Clinical trial NCT02202746
Conditions: Breast Cancer Metastatic Breast Cancer MBC HER2 Positive HER2 Estrogen Receptor Positive ER Triple Negative
Keywords: Breast cancer Metastatic breast cancer MBC HER2 positive HER2+ Estrogen receptor positive ER+ Triple negative FGFR1 11q FGF aberrant Biomarker negative FGF non-aberrant
Sponsor: Clovis Oncology, Inc.
Start date: 2014-09-09; Completion date: 2017-01-18
Enrollment: 178 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether lucitanib is safe and effective in the treatment of patients with FGF aberrant metastatic breast cancer, as well as in the treatment of patients with biomarker negative (FGF non-aberrant) metastatic breast cancer.

Detailed description:
Lucitanib is a selective, orally available tyrosine kinase inhibitor targeting FGFR1-3, VEGFR1-3, and PDGFRα and β, with activity in relevant cell lines and animal models.

The first in human trial of lucitanib demonstrated that daily dosing with lucitanib can provide durable clinical responses in patients with FGFR1- or 11q (FGF3, FGF4, Cyclin D1, or FGF19)-amplified breast cancer. RECIST partial responses (PRs) were also observed in patients not known to have FGF abnormalities.

Based on these results, this study is designed to explore the safety and anti-tumor activity of daily lucitanib in breast cancer patients with and without alterations of the FGF pathway.

Arms: arm 1: 10 mg of lucitanib daily in patients with FGFR1-amplified or 11q-amplified metastatic breast cancer. arm 2: 15 mg of lucitanib daily in patients with FGFR1-amplified and 11q-amplified metastatic breast cancer. arm 3: 10 mg of lucitanib daily in patients with FGFR1 non-amplified and 11q non-amplified metastatic breast cancer.
Interventions: intervention 1: Lucitanib
Intervention descriptions: intervention 1: Lucitanib is a potent, orally available selective inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors (FGFR1-3), vascular endothelial growth factor receptors (VEGFR1-3), and platelet-derived growth factor receptors alpha and beta (PDGFR alpha and beta)

Protocol documents:
Prot_000.pdf: 
Clovis Oncology, Inc. 
 
Clinical Protocol 
Lucitanib 
CO-3810-025 
 
 27 January 2016 
 
 
 
Page 1 of 126 
Confidential 
 
A phase 2, open-label, multicenter, safety and efficacy study of oral 
lucitanib in patients with FGF aberrant metastatic breast cancer 
 
Protocol Number: 
CO-3810-025 
Investigational Product: 
Lucitanib (S 80881/CO-3810) 
IND Number: 
 
Development Phase: 
Phase 2 
Indication Studied: 
Fibroblast growth factor receptor 1 (FGFR1)- or 11q (FGF3, 
FGF4, Cyclin D1, or FGF19)-amplified metastatic breast 
cancer 
Sponsor Name and Address: 
Clovis Oncology, Inc. 
5500 Flatiron Parkway 
Boulder, CO 80301 USA 
 
 
 
Responsible Medical Officer: 
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of 
Helsinki, clinical research guidelines established by the Code 
of Federal Regulations (Title 21, CFR Parts 50, 56, and 312), 
and ICH GCP Guidelines.  Essential study documents will be 
archived in accordance with applicable regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are 
privileged or confidential and may not be disclosed unless such disclosure is required by 
applicable laws and regulations.  In any event, persons to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further 
disclosed by them.  These restrictions on disclosure will apply equally to all future 
information supplied to you which is indicated as privileged or confidential. 




Clovis Oncology, Inc. 
 
Clinical Protocol 
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CO-3810-025 
 
 27 January 2016 
 
 
 
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Protocol Acceptance Form 
Protocol: 
CO-3810-025 
Title: 
A phase 2, open-label, multicenter, safety and efficacy study of oral 
lucitanib in patients with FGF aberrant metastatic breast cancer 
Date: 
27 January 2016 
Version: 
Reviewed and Approved by: 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study.  I agree to conduct this study as described and according to the 
Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory requirements. 
 
 
 
  
Investigator’s Signature 
 Date 
 
 
 
  
Name (printed) 
  
 


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Clinical Protocol 
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Table of Contents  
Description 
Page 
1 
SYNOPSIS ............................................................................................ 12 
2 
LIST OF ABBREVIATIONS AND 
DEFINITIONS OF TERMS ............................................................... 28 
3 
INTRODUCTION ............................................................................... 31 
3.1 
CURRENT STANDARD OF CARE FOR 
METASTATIC BREAST CANCER...............................................................31 
3.2 
TARGETING FGF PATHWAY 
METASTATIC BREAST CANCER...............................................................31 
3.3 
TARGETING ANGIOGENESIS IN 
METASTATIC BREAST CANCER...............................................................32 
3.4 
LUCITANIB FOR THE TREATMENT OF 
FGF-ABERRANT METASTATIC BREAST 
CANCER .........................................................................................................32 
3.5 
NONCLINICAL OVERVIEW ........................................................................32 
3.5.1 
Nonclinical pharmacology ...............................................................................32 
3.5.1.1 
Pharmacodynamics ..........................................................................................32 
3.5.1.2 
Safety pharmacology .......................................................................................33 
3.5.2 
Nonclinical pharmacokinetics and metabolism ...............................................33 
3.5.3 
Toxicology .......................................................................................................33 
3.6 
CLINICAL EXPERIENCE WITH LUCITANIB ...........................................34 
3.6.1 
Clinical study #E-3810-I-01/CL1-80881-007 .................................................34 
3.6.1.1 
Pharmacokinetics .............................................................................................34 
3.6.1.2 
Preliminary clinical efficacy ............................................................................34 
3.6.1.3 
Summary of clinical safety ..............................................................................35 
3.7 
RATIONALE FOR STUDY ...........................................................................36 
4 
STUDY OBJECTIVES AND 
ENDPOINTS ........................................................................................ 38 
4.1 
OBJECTIVES ..................................................................................................38 
4.1.1 
Primary Objective ............................................................................................38 
4.1.2 
Secondary Objectives ......................................................................................38 
4.1.3 
Exploratory Objectives ....................................................................................38 
4.2 
ENDPOINTS ...................................................................................................38 
4.2.1 
Primary Endpoint .............................................................................................38 
4.2.2 
Secondary Endpoints .......................................................................................38 


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4.2.3 
Exploratory Endpoints .....................................................................................39 
5 
STUDY DESIGN ................................................................................. 40 
5.1 
OVERALL STUDY DESIGN AND PLAN ....................................................40 
5.1.1 
Screening Period ..............................................................................................41 
5.1.2 
Treatment Period ..............................................................................................41 
5.1.3 
End-of-Study ....................................................................................................41 
5.1.4 
Long Term Follow-Up .....................................................................................42 
5.2 
STUDY SCHEMA ..........................................................................................42 
6 
STUDY POPULATION ...................................................................... 44 
6.1 
NUMBER OF PATIENTS AND SITES .........................................................44 
6.2 
INCLUSION CRITERIA ................................................................................44 
6.3 
EXCLUSION CRITERIA ...............................................................................46 
6.4 
PATIENTS OR PARTNERS OF PATIENTS 
OF REPRODUCTIVE POTENTIAL ..............................................................47 
6.5 
WAIVERS OF INCLUSION/EXCLUSION 
CRITERIA .......................................................................................................48 
7 
DESCRIPTION OF STUDY 
TREATMENTS AND DOSE 
MODIFICATIONS .............................................................................. 49 
7.1 
DESCRIPTION OF STUDY TREATMENTS................................................49 
7.2 
METHOD OF ASSIGNING PATIENTS TO 
TREATMENT GROUPS ................................................................................49 
7.3 
PREPARATION AND ADMINISTRATION 
OF PROTOCOL-SPECIFIED TREATMENT ................................................50 
7.4 
DOSE MODIFICATION CRITERIA AND 
TOXICITY MANAGEMENT .........................................................................51 
7.4.1 
Hypertension ....................................................................................................51 
7.4.2 
Proteinuria ........................................................................................................57 
7.4.3 
Sub-clinical hypothyroidism ............................................................................58 
7.4.4 
Decrease in LVEF ............................................................................................58 
7.4.5 
QTC prolongation .............................................................................................58 
7.4.6 
Liver function test abnormalities .....................................................................58 
7.4.7 
Management of Posterior Reversible 
Encephalopathy Syndrome (PRES) .................................................................59 
7.4.8 
Other toxicities .................................................................................................59 
7.4.9 
Planned Surgery ...............................................................................................60 


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7.5 
ACCOUNTABILITY OF PROTOCOL-
SPECIFIED TREATMENT ............................................................................60 
7.6 
BLINDING/MASKING OF TREATMENT ...................................................60 
7.7 
TREATMENT COMPLIANCE ......................................................................60 
8 
PRIOR AND CONCOMITANT 
THERAPIES ........................................................................................ 62 
8.1.1 
Permitted Concomitant Medication and 
Medications that Should be Used with Caution ...............................................62 
8.1.2 
Prohibited Concomitant Medications ..............................................................62 
9 
STUDY PROCEDURES ..................................................................... 64 
9.1 
SCREENING PERIOD ....................................................................................71 
9.2 
TREATMENT PERIOD ..................................................................................72 
9.2.1 
Day –7 PK Sub Study ......................................................................................73 
9.2.2 
Day 1 of Cycle 1 (C1D1:PK sub study patients) .............................................74 
9.2.3 
Day 1 of Cycle 1 (C1D1; all patients with 
exception of PK sub study) ..............................................................................75 
9.2.4 
Day 4 of Cycle 1 (C1D4; all patients) .............................................................76 
9.2.5 
Day 15 of Cycle 1 (C1D15; all patients) .........................................................76 
9.2.6 
Day 1 of Cycle 2 (C2D1) and Subsequent 
Cycles (all patients) .........................................................................................77 
9.2.7 
Day 15 of Cycle 2 (C2D15; all patients) .........................................................78 
9.3 
END-OF-STUDY VISIT (ALL PATIENTS) ..................................................78 
9.4 
TWO MONTHLY FOLLOW-UP (ALL 
COHORTS) .....................................................................................................79 
9.5 
METHODS OF DATA COLLECTION ..........................................................79 
9.5.1 
Safety Evaluations ...........................................................................................79 
9.5.1.1 
Adverse Event Assessment ..............................................................................79 
9.5.1.2 
Clinical Laboratory Investigations ...................................................................79 
9.5.1.3 
Vital Signs ........................................................................................................80 
9.5.1.4 
12-Lead Electrocardiograms ............................................................................80 
9.5.1.5 
LVEF ...............................................................................................................81 
9.5.1.6 
Body Weight and Height .................................................................................81 
9.5.1.7 
Physical Examinations .....................................................................................81 
9.5.1.8 
ECOG Performance Status ..............................................................................81 
9.5.2 
Efficacy Evaluations ........................................................................................81 
9.5.2.1 
Tumor Assessments .........................................................................................81 


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9.5.3 
Biomarker Assessments ...................................................................................82 
9.5.4 
Population PK Assessments.............................................................................82 
9.5.5 
PK Sub Study ...................................................................................................82 
9.5.6 
Pharmacogenomic Assessment ........................................................................83 
9.5.7 
Pharmacodynamic Evaluations ........................................................................83 
9.5.8 
Quality-of-Life Assessments ...........................................................................83 
9.5.9 
Patient Diary ....................................................................................................84 
10 
ADVERSE EVENT MANAGEMENT .............................................. 85 
10.1 
DEFINITION OF AN ADVERSE EVENT ....................................................85 
10.2 
DEFINITION OF A SERIOUS ADVERSE 
EVENT ............................................................................................................85 
10.3 
EVENTS OR OUTCOMES NOT 
QUALIFYING AS SERIOUS ADVERSE 
EVENTS ..........................................................................................................86 
10.4 
CLINICAL LABORATORY ASSESSMENTS 
AS ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................86 
10.5 
PREGNANCY OR DRUG EXPOSURE 
DURING PREGNANCY ................................................................................86 
10.6 
RECORDING OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS .....................................................................87 
10.6.1 
Intensity of Adverse Events .............................................................................87 
10.6.2 
Causal Relationship of Adverse Events to 
Investigational Medicinal Products .................................................................87 
10.6.3 
Outcome and Action Taken .............................................................................88 
10.7 
FOLLOW-UP OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS .....................................................................89 
10.8 
REGULATORY ASPECTS OF SERIOUS 
ADVERSE EVENT REPORTING .................................................................89 
11 
STATISTICAL METHODS ............................................................... 90 
11.1 
ANALYSIS POPULATIONS .........................................................................90 
11.2 
STATISTICAL METHODS ............................................................................90 
11.2.1 
General Considerations ....................................................................................90 
11.2.2 
Patient Disposition ...........................................................................................90 
11.2.3 
Baseline Characteristics ...................................................................................90 
11.2.4 
Efficacy Analyses ............................................................................................90 
11.2.4.1 
Progression Free Survival (PFS) ......................................................................91 
11.2.4.2 
Objective Response Rate (ORR) .....................................................................91 


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11.2.4.3 
Duration of Response (DR) .............................................................................91 
11.2.4.4 
Disease Control Rate (DCR) ............................................................................91 
11.2.4.5 
Overall Survival (OS) ......................................................................................91 
11.2.4.6 
PK Sub-Study ..................................................................................................91 
11.2.5 
Safety Analyses ................................................................................................91 
11.2.5.1 
Extent of Exposure ...........................................................................................92 
11.2.5.2 
Adverse Events ................................................................................................92 
11.2.5.3 
Clinical Laboratory Evaluations ......................................................................93 
11.2.5.4 
Vital Signs Measurements ...............................................................................93 
11.2.5.5 
12-Lead Electrocardiograms ............................................................................93 
11.2.5.6 
Other Safety Measurements .............................................................................94 
11.2.6 
Patient Reported Outcomes .............................................................................94 
11.2.7 
Population PK Analyses ..................................................................................94 
11.2.8 
Exploratory Analyses .......................................................................................94 
11.3 
SAMPLE SIZE CONSIDERATIONS.............................................................94 
11.4 
INTERIM ANALYSIS ....................................................................................95 
12 
PATIENT DISPOSITION .................................................................. 96 
12.1 
PATIENT DISCONTINUATIONS .................................................................96 
13 
STUDY ADMINISTRATION ............................................................ 97 
13.1 
REGULATORY AND ETHICAL 
CONSIDERATIONS .......................................................................................97 
13.1.1 
Regulatory Authority Approvals .....................................................................97 
13.1.2 
Independent Ethics Committee/Institutional 
Review Board ..................................................................................................97 
13.2 
CONFIDENTIALITY OF INFORMATION ..................................................98 
13.3 
PATIENT INFORMED CONSENT ...............................................................98 
13.4 
STUDY MONITORING .................................................................................99 
13.5 
CASE REPORT FORM...................................................................................99 
13.6 
STUDY TERMINATION AND SITE 
CLOSURE .....................................................................................................100 
13.7 
MODIFICATION OF THE STUDY 
PROTOCOL ..................................................................................................100 
13.8 
RETENTION OF STUDY DOCUMENTS ...................................................100 
13.9 
CLINICAL STUDY REPORT ......................................................................101 
13.10 
STUDY PUBLICATION ..............................................................................101 
13.11 
QUALITY ASSURANCE AUDITS .............................................................101 


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14 
REFERENCES .................................................................................. 102 
15 
APPENDICES .................................................................................... 107 
Appendix A 
 Response Evaluation Criteria in Solid Tumors 
Criteria ........................................................................................................... 108 
Appendix B 
 Eastern Cooperative Oncology Group Performance 
Status Scale .................................................................................................... 119 
Appendix C 
 List of concomitant medications that can prolong the 
QT interval and increase the risk of causing Torsades 
de Pointes ....................................................................................................... 120 
Appendix D 
 FACT-B Version 4.057 .................................................................................. 121 
Appendix E. 
 Inhibitors and Inducers of CYP2C8 and CYP3A4 ....................................... 126 
 
 


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List of Tables 
Description 
Page 
Table 1:  Hypertension Guidance Algorithm ............................................................................... 52 
Table 2:   Grading scale for hypertension (NCI CTCAE Version 4.0) ........................................ 56 
Table 3:   Proteinuria Management Algorithm ............................................................................ 57 
Table 4: Schedule of Assessments (All Cohorts) ...................................................................... 65 
Table 5: Schedule of Assessments (PK Sub Study) .................................................................. 68 
Table 6: Evaluation of Target Lesions .................................................................................... 111 
Table 7: Evaluation of Target Lesions .................................................................................... 112 
Table 8: Evaluation of best overall response: patients with measurable and non-
measurable disease .................................................................................................... 115 
Table 9: Evaluation of best overall response: patients with non-measurable disease ............. 115 
Table 10: Best overall response when confirmation of CR and PR is required ........................ 116 
 
 


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List of Figures 
Description 
Page 
Figure 1: Study Schema .............................................................................................................. 43 
 


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1 
SYNOPSIS 
Protocol Number 
CO-3810-025 
Title 
A phase 2, open-label, multicenter, safety and efficacy study of oral lucitanib 
in patients with FGF aberrant metastatic breast cancer 
Phase 
Phase 2  
Introduction  
Lucitanib is a potent, orally available selective inhibitor of the tyrosine 
kinase activity of fibroblast growth factor receptors (FGFR1–3), vascular 
endothelial growth factor receptors (VEGFR1–3), and platelet-derived 
growth factor receptors alpha and beta (PDGFRα/β) with activity in relevant 
cell lines and animal models.  A phase 1/2 clinical trial demonstrated 
multiple objective responses in women with FGFR1- or 11q (FGF3, FGF4, 
Cyclin D1, or FGF19)-amplified breast cancer (Response Evaluation Criteria 
in Solid Tumors [RECIST] objective response rate [ORR] 50%).  The 11q 
amplicon contains genes for FGF3, FGF4, and FGF19 proteins that are 
ligands of FGFR1.  These responses are notable in breast cancer where 
FGF-aberrancy is recognized as an early, common, and stable event in breast 
carcinogenesis.  Further, preclinical evidence supports up-regulation of 
FGF-related activity as a mechanism of resistance to endocrine therapy in 
estrogen receptor positive (ER+) breast cancer.  Toxicities are those typically 
seen with potent VEGFR inhibitors, such as hypertension, hypothyroidism, 
and proteinuria.  Other common adverse events (AEs) include asthenia, 
thrombotic microangiopathy (TMA), thrombocytopenia, abdominal pain, 
anorexia, nausea, vomiting, and diarrhea. 
Based on the phase 1/2 study results, 15 mg daily was previously advanced 
as the recommended phase 2 dose of lucitanib.  However, interim data from 
ongoing lucitanib studies has shown that the daily dose of 15 mg is difficult 
for many patients to sustain and dose reductions have been frequently 
required.  Further, clinical responses have been observed at both 10 mg and 
15 mg daily dosing schedules.  Therefore, beginning in mid-2015, the 
decision was made to implement lucitanib at 10 mg daily across the clinical 
development program. 
Under prior versions of this protocol, patients with FGFR1 or 11q 
amplification were randomized to receive either 10 (Cohort A) or 15 mg 
(Cohort B) of lucitanib daily.  With this version of the protocol (amendment 
#4), randomization has been removed.  Instead, enrollment to the 15 mg 
cohort (Cohort B) will stop and enrollment to the 10 mg cohort (Cohort A) 
will continue.   
Likewise, Patients without FGFR1 or 11q amplification (Cohort C) were 
previously enrolled to receive 15 mg of lucitanib daily.  With this version of 
the protocol (amendment #4) Cohort C patients will receive 10 mg daily.   
Planned Number 
of Patients 
FGFR1-amplified and 11q-amplified patients will be enrolled* as follows: 
• 
Cohort A (10 mg): approximately 80 patients (no more than forty 
11q-amplified patients) 
• 
Cohort C (10 mg):  up to 40 patients 
 *1:1 randomization to Cohorts A and B was removed with amendment #4.  
Up to 80 patients were enrolled into Cohort B under prior versions of this 


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protocol. 
Planned Number 
of Sites 
Approximately 30–40 investigative sites in the United States.  Accrual to 
Cohort C will be limited to 10–15 sites participating in the pharmacokinetics 
(PK) sub study, until enrollment in the sub study has been filled. 
Study Objectives 
and Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Objective 
Primary Endpoint 
To estimate the anti-tumor efficacy 
of oral single-agent lucitanib as 
measured by investigator assessed 
PFS, when administered to patients 
with FGFR1- or 11q-amplified 
breast cancer after failure of 
currently available standard therapies 
PFS per RECIST Version 1.1 as 
determined by the investigator 
Secondary Objectives 
Secondary Endpoints 
To estimate anti-tumor efficacy of 
oral single-agent lucitanib as 
measured by ORR, duration of 
response (DR), disease control rate 
(DCR), and overall survival (OS) 
• 
ORR according to RECIST 
Version 1.1  
• 
DR and DCR according to 
RECIST Version 1.1 
• 
OS 
To estimate patient-reported 
outcomes (PRO) following treatment 
with lucitanib 
Change from baseline in PRO using 
the Functional Assessment of Cancer 
Therapy-Breast (FACT-B) 
questionnaire 
To evaluate safety and tolerability of 
lucitanib  
Treatment emergent AEs, laboratory 
abnormalities, physical examinations 
including vital signs and 
electrocardiogram (ECG) 
abnormalities 
To assess the comparative 
pharmacokinetics (PK) of the 
lucitanib tablet formulation with the 
lucitanib capsule formulation 
PK parameters including area under 
the concentration curve from time 
zero to time t (AUC0–t), maximum 
concentration (Cmax), time to 
maximum concentration (tmax), 
elimination half-life (t1/2), volume of 
distribution at steady state (VSS/F), 
and total plasma clearance (Cl/F) for 
lucitanib, if data allow 
Exploratory Objectives 
Exploratory Endpoints 
To explore tumor tissue and 
blood-based biomarkers that may be 
predictive of response or primary 
resistance to treatment with lucitanib 
• 
Concordance of tumor tissue 
FGFR1 and 11q amplification   
assessed across different 
technical platforms (fluorescence 
in-situ hybridization [FISH], 
Next Generation Sequencing 
[NGS], comparative genomic 
hybridization [CGH], 


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Study Objectives 
and Endpoints 
(continued) 
chromogenic in-situ 
hybridization [CISH],  
quantitative polymerase chain 
reaction [qPCR], or circulating 
tumor cells [CTCs/ctDNA]) 
• 
Exploration of different cut-off 
values for determining FGFR1 
and 11q amplification in tumor 
tissue by FISH and correlation 
with clinical efficacy 
• 
Ribonucleic acid (RNA) 
expression of FGFR1, 
FGF3/4/19, and additional FGF 
family members; correlation 
with FGFR1 and 11q 
amplification status and clinical 
efficacy 
• 
Protein expression of FGFR1 as 
determined by 
immunohistochemistry (IHC) in 
tumor tissue; correlation with 
FGFR1 amplification status 
• 
Genomic analysis of circulating 
tumor DNA (ctDNA) 
To explore blood-based 
pharmacodynamic (PD) biomarkers 
of lucitanib activity 
• 
PD biomarker analysis 
measurement of circulating 
plasma biomarker levels 
including but not limited to 
FGF-2, FGF-23, sVEGFR1, 
VEGF-A, sCSF-1R, and CSF-1 
• 
Pharmacogenomic analysis of 
variations in genes encoding 
proteins involved in 
absorption/distribution/ 
metabolism/excretion (ADME) 
 
To determine pharmacokinetics (PK) 
of lucitanib in this patient population 
using population pharmacokinetic 
(POPPK) methods and explore 
correlations between exposure, 
response, and/or safety findings 
Plasma PK parameters for lucitanib 
based on sparse sampling for POPPK 
analysis 


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Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a Phase 2, open-label, multicenter study evaluating the efficacy and 
safety of lucitanib administered orally to patients with metastatic breast 
cancer.  Patients with metastatic breast cancer will be enrolled into one of 
two different cohorts (Cohort A: FGF-amplified or Cohort C: FGF 
non-amplified) both receiving 10 mg daily.     
For patients with local FGFR1 or 11q test results, a central laboratory will 
confirm the presence or absence of the FGFR1 or 11q amplification.  Central 
testing prior to enrollment for these patients is not required for study 
enrollment.  Patients with local FGFR1 and 11q results for whom central 
reading does not confirm amplification status can continue the study at the 
discretion of the investigator if clinical benefit is observed.  If there are a 
significant number of patients with discordant local and central testing 
results, additional patients may be enrolled. 
For patients without a local FGFR1 or 11q test result, tissue must be 
submitted for central testing under a prescreening process.  Under the 
prescreening process, a confirmed central laboratory test result is required 
for screening and enrollment into Cohort A (FGFR1- or 11q-amplified) or 
enrollment into Cohort C (FGF non-amplified).   
Up to 20 enrolled patients will participate in a PK sub-study to assess the 
comparative PK of the lucitanib tablet formulation with the lucitanib capsule 
formulation.   
Cycles are defined as 28 days in duration.  Protocol-specified treatment will 
continue until there is clinical tumor progression or unacceptable toxicity.  
Patients will undergo serial assessments for anti-tumor efficacy, drug safety, 
and PROs.  Sparse blood sampling for POPPK analyses will be conducted in 
all patients treated with lucitanib.  Tumor scans will be acquired by the 
investigative site and evaluated locally for patient treatment decisions.  
Patients who provide additional consent will undergo an optional 
post-treatment biopsy for PD analyses. 
AEs will be assessed from the time of first dose of lucitanib through 28 days 
after the last protocol-specified treatment administration.  For the first 
6 cycles, patients will undergo tumor scans within 28 days prior to the first 
drug administration, 4 weeks after first drug administration, and every 
8 weeks thereafter.  Patients with stable disease or better after their Cycle 6 
scan will continue to have tumor scans every 12 ± 1 weeks until tumor 
progression.  All patients will be followed at approximately two monthly 
intervals to determine survival status, until death or sponsor decision to end 
the trial, whichever comes first.  After discontinuation of protocol-specified 
treatment, subsequent anticancer therapy use will be recorded. 
Study Population 
 
 
 
 
 
 
 
Inclusion Criteria 
1. Histologically or cytologically confirmed metastatic breast cancer 
relapsed or refractory to approved standard available treatment 
° 
Specifically, patients with human epidermal growth factor 
receptor 2 (HER2)-positive disease, as defined by the 
American Society of Clinical Oncology/College of 
American Pathologists (ASCO/CAP) guidelines, must have 
exhausted approved HER2-directed therapies prior to 
enrollment 
2. Prior treatment with standard first line therapy in the metastatic setting 


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Study Population 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. FGFR1 amplification or 11q amplification status determined on the most 
recent tumor tissue available, or detected in blood using validated 
methods for detecting circulating tumor cells (CTCs) or ctDNA: 
a) Patients in Cohorts A and B: FGFR1- or 11q-amplified 
b) Patients in Cohort C:  neither FGFR1- nor 11q-amplified  
Patient amplification status will be based on:  
° 
local assessment by FISH, NGS, CGH,  CISH, or qPCR; or 
° 
local assessment in blood using validated methods for 
detecting circulating tumor cells (CTCs) or ctDNA; or 
° 
central assessment by FISH, as confirmed by a prescreening 
process   
4. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue 
sufficient for the central confirmation by FISH of FGFR1 amplification 
or 11q amplification status.  Detailed sample handling instructions are 
provided in the Laboratory Manual 
5. Demonstrated progression of disease by radiological or clinical 
assessment 
° 
Measurable disease according to RECIST Version 1.1 is 
NOT required for enrollment 
6. Patient aged ≥18 years old 
7. Eastern Cooperative Oncology group (ECOG) Performance status 0 or 1 
8. Estimated life expectancy >6 months 
9. Normal left ventricular function defined as a left ventricular ejection 
fraction (LVEF) ≥50% by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) scan 
10. Screening for laboratory values within the following parameters: 
° 
Hematology: absolute neutrophil count (ANC) ≥1000/mm3; 
platelet count ≥100,000/mm3; hemoglobin ≥9 g/dL 
° 
Renal function: 
− 
Serum creatinine <1.5 mg/dL or creatinine clearance 
>45 mL/min (Modification of Diet in Renal Disease 
formula [MDRD]) 
− 
Dipstick protein measurement <2+. If dipstick ≥2+ then 
perform 24-hour urine protein measurements and if 
proteinuria <300 mg patient is eligible for inclusion 
° 
Liver function tests: total bilirubin ≤1.5 upper limit of 
normal (ULN; unless evidence of Gilbert’s disease 
confirmed by uridine diphosphate-glucuronyltransferase 
[UGT] polymorphism); aspartate transaminase (AST) and 
alanine transaminase (ALT) ≤3 ULN; AST and ALT 
≤5 ULN in case of liver metastases 
11. For women of childbearing potential, a negative pregnancy test within 
7 days prior to initiation of the study drug 
12. Willingness to use an effective contraceptive method during the study 
and up to six months after the last dose is administered.  Effective 
methods include the following: non-hormonal intrauterine device, barrier 
method (condoms, diaphragm) also in conjugation with spermicidal 
jelly, or total abstinence.  Oral, injectable, or implant hormonal 
contraceptives are discouraged 


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Study Population 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. Written consent on an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved Informed Consent Form (ICF) prior 
to any protocol-specific evaluation 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 
1. Current or recent treatment with biologic anticancer therapies.  Required 
washout for prior biologic anticancer therapies: 
° 
3 months for bevacizumab 
° 
28 days or five half-lives, whichever is shorter, for all other 
biologic therapies 
2. Ongoing AEs from prior anticancer therapies, including radiation, 
targeted or cytotoxic therapies without resolution of any Grade 2 or 
greater side effects to Grade ≤1 
3. Current treatment with any prohibited medications associated with 
prolongation of QT interval and known risk of Torsades de Pointes (see 
Appendix C) 
4. Active central nervous system (CNS) metastases, as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth (patients with 
history of CNS metastases or cord compression are eligible if they are 
clinically stable for at least 4 weeks before first dose of lucitanib and do 
not require high-dose steroid treatment) 
5. History of clinically significant or uncontrolled cardiac disease, 
including congestive heart failure (HF; New York Heart Association 
functional classification ≥3), angina, myocardial infarction within 
6 months, or ventricular arrhythmia 
6. QTC prolongation (defined as a QTC interval >470 msec according to 
Fridericia’s correction)  
7. Uncontrolled hypertension (defined as systolic blood pressure [SBP] 
≥140 mmHg and/or diastolic blood pressure [DBP] ≥90 mmHg with 
optimized anti-hypertensive therapy) 
° 
The requirement for >2 anti-hypertensives to control 
hypertension at time of enrollment is exclusionary  
8. Active second malignancy, i.e., patient known to have potentially fatal 
cancer present for which he/she may be (but is not necessarily) currently 
receiving treatment  
° 
Patients with a history of malignancy that has been 
completely treated, with no evidence of that cancer 
currently, are permitted to enroll in the trial provided all 
chemotherapy was completed >6 months prior and/or bone 
marrow transplant (BMT) >2 years prior 
9. Uncontrolled hypothyroidism defined as serum thyroid stimulating 
hormone (TSH) higher than 5 mIU/mL while receiving optimized 
thyroid hormone replacement therapy 
10. Patient with history of thrombotic disorders: 
° 
Any history of venous thrombotic events, deep vein 
thrombosis (with the exception of catheter related deep vein 
thrombosis), or pulmonary embolism within 6 months prior 
to the first dose of lucitanib 
° 
Any history of arterial thrombotic events, cerebrovascular 


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accident, or transient ischemic accident within 6 months 
prior to the first dose of lucitanib 
° 
Any peripheral vascular disease or vasculitis which required 
treatment within 6 months prior to the first dose of lucitanib 
° 
Patient with hereditary risk factors of thromboembolic 
events (e.g., mutation of the Factor V of Leiden) 
11. Received administration of strong inhibitors of CYP2C8 or CYP3A4 or 
strong inducers of CYP3A4 ≤7 days prior to first dose of lucitanib or 
have on-going requirements for these medications (Appendix E) 
12. Received investigational treatment within 28 days prior to enrollment in 
this study  
13. Non-study related minor surgical procedures ≤14 days prior to 
administration of lucitanib.  In all cases, the patient must be sufficiently 
recovered and stable before treatment administration 
14. History of major surgical procedure or significant trauma within 28 days 
prior to lucitanib.  In all cases, the patient must be sufficiently recovered 
and stable before treatment administration 
15. Females who are pregnant or breastfeeding 
16. Presence of any serious or unstable concomitant systemic disorder 
incompatible with the clinical study (e.g., substance abuse, uncontrolled 
psychiatric condition, uncontrolled intercurrent illness including active 
infection, arterial thrombosis, and symptomatic pulmonary embolism) 
17. Foreseeable poor compliance to the study procedures 
18. Any other reason the investigator considers the patient should not 
participate in the study 
Study Treatment 
 
Lucitanib (capsule or tablet formulation) will be administered at a dose of 10 
mg once daily and swallowed with water  
(240 mL or 8 ounces).  Patients should take lucitanib at approximately the 
same time each day, on an empty stomach, at least 2 hours before and 2 
hours after a meal (fasting window is a total of 4 hours). 
Patients enrolled in the PK sub study will receive a single dose of lucitanib 
in a tablet formulation on Day –7 followed by a single dose of lucitanib in a 
capsule formulation on Day 1. From Cycle 1 Day 2 onward, lucitanib may be 
given as capsules or tablets, as per sponsor guidance. 
 
Dose-Modification 
Criteria and 
Toxicity 
Management 
 
 
 
 
 
 
 
Patients are allowed dose reductions by 2.5 mg increments after Cycle 1, 
Day 1 (C1D1).  Dose re-escalation in 2.5 mg increments is permitted at the 
start of a cycle as long as the cause of the dose reduction has resolved to 
Grade 1 or better (see Section 7.4.8).  Dose escalations above the starting 
dose are not permitted. 
Management of hypertension 
Hypertension should be closely monitored and treated if required.  Abnormal 
blood pressure (BP) measurements in clinic should be repeated within an 
hour to confirm findings. 
Additionally, patients should be instructed to self-measure their BP at home 
at least two times per week while receiving lucitanib treatment.  
Patient-monitored BP should be followed by the investigator at all clinic 


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Dose-Modification 
Criteria and 
Toxicity 
Management 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose-Modification 
Criteria and 
Toxicity 
Management 
visits to evaluate the effectiveness of anti-hypertensive treatment. 
The early detection and effective management of hypertension are important 
to minimize risk for the patient and the need for lucitanib dose interruptions 
and reductions. 
The following treatment and lucitanib dose adjustments algorithm should be 
followed in case hypertension is encountered: 
Observation 
Action 
Patient experiences hypertension for 
the first time or patient with 
previously controlled hypertension 
experiences worsening in BP values 
with SBP from 140 to 159 mmHg 
and/or DBP from 90 to 99 mmHg.  
 
 
Patients without pre-existing 
hypertension 
Initiate anti-hypertensive therapy 
immediately.   
Immediate use of two anti-hypertensive 
agents can be considered in case of rapid 
elevation of BP.  The anti-hypertensive 
therapy can be adjusted over a period of 
14 days.  The patient should be followed 
by the investigator at least once a week to 
evaluate the response to the 
anti-hypertensive treatment.  During this 
period, interruption of lucitanib or dose 
modification is not necessary.  
If BP decreases to < 140/90 mmHg in 
14 days, continue lucitanib at the same 
dose. 
 
Patients with pre-existing hypertension 
 
Intensify/adapt current any current 
anti-hypertensive treatment.  Immediate 
dose and therapeutic class optimization 
should be performed.  Up to three anti-
hypertensive agents should be considered. 
The anti-hypertensive agent can be 
adjusted over a period of 14 days.  The 
patient should be followed by the 
investigator at least once a week to 
evaluate the response to anti-hypertensive 
treatment.  During this period, interruption 
of lucitanib or dose modification is not 
necessary.  
If BP decreases to < 140/90 mmHg within 
14 days, continue lucitanib at the same 
dose. 
In case of persisting hypertension with 
SBP from 140 to 159 mmHg and/or 
DBP from 90 to 99 mmHg despite 
optimized anti-hypertensive treatment 
after 14 days.  
 
 
Reduce lucitanib dose by 2.5 mg. 
Ensure adequate control of BP below 
140/90 mