Randomization.  Details for sample collection and handling are provided in the laboratory manual. 
m: Serum farletuzumab samples are to be drawn pre- and postinfusion (within 1 hour after the completion of the infusion) of Test Article on Week 1 of each cycle during the 
Combination Treatment Phase, on Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- 
and 60-Day Follow-up Phase visits.   
n: Serum ADA samples are to be drawn prior to infusion of Test Article on Week 1 of each cycle during the Combination Treatment Phase, on Week 1 of every sixth cycle during 
the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
o: All subjects must be premedicated within 4 hours prior to each infusion of Test Article with acetaminophen 650 mg, or the local equivalent.  Premedications for carboplatin and 
paclitaxel should be given according to country-specific labeling.  All premedications must be recorded on the Premedications eCRF page. 
p: The first dose of Test Article should be administered as close to the day of Randomization as possible but no more than 7 days following randomization; otherwise, medical 
monitor approval is required.  Test Article will be administered IV once weekly prior to chemotherapy during the Combination Treatment Phase and once weekly during the 
Maintenance Treatment Phase.  All subjects will receive a loading dose for the first 2 weeks (Cycle 1, Weeks 1 and 2) of farletuzumab (or placebo) 10 mg/kg, followed by 
5 mg/kg weekly until disease progression or discontinuation of Test Article.  
q: Concomitant medications are any new, discontinued, or ongoing medications (excluding protocol-required premedications) that have been taken within 30 days prior to the first 
dose of Test Article until 30 days after the last dose of Test Article (first follow-up visit). 
r: All AEs occurring after the subject signs the IC form and continuing through 30 days after the last infusion of Test Article should be recorded.  Serious AEs that are ongoing at 
the time of discontinuation of Test Article will be followed until resolution (or until stable if resolution is not expected). 


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Clinical Study Protocol 
incorporating Amendment 03  
MORAb-003-011 / ENGOT-ov27 / BGOG-ov18 
 
 
Eisai 
FINAL:  06 Nov 2018 
Confidential 
Page 68 of 101 
 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the CRO 
monitor to be filed in the sponsor’s trial master file (TMF). 
9.5.4.2 
Reporting of Pregnancy and Exposure to Test Article Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the EOT Visit of 
the study or within 6 months following Test Article (farletuzumab or placebo) 
discontinuation, whichever is longer, or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of the last Test Article administration, must be 
reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1 Reporting of Serious Adverse Events). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 


 
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9.5.4.3 
Reporting of Other Events of Interest 
9.5.4.3.1 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of Test Article in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of Test Article not in accordance 
with the protocol 
Abuse 
Sporadic or persistent intentional excessive use of Test Article 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate Test 
Article use or subject harm while Test Article is in the control of site 
personnel or the subject. 
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Section 9.5.4.1 
Reporting of Serious Adverse Events, even if the AEs do not meet serious criteria.  Abuse is 
always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as non-serious on the SAE form and the 
Adverse Event eCRF. 
9.5.4.3.2 
REPORTING OF STUDY-SPECIFIC EVENTS 
Hypersensitivity AEs and Interstitial lung disease (ILD) AEs will be monitored in this study 
and analyzed by CTCAE grade separately from other AEs.  Separate summaries and listings 
of hypersensitivity and ILD AEs will be presented.  Hypersensitivity AEs and ILD AEs 
meeting serious criteria should be reported in the same manner and timeframe as any SAE. 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above. 


 
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9.5.4.5 
Breaking the Blind 
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the Test Article given (farletuzumab or placebo), the investigator may break 
the randomization code for an individual subject.  In all such cases, the AE necessitating the 
emergency blind break will be handled as an SAE in accordance with the procedures 
indicated above.  Any broken code will be clearly justified and documented.  The medical 
monitor must be notified immediately of the blind break.  Refer to Section 9.4.7 for 
additional details regarding blinding of treatment assignments. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
SUSARs will be reported, as required, to the competent authorities of all involved European 
member states. 
9.5.5 
Completion/Discontinuation of Subjects from Study (EOS) 
Once a subject discontinues Test Article for any reason, the EOT procedures should be 
completed and documented in the eCRF and the EOT form should be completed.   
Subjects who choose to discontinue Test Article administration but agree to continue 
participation in the study should still continue to be followed for OS.  In addition, subjects 
who discontinue Test Article prior to having documented disease progression by RECIST 1.1 
(Appendix 4) should continue to be followed radiographically to progression.   
A subject may elect to discontinue participation in the study at any time for any reason.  All 
subjects who discontinue the study are to complete the study’s EOT procedures indicated in 
the Schedule of Procedures/Assessments (Table 6 and Table 7).  In addition, the EOT and 
EOS eCRF forms should be completed.  The investigator will promptly explain to the subject 
involved that all study procedures will be discontinued for that subject and provide 
appropriate medical treatment and other necessary measures for the subject.  A subject who 
has ceased to return for visits will be followed up by mail, phone, or other means to gather 
information such as the reason for failure to return, the status of treatment compliance, the 
presence or absence of AEs, and clinical courses of signs and symptoms.   
Following discontinuation of survival follow-up, disposition information will be collected on 
the EOS eCRF. 
A subject removed from the study for any reason may not be replaced. 


 
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9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether she has received medical care by another physician since the last visit or is planning 
to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
9.5.8 
Data Monitoring Committee  
A DMC will be established for this protocol to enhance safety monitoring by providing 
unblinded, independent oversight of the safety of study participants.  The unblinded DMC 
will comprise 3 clinicians, all independent from Eisai and investigative sites and selected as 
to avoid conflict of interest.  Eisai representatives from the study team will be appointed to 
attend the DMC open portion of meetings but will be independent of the recommendations 
derived from any closed portions of meetings. 
The primary objectives of this DMC are to provide independent safety monitoring of 
unblinded data comparing adverse event rates between treatment arms, and to provide 
recommendations at each planned analysis.  The DMC will review summary tabulations and 
comparative statistics to determine whether there appears to be an excess of any important 
AEs in either of the study treatment arms. 
The safety evaluation will focus on AEs, tolerability, and clinical laboratory measurements.  
All subjects included in the Safety Population will be evaluated by treatment.  All treatment 
emergent AEs will be summarized (by incidence) for each treatment arm and listed by the 
System Organ Class (SOC), preferred term, toxicity/severity grade, and causal relationship to 
Test Article.  In addition, separate summaries of SAEs, deaths on study, Grade 3 or 4 AEs, 
and drug hypersensitivity and ILD AEs will be presented for each treatment arm. 
In addition, the DMC may review any individual event thought to be of major significance as 
requested by the DMC; such events would generally include deaths or other serious 
outcomes for which a causal connection with the intervention is plausible. 
Interim reports will be prepared for review and analysis by a statistician independent of Eisai 
and investigators to protect against inadvertent or inappropriate access.  The independent 
statistician will retain the randomization code for unblinding data as outlined in the charter or 
as requested by the DMC.  Unblinded interim data will not be accessible by anyone other 
than DMC members or the independent statistician(s) performing these analyses and 
presenting them to the DMC. 


 
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The first DMC review of safety data will occur when the 15th subject completes Cycle 1 of 
the Combination Treatment Phase to assure that the tolerability of the modified farletuzumab 
dosing and chemotherapy combinations are acceptable.  This will be followed by ongoing 
DMC safety reviews, to be conducted at a minimum frequency of every 6 months.  The 
frequency of planned data reviews may also be increased as needed, based on accrual rates or 
emerging safety information as outlined in the DMC charter, and ad hoc safety reviews may 
also be convened when warranted to enhance safety oversight. 
A DMC charter will be written to establish well-defined standard operating procedures 
including meeting proceedings and structure, data assessments, documentation and 
recordkeeping, process for DMC recommendations, and regulatory reporting as applicable.  
The charter will be written with procedures to ensure the minimization of bias, such as 
maintaining confidentiality of any interim data. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines.   
Before any subjects can be enrolled at an investigational site and prior to the conduct of any 
protocol-specific procedures, formal training of investigational site personnel will be 
conducted.  The investigator and all relevant investigational site staff are to be trained on 
aspects of the trial for which they are responsible.  Site personnel may be trained at a formal 
initiation visit, at an Investigator’s Meeting, or by another means, as necessary.   
Imaging-Related Data 
Investigator-assessed PFS is the primary efficacy endpoint for this study.  However, all CT or 
MRI scans will be collected and stored in an independent central imaging laboratory for 
quality control purposes.  The central imaging laboratory assessment of the study images will 
address the following objectives:   
 
Review of baseline CT/MRI images to confirm the eligibility status of each subject in 
terms of evaluable disease based on the protocol inclusion criteria 
 
Review of the images to monitor the investigator assessment of disease progression based 
on RECIST 1.1 
Details on the collection and assessment of the study images and communication between the 
central imaging laboratory and the study sites will be included in the imaging manual. 


 
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eCRF-Related Data 
Onsite verification of the eCRFs for completeness and clarity, crosschecking with source 
documents, and clarification of administrative matters will be performed on a regular basis.  
Where appropriate, remote verification of source information will also be performed.  The 
investigational site will be monitored immediately following enrollment of the first subject at 
the site (ie, within approximately 2 weeks or the earliest time point feasible) to verify that 
inclusion/exclusion criteria have been fulfilled.  Subsequent monitoring visits will occur at 
regular intervals while subjects are actively enrolled into the clinical trial.  Through frequent 
communications with the investigational site, the CRA will ensure that the investigation is 
conducted according to protocol design and all applicable regulatory requirements.  
Additional details on the monitoring of this clinical trial are provided in Section 11.3. 
Additionally, ongoing data review of eCRF data will be performed by Data Management.  
External validation checks will be applied to assess data quality for completeness, 
consistency and conformance with the requirements of the protocol.  Data review findings 
that impact eligibility will be reviewed by the Study Team and findings will be documented 
in the sponsor’s TMF. 
Site audits will be made periodically by the sponsor’s or the CRO’s qualified compliance 
auditing team, which is an independent function from the study team responsible for conduct 
of the study.  During the course of the clinical trial, investigational sites, the clinical trial 
database, and all associated clinical trial documentation may be subject to quality assurance 
audits by the sponsor, or their appointed representatives, on a planned or an as-needed basis.  
In addition, representatives of associated regulatory bodies may conduct inspections at their 
discretion.  The investigator is responsible for assuring direct access to all study-related 
materials for the purpose of these activities.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the electronic CRFs (eCRFs) and entered 
into a validated data management system that is compliant with all regulatory requirements.  
As defined by ICH guidelines, the eCRF is a printed, optical, or electronic document 
designed to record all of the protocol-required information to be reported to the sponsor on 
each study subject. 
Data collection on the eCRF must follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed eCRF to attest to its accuracy, authenticity, and 
completeness. 
Completed eCRFs are the sole property of Eisai and should not be made available in any 
form to third parties without written permission fromEisai, except for authorized 
representatives Eisai or appropriate regulatory authorities. 


 
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The following apply to eCRFs: 
 
The sponsor will supply the eCRFs for data collection 
 
All eCRFs are to be completed by authorized study personnel and reviewed and signed 
by the investigator(s) 
 
Each investigator is responsible for ensuring that all discontinued orders or changes in the 
study or other medications entered on the subject’s eCRF correspond to the entries on the 
subject’s medical records 
 
eCRFs should be completed within 10 business days of the subject visit completion 
 
eCRFs must accurately reflect data contained in subject’s records (eg, source documents) 
At the beginning of the study, an investigator’s study file will be established at the study 
center.  The investigator/institution is responsible for maintaining the study documents as 
specified in the guideline for ICH GCP and US 21 CFR Part 312 and as required by the 
applicable regulatory requirement(s).  The investigator/institution must take measures to 
prevent accidental or premature destruction of these documents.  
The following guidelines, instructions, and certifications are regarded as relevant 
supplements and will be provided for the investigator's study file at each center: 
 
Global Investigator’s Brochure 
 
Instructions for completion of the eCRF 
 
Sample shipment details 
 
Pharmacy Manual 
 
Laboratory Manual 
 
Imaging Manual 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  
Data, both eCRF and external (eg, Central laboratory data), will be entered into a clinical 
system. 
This clinical trial will utilize an electronic data capture system for the management of clinical 
data.  The data will be collected in electronic form (ie, via an eCRF) to allow for data entry at 
the investigational site from source documentation directly into the electronic database.  
Source documentation will be collected in accordance with ICH GCP, US 21 CFR Part 312, 
and the site’s standard procedures. 
The eCRF and eCRF Completion Guidelines will be supplied by the sponsor or its designee.  
Access to the electronic system will be restricted, and only authorized users will be able to 
access the system via individualized, password-protected accounts.  Authorized site 
personnel will enter the information required by the protocol onto the eCRFs in accordance 


 
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with the eCRF Completion Guidelines.  All changes to data in the database will be tracked 
and time stamped automatically, including updates to data entries and resolution of data 
queries generated by the CRA or data reviewer.  Each investigator must review the subject 
data and approve the eCRFs by providing electronic signature.  
Training will be provided to all system users based on their individual access role and use 
requirements prior to granting access and ongoing throughout the course of the clinical trial 
as needed.  Documentation of training will be kept in the investigational site regulatory file 
and the sponsor’s TMF. 
A comprehensive set of data management documents that describe database set-up, testing, 
data review, and external data handling procedures will be prepared and filed in the sponsor’s 
TMF.  The standard operating procedures, internal/external security safeguards, system and 
change controls, and training procedures utilized to manage the trial will be outlined.  A 
cumulative record will also be kept of the user access privileges for all authorized users 
across the clinical trial.  
The system and procedures for electronic database set-up, entry, review, access, security, and 
auditing are designed in specific compliance with 21 CFR Part 11 and the FDA’s Part 11 
Guidance for Industry supplement “Computerized Systems Used in Clinical Investigations” 
(US Department of Health and Human Services, FDA, 2007).  Any additional electronic 
systems that may be used by vendors (eg, PK) must comply with the same regulatory 
standards.  Clinical sites (eg, electronic medical records used as source documents) must 
comply with local standards. 
9.7 
Statistical Methods 
9.7.1 
Statistical and Analytical Plans 
A detailed statistical analysis plan (SAP) will be prepared as a separate document.  The SAP 
includes a more technical and detailed description (including templates for tables, listings, 
and figures) of the planned statistical summaries.  The SAP will supersede the study protocol 
for any differences between the two documents in the plans for data analysis.  Details on 
censoring rules and handling rules for missing values will be specified in the SAP, as well as 
an outline of potential sensitivity analyses with regard to missing values.  The SAP will be 
finalized and approved before database lock and treatment unblinding.   
9.7.1.1 
Study Endpoints 
9.7.1.1.1 
PRIMARY ENDPOINT 
The primary efficacy endpoint for this study is PFS based on the investigators’ radiographic 
assessments utilizing RECIST 1.1 criteria (Appendix 4).  PFS is defined as the time (in 
months) from the date of randomization to the date of the first observation of progression 
(RECIST 1.1), or date of death, whatever the cause.  If progression or death is not observed 
for a subject, the PFS time will be censored at the date of last tumor assessment without 


 
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evidence of progression prior to the date of initiation of further anticancer treatment or the 
cut-off date, whichever is earliest.  Detailed censoring rules will be outlined in the SAP. 
9.7.1.1.2 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints for the study are as follows: 
OS:  Defined as the time from the date of randomization to the date of death, due to all 
causes.  If death is not observed for a subject, the OS time will be censored at the last date 
known to be alive or the cut-off date, whichever is earliest.   
Length of First vs Second Platinum-Free Interval:  Length of first platinum-free interval 
is defined as the period of time (in months) from the date of completion of previous platinum 
based chemotherapy until date of first relapse (ie, first observation of progression), as 
recorded on the eCRF.  The date of first relapse is the progression date based on a 
radiographic assessment.  Similarly, length of second platinum-free interval is defined as the 
period of time (in months) from the date of completion of platinum based chemotherapy (last 
dosing date) during the study until the date of progression based on the investigator’s 
radiographic assessment (RECIST 1.1 [Appendix 4]). 
Tumor Response (OR, TTR, DR per RECIST 1.1):  OR is defined as either a CR or a PR 
using RECIST 1.1 criteria (Appendix 4).  Tumor assessments performed up to the initiation 
of further anticancer treatment will be considered.  TTR is defined as the time (in months) 
from the date of randomization to the date of first observation of response (PR or CR).  DR is 
defined as the time (in months) from the date of first observation of response (PR or CR) to 
the date of the first observation of progression based on the investigator’s radiographic 
assessment (RECIST 1.1), or date of death, whatever the cause. 
9.7.1.1.3 
EXPLORATORY ENDPOINTS 
The exploratory endpoints for the study are:  a) changes in CA125 from baseline; and b) to 
identify a potential predictive biomarker or elucidation of correlation between key 
biomarkers and potential farletuzumab PK or clinical benefit. 
9.7.1.2 
Definitions of Analysis Sets 
The Intent-to-Treat Population (ITT) (also called the Full Analysis Set) is defined as all 
randomized subjects according to the treatment assigned by IRT system.  This is the primary 
analysis population for all efficacy endpoints. 
The Safety Analysis Set (SAS) is defined as all randomized subjects who received at least 
1 dose of Test Article and who had at least 1 safety assessment following the first dose of 
Test Article, analyzed by the treatment received.  All safety endpoints will be analyzed using 
this set of subjects. 


 
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The Evaluable Population is defined as all randomized subjects who received at least 1 dose 
of Test Article and who had a baseline and at least 1 on-treatment assessment performed.  
They will be used to evaluate tumor response, farletuzumab serum drug levels, ADA, and 
other biomarker defined populations. 
9.7.1.3 
Subject Disposition 
The number of subjects in each analysis population and the reasons for exclusion, along with 
any randomization errors will be summarized by treatment group.  In addition, subjects that 
discontinue study treatment or study follow-up will also be summarized by treatment group, 
along with reasons for discontinuation of study treatment and study follow-up. 
9.7.1.4 
Demographic and Other Baseline Characteristics 
Subject demographics and characteristics at baseline will be summarized by treatment group 
in frequency tables or with summary statistics for continuous variables in the ITT population.  
Unless specified otherwise, the baseline value will be taken as the last value prior to the first 
study drug administration (or closest to date of enrollment for subjects not treated).  
Laboratory values will be graded, when possible, using CTCAE criteria. 
The stratification factor profiles will be evaluated among the treatment groups, as well as 
other potential imbalances in subject characteristics. 
Continuous demographic and baseline variables include, but are not limited to:  age, weight, 
BSA, CA125, and length of first platinum-free interval, etc.  Categorical variables include, 
but are not limited to:  race, ethnicity, reproductive status, ovarian cancer primary site, 
original disease stage, ECOG status, and ascites, etc.   
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (March 2014 release, or 
later).  The number (percentage) of subjects who took prior and concomitant medications will 
be summarized on the SAS population by treatment group, Anatomical Therapeutic 
Chemical (ATC4) class, and WHO DD preferred term.  Prior medications will be defined as 
medications that stopped before the first dose of Test Article.  Concomitant medications will 
be defined as medications that (1) started before the first dose of Test Article and were 
continuing at the time of the first dose of Test Article, or (2) started on or after the date of the 
first dose of Test Article up to 30 days after the subject’s last dose.  All medications will be 
presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
9.7.1.6.1 
PRIMARY EFFICACY ANALYSIS 
PFS is defined in Section 9.7.1.1.1.  The cut-off date for PFS will be based on one of the 
following milestones:  a) at least a total number of 143 PFS events, or b) a minimum of 


 
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6 months PFS follow-up from last subject enrolled, whichever occurs later.  The cut-off date 
for PFS will be used for all secondary efficacy variables, as well as survival data supporting 
the interim survival analysis. 
The stratified log rank test will be utilized to compare PFS between farletuzumab and 
placebo at the 1-sided 10% level of significance.  Both one-sided and two-sided P values of 
the stratified log rank test will be calculated.  The stratification factors are:  (1) chemotherapy 
(carboplatin plus paclitaxel vs. carboplatin plus PLD), and (2) length of platinum-free 
interval following first line therapy (6-12 months vs. >12-36 months).  The HR will be 
estimated based on Cox’s proportional hazards model stratified by the same two factors.  PFS 
will be summarized using Kaplan-Meier curves and will be further characterized in terms of 
the median and PFS probabilities at 6, 12, 18, and 24 months.  Sensitivity analysis will be 
performed using the unstratified log-rank test.  Multivariate Cox’s proportional hazards 
model will be utilized to evaluate the treatment effect modified by prognostic factors, which 
will be specified in the SAP.  Additional sensitivity analysis could be specified in the SAP.  
9.7.1.6.2 
SECONDARY EFFICACY ANALYSES 
OS is defined in Section 9.7.1.1.2.  An additional cut-off date for final OS analysis will be 
determined based on the time when there are  at least a total number of 124 OS events.  OS 
will be analyzed using methods similar to the PFS analyses. 
DR will be analyzed using the methods described in Section 9.7.1.6.1 except for the 
multivariate and additional sensitivity analyses.  Time to tumor response will be 
characterized with descriptive statistics.  Both time-to-tumor response and DR are analyzed 
on responders. 
The proportion of subjects in the ITT population who experienced a platinum-free interval 
during the study that is longer than their first platinum-free interval will be summarized 
within each treatment group, stratified by length of first platinum-free interval (6-12 months, 
>12-36 months).  Treatment estimates and two-sided 95% CIs will be presented. 
For OR, the RR is defined in Section 9.7.1.1.2, and will be compared between farletuzumab 
and placebo using the Cochran-Mantel-Haenszel (CMH) test stratified by the same factors 
used in the primary PFS analysis.  The CMH analysis will be conducted in the ITT (primary) 
and Tumor Response Evaluable (secondary) populations.  Treatment estimates and 
differences in proportions will be presented with corresponding two-sided 95% CIs. 
9.7.1.6.3 
EXPLORATORY EFFICACY ANALYSES 
Serum CA125 change pattern during the study will be explored to assess if there is treatment 
effect on CA125 in this predefined population with baseline serum CA125 ≤ 3 x ULN 
(105 U/mL).  
Exploratory analyses for  efficacy endpoints including PFS, OS, OR, and DR will also be 
conducted in each of the two chemotherapy strata (paclitaxel, PLD).  


 
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9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 
PHARMACOKINETIC ANALYSES 
Descriptive statistics (n, median, minimum [min], maximum [max], etc.) will be used to 
summarize farletuzumab serum level data at each planned relative time point in the 
farletuzumab serum level evaluable population.  Below limit of quantitation (BLQ) values 
will be set to zero prior to calculations of descriptive statistics.  If the mean (or median) 
results in a BLQ value, it will be reported as such.  The Safety Analysis Set will be used for 
analysis on individual serum concentrations. 
Farletuzumab serum level data will be analyzed using a population PK approach to estimate 
population PK parameters.  Exposure-response relationships between farletuzumab exposure 
and key efficacy variables, including PFS and OS, will be analyzed via a population 
PK/Pharmacodynamic analyses.  Details of the planned population PK and 
PK/Pharmacodynamic analyses will be outlined in a separate analysis plan. 
9.7.1.7.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Correlation analysis will be conducted to evaluate the relationship between serum and tissue 
CA125 levels, as well as the relationship between serum and tissue folate receptor alpha 
levels. 
Exploratory analyses of molecular markers (DNA, RNA, miRNA, tumor gene/protein 
expression and/or serum/plasma proteins) will be performed to determine if a correlation can 
be established between the presence or change in level of a marker and the response to 
therapy.  They may be performed and reported separately.  Details of these analyses may be 
described in a separate analysis plan. 
9.7.1.8 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, and maximum for continuous variables; 
n [%] for categorical variables).  Safety variables include treatment-emergent adverse events 
(TEAEs), treatment-related adverse events (TRAEs), clinical laboratory parameters, 
tolerability (treatment discontinuations, treatment delays, and dose reductions), 12-lead ECG 
results, ECOG performance status, and ADA.  Study Day 1 for all safety analyses will be 
defined as the date of the first dose of Test Article. 
All subjects included in the SAS population will be evaluated by treatment group in the 
safety analysis.  In addition, analyses will be provided for the Combination Treatment and 
single-agent Maintenance Treatment safety sub-populations.  All these analyses will also be 
repeated for each chemotherapy (paclitaxel vs. PLD). 


 
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9.7.1.8.1 
EXTENT OF EXPOSURE 
The study drug administration profile will be summarized for each treatment group with 
respect to the number of infusions/cycles taken, the dose intensity, dose modifications, dose 
omissions, and reasons for deviation from the planned regimen. 
Extent of exposure parameters will be summarized by treatment group in the SAS population 
and in the combination therapy and single-agent maintenance therapy sub-populations using 
descriptive statistics.  Summaries for the carboplatin plus paclitaxel or carboplatin plus PLD 
regimen in each treatment group will include duration of exposure, number of cycles 
received, number of dose reductions, number of dose delays.  A summary of AEs leading to 
dose delay and/or reduction will also be provided.  Additionally, cumulative dose, dose 
intensity, and relative dose intensity (actual dose intensity divided by the planned dose 
intensity) will also be summarized by treatment group.  Summaries for the farletuzumab 
treatment will include duration of exposure, number of infusions received, and number of 
dose delays.  A summary of AEs leading to dose delay will also be provided.  Additionally, 
cumulative dose (mg/kg), dose intensity (mg/kg/week) and relative dose intensity (actual 
dose intensity divided by the planned dose intensity) will also be summarized by treatment 
group. 
9.7.1.8.2 
ADVERSE EVENTS 
AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA) 
(version 17.0 or higher) terminology and the severity of the toxicities will be graded 
according to the CTCAE.  
The focus of the analyses will be on TEAEs and TRAEs.  A TEAE is defined as an AE that 
developed or worsened in severity during the on-treatment period (from the first dose of Test 
Article to 30 days after the last dose of Test Article).  A TRAE is defined as a TEAE that was 
classified by the investigator as related to treatment with Test Article.  All TEAEs and 
TRAEs will be summarized (by incidence) and listed by the System Organ Class (SOC), 
preferred term, toxicity/severity grade, and causal relationship to study drugs (only TEAEs).  
In addition, separate summaries of SAEs and Treatment-related SAEs, TEAEs and TRAEs 
leading to death on study, TEAEs and TRAEs leading to study drug discontinuation, Grade 3 
and 4 AEs, hypersensitivity AEs, and ILD AEs, as well as separate listings, will be presented.  
Drug Hypersensitivity Adverse Events (DHAEs) are defined as the subset of 
programmatically-identified hypersensitivity AEs noted in Section 9.5.1.4.7 that also have 
serologic evidence of an immunologic response to the Test Article (ie, positive ADA which 
is defined as a treatment induced or treatment-boosted ADA).  The determination of DHAE 
status for each of the programmatically-identified AEs described in Section 9.5.1.4.7 is 
dependent upon serum ADA sample results obtained on or subsequent to the onset date of the 
AE.  There could be multiple subsequent ADA samples.  If the serum ADA results are 
positive for at least 1 of these samples, the AE will be considered a DHAE.  Any event 
captured within the predetermined MedDRA codes for hypersensitivity AEs and having a 


 
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positive ADA titer on that day or subsequent to the occurrence of the hypersensitivity AE 
will be considered a DHAE.   
9.7.1.8.3 
LABORATORY VALUES 
Hematology and chemistry laboratory parameters will be graded according to the CTCAE 
criteria where applicable.  For each parameter based on the worst grade observed by the 
subject during the on-treatment period, the number and percentage of subjects with any 
abnormality (ie, Grade 1 or higher) and with Grade 3 or 4 will be tabulated by treatment 
group.  Shift tables (comparing worst on-study grade vs. baseline) may also be used to 
summarize selected parameters of interest.  When the CTCAE scale is not applicable for a 
parameter, analyses will be performed based on out-of-normal laboratory range values. 
9.7.1.8.4 
CARDIAC SAFETY EVALUATION 
Descriptive statistics for ECG results and changes from baseline will be presented by visit 
and treatment group. 
All cardiac function data, including cardiac assessment, will be presented in a data listing. 
9.7.1.8.5 
OTHER SAFETY ANALYSES 
Blood samples will be drawn before the administration of Test Article at time points 
specified in the Schedule of Procedures/Assessments (Table 6 and Table 7) for the evaluation 
of the development of immunogenicity (ADA) responses.  The following endpoints will be 
summarized for the ADA evaluable population: 
 
ADA Positive Subjects - the number (%) of subjects with at least 1 treatment-induced or 
treatment-boosted ADA positive sample (see definitions below) at any time after the 
initial Test Article administration in the ADA evaluable population 
 
ADA Negative Subjects – the number (%) of subjects without a treatment-induced or 
treatment-boosted ADA positive sample at any time after the initial Test Article 
administration in the ADA evaluable population 
 
Baseline ADA Prevalence – the number of subjects with baseline ADA as a percentage of 
the total number of subjects tested at baseline for ADA 
 
Treatment-induced ADA – the number of subjects who were baseline ADA negative and 
developed an ADA response 
 
Treatment-boosted ADA – the number of subjects with pre-existing (baseline) ADA that 
was boosted to a higher titer any time after initial Test Article administration. 
 
ADA Incidence – the proportion of subjects with either treatment-induced ADA or 
treatment-boosted ADA 
 
Occurrence and titer of neutralizing antibodies 
As appropriate, the kinetics of binding and neutralizing ADA responses will be analyzed.  
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the first instance of treatment-induced ADA among baseline ADA negative subjects; and 
duration, defined as the number of days from the first instance of treatment-induced ADA to 
a subsequent instance of negative ADA among baseline ADA negative subjects.  Persistent 
ADA responses are categorized by measurable ADA levels exceeding 16 weeks 
(approximately 5 half-lives for a typical IgG response). 
9.7.2 
Determination of Sample Size 
Sample size considerations are based on the primary PFS endpoint comparing the effect of 
farletuzumab versus placebo on PFS irrespective of the chemotherapy (the 2 strata 
combined). 
The study is designed to detect with approximately 85% power a PFS HR of 0.667 (33.3% 
risk reduction) in the farletuzumab arm compared with the placebo arm with a 1-sided type I 
error of 0.10, which translates into a 50% increase in median PFS from 11 months in the 
placebo arm [10 months for carboplatin plus paclitaxel (Data on file), and 11.3 months for 
carboplatin plus PLD (Pujade-Lauraine, et al., 2010)] to approximately 16 months in the 
farletuzumab arm.  A variable accrual period of approximately 38  months and a 20% loss to 
imaging follow-up rate has been assumed.  Using a treatment allocation of 2:1 (farletuzumab: 
placebo), 210 subjects will be enrolled in the study and a target of at least 143 PFS events in 
the combined chemotherapy strata will be required for the primary analysis. 
Assuming a median PFS time of approximately 11 months in the control arm, the primary 
PFS analysis target events milestone is projected to be reached approximately 12 months 
after the last subject is randomized in the study. 
Survival follow-up considerations were based on the same target HR and significance level, 
but 80% power.  A 5% per year loss to survival follow-up rate was assumed.  Based on a 
median survival time of approximately 32 months in the control arm, the final OS analysis 
target events milestone is projected to be reached approximately 35 months after the last 
subject is randomized in the study. 
In order to preserve the overall type 1 error at 1-sided 10%, the following sequential testing 
scheme will be employed for the PFS primary analysis and the OS analyses: 
1. PFS comparison in combined chemotherapy strata 
2. OS comparison in combined chemotherapy strata 
 
9.7.3 
Interim Analysis 
The first DMC review of safety data will occur when the 15th subject completes Cycle 1 of 
the Combination Treatment Phase to assure that the tolerability of the modified farletuzumab 
dosing and chemotherapy combinations are acceptable. 


 
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An interim analysis for OS will be performed to accompany the primary PFS analysis of the 
study.  Survival status reported up to the primary analysis cut-off date will be included in this 
analysis.  Study follow-up for survival will continue after the interim OS analysis.  The alpha 
allocation between the interim and final OS analyses will be determined based on the Lan-
DeMets spending function with O’Brien-Fleming boundary. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
The SAP will be finalized at the earliest time possible, at minimum prior to formal database 
lock for analysis.  The details of any revisions to protocol specified analyses or changes to 
the planned analyses outlined in the final SAP will be documented and described in the 
clinical study report. 


 
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10 REFERENCE LIST 
American Cancer Society [Internet] What is Ovarian Cancer? [Last Medical Review: 
05 Aug 2014; Last Revised: 11 Aug 2014; cited 2014 Oct 29].  Available from:  
http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-what-is-ovarian-
cancer 
DeVita V, Rosenberg S. Cancer: Principles and Practice of Oncology, Ovarian Cancer. 
9th Edition, 2011: 1368-85. 
DeVita VT, Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg's cancer: 
principles & practice of oncology. 10th edition. New York, NY: Wolters Kluwer; 2011. pp 
1568-1592. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. 
European Clinical Trial Directive 2001/20/EC. 04 Apr 2001 (original date Oct 1995). 
Felder M, Kapur A, Gonzalez-Bosquet J, Horibata S, Heintz J, Albrecht R, et al. MUC16 
(CA125): Tumor biomarker to cancer therapy, a work in progress. Molecular Cancer. 
2014;13:129. 
Gershenson DM, Ramirez PT. The Merck Manual Professional Edition. Merck Manual> 
Health Care Professionals>Gynecology and Obstetrics>Gynecologic Tumors; Ovarian 
Cancer. Nov 2008. Revised May 2013. 
Guarneri V, Piacentini F, Barbieri E, Conte PF. Achievements and unmet needs in the 
management of advanced ovarian cancer. Gynecol Oncol. 2010;117(2):152-8. 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R1) 
(CPMP/ICH/135/95). 1996 Jun 10. 
ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports E3 
(CPMP/ICH/137/95). 1995 Nov 30. 
Janssen Home Page [Internet]; Caelyx Product Information sheet [updated 2013 Oct 22; cited 
2014 Oct 24].  Available from:  https://www.janssen.com.au/Products/Caelyx. 
Ledermann JA, Kristeleit RS. Optimal treatment for relapsing ovarian cancer. Ann Oncol. 
2010 Oct;21 Suppl 7:vii218-22. 
Lenz HJ. Management and Preparedness for Infusion and Hypersensitivity Reactions. Oncol. 
2007 May;12(5):601-9. 


 
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Markman M, Gordon AN, McGuire WP, Muggia FM. Liposomal anthracycline treatment for 
ovarian cancer. Semin Oncol. 2004 Dec;31(6 Suppl 13):91-105. 
Markman M. The Role of CA-125 in the management of ovarian cancer. Oncologist. 
1997;2:6-9.  
Markman M, Liu PY, Rothenberg ML, Monk BJ, Brady M, Alberts DS. Pretreatment CA-
125 and risk of relapse in advanced ovarian cancer. J Clin Oncol. 2006;24:1454-1458.  
MORAb-003 Global Investigators Brochure Edition 4 (October 2014). 
Morgan R, Alvarez R, Armstrong DK, Burger RA, Castells M, Chen L, et al. Ovarian cancer, 
version 3.2012. J Natl Compr Canc Netw. 2012;10:1339-1349. 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Onc. 
1982;5:649-655. 
Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, et al. 
Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin 
for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Onc. 
2010;28(20)3323-3329. 
US 21 Code of Federal Regulations. 01 Apr 2011. 
US Department of Health and Human Services, FDA. Guidance for Industry: Computerized 
Systems Used in Clinical Investigations. May 2007. 
World Medical Association Declaration of Helsinki Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly. Fortaleza, Brazil. Oct 2013. 
 


 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
In general, protocol violations include deviations from inclusion/exclusion criteria, from 
concomitant medication restrictions, and from any other protocol requirement that could, at 
least hypothetically, result in significant risk to the subject and/or affect the outcome of the 
clinical trial.  Protocol violations will be noted in the final CSR.   
A deviation is defined as nonadherence to the protocol procedures or schedule as defined by 
the protocol or the primary endpoint that does not place the subject at any added or 
significant risk or affect the data quality or the outcome of the clinical trial (eg, a missed 
procedure, an out-of-window site visit).   
Only subjects who meet protocol-defined eligibility criteria may be enrolled in this clinical 
trial.  If any protocol eligibility criteria or procedures are unclear, the investigator or 
investigational site personnel should contact the CRA.  If the question requires medical 
interpretation, the sponsor’s medical monitor should be consulted.  All protocol violations 
should be reported to the IRB/IEC according to the standard practices of the investigational 
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Data and document review will be performed in an ongoing manner during trial conduct to 
assess protocol deviations and violations.  The sponsor will convene a data review meeting at 
least once prior to database lock to classify findings as either protocol deviations or 
violations. 
11.3 Monitoring Procedures 
The sponsor’s and/or the CRO’s CRA will maintain contact with the investigator and 
designated staff by telephone, letter, or email between study visits.  Monitoring visits to each 
site will be conducted by the assigned blinded and unblinded CRAs, as described in the 
monitoring plan.  For the purpose of maintaining the blind of this study, all pharmacy and 
study drug accountability monitoring will be performed by an unblinded CRA assigned by 
the sponsor or CRO.  The investigator (or if regionally required, the head of the medical 
institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to 
assure compliance with ICH GCP and local regulatory requirements.  The CRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and to IRB/IEC 
review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following: 
 
Clinic, office, or hospital charts 
 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
 
Recorded data from automated instruments such as x-rays, and other imaging reports (eg, 
sonograms, CT scans, MRIs, radioactive images, ECGs, rhythm strips, 
electroencephalograms, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives 
 
Pain, quality of life, or medical history questionnaires completed by subjects 
 
Records of telephone contacts 
 
Diaries or evaluation checklists 
 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
 
Laboratory results  
 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
 
eCRF components (eg, questionnaires) that are completed directly by subjects and serve 
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Prior to the start of the clinical trial, each investigational site will be initiated with training on 
the protocol and discussion of the responsibilities of the investigator.  The investigator must 
participate in this meeting, as must any other investigational site personnel who are involved 
in the conduct of the clinical trial. 
The CRA will perform the first onsite monitoring visit at each site approximately 2 weeks 
after the first subject is enrolled at that site to ensure that clinical trial procedures are being 
followed.  After the first visit, monitoring visits will occur at regular intervals, as agreed 
upon with the sponsor.  At these interim monitoring visits, the CRA (or unblinded CRA, 
where noted) will perform the following tasks: 
 
Compare data entered into the eCRFs with the corresponding source documents 
 
Check for protocol compliance (including documentation of adequate written informed 
consent, appropriate subject visit dates, documentation of AEs and concomitant 
medications, key safety and biological endpoint observations, and study agent dosing) 
 
Review the site regulatory binder to ensure that all regulatory documentation has been 
updated as necessary and filed appropriately, and reconcile the contents of the site 
regulatory binder against the TMF   
 
(Unblinded CRA only) Review Test Article accountability (and chemotherapy 
accountability [only if provided by the sponsor]) and verify compliance with the study 
Protocol and the Pharmacy Manual   
After the last subject at the site has completed the clinical trial, the CRA will return to the 
site for final source data verification and close-out visit.  At this visit, any outstanding issues 
will be resolved and the investigator’s responsibilities for retention of clinical trial 
documentation will be reviewed. 
11.4 Recording of Data 
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF must be documented in a valid audit trail where the correction is dated, 
the individual making the correction is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.  The investigator must electronically sign each subject’s eCRF.   
11.5 Identification of Source Data 
All data to be recorded on the eCRF must reflect the corresponding source documents.   
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 


 
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representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of eCRFs, the Global Investigator's Brochure, and regulatory agency 
registration documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In 
addition, the sponsor will send a list of treatment codes by study subject to the investigator 
after the clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor and as required per local regulations, for at least 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 3 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. 
At the completion of the required retention period or in the event that the investigator retires 
or relocates during the retention period, the investigator is asked to contact the sponsor to 
provide the location where the records are archived, including contact information for the 
responsible party(ies).  This will allow the sponsor to assist in arranging for permanent 
archiving of the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Test Article 
All farletuzumab will be supplied to the designated, unblinded pharmacist by the sponsor.  
Drug supplies must be kept in an appropriate secure area (eg, locked) in its original 
packaging, and stored according to the conditions specified on the label.  The unblinded 
pharmacist must maintain records of farletuzumab delivery to the study site, inventory at the 
site, use for each subject, and farletuzumab destruction or return.  Throughout the study, 
partially-used and empty vials, as well as any investigational product deemed unusable (eg, 
as a result of a temperature excursion) must be accounted for.   
On close-out of the site, all remaining used vials and unused vials may be destroyed onsite, 
according to the investigational site’s local destruction policy/standard operating procedures, 
following review of drug accountability records by the unblinded site monitor.  The 
investigational product may also be returned to the sponsor’s designated location if 
previously arranged with the sponsor.  The sponsor will assure that a final report of drug 
accountability to the vial level is prepared and maintained by the investigative site.   


 
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A Drug Dispensing Log will be supplied by the sponsor.  This log must be kept current and 
should contain the following information: 
 
Initial and subsequent inventory on receipt of farletuzumab at the investigational site 
 
Identification (subject number) of each subject to whom the farletuzumab was dispensed 
 
Number of vials of farletuzumab used at each visit per subject 
 
Dates and lot numbers of all farletuzumab dispensed  
 
Number and lot numbers of farletuzumab vials destroyed  
 
Number and lot numbers of farletuzumab vials returned 
All records and inventory must be available for inspection by the sponsor or its designee (ie, 
the unblinded clinical study monitor), the IRB/IEC, and the relevant regulatory agencies. 
Additional details on the storage, handling and inventory of farletuzumab will be provided in 
the Pharmacy Manual.   
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC, and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 


 
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The study will be listed on www.clinicaltrials.gov and other registries, as appropriate. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.  The terms of insurance will be kept in the 
regulatory files. 


 
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12 APPENDICES 
 


 
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Appendix 1 
Sample Collection Procedures and Bioanalytical 
Methods for Serum Farletuzumab levels and ADA 
METHODS: 
Blood samples for farletuzumab level analyses and ADA in the clinical studies with 
farletuzumab should be processed for serum.  A blood sample (5.0 mL) will be collected for 
each test into sterile tubes and placed at room temperature for at least 30 minutes to allow 
clot formation.  Centrifuge within 1 hour of collection at approximately 3000-3500 rpm for 
15 minutes.  Serum will be removed from the clot and divided into 2 equal aliquots.  Within 
2 hours of collection time, freeze and store samples at -70°C to -80°C (if not available -20°C) 
until instructed to ship to central laboratory.   
Complete instructions for processing and shipping samples will be located in the laboratory 
manual. 
FARLETUZUMAB LEVEL IN SERUM: 
This fluorescent immunoassay format measures free forms of farletuzumab in human serum 
based on direct capture by a biotin-farletuzumab complementarity determining region 
(CDR)-specific bivalent Fab mini-antibody immobilized on streptavidin coated columns 
within a bioaffy 200 CD, followed by direct detection using an Alexa Flour labeled murine 
antifarletuzumab and subsequent fluorescence detection via Gyros Workstation. 
FARLETUZUMAB ANTI-DRUG ANTIBODY (ADA) ASSAY: 
A tiered analysis approach will be employed using risk-based statistical methods to detect, 
confirm and characterize the presence of farletuzumab-specific human anti-drug antibodies in 
subject samples.  First, samples generating a signal at or above an established floating 
screening cut point (one-tailed, upper 95% CI), will be identified as potential ADA positives.  
These samples will be subsequently assessed for ADA specificity to farletuzumab through 
competitive inhibition of immuno-complex formation by addition of excess unlabeled 
farletuzumab and evaluating the relative change in signal responses compared to unspiked 
samples.  Lastly, positive and specific ADA samples are serially diluted to generate a relative 
titer value to establish the magnitude of the ADA response. 
The validated bridging format immunoassay detects the presence of farletuzumab-specific 
immunoglobulins based on the formation and capture of immuno-complexes between 
biotinylated farletuzumab, antifarletuzumab and reporter labeled farletuzumab antibody.  
Bound anti-drug antibody immuno-complexes are then detected in a quasi-quantitative 
manner via electrochemiluminescence signal generation.  Sample signal responses are 
evaluated against a statistical threshold derived from drug naïve individuals, and confirmed 
for specificity to farletuzumab via competitive binding signal depletion. 


 
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Appendix 2 
Quantity of Fluid and Tissue to be Collected 
The anatomical sites from which blood samples are drawn and drug is administered must be 
documented in the medical record.  A breakdown of the approximate amounts of blood to be 
collected for each investigation, as specified in the Schedule of Procedures/Assessments 
(Table 6 and Table 7), is provided below.  
Investigation 
Quantity/Volume 
Additional Notes 
Archived tumor 
tissue 
Tumor block 
or 15-20 
(4-5 micron) slides 
Slides to be created from serial sections cut 
from the archival tumor tissue sample taken 
at the time of initial diagnosis of ovarian 
cancer; serial sections to be identified 
sequentially as cut.  If a minimum of 
15 slides are not available, contact the CRA 
to discuss. 
Hematology panel 
3.0 mL 
 
Chemistry panel 
4.0 mL 
Screening pregnancy test analyzed from the 
same vial as the Chemistry panel 
hCG pregnancy test 
CA125 
5.0 mL 
 
Biomarker levels 
11.0 mL* 
5.0 mL for serum, 6.0 mL for plasma;  
*add an additional 11.0 mL at Screening; to 
be collected within 2 weeks of 
Randomization 
Urine biomarker 
10.0-20.0 mL 
Screening only; to be collected within 
2 weeks of Randomization 
Farletuzumab levels 
5.0 mL 
10.0 mL total per specified visit 
ADA levels 
5.0 mL 
 
 


 
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Appendix 3 
Eastern Cooperative Oncology Group Performance 
Status 
Grade 
ECOG 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
(Oken, et al., 1982) 
The ECOG Performance Status is in the public domain and made available by the Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Co-Chair.  
 


 
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Appendix 4 
Protocol-Specific Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 Quick Reference 
Source:  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) 
Eur J Cancer. 2009;45:228–247. 
Methods of Measurement 
 
As part of the disease assessment by RECIST 1.1 criteria, CT with IV and oral contrast of 
the chest, abdomen and pelvis will be performed.  Following baseline, subsequent chest 
CT is only required if a lesion is identified in the chest or metastasis to the chest is 
suspected at any point during the study. 
 
In subjects who have been followed previously by MRI, those who are intolerant of CT 
contrast media, or where there is a preference for MRI, MRI is acceptable.  If MRI of the 
chest, abdomen, and pelvis is performed, CT of the chest without contrast must also be 
performed at baseline.  Following baseline, subsequent non-contrast CT of the chest is 
only required if a target lesion is identified in the chest or metastasis to the chest is 
suspected at any point during the study. 
 
This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5mm or less.  When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness.   
 
Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions.  
However, lesions on chest x-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung 
 
When effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or SD in order to 
differentiate between response (or SD) and PD 
 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and within 4 weeks of the randomization 
 
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.   


 
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Evaluable disease includes lesions that meet criteria for measurable disease per RECIST 1.1 
or radiographically visible and evaluable lesions.  Examples of evaluable but not measurable 
lesion include: 
- 
small liver lesions, omental implants, serosal bowel implants, pelvic masses, or skin 
lesion that do not meet criteria for the size of measurable (<1cm) but can be 
considered  non-measurable evaluable lesions at eligibility/screening 
- 
pathologic lymph nodes with a short axis measuring > 10 mm and < 15 mm 
Subjects with only ascites or pleural effusion are not considered eligible for this protocol. 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
- 
10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
- 
15 mm in short axis for a lymph node when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm) 
Baseline Documentation of “Target” and “Non-Target” Lesions 
 
For subjects without measurable disease, all evaluable lesions are considered as non-
target lesions 
 
When more than one measurable lesion is present at Baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured 
at Baseline.  (This means in instances where patients have only one or 2 organ sites 
involved a maximum of 2 and 4 lesions respectively will be recorded.) 
 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements 
 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  Pathological nodes which 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.  Only the short axis of these nodes will contribute to 
the baseline sum.  The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as 2 dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or 
coronal).  The smaller of these measures is the short axis.  All other pathological nodes 
(those with short axis ≥10 mm but <15 mm) should be considered non-target lesions.   


 
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 
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but they 
should be followed as ‘present’, ‘absent’, or ‘unequivocal progression’.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’) 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target and non-target lesions. 
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.   
 
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. 
NOTE:  For Special notes on the assessment of target lesions that are lymph nodes, target 
lesions that become ‘too small to measure,’ and lesions that split or coalesce on treatment, 
please refer to the RECIST 1.1 guidelines (Eisenhauer, et al., 2009). 


 
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Evaluation of Non-Target Lesions: 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10mm 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 (see comments below) of existing 
non-target lesions.  (Note:  the appearance of one or more new lesions is also considered 
progression). 
NOTE:  For special notes on the assessment of progression of non-target disease, as well as 
new lesions, please refer to the RECIST 1.1 guidelines (Eisenhauer, et al., 2009). 
Evaluation of Time Point Response 
The Time Point Response Table below provides a summary of the overall response status 
calculation at each time point for patients who have measurable disease at baseline. 
Time Point Response:  Patients With Target (+/– Non-target) Disease 
 
Target 
Non-target 
New 
Overall 
Lesions 
Lesions 
Lesions 
Response 
CR 
CR 
No 
CR  
CR 
Non-CR/non-PD 
No 
PR  
CR 
Not evaluated 
No 
PR  
PR 
Non-PD or  
No 
PR 
 
not all evaluated 
SD  
Non-PD or 
No  
SD 
 
not all evaluated 
Not all 
Non-PD 
No 
NE 
evaluated 
PD  
Any 
Yes or No 
PD  
Any  
PD 
Yes or No 
PD  
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable 
disease; PD = progressive disease; NE = inevaluable 
For additional guidance on evaluation of tumor response according to RECIST 1.1, please 
refer to the RECIST 1.1 guideline (Eisenhauer, et al., 2009).  


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
MORAb-003-011 
Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Study to Assess the Efficacy and Safety of Farletuzumab 
(MORAb-003) in Combination with Carboplatin plus Paclitaxel 
or Carboplatin plus Pegylated Liposomal Doxorubicin (PLD) in 
Subjects with Low CA125 Platinum-Sensitive Ovarian Cancer 
Investigational Product 
Name: 
Farletuzumab (MORAb-003) 
IND Number: 
BB12219 
EudraCT Number: 
2014-003812-36 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Eisai Inc. 
MORAb-003-011 
 
 
 
CONFIDENTIAL 
Page 1 of 42 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Protocol 
Number: 
MORAb-003-011 
Study Protocol 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to 
Assess the Efficacy and Safety of Farletuzumab (MORAb-003) in 
Combination with Carboplatin plus Paclitaxel or Carboplatin plus 
Pegylated Liposomal Doxorubicin (PLD) in Subjects with Low CA125 
Platinum-Sensitive Ovarian Cancer 
Date: 
31-OCT-2019 
Version: 
Version 1.0 (Final) 
 
 
 
 
 
 
 
 
 
This document contains confidential information of Eisai, Inc.  Any viewing or disclosure of such 
information that is not authorized in writing by Eisai, Inc. is strictly prohibited.  Such information may be 
used solely for the purpose of reviewing or performing this study.  
 
 


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CONFIDENTIAL 
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Revision History 
 
Date 
Version 
number 
High-level Summary of Changes (Section/Change) 
31-OCT-2019 
V1.0 
Original statistical analysis plan 
 
 
 
 


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1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................... 3 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 6 
3 
INTRODUCTION .................................................................................................................. 8 
3.1 
Study Objectives........................................................................................................... 8 
3.1.1 
Primary Objective ................................................................................................... 8 
3.1.2 
Secondary Objectives ............................................................................................ 8 
3.1.3 
Exploratory Objectives........................................................................................... 8 
3.2 
Overall Study Design and Plan .................................................................................. 9 
3.3 
Schedule of Assessments ........................................................................................ 10 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................... 11 
5 
STATISTICAL METHODS ................................................................................................ 11 
5.1 
Study Endpoints ......................................................................................................... 12 
5.1.1 
Primary Endpoint .................................................................................................. 12 
5.1.2 
Secondary Endpoints .......................................................................................... 12 
5.1.3 
Exploratory Endpoints ......................................................................................... 12 
5.2 
Study Subjects ............................................................................................................ 13 
5.2.1 
Definitions of Analysis Sets ................................................................................ 13 
5.2.2 
Subject Disposition............................................................................................... 13 
5.2.3 
Protocol Deviations .............................................................................................. 13 
5.2.4 
Demographic and Other Baseline Characteristics .......................................... 14 
5.2.4.1 
Disease Characteristics ............................................................................... 14 
5.2.4.2 
Exposure to Study Medication .................................................................... 14 
5.2.5 
Prior and Concomitant Therapy ......................................................................... 14 
5.2.6 
Medical History ..................................................................................................... 15 
5.3 
Data Analysis General Considerations ................................................................... 15 
5.3.1 
Pooling of Centers ................................................................................................ 15 
5.3.2 
Coding Dictionaries .............................................................................................. 15 
5.4 
Efficacy Analysis......................................................................................................... 15 
5.4.1 
Primary Efficacy Analysis .................................................................................... 15 


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5.4.1.1 
Progression-Free Survival ........................................................................... 15 
5.4.2 
Secondary Efficacy Analyses ............................................................................. 16 
5.4.2.1 
Overall Survival ............................................................................................. 16 
5.4.2.1.1  Overall Survival at PFS lock – Interim OS .......................................... 16 
5.4.2.1.2  Overall Survival – Final OS ................................................................... 16 
5.4.2.2 
Length of First versus Second Platinum-Free Interval ............................ 17 
5.4.2.3 
Objective Response Rate ............................................................................ 17 
5.4.2.4 
Disease Control Rate ................................................................................... 17 
5.4.2.5 
Time to Response ......................................................................................... 18 
5.4.2.6 
Duration of Response .................................................................................. 18 
5.4.2.7 
Exposure-Response ..................................................................................... 18 
5.4.3 
Exploratory Efficacy Analysis ............................................................................. 18 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
 
Analyses ...................................................................................................................... 19 
5.5.1 
Phamacokinetic Analyses ................................................................................... 19 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ... 19 
5.6 
Safety Analysis ........................................................................................................... 19 
5.6.1 
Adverse Events .................................................................................................... 20 
5.6.2 
Laboratory Values ................................................................................................ 20 
5.6.3 
Vital Signs .............................................................................................................. 21 
5.6.4 
Electrocardiograms .............................................................................................. 21 
5.6.5 
Other Safety Analyses ......................................................................................... 21 
5.6.5.1 
Human Anti-Drug Antibodies ...................................................................... 21 
5.7 
Subgroup Analyses .................................................................................................... 22 
6 
DATA MONITORING COMMITTEE AND INTERIM ANALYSIS ................................ 22 
6.1 
Data Monitoring Committee ...................................................................................... 22 
6.2 
Interim Analysis .......................................................................................................... 23 
7 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .................................. 23 
7.1 
Missing Data, Handling of Partial Adverse Event Start/Stop Dates ................... 23 
7.1.1 
Adverse Events .................................................................................................... 23 
7.1.2 
Prior and Concomitant Therapy ......................................................................... 24 


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8 
PROGRAMMING SPECIFICATIONS ............................................................................. 24 
9 
STATISTICAL SOFTWARE ............................................................................................. 26 
10  MOCK TABLES, LISTINGS, AND GRAPHS ................................................................. 26 
11  REFERENCES ................................................................................................................... 27 
12  APPENDICES ..................................................................................................................... 28 
12.1 
Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm 
 
…………………………………………………………………………………………28 
12.2 
Schedule of Procedures/Assessments for Paclitaxel/Carboplatin 
 
Chemotherapy Arm .................................................................................................... 31 
12.3 
Quick Reference for Protocol-Specific Response Criteria ................................... 34 
12.4 
Censoring Rules ......................................................................................................... 38 
12.4.1  Censoring Rules for Overall Survival ................................................................ 38 
12.4.2  Censoring Rules for Progression-Free Survival Based on Investigator 
 
Assessment ........................................................................................................... 39 
12.5 
General Considerations for Secondary Efficacy Endpoints: ORR, TTR, and 
 
Length of Remission .................................................................................................. 40 
12.6 
Adverse Events of Interest (AEI) ............................................................................. 41 
12.6.1  Hypersensitivity AEs ............................................................................................ 41 
12.6.1.1  Overall Hypersensitivity AEs ...................................................................... 41 
12.6.1.2  Hypersensitivity AEs with Positive ADA (DHAEs) .................................. 41 
12.6.2  Interstitial Lung Disease (ILD) ............................................................................ 41 
 
LIST OF FIGURES 
Figure 1. 
STUDY DESIGN..................................................................................................... 10 
 
 


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2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
ADA 
(Human) Anti-Drug Antibody 
AE 
Adverse Event 
AEI 
Adverse Event of Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC4 
Anatomical Therapeutic Chemical (Classification) 
BSA 
Body Surface Area 
CA125 
Cancer Antigen 125 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DHAE 
Drug Hypersensitivity Adverse Event 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
HR 
Hazards Ratio 
kg 
Kilogram 
KM 
Kaplan-Meier 
IgG 
Immunoglobulin Isotype G 
ILD 
Interstitial Lung Disease 
IRT 
Interactive Response Technology (web or voice 
randomization system) 
LLN 
Lower Limit of Normal 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
Min 
Minimum 
MRI 
Magnetic Resonance Imaging 
ORR 
Objective Response Rate 


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OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PH 
Proportional Hazards 
PK 
Pharmacokinetic 
PLD 
Pegylated Liposomal Doxorubicin 
PR 
Partial Response 
PT 
(MedDRA) Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SMQ 
Standardized Medical Dictionary for Regulatory 
Affairs Query 
SOC 
(MedDRA) System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TRAE 
Treatment-Related Adverse Event 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


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CONFIDENTIAL 
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3 INTRODUCTION 
The purpose of the statistical analysis plan (SAP) is to document and describe the statistical 
analyses planned for the protocol MORAb-003-011 titled “A Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Study to Assess the Efficacy and Safety of Farletuzumab (MORAb-
003) in Combination with Carboplatin plus Paclitaxel or Carboplatin plus Pegylated Liposomal 
Doxorubicin (PLD) in Subjects with Low Cancer Antigen 125 (CA125) Platinum-Sensitive 
Ovarian Cancer.” This SAP corresponds to version 4.0, amendment 3.0, of the study protocol 
dated 06 November 2018. 
Any deviations between this SAP and the statistical methods and analyses applied to data 
collected during the study will be described in the final clinical study report. 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective of the study is to demonstrate that farletuzumab has superior efficacy 
compared with placebo in improving Progression-Free Survival (PFS), as determined by 
Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, when added to the standard 
chemotherapy regimens of carboplatin plus paclitaxel or carboplatin plus PLD, in subjects with 
platinum-sensitive ovarian cancer in first relapse who have a CA125 ≤ 3x Upper Limit of 
Normal (ULN) (105 U/mL) at study entry. 
3.1.2 Secondary Objectives 
The secondary objectives of the study are: 
 To assess the effect of farletuzumab on Overall Survival (OS) in this population (key 
secondary endpoint) 
 To assess the effect of farletuzumab in prolonging second platinum-free interval longer 
than first platinum-free interval 
 To assess the effect of farletuzumab on best Objective Response Rate (ORR), Time to 
Response (TTR), and Duration of Response (DOR) by RECIST 1.1 criteria 
 To assess the safety and tolerability of farletuzumab 
 To assess the Pharmacokinetics (PK) and exposure-response relationships between 
farletuzumab and PFS and OS 
3.1.3 Exploratory Objectives 
The exploratory objectives of the study are: 
 To explore blood/serum CA125 levels and evaluate changes during study 
 To explore biomarkers that may correlate with the efficacy-related endpoints and 
farletuzumab mechanism of action 


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 To explore expression of CA125 and folate receptor alpha in blood, urine, and tissue to 
correlate to disease characteristics, exposure, efficacy-related endpoints, farletuzumab 
mechanism of action, and other biomarkers 
3.2 Overall Study Design and Plan 
This is a global, multicenter, double-blind, randomized placebo-controlled study in subjects with 
platinum-sensitive ovarian cancer in first relapse that have low serum CA125 levels (≤ 3xULN, 
or 105 U/mL). 
The study is being conducted in approximately 210 subjects enrolled into 1 of 2 chemotherapy 
treatment arms at the investigator’s discretion: either carboplatin (AUC 5) plus paclitaxel (175 
mg/m2 IV every 3 weeks) or carboplatin (AUC 5) plus PLD (30 mg/m2 IV every 4 weeks). 
Subjects will then be randomized in a 2:1 ratio to receive farletuzumab or placebo. All subjects 
will receive a loading dose for the first 2 weeks of 10 mg/kg farletuzumab (or matching placebo), 
followed by 5 mg/kg weekly. Subjects will be stratified at randomization by individual 
chemotherapy treatment regimen and platinum-free interval following first-line therapy (6-12 
months versus >12-36 months).  
All subjects will have serum CA125 ≤ 3xULN (105 U/mL) confirmed for study entry at 
Screening using a central laboratory designated by the sponsor to assure the use of a standardized 
assay (Architect CA 125 II assay). An archival tumor tissue sample taken at the time of initial 
diagnosis of ovarian cancer will be provided at Screening for analysis. In addition, blood and 
urine samples will be collected at time points throughout the study for other supporting 
exploratory analyses. 
An independent, unblinded Data Monitoring Committee (DMC) will be utilized to monitor the 
safety profile of the study and to enhance safety oversight. The first DMC review of safety data 
will occur when the 15th subject completes Cycle 1 of the Combination Treatment Phase to 
assure that the tolerability of the modified farletuzumab dosing and chemotherapy combinations 
are acceptable. 
The study will consist of 4 phases: Screening, Combination Treatment, Maintenance, and 
Follow-up. At the end of the Combination Treatment Phase, subjects who have not experienced 
disease progression will enter the Maintenance Phase until disease progression. 
For this study, either farletuzumab or placebo is considered Test Article. Subjects who 
discontinue Test Article for reasons other than disease progression will be followed 
radiographically until documentation of disease progression or start of any new anticancer 
therapy. All subjects who discontinue Test Article for any reason, except for withdrawal of 
consent from the study, will be followed for survival. Subjects may choose to discontinue Test 
Article therapy and continue to be followed for disease progression and survival. 
The study design is presented in Figure 1. 


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FIGURE 1. 
STUDY DESIGN 
 
 
3.3 Schedule of Assessments 
The schedule of events for the carboplatin plus PLD chemotherapy and the carboplatin plus 
paclitaxel chemotherapy are published in the study protocol (Table 6 and 7) and are copied in 
Appendices 12.1 and 12.2, respectively. 


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4 DETERMINATION OF SAMPLE SIZE 
Sample size considerations are based on the primary PFS endpoint to compare the effect of 
farletuzumab versus placebo on PFS irrespective of the chemotherapy (the 2 strata combined). 
The study is designed to detect with approximately 85% power a PFS HR of 0.667 (33.3% risk 
reduction) in the farletuzumab arm compared with the placebo arm with a 1-sided type I error 
rate of 0.10, which translates into a 50% increase in median PFS from 11 months in the placebo 
arm: 10 months for carboplatin plus paclitaxel (Data on file), and 11.3 months for carboplatin 
plus PLD (Pujade-Lauraine, et al., 2010) to approximately 16 months in the farletuzumab arm. A 
variable accrual period of approximately 38 months and a 20% loss to imaging follow-up rate 
has been assumed. Using a treatment allocation of 2:1 (farletuzumab: placebo), 210 subjects will 
be enrolled in the study and a target of at least 143 PFS events in the combined chemotherapy 
strata will be required for the primary analysis. 
Assuming a median PFS time of approximately 11 months in the control arm, the primary PFS 
analysis target events milestone is projected to be reached approximately 12 months after the last 
subject is randomized in the study. 
Survival follow-up considerations were based on the same target HR and significance level, but 
80% power. A 5% per year loss to survival follow-up rate was assumed. Based on a median 
survival time of approximately 32 months in the control arm, the final OS analysis target events 
milestone (a total 124 death events) is projected to be reached approximately 35 months after the 
last subject is randomized in the study. 
In order to preserve the overall type 1 error rate at 1-sided 10%, the following sequential testing 
scheme will be employed for the PFS primary analysis and OS analyses: 
1. PFS comparison in combined chemotherapy strata 
2. OS comparison in combined chemotherapy strata 
5 STATISTICAL METHODS 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum) 
will be calculated for continuous data, and the number and percentage of subjects in each 
category will be displayed for categorical data. Kaplan-Meier (KM) curves will be produced for 
time-to-event endpoints. Durations of time (e.g., times-to-event endpoints) will be reported in 
proportional “months” according to the formula 
months ൌ
12
365.25 × days 
Baseline value of a characteristic is defined as the last measured value prior to the first dose of 
any study medication (or prior to randomization for subjects not treated). Study Day 1 is defined 
as the date of the first dose of Test Article. 


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Statistical p-values will be rounded for display at the fourth digit following the decimal point. P-
values below 0.0001 will be displayed as “<0.0001.” 
All data collected via electronic CRFs will be included in subject data listings. At a minimum, 
data listings will include the subject’s ID number, assigned chemotherapy regimen, and 
randomized treatment arm.  
5.1 Study Endpoints 
5.1.1 Primary Endpoint 
The primary efficacy endpoint for this study is the PFS based on the investigators’ radiographic 
assessments utilizing RECIST 1.1 criteria. PFS is defined as the time (in months) from the date 
of randomization to the date of the first observation of progression (RECIST 1.1), or date of 
death, whatever the cause. If progression or death is not observed for a subject, the PFS will be 
censored at the date of last tumor assessment without evidence of progression prior to the date of 
initiation of further anticancer treatment of the cut-off date. 
5.1.2 Secondary Endpoints 
The secondary efficacy endpoints for the study are as follows: 
Overall Survival (OS): Defined as the time from the date of randomization to the date of death, 
due to all causes. If death is not observed for a subject, the OS time will be censored at the last 
date known to be alive or the cut-off date, whichever is earliest. 
Length of First versus Second Platinum-Free Interval: Length of first platinum-free interval 
(from end of previous platinum based chemotherapy to the first relapse) is a randomization 
stratification factor (6-12 months,  >12-36 months), and its value will be based on IRT data. 
Length of second platinum-free interval is defined as the period of time (in months) from the 
date of completion of platinum based chemotherapy (last dosing date) during the study to the 
date of progression or death, with its ending point, with censoring if applicable, same as PFS.  
Tumor Response (ORR, TTR, and DOR per RECIST 1.1): ORR is defined as either a CR or 
a PR using RECIST 1.1 criteria. Tumor assessments performed up to the initiation of further 
anticancer treatment will be considered. TTR is defined as the time (in months) from the date of 
randomization to the date of first observation of response (PR or CR). DOR is defined as the 
time (in months) from the date of first observation of response (PR or CR) to the date of the first 
observation of progression based on the investigator’s radiographic assessment (RECIST 1.1), or 
date of death, whatever the cause. 
5.1.3 Exploratory Endpoints 
The exploratory endpoints for the study are: (a) changes in CA125 from baseline, and (b) to 
identify a potential predictive biomarker or elucidation of correlation between key biomarkers 
and potential farletuzumab PK or clinical benefit. 


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5.2 Study Subjects 
5.2.1 Definitions of Analysis Sets 
There will be 4 analysis sets, and 2 safety subsets for this study. The analysis sets are as follows: 
Intent-to-Treat (ITT) Population (also called the Full Analysis Set) is defined as all 
randomized subjects, analyzed by the treatment assigned according to the IRT system. 
This is the primary analysis population for all efficacy endpoints. 
Safety Analysis Set is defined as all randomized subjects who received at least 1 
dose of Test Article and who had at least 1 safety assessment following the first dose 
of Test Article. Treatment assignments will be designated according to the actual 
study treatment received. This is the primary analysis population for safety 
evaluation. Two additional safety analysis subpopulations will also be defined: 
 
Combination Therapy Analysis Set: based on exposure to farletuzumab or 
placebo in combination with carboplatin and taxane (combination therapy); 
Single Agent Maintenance Therapy Analysis Set: based on exposure to 
single-agent maintenance therapy. 
Tumor Response (TR) Evaluable Analysis Set is defined as all randomized subjects who 
received at least 1 dose of Test Article and who had a baseline and at least 1 on-treatment 
tumor assessment performed.  This population will be used as a secondary analysis 
population for tumor response, according to treatment as randomized.  
 
Pharmacokinetic (PK) Analysis Set is defined as all subjects who have at least one 
measureable farletuzumb serum concentration data value. 
Data summaries will, in most cases, be presented by treatment group (farletuzumab or placebo) 
unless otherwise specified.  
5.2.2 Subject Disposition 
The numbers of subjects who have been screened (if available), randomized and dosed will be 
summarized by treatment group. The number of subjects who discontinued study treatment or 
study follow-up will be summarized by treatment group, along with the reasons for 
discontinuation. In addition, the number of subjects in each analysis population and the reason 
for exclusion will be summarized by treatment group and a listing of each subject’s status within 
a given analysis population (i.e., included versus excluded) will be provided. 
5.2.3 Protocol Deviations 
Major protocol deviations will be presented in a data listing. 


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5.2.4 Demographic and Other Baseline Characteristics 
Demographic information (e.g., age, sex, race, height, weight, Body Surface Area [BSA], and 
ECOG) and stratification factors (i.e., individual chemotherapy treatment regimen and platinum-
free interval following first-line therapy) will be summarized, for the ITT population, by 
treatment group and overall with summary statistics for continuous/categorical variables. 
5.2.4.1 Disease Characteristics 
Ovarian cancer histology, ovarian cancer primary site, stage of disease at initial diagnosis, prior 
ovarian cancer medications, length of first platinum-free interval, and baseline CA125 will be 
summarized, for the ITT population, by treatment group and overall with summary statistics for 
continuous/categorical variables. CA125 will be summarized by categories: ≤1 ULN, >1 to ≤2 
ULN, >2 to ≤3 ULN, and >3 ULN. Ovarian cancer history and prior ovarian cancer surgeries 
will be presented in data listings. 
5.2.4.2  Exposure to Study Medication 
The study drug administration profile will be summarized for each treatment group with respect 
to the number of infusions/cycles taken, dose intensity, dose modifications, dose omissions, and 
reasons for deviations from the planned regimen. 
Study Drug tolerability will be summarized within treatment groups by the numbers of treatment 
discontinuations, treatment delays, and dose reductions. 
Extent of exposure parameters will be summarized by treatment group for the Safety Analysis 
Set in the combination therapy and single-agent maintenance therapy sub-populations using 
descriptive statistics. Summaries for the carboplatin plus paclitaxel or carboplatin plus PLD 
regimen in each treatment group will include duration of exposure, number of cycles received, 
number of dose reductions, and number of dose delays. A summary of AEs leading to dose delay 
and/or reduction will also be provided. Additionally, cumulative dose (mg/kg), actual dose 
intensity (mg/kg/week), and relative dose intensity (actual dose intensity divided by the planned 
dose intensity) will be summarized by treatment group. Summaries for the farletuzumab 
treatment will include duration of exposure, number of infusions received, and dose delays.  
5.2.5  Prior and Concomitant Therapy 
The counts and percentages of subjects who took prior medications will be summarized on the 
Safety Analysis Set by treatment group and overall. Prior medication is defined as medications 
that stopped before the first dose of Test Article. Summaries will include the ATC4 classification 
and WHO DD preferred term (see section 5.3.2).  
A similar summary will be produced for concomitant medications by treatment group. 
Concomitant medication is defined as medication that was taken any day from the first dose of 
Test Article until 30 days after the last dose, regardless of whether the medication was initiated 
prior to the first dose of Test Article.  


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For the purpose of this study, if a partial date is reported, then missing date imputations will be 
utilized (see section 7.1.2). Prior and concomitant medication use will be presented in subject 
data listings. 
5.2.6 Medical History 
General medical history will be summarized by frequency tables by treatment group and overall 
on the ITT population. General medical history will be presented in subject data listings.  
5.3 Data Analysis General Considerations 
5.3.1 Pooling of Centers 
Subjects from all centers will be pooled for all analyses. 
5.3.2 Coding Dictionaries 
Reported medical history and adverse event terms will be mapped to standard terminology in the 
Medical Dictionary for Regulatory Activities (MedDRA) version 17.1or higher. Pre-study and 
concomitant medications will be mapped to standard drug names in the World Health 
Organization Drug Dictionary (WHO DD) September 2014 release or later. Reported terms 
paired with preferred terms will be shown in data listings, but summaries of medical history, 
adverse events, and medications received will be based exclusively on preferred terminology. 
5.4 Efficacy Analysis 
The data cutoff date of the primary PFS analysis will be determined prior to database lock and 
treatment unblinding. The data cutoff date of the primary PFS analysis will be determined as the 
latest of the following two occurrences: 
1. The date of occurrence of the 143rd PFS event among all study subjects 
2. Six months (183 days) following the date the last subject was randomized  
The cut-off date for the PFS will be used for all secondary efficacy variables, as well as survival 
data supporting the interim survival analysis. 
5.4.1 Primary Efficacy Analysis  
5.4.1.1 Progression-Free Survival 
PFS is defined as the number of months from the date of randomization to the date of the first 
observation of RECIST 1.1 disease progression or date of death regardless of cause. If RECIST 
1.1 disease progression or death is not observed for a subject, PFS time will be censored on the 
last on study tumor assessment (radiographic imaging) date prior to data cutoff. The PFS 
censoring rules will follow the FDA guidelines. 
The stratified log rank test will be used to compare PFS between farletuzumab and placebo at the 
1-sided 10% level of significance. Both one-sided and two-sided p-values of the stratified log 
rank test will be calculated. The stratification factors are: (1) chemotherapy (carboplatin plus 


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paclitaxel versus carboplatin plus PLD), and (2) length of platinum-free interval following first 
line therapy (6-12 months versus >12-36 months). PFS will be summarized using Kaplan-Meier 
curves and will be further characterized in terms of median PFS and PFS probabilities at 6, 12, 
18, and 24 months. Hazard ratio (HR) and its 2-sided 80% CI will be estimated using a Cox 
proportional hazard (PH) model stratified by the same two factors, with treatment as a covariate.  
 
A sensitivity analysis will be performed using the unstratified log rank test. An additional 
stratified Cox PH model will be used to evaluate the treatment effect controlling for the 
following potential prognostic baseline factors: age (<65 years, ≥65 years), race (white, non-
white), ECOG (0, 1/2), stage of disease at initial diagnosis [4 categories: I/II (combining IA, IB, 
IC, IIA, IIB, IIC), IIIA/B (combining IIIA, IIIB), IIIC, IV], baseline albumin level (lower 10% of 
distribution, other), baseline total protein level (lower 10% of distribution, other), baseline liver 
and/or brain lesions (yes, no), and baseline CA125 (≤1 ULN, >1 to ≤2 ULN, >2 to ≤3 ULN, >3 
ULN).  
 
5.4.2 Secondary Efficacy Analyses  
5.4.2.1 Overall Survival  
OS is defined as the number of months from the date of randomization to the date of death 
regardless of cause. If death is not observed for a subject, the OS time will be censored at the last 
date known to be alive or the cutoff date, whichever is earliest.  
An interim and final analysis of OS are planned to be performed.  The alpha allocation between 
the interim and final OS analyses will be determined based on the Lan-DeMets spending 
function with O’Brien-Fleming boundary.  
5.4.2.1.1 Overall Survival at PFS lock – Interim OS 
Overall survival will be assessed in the interim at the time of the PFS lock. A stratified log rank 
test will be utilized to compare OS between farletuzumab and placebo. One-sided p-value of the 
stratified log rank test will be calculated. The stratification factors are: (1) chemotherapy 
(carboplatin plus paclitaxel versus carboplatin plus PLD), and (2) length of platinum-free 
interval following first line therapy (6-12 months versus >12-36 months). OS will be 
summarized using Kaplan-Meier curves and will be further characterized in terms of median OS 
and OS probabilities at 6, 12, 18, and 24 months. The HR and its 80% CI will be estimated based 
on Cox’s proportional hazards model stratified by the same two factors. 
In addition to the OS analysis, anti-cancer therapy after on-study disease progression will also be 
summarized. Time to the first non-study anti-cancer therapy will be summarized by Kaplan-
Meier curves by treatment. 
5.4.2.1.2 Overall Survival – Final OS 
An additional cut-off date for final OS analysis will be determined based on the time when there 
are at least a total number of 124 OS events. The final OS analysis is estimated to occur 
approximately 3 years after the last subject is randomized.  


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OS will be analyzed using methods similar to the interim OS analysis. Additionally, the time to 
first non-study anti-cancer therapy will be summarized by Kaplan-Meier curves by treatment and 
the anti-cancer therapy after on-study disease progression will also be summarized. 
 
5.4.2.2 Length of First versus Second Platinum-Free Interval 
Length of first platinum-free interval (from end of previous platinum based chemotherapy to the 
first relapse) is a randomization stratification factor (6-12 months,  >12-36 months), and its value 
will be based on IRT data. Length of second platinum-free interval is defined as the period of 
time (in months) from the date of completion of platinum based chemotherapy (last dosing date) 
during the study to the date of progression or death, with its ending point, with censoring if 
applicale, same as PFS. 
The number and proportion of subjects (with 95% CI) in each length category of second 
platinum-free interval will be presented within each treatment group and by length of first 
platinum-free interval (6-12 months versus >12-36 months).  
5.4.2.3 Objective Response Rate 
The Objective Response Rate (ORR) is defined as percentage of subjects achieving either a 
complete response (CR) or partial response (PR) according to RECIST 1.1 criteria. Tumor 
assessments performed up to the initiation of further anticancer treatment will be considered. 
Subjects who have no radiographic evaluations subsequent to the first dose of Test Article will 
be included in the count of subjects who fail to achieve a Complete Response (CR) or Partial 
Response (PR). In addition, the best of response (complete response, partial response, stable 
disease, progressive disease, not evaluable, or not applicable) will be summarized by treatment 
group. 
A stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare ORR. Stratification 
factors are: (1) chemotherapy (carboplatin plus paclitaxel versus carboplatin plus PLD), and (2) 
length of platinum-free interval following first line therapy (6-12 months versus >12-36 months). 
Treatment estimates and differences in proportions will be presented with corresponding two-
sided 95% CIs.  
5.4.2.4 Disease Control Rate 
The Disease Control Rate (DCR) is defined as percentage of subjects achieving a CR, PR or 
stable disease (SD) according to RECIST 1.1 criteria. Tumor assessments performed up to the 
initiation of further anticancer treatment will be considered. Subjects who have no radiographic 
evaluations subsequent to the first dose of Test Article will be included in the count of subjects 
who fail to achieve a CR, PR or SD. 
A stratified CMH test will be used to compare DCR utilizing a method similar to comparisons of 
ORR (see section 5.4.2.3).  


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5.4.2.5 Time to Response  
The Time to Response (TTR) will be defined among CR and PR responders only. TTR is defined 
as the number of months from the date of randomization to the date of first observation of CR or 
PR according to RECIST 1.1 criteria.  
TTR will be summarized using descriptive statistics and KM curves. 
5.4.2.6 Duration of Response  
The DOR is defined as the number of months from the date of first observation of CR or PR to 
the first observation of disease progression according to RECIST 1.1 criteria or the date of death 
regardless of cause. DOR will be defined only for subjects who achieve a CR or PR according to 
RECIST 1.1 criteria. If RECIST 1.1 disease progression or death is not observed for a subject, 
DOR time will be censored on the last on-study tumor assessment (radiographic imaging) date 
prior to data cutoff. 
DOR will be summarized using descriptive statistics and KM curves for both the PFS data cutoff 
and final data. 
5.4.2.7 Exposure-Response 
Exposure response analysis will be presented in a separate document. 
5.4.3 Exploratory Efficacy Analysis 
Serum CA125 change pattern during the study will be explored to assess if there is treatment 
effect on CA125 in this predefined population with baseline serum CA125 3xULN (105 U/mL). 
Longitudinal serum CA125 levels will be collected during the study. Change pattern in CA125 
will be explored. Average of time point CA125 will be summarized by treatment group, and will 
also be plotted.  
Exploratory analyses for efficacy endpoints including PFS, OS, ORR, and DOR will also be 
conducted in each of the two chemotherapy strata (carboplatin plus paclitaxel and carboplatin 
plus PLD).  Similar analyses described for the two chemotherapy strata combined will be 
conducted in each of the two chemotherapy strata, in which the stratified analyses will be 
stratified only by length of platinum-free-interval following first line therapy (6-12 months 
versus >12-36 months). 
CMH analyses will be conducted specifically for: 
 ORR in each of the two chemotherapy strata, in which the stratified analyses will be 
stratified only by length of platinum-free interval following first line therapy (6-12 versus 
>12-36 months). 
  DCR in each of the two chemotherapy strata. 


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5.5 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
5.5.1 Phamacokinetic Analyses  
PK concentrations will be measured by the Sponsor Bioanalytical group. Listing and summary 
tables will be provided by Syneos Health. 
Descriptive statistics (n, median, minimum [min], maximum [max], etc.) will be used to 
summarize farletuzumab serum level data at each planned relative time point in the farletuzumab 
serum level evaluable population. Below limit of quantitation (BLQ) values will be set to zero 
prior to calculations of descriptive statistics. If the mean (or median) results in a BLQ value, it 
will be reported as such. The Safety Analysis Set will be used for analysis on individual serum 
concentrations. 
Farletuzumab serum level data will be analyzed using a population PK approach to estimate 
population PK parameters. Exposure-response relationships between farletuzumab exposure and 
key efficacy variables, including PFS and OS, will be analyzed via a population 
PK/Pharmacodynamic analyses. Details of the planned population PK and PK/Pharmacodynamic 
analyses will be outlined in a separate analysis plan.  
5.5.2 Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses  
Correlation analysis will be conducted to evaluate the relationship between serum and tissue 
CA125 levels, as well as the relationship between serum and tissue folate receptor alpha levels. 
Exploratory analyses of molecular markers (DNA, RNA, miRNA, tumor gene/protein expression 
and/or serum/plasma proteins) will be performed to determine if a correlation can be established 
between the presence or change in level of a marker and the response to therapy. They may be 
performed and reported separately. Details of these analyses may be described in a separate 
analysis plan. 
5.6 Safety Analysis  
Safety data, presented by treatment group, will be summarized on the Safety Analysis Set. Data 
will be summarized by n, mean, standard deviation, median, minimum, and maximum for 
continuous variables; and, n [%] for categorical variables. 
Safety variables include extent of exposure to study drugs, measures of drug tolerability 
(treatment discontinuations, treatment delays, and dose reductions), Treatment-Emergent 
Adverse Events (TEAEs), Treatment-Related Adverse Events (TRAEs), clinical laboratory 
parameters, 12-lead ECG results, Eastern Cooperative Oncology Group (ECOG) performance 
status assessments, and Anti-Drug Antibody (ADA).  
Study Day 1 for all safety analyses will be defined as the date of the first dose of Test Article. 
All subjects included in the Safety Analysis Set will be evaluated by treatment group. In 
addition, analyses will be provided for the Combination Treatment and single-agent Maintenance 


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Treatment safety sub-populations. Exposure and dosing modification summaries will be repeated 
for each chemotherapy (carboplatin, paclitaxel, PLD). 
5.6.1 Adverse Events 
Adverse events for this study will be reported in many forms; i.e., TEAEs, TRAEs, DHAEs, 
ILDs, and SAEs. For the purpose of this study, if an AE is reported as a partial date, then missing 
date imputations will be utilized (see section 7.1.1). Below is a descriptive list of AEs which will 
be reported for this study: 
 A treatment-emergent adverse event (TEAE) is any AE that developed or worsened in 
severity during the on-treatment period (from the first dose of Test Article to 30 days 
after the last dose of Test Article). 
 A treatment-related adverse event (TRAE) is defined as a TEAE that was classified by 
the investigator as related to Test Article exposure. 
 A hypersensitivity AE is defined as a TEAE with an onset date occurring the same day or 
the day after exposure to Test Article from a pre-defined list of AE terms (see section 
12.6.1.1).  
 A drug hypersensitivity adverse event (DHAE) is any hypersensitivity AE accompanied 
by a positive titer for ADA observed in any sample on or subsequent to the onset of the 
AE (see section 12.6.1.2). 
 Interstitial lung disease (ILD) AEs are defined using the MedDRA preferred terms and 
codes from the narrow search SMQ for ILD (see section 12.6.2). The ILD terms are used 
to identify pulmonary AEs.  
 A serious adverse event (SAE) is defined as any AE that causes death, is life threatening, 
requires or prolongs hospitalization, leads to a persistent or significant disability, is a 
congenital anomaly or birth defect, or is classified by the investigator as an important 
medical event. 
Adverse events will be summarized by incidence and listed by the MedDRA system organ class 
(SOC) and preferred term (PT), Common Terminology Criteria for Adverse Events (CTCAE) 
toxicity (severity) grade, and causal relationship to study drugs. In addition, separate summaries 
of interstitial lung disease (ILD), CTCAE grade 3 and 4 AEs, SAEs, treatment-related SAEs, 
TEAEs/TRAEs leading to death on study, and TEAEs/TRAEs leading to study drug 
discontinuation will be presented. 
5.6.2 Laboratory Values 
Actual values and changes from baseline in continuous laboratory parameters will be 
summarized using descriptive statistics by treatment group and time point. 
Hematological and chemistry laboratory parameters will be graded according to the NCI CTCAE 
criteria v4.03, where applicable. Shift tables (comparing worst on-study grade versus baseline) 
will be used to summarize parameters where NCI-CTCAE criteria have been defined. When the 


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NCI CTCAE scale is not applicable for a parameter, analyses will be performed based on out-of-
normal laboratory range values. 
The frequency and percentage of subjects having degrees of serum liver function abnormalities 
(i.e. ≥ 3x-, 5x-, 10x-, or 20x-ULN for alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST); >= 2x-ULN for bilirubin; >= 1.5x-ULN for ALP) will be summarized 
by treatment group. Serum liver function abnormalities will also be summarized using Hy’s Law 
(AST or ALT>3xULN, bilirubin>2xULN, and ALP<= 1.5xULN). 
All laboratory data will be presented in data listings and abnormal values will be noted. 
Categorical urinalysis data will be listed, but will not be tabulated. 
5.6.3 Vital Signs 
Physical examination dates will be listed for each subject. 
5.6.4 Electrocardiograms 
Shift in 12-lead ECG result from baseline to end-of-treatment will be summarized by treatment. 
5.6.5 Other Safety Analyses 
5.6.5.1 Human Anti-Drug Antibodies 
Human Anti-Drug Antibody related summaries will be completed by the Sponsor Bioanalytical 
group. 
The following endpoints will be summarized for the ADA Evaluable Population: 
 ADA Positive Subjects - the number (%) of subjects with at least 1 treatment-induced or 
treatment-boosted ADA positive sample (see definitions below) at any time after the 
initial Test Article administration in the ADA evaluable population 
 ADA Negative Subjects – the number (%) of subjects without a treatment-induced or 
treatment-boosted ADA positive sample at any time after the initial Test Article 
administration in the ADA evaluable population 
 Baseline ADA Prevalence – the number of subjects with baseline ADA as a percentage of 
the total number of subjects tested at baseline for ADA 
 Treatment-induced ADA – the number of subjects who were baseline ADA negative and 
developed an ADA response 
 Treatment-boosted ADA – the number of subjects with pre-existing (baseline) ADA that 
was boosted to a higher titer any time after initial Test Article administration. 
 ADA Incidence – the proportion of subjects with either treatment-induced ADA or 
treatment-boosted ADA 
 Occurrence and titer of neutralizing antibodies 


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As appropriate, the kinetics of binding and neutralizing ADA responses will be analyzed. This 
includes onset, defined as the number of days from initial Test Article administration to the first 
instance of treatment induced ADA among baseline ADA negative subjects; and duration, 
defined as the number of days from the first instance of treatment-induced ADA to a subsequent 
instance of negative ADA among baseline ADA negative subjects. Persistent ADA responses are 
categorized by measurable ADA levels exceeding 16 weeks (approximately 5 half-lives for a 
typical IgG response). 
5.7 Subgroup Analyses 
Subgroup analyses will be conducted on the ITT population for the following subgroups:  
 strata used in randomization 
 age (<65 years, ≥65 years old) 
 race (white, non-white) 
 ECOG (0, 1/2) 
 stage of disease at initial diagnosis [4 categories: I/II (combining IA, IB, IC, IIA, IIB, 
IIC), IIIA/B (combining IIIA, IIIB), IIIC, IV] 
 baseline CA125 (≤1 ULN, >1 to ≤2 ULN, >2 to ≤3 ULN, >3 ULN) 
 baseline albumin level (lower 10% of distribution, other) 
 baseline total protein level (lower 10% of distribution, other) 
 baseline liver and/or brain lesions (yes, no) 
 
Forest plots will be generated for HR (and CI) for PFS and OS. The plots will be generated for 
overall and within subgroups defined by each stratification factor. The HR (and CI) in the Forest 
plots for the each of the two chemotherapy strata will be calculated using stratified Cox PH 
model in which it will be stratified only by the platinum-free-interval strata. Similarly, the HR 
(and CI) in the Forest plots for the each of the two platinum-free-interval strata will be calculated 
using stratified Cox PH model in which it will be stratified only by the chemotherapy strata. 
Other subgroup analyses may be explored. 
6 DATA MONITORING COMMITTEE AND INTERIM ANALYSIS 
6.1 Data Monitoring Committee 
The first DMC review of safety data will occur when the 15th subject completes Cycle 1 of the 
Combination Treatment Phase to assure that the tolerability of the modified farletuzumab dosing 
and chemotherapy combinations are acceptable. No formal statistical hypothesis testing is 
planned for the first DMC review; therefore no adjustments to the level of significance (α) are 
necessary. 
The DMC will be composed of 3 voting members, all with oncology experience. An additional 
non-voting Syneos Health DMC support biostatistician will also be present to provide 


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consultation regarding the information presented. Following the first meeting, the DMC will 
conduct ongoing safety reviews at a minimum frequency of every 6 months. 
Additional information regarding the DMC can be found in the Data Monitoring Committee 
Charter.  
6.2 Interim Analysis 
An interim analysis for OS will be performed to accompany the primary PFS analysis lock of the 
study (see section 5.4.2.1.1). Survival status reported up to the primary analysis cut-off date will 
be included in this analysis. Study follow-up for survival will continue after the interim OS 
analysis. The alpha allocation between the interim and final OS analyses will be determined 
based on the Lan-DeMets spending function with O’Brien-Fleming boundary. 
7 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
7.1 Missing Data, Handling of Partial Adverse Event Start/Stop Dates 
7.1.1 Adverse Events 
The following algorithm should be used to estimate adverse event start dates for which only 
partial information is known: 
 Missing day and month 
o If the year is the same as the year of first day on farletuzumab, then the day and 
month of the start date of drug will be assigned to the missing fields. 
o If the year is prior to the year of first day on farletuzumab, then December 31 will 
be assigned to the missing fields. 
o If the year is after the year of first day on farletuzumab, then January 1 will be 
assigned to the missing fields. 
 Missing month only 
o Treat data as missing and replace both month and day according to the above 
procedure. 
 Missing day only 
o If the month and year are the same as the month and year of the first day on drug, 
then the start date of farletuzumab will be assigned to the missing day. 
o If the month and year are before the month and year of the first day on 
farletuzumab, then the last day of the month will be assigned to the missing day. 
o If the month and year are after the month and year of the first day on 
farletuzumab, then the first day of the month will be assigned to the missing day. 
If the resultant imputed start date is after the AE stop date (and the AE stop date is complete), the 
imputed start date will be reset to the AE stop date. 


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The following algorithm should be used to estimate adverse event stop dates, which are not 
ongoing at final visit, for which only partial information is known: 
 Year is missing  
o Date left missing. 
 Month is missing 
o Impute ‘December’. 
 Day is missing 
o Impute last date of that month. 
If the resultant imputed stop date is after the last subject visit or death date, the imputed stop date 
will be reset to the last subject visit or death date. 
7.1.2 Prior and Concomitant Therapy 
The following algorithms should be used to estimate partial and missing start or stop dates:  
 Missing start date where the stop date is recorded in full 
o If the stop date is before the date of first dose of Test Article, it will be considered 
a prior medication.  
o If the stop date is after the date of first dose of Test Article, it will be considered a 
concomitant medication.  
 Missing stop date where the start date is recorded in full  
o If the start date is after the first dose of Test Article, it will be considered a 
concomitant medication.  
 Partial start and stop dates 
o The month and year of the stop date will be used to assess whether the medication 
is prior or concomitant. For instance, if month and year exist for the stop date, this 
data will be compared with the first dose of Test Article and if the month or year 
show evidence of being after this date or on the same date (same month/year), the 
medication will be considered concomitant.  
 Missing both the start and stop dates  
o These medications will be considered concomitant. 
8 PROGRAMMING SPECIFICATIONS 
The standard operating procedures (SOPs) of InVentiv Health Clinical will be followed in the 
creation and quality control of all tables, listings, and analyses. 
 
Format of Output 
1. Unless otherwise specified, all computer-generated output should be produced in landscape 
mode.  Required margins: 1 inch on top and bottom and 1 inch on the left and right; required 


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font: Courier New; and required font size: 9. All outputs should have the following header 
line at the top of the page: 
 
Eisai Protocol: MORAb-003-011 
 
 
 
 
Page x of y 
 
 
Each output has the following footer line at the bottom of the page: 
 
Program:\...\...\<program name>.sas       Data Cutoff: ddMMMyyyy       ddMMMyyyy HH:mm  
 
 
All output should have date (date output was generated) and page number. 
Tables/listings/figures should be internally paginated in relation to total length (i.e., page 
number should appear sequentially as page n of N, where N is the total number of pages in 
the table).    
   
2. Each output should be identified by a numeral, and the output designation (e.g., Table 1) 
should be listed on the same line, before the title. A decimal system (x.y and x.y.z) should be 
used to identify tables and listings with related contents. The title is centered in initial capital 
characters. 
 
Table No. 
Table Title 
Study Population 
 
The study population should be identified immediately following the title. 
 
3. Column headings should be in initial upper-case characters. 
4. For numeric variables, include “unit” in column or row headings when appropriate. 
5. Footnotes should be single spaced, but separated by at least a double space from the bottom 
line of the table. The notes are aligned vertically by the left vertical border of the table.    
6. If the categories are not ordered (e.g., race), then only those categories for which there is at 
least 1 subject represented in 1 or more groups should be included. 
7. An Unknown or Missing category should be added to any parameter for which information is 
not available for 1 or more subjects. 
8. Listings should be sorted by treatment, subject number, and study visit, unless otherwise 
specified. 
9. In a listing, display the subject number only once for the subject with multiple records. If a 
subject’s records run across multiple pages, display the subject number once for every page. 
 
Data format 
1. Unless otherwise specified, the estimated mean and median for a set of values should be 
printed out to 1 more significant digit than the individual units of measurement and the 
standard deviation for a set of values should be printed out to 2 more significant digits than 


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the individual units of measurement. The minimum and maximum should report the same 
significant digits as the original values.  For example, for age (with raw data in whole 
years): 
           n                                    XX 
           Mean (STD) 
XX.X (XX.XX) 
           Median 
      XX.X 
           Min, Max 
     XX, XX 
2. Unless otherwise specified, data in columns of a table should be formatted as follows: 
 Alphanumeric values are left-justified.  
 Whole numbers (e.g., counts) are right-justified. 
 Numbers containing fractional portions are decimal aligned. 
3. Unless otherwise specified, percentage values should be printed with 1 digit to the right of 
the decimal point (e.g., 12.8%, 5.4%). Less-than-signs “0.1%” should be printed when 
values are 0.0 and 0.1% (not 0.0%). 
4. Unless otherwise specified, missing data should be represented on subject listings as either a 
hyphen (“-“) with a corresponding footnote (“- = unknown or not evaluated”), or as “N/A,” 
with the footnote “N/A = not applicable,” whichever is appropriate.  
5. Dates should be printed in SAS® DATE9.format (“DDMMMYYYY”: 01JUL2000). 
Missing portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as “N/A”, 
unless otherwise specified. 
 
Unless otherwise specified, time should be printed in SAS® TIME5.format (“HH:MM”: 17:30). 
Missing portions of time should be represented on subject listings as dashes (--:30). Times that 
are missing because they are not applicable for the subject are output as “N/A”, unless otherwise 
specified. 
9 STATISTICAL SOFTWARE 
Unless otherwise specified, all statistical analyses will be performed using SAS® version 9.3 or 
greater. 
10 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs. 
 


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11 REFERENCES 
Agresti, Alan. Categorical Data Analysis. 2nd Edition, 2002.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guidance (version 1.1). Eur J Cancer. 2009;45:228-47. 
FDA (2009). Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. U.S. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research 
(CBER), July 2009.  
Kleinbaum , D.G. and Klein, M. Survival Analysis. A self-learning text. 2005. 
 


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12 APPENDICES 
12.1 Schedule of Procedures/Assessments for PLD/Carboplatin Chemotherapy Arm 
Schedule for PLD/Carboplatin Chemotherapy Arm  
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
IC, demography, eligibility 
X 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor histology, disease staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
 
X 
 
X 
 
X 
 
Height/BSA/weighte 
X 
X 
 
X 
 
X 
 
X 
 
ECOG assessment 
X 
X 
 
X 
 
X 
 
X 
 
RECIST imaging—CT or MRIf 
X 
 
Xf 
Xf 
Xf 
 
X 
 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Archived tumor blockh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Chemistryi 
X 
X 
 
X 
 
X 
 
 
X 
 
Serum CA125j 
X 
X 
 
 
 
X 
 
 
 
Xj 
 
 
 
X 
 
 
 
Pregnancy test (serum, urine)k 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Biomarker blood samplel 
X 
X 
 
X 
 
Xl 
 
X 
 
 
Biomarker urine samplel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum farletuzumab samplem 
X 
 
X 
 
Xm 
 
X 
X 
X 
 
Serum ADA samplen 
X 
 
X 
 
Xn 
 
X 
X 
X 
 
Premedication (required)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Test Article administrationp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Carbo + PLD administration 
X 
 
X 
 
 
 


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Schedule for PLD/Carboplatin Chemotherapy Arm  
Concomitant medicationsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival contact, anticancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
ADA = human anti-drug antibody; AE = adverse event; BSA = body surface area; CA125 = cancer antigen 125; Carbo = carboplatin; CT =computerized tomography; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; hCG = human chorionic gonadotropin; IC = Informed Consent; IV = intravenous; 
MRI = magnetic resonance imaging; PE = physical examination; PLD = pegylated liposomal doxorubicin; Rand. = Randomization; RECIST = Response Evaluation Criteria In Solid 
Tumors. 
a: All Screening procedures are to be completed within 30 days prior to and including the date of Randomization unless otherwise specified.  Procedures for the Cycle 1 Week 1 
Visit do not need to be repeated if they were conducted within 14 days of Randomization. 
b: All visits should be scheduled to occur within ±2 days of the target visit date, unless otherwise specified.  The EOT Visit must be performed within 7 days of the last infusion of 
Test Article (farletuzumab or placebo), unless the subject’s medical management warrants otherwise.  Scans performed within 2 week of the last infusion of Test Article do not 
need to be repeated.  
c: Follow-up visits will be performed at 30 and 60 days (within ±7 days) after the date of last Test Article administration.  Thereafter, subjects will be contacted by phone monthly 
for the next 7 months and then every other month until death or the end of the study.  During these visits and calls, anticancer therapy treatments will be collected and recorded.  
Subjects who discontinue treatment for reasons other than disease progression (radiographic) will be followed radiographically until disease progression or initiation of another 
anticancer therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), where possible. 
d: Comprehensive PEs will be conducted during Screening and at the EOT Visit.  Abbreviated PEs (including follow-up of interval complaints and review of the cardiorespiratory 
system) will be conducted at Week 1 of each cycle during the Combination Treatment Phase and Week 1 of every third cycle during the Maintenance Treatment Phase 
(beginning with Maintenance Cycle 3). 
e: Height will be collected during Screening only.  Body weight will be measured during Screening, prior to Test Article administration on Week 1 of each cycle, and at the EOT 
Visit.  BSA should only be recalculated for the purpose of chemotherapy dose modification if the subject experiences a > 10% change in body weight.   
f: RECIST 1.1 will be used for this study.  CT or MRI scans may be obtained any time during the week prior to the next scheduled visit.  Scans will be performed during Screening; 
every 6 weeks during Combination Treatment Phase (eg, Cycle 2 Week 2, Cycle 3 Week 4, Cycle 5 Week 2, and Cycle 6 Week 4); every 9 weeks during the Maintenance 
Treatment Phase (Week 3 of every third cycle beginning with Maintenance Cycle 3), and at the EOT Visit.  Subjects who discontinue treatment for reasons other than disease 
progression (radiographic) will be followed radiographically until disease progression or initiation of another anticancer therapy, on the same schedule as the Maintenance 
Treatment Phase (ie, every 9 weeks), where possible.  Scans performed within 2 weeks of the last Test Article administration do not need to be repeated. 
g: 12-lead ECG will be performed during Screening and at the EOT Visit. 
h: At Screening, the archival tumor tissue sample (taken at the time of initial diagnosis of ovarian cancer) will be collected for central histology confirmation and exploratory 
analyses of potential biomarkers.  In the absence of the original primary tumor block, 15 to 20 unstained slides are required.  If a minimum of 15 slides are not available, contact 
the CRA to discuss.   
 
i: Hematology and Chemistry will be obtained during Screening, prior to Test Article infusion on Week 1 of every cycle during the Combination Treatment Phase, Week 1 of every 
third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.  Hematology and Chemistry for the Combination Treatment 
Phase Cycle 1 Week 1 visit do not need to be repeated if the Screening samples were obtained within 14 days of Cycle 1 Day 1 
j: Screening CA125 must be assessed by the central laboratory within 2 weeks prior to randomization.  On-study CA125 samples will be obtained at Week 1 of every cycle during 
the Combination Treatment Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.   
k: Only for female subjects of childbearing potential.  At Screening, a serum pregnancy test (hCG) is to be conducted, which will be analyzed by the central laboratory from the 
same vial of blood drawn for the chemistry panel.  Prior to Test Article administration at the following timepoints, a highly-sensitive urine pregnancy test (hCG) will be 


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Schedule for PLD/Carboplatin Chemotherapy Arm  
conducted locally at the site:  Cycle 1 Day 1, Week 1 of all Combination and Maintenance Treatment cycles, the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
l: Blood samples for biomarker analysis will be collected during Screening within 2 weeks prior to Randomization, at Week 1 of every cycle during the Combination Treatment 
Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT visit.  Urine samples will be collected at 
the Screening visit only, within 2 weeks prior to Randomization.  Details for sample collection and handling are provided in the laboratory manual. 
m: Serum farletuzumab samples are to be drawn pre- and postinfusion (within 1 hour after the completion of the infusion) of Test Article at Week 1 of each cycle during the 
Combination Treatment Phase, at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- 
and 60-Day Follow-up Phase visits.   
n: Serum ADA samples are to be drawn prior to infusion of Test Article at Week 1 of each cycle during the Combination Treatment Phase, at Week 1 of every sixth cycle during the 
Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
o: All subjects must be premedicated within 4 hours prior to each infusion of Test Article with acetaminophen 650 mg, or the local equivalent.  Premedications for carboplatin 
should be given according to country-specific labeling.  All premedications must be recorded on the Premedications eCRF page. 
p: The first dose of Test Article should be administered as close to the day of Randomization as possible but no more than 7 days following randomization; otherwise, medical 
monitor approval is required.  Test Article will be administered IV once weekly prior to chemotherapy during the Combination Treatment Phase and once weekly during the 
Maintenance Treatment Phase.  All subjects will receive a loading dose for the first 2 weeks (Cycle 1, Weeks 1 and 2) of farletuzumab (or placebo) 10 mg/kg, followed by 
5 mg/kg weekly until disease progression or discontinuation of Test Article.  
q: Concomitant medications are any new, discontinued, or ongoing medications (excluding protocol-required premedications) that have been taken within 30 days prior to the first 
dose of Test Article until 30 days after the last dose of Test Article (first follow-up visit).   
r: All AEs occurring after the subject signs the IC form and continuing through 30 days after the last infusion of Test Article should be recorded.  Serious AEs that are ongoing at 
the time of discontinuation of Test Article will be followed until resolution (or until stable if resolution is not expected). 
 
 


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12.2 Schedule of Procedures/Assessments for Paclitaxel/Carboplatin Chemotherapy Arm 
Schedule for Paclitaxel/Carboplatin Chemotherapy Arm 
Evaluations 
Screen 
Phasea 
Combination 
Treatment Phase 
Maintenance 
Treatment Phase 
Test 
Article 
Admin 
Only 
Visits 
EOT 
Visitb 
Follow-up Phasec 
Cycle 1b 
Cycles 2 – 6b 
Cycle(s) 1 – Xb 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
Wk 
1 
Wk 
2 
Wk 
3 
30-
Day 
Safety 
Visit 
60-
Day 
Visit 
Follow-
up 
Phone 
Call 
Day 
˗30 to 
Rand. 
Day 
1 
Day 
8 
Day 15 
Day 
1 
Day 
8 
Day 15 
Day 
1 
Day 
8 
Day 
15 
IC, demography, eligibility 
X 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor histology, disease staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
 
X 
 
Height/BSA/weighte 
X 
X 
X 
X 
 
X 
 
ECOG assessment 
X 
X 
X 
X 
 
X 
 
RECIST imaging—CT or MRIf 
X 
Xf 
Xf 
 
X 
 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Archived tumor blockh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Chemistryi 
X 
X 
X 
X 
 
 
X 
 
Serum CA125j 
X 
X 
 
 
Xj 
 
 
Xj 
 
 
 
X 
 
 
 
Pregnancy test (serum, urine)k 
X 
X 
X 
X 
 
X 
X 
X 
 
Biomarker blood samplel 
X 
X 
X 
Xl 
 
X 
 
 
Biomarker urine samplel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum farletuzumab samplem 
X 
X 
Xm 
 
X 
X 
X 
 
Serum ADA samplen 
X 
X 
Xn 
 
X 
X 
X 
 
Premedication (required)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Test Article administrationp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Carbo + Pacli administration 
X 
X 
 
 
Concomitant medicationsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Schedule for Paclitaxel/Carboplatin Chemotherapy Arm 
Survival contact, anticancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
ADA = human anti-drug antibody; AE = adverse event; BSA = body surface area; CA125 = cancer antigen 125; Carbo = carboplatin; CT =computerized tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; hCG = uman chorionic gonadotropin; IC = informed consent; 
IV = intravenous; MRI = magnetic resonance imaging; Pacli = paclitaxel; PE = physical examination; Rand. = Randomization; RECIST = Response Evaluation Criteria In Solid 
Tumors. 
a: All Screening procedures are to be completed within 30 days prior to and including Randomization unless otherwise specified.  Procedures for the Cycle 1 Week 1 Visit do not 
need to be repeated if they were conducted within 14 days of Randomization.   
b: All visits should be scheduled to occur within ±2 days of the target visit date, unless otherwise specified.  The EOT Visit must be performed within 7 days of the last infusion of 
Test Article (farletuzumab or placebo), unless the subject’s medical management warrants otherwise.  Scans performed within 2 week of the last infusion of Test Article do not 
need to be repeated. 
c: Follow-up visits will be performed at 30 and 60 days (within ±7 days) after the date of last Test Article administration.  Thereafter, subjects will be contacted by phone monthly 
for the next 7 months and then every other month until death or the end of the study.  During these visits and calls, anticancer therapy treatments will be collected and recorded.  
Subjects who discontinue treatment for reasons other than disease progression (radiographic) will be followed radiographically until disease progression or initiation of another 
anticancer therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), where possible. 
d: Comprehensive PEs will be conducted during Screening and at the EOT Visit.  Abbreviated PEs (including follow-up of interval complaints and review of the cardiorespiratory 
system) will be conducted at Week 1 of each cycle during the Combination Treatment Phase and at Week 1 of every third cycle during the Maintenance Treatment Phase 
(beginning with Maintenance Cycle 3). 
e: Height will be collected during Screening only.  Body weight will be measured during Screening, prior to Test Article administration on Week 1 of each cycle, and at the EOT 
Visit.  BSA should only be recalculated for the purpose of chemotherapy dose modification if the subject experiences a > 10% change in body weight.   
f: RECIST 1.1 will be used for this study.  CT or MRI scans may be obtained any time during the week prior to the next scheduled visit.  Scans will be performed during Screening; 
every 6 weeks during the Combination Treatment Phase (Week 3 of every second cycle); and then every 9 weeks (Week 3 of every third cycle beginning with Maintenance Cycle 
3 ) thereafter during the Maintenance Treatment Phase, and at the EOT Visit.  Subjects who discontinue treatment for reasons other than disease progression (radiographic) will 
be followed radiographically until disease progression or initiation of another anticancer therapy, on the same schedule as the Maintenance Treatment Phase (ie, every 9 weeks), 
where possible.  Scans performed within 2 weeks of the last Test Article administration do not need to be repeated. 
g: 12-lead ECG will be performed during Screening and at the EOT Visit. 
h: At Screening, the archival tumor tissue sample (taken at the time of initial diagnosis of ovarian cancer) will be collected for central histology confirmation and exploratory 
analyses of potential biomarkers.  In the absence of the original primary tumor block, 15 to 20 unstained slides are required.  If a minimum of 15 slides are not available, contact 
the CRA to discuss.   
 
i: Hematology and Chemistry will be obtained during Screening, prior to Test Article infusion at Week 1 of every cycle during the Combination Treatment Phase, Week 1 of every 
third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.  Hematology and Chemistry for the Combination Treatment 
Phase Cycle 1 Week 1 visit do not need to be repeated if the Screening samples were obtained within 14 days of Cycle 1 Day 1. 
j: Screening CA125 must be assessed by the central laboratory within 2 weeks prior to randomization.  On-study CA125 samples will be obtained at Week 1 of every cycle during 
the Combination Treatment Phase; at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), and at the EOT Visit.   
k: Only for female subjects of childbearing potential.  At Screening, a serum pregnancy test (hCG) is to be conducted, which will be analyzed by the central laboratory from the 
same vial of blood drawn for the chemistry panel.  Prior to Test Article administration at the following timepoints, a highly-sensitive urine pregnancy test (hCG) will be 


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Schedule for Paclitaxel/Carboplatin Chemotherapy Arm 
conducted locally at the site:  Cycle 1 Day 1, Week 1 of all Combination and Maintenance Treatment cycles, the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
l: Blood samples for biomarker analysis will be collected during Screening within 2 weeks prior to randomization, at Week 1 of every cycle during the Combination Treatment 
Phase; at Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3);  and at the EOT visit.  Urine samples will be collected at 
the Screening visit only, within 2 weeks prior to Randomization.  Details for sample collection and handling are provided in the laboratory manual. 
m: Serum farletuzumab samples are to be drawn pre- and postinfusion (within 1 hour after the completion of the infusion) of Test Article on Week 1 of each cycle during the 
Combination Treatment Phase, on Week 1 of every third cycle during the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- 
and 60-Day Follow-up Phase visits.   
n: Serum ADA samples are to be drawn prior to infusion of Test Article on Week 1 of each cycle during the Combination Treatment Phase, on Week 1 of every sixth cycle during 
the Maintenance Treatment Phase (beginning with Maintenance Cycle 3), at the EOT Visit, and at the 30- and 60-Day Follow-up visits. 
o: All subjects must be premedicated within 4 hours prior to each infusion of Test Article with acetaminophen 650 mg, or the local equivalent.  Premedications for carboplatin and 
paclitaxel should be given according to country-specific labeling.  All premedications must be recorded on the Premedications eCRF page. 
p: The first dose of Test Article should be administered as close to the day of Randomization as possible but no more than 7 days following randomization; otherwise, medical 
monitor approval is required.  Test Article will be administered IV once weekly prior to chemotherapy during the Combination Treatment Phase and once weekly during the 
Maintenance Treatment Phase.  All subjects will receive a loading dose for the first 2 weeks (Cycle 1, Weeks 1 and 2) of farletuzumab (or placebo) 10 mg/kg, followed by 
5 mg/kg weekly until disease progression or discontinuation of Test Article.  
q: Concomitant medications are any new, discontinued, or ongoing medications (excluding protocol-required premedications) that have been taken within 30 days prior to the first 
dose of Test Article until 30 days after the last dose of Test Article (first follow-up visit). 
r: All AEs occurring after the subject signs the IC form and continuing through 30 days after the last infusion of Test Article should be recorded.  Serious AEs that are ongoing at 
the time of discontinuation of Test Article will be followed until resolution (or until stable if resolution is not expected). 
 
 


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12.3 Quick Reference for Protocol-Specific Response Criteria 
The following protocol-specific response criteria (copied from Appendix 4 of the study protocol) 
are based on RECIST (version 1.1) criteria. 
Methods of Measurement 
 
 
As part of the disease assessment by RECIST 1.1 criteria, Computer Tomography (CT) with 
IV and oral contrast of the chest, abdomen and pelvis will be performed. Following baseline, 
subsequent chest CT is only required if a lesion is identified in the chest or metastasis to the 
chest is suspected at any point during the study. 
 
In subjects who have been followed previously by Magnetic Resonance Imaging (MRI), 
those who are intolerant of CT contrast media, or where there is a preference for MRI, MRI 
is acceptable. If MRI of the chest, abdomen, and pelvis is performed, CT of the chest without 
contrast must also be performed at baseline. Following baseline, subsequent non-contrast CT 
of the chest is only required if a target lesion is identified in the chest or metastasis to the 
chest is suspected at any point during the study. 
 
This guideline has defined measurability of lesions on CT scan based on the assumption that 
CT slice thickness is 5mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. 
 
Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions. 
However, lesions on chest x-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung 
 
When effusions are known to be a potential adverse effect of treatment (e.g., with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or SD in order to differentiate between 
response (or SD) and progressive disease (PD) 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
within 4 weeks of the randomization 
 
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. 
 
 
 


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Evaluable disease  
An evaluable disease includes lesions that meet criteria for measurable disease per RECIST 1.1 
or radiographically visible and evaluable lesions. Examples of evaluable but not measurable 
lesion include: 
- 
small liver lesions, omental implants, serosal bowel implants, pelvic masses, or skin 
lesion that do not meet criteria for the size of measurable (<1cm) but can be considered 
non-measurable evaluable lesions at eligibility/screening 
- 
pathologic lymph nodes with a short axis measuring > 10 mm and < 15 mm 
Subjects with only ascites or pleural effusion are not considered eligible for this protocol. 
 
Measurable disease 
A measureable disease is defined as the presence of at least one measurable lesion. 
 
Measurable lesions  
A measurable lesion must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
- 
10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
- 
15 mm in short axis for a lymph node when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm) 
 
 


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Baseline Documentation of “Target” and “Non-Target” Lesions 
 
For subjects without measurable disease, all evaluable lesions are considered as non-target 
lesions 
 
When more than one measurable lesion is present at Baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at Baseline. (This 
means in instances where subjects have only one or 2 organ sites involved a maximum of 2 
and 4 lesions respectively will be recorded.) 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements 
 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. Pathological nodes which 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. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should 
be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but they should 
be followed as ‘present’, ‘absent’, or ‘unequivocal progression’. In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case 
report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
 
 


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Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target and non-target lesions. 
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. 
 
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. 
NOTE: For Special notes on the assessment of target lesions that are lymph nodes, target lesions 
that become ‘too small to measure,’ and lesions that split or coalesce on treatment, please refer to 
the RECIST 1.1 guidelines (Eisenhauer, et al., 2009). 
Evaluation of Non-Target Lesions: 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10mm 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 (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
NOTE: For special notes on the assessment of progression of non-target disease, as well as new 
lesions, please refer to the RECIST 1.1 guidelines (Eisenhauer, et al., 2009). 
 
 


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Evaluation of Time Point Response 
The Time Point Response Table below provides a summary of the overall response status 
calculation at each time point for subjects who have measurable disease at baseline. 
Time Point Response: Subjects with Target (+/– Non-target) Disease 
Target Lesions 
Non-target 
Lesions 
New 
Lesions 
Overall 
CR 
CR 
No 
CR 
CR 
Non-CR /  
non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or  
not all evaluated 
No 
PR 
SD 
Non-PD or  
not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
CR = Complete Response; PR = Partial Response; SD = Stable 
Disease; PD = Progressive Disease; NE = Not Evaluable 
 
 
12.4 Censoring Rules 
12.4.1 Censoring Rules for Overall Survival 
Situation 
End Date 
Censored 
Death before or on data cut-off date 
Date of Death 
No 
Death after data cut-off date 
Date of data cut-off 
Yes 
Alive at data cut-off date 
Date of data cut-off 
Yes 
Lost to follow-up prior to cut-off data 
Last known date to be alive 
Yes 
Withdrawal of consent prior to cut-off 
Last known date to be alive 
Yes 
 
 
 


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12.4.2 Censoring Rules for Progression-Free Survival Based on Investigator 
Assessment 
 
Situation 
End Date 
Censored 
Investigator documented PD 
Date of the first assessment of the series of 
the tests that determined PD 
No 
Death during the study before PD 
Date of death 
No 
No baseline or post baseline tumor 
assessment 
Date of randomization 
Yes 
No progression and no death at the time of 
data cutoff 
Date of last adequate tumor assessment prior to 
data cutoff 
Yes 
Non-study anti-cancer treatment initiated 
before progression or death 
Date of last adequate tumor assessment prior to 
initiation of non-study anti-cancer treatment 
Yes 
Death or progression after two or more 
missed tumor assessments 
Date of last adequate tumor assessment prior to 
missed tumor assessment 
Yes 
General Considerations: 
 
Investigator-based PFS = (End Date – Randomization Date) + 1 
 
Tumor response assessments will be considered “adequate” for analysis if they are assigned as CR, 
PR, SD, PD, or Non-CR/Non-PD, and are not censored (e.g., obtained prior to initiation of nonstudy 
antitumor treatment). 
 
Tumor response assessment dates will be assigned based on the date the image was performed, not 
the date the image was assessed. 
 
Tumor response assessments obtained after initiation of nonstudy antitumor treatment will be 
considered “inadequate” for analysis, flagged in the data listings, and excluded from all tumor 
response based efficacy analyses. Tumor response assessments obtained the same day as 
initiation of nonstudy antitumor treatment will not be excluded. 
 
Two or more tumor response assessments will be considered missed if more than 13 weeks (during 
combination therapy), more than 19 weeks (during single-agent maintenance therapy), or more 
than 16 weeks (across combination therapy and single-agent maintenance therapy) have elapsed 
since the last tumor response assessment. If a subject develops progressive disease or dies after 
this interval, the tumor response assessment will be excluded from the analysis. However, if an 
adequate tumor response assessment assigned as CR, PR, or SD is obtained after this interval, then 
the tumor response assessment will not be excluded from the analysis. 
       Abbreviations: CR=Complete Response; NE=Not Evaluable; PD=Progressive Disease; SD=Stable Disease


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12.5 General Considerations for Secondary Efficacy Endpoints: ORR, TTR, 
and Length of Remission 
 
Tumor response assessments will be considered “adequate” for analysis if they are 
assigned as CR, PR, SD, or PD and are not censored (e.g., obtained prior to initiation of 
nonstudy antitumor treatment). 
 
 
Tumor response assessment dates will be assigned based on the date the image was 
performed, not the date the image was assessed. 
 
 
Tumor response assessments obtained after initiation of nonstudy antitumor treatment 
will be considered “inadequate” for analysis, flagged in the data listings, and excluded 
from all tumor response based efficacy analyses. Tumor response assessments obtained 
the same day as initiation of nonstudy antitumor treatment will not be excluded. 
 
 
Two or more tumor response assessments will be considered missed if more than 13 weeks 
(during combination therapy), more than 19 weeks (during single-agent maintenance 
therapy), or more than 16 weeks (across combination therapy and single-agent 
maintenance therapy) have elapsed since the last tumor response assessment. If a subject 
develops progressive disease or dies after this interval, the tumor response assessment will 
be excluded from the analysis. However, if an adequate tumor response assessment 
assigned as CR, PR, or SD is obtained after this interval, then the tumor response 
assessment will not be excluded from the analysis. 
 


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12.6 Adverse Events of Interest (AEI)  
12.6.1 Hypersensitivity AEs 
12.6.1.1 Overall Hypersensitivity AEs 
A Hypersensitivity AE is defined as a TEAE with an onset date occurring the same day or the 
day immediately after exposure to Test Article for a pre-specified list of terms. The terms 
include, but are not limited to, the following signs and symptoms: 
o Cytokine Release Syndrome 
o Flushing 
o Fever 
o Rigors/chills 
o Sweating/diaphoresis 
o Pruritus/itching 
 
o Urticaria 
o Bronchospasm/wheezing 
o Bronchial edema 
 
In order for an AE to be classified as hypersensitivity AE, the following criteria are 
simultaneously required: 
1. The AE term must meet a pre-identified MedDRA term in a pre-defined group search 
basket for hypersensitivity AEs.  
2. The AE term must be a TEAE. 
3. The AE must follow the 2-day rule; that is, the AE must have an onset date occurring the 
same day or the day after exposure to Test Article. 
12.6.1.2 Hypersensitivity AEs with Positive ADA (DHAEs)  
For farletuzumab, a DHAE is a hypersensitivity AE (programmably identified as specified in 
12.6.1.1) accompanied by a positive titer for ADA. The determination of DHAE status for each 
hypersensitivity AE is dependent on the ADA sample results obtained on or subsequent to the 
onset date of the AEI. There could be multiple subsequent ADA samples. If the ADA results are 
positive for at least one of these samples, the hypersensitivity AE will be considered a DHAE. 
 
12.6.2 Interstitial Lung Disease (ILD)  
A separate excel spreadsheet containing a group search basket for Interstitial Lung Disease, 
using MedDRA query narrow search SMQ, will be used to identify ILD AEs. ILD AEs will 
include, but not limited to the following terms: 
o Interstitial lung disease 
o Pulmonary fibrosis 
o Pneumonitis   
 


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SIGNATURE PAGE 
Author(s):   
 
 
 
 
, Oncology Business Group, Eisai, Inc. 
 
Date 
 
 
 
 
 
Syneos Health 
 
 
Date 
Approval: 
 
 
 
 
 
 
 
, Oncology Business Group, Eisai, Inc. 
 
 
Date 
 
 
 
t, Oncology Business Group, Eisai, Inc. 
 
 
Date 
 
 
 
 
Syneos Health 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD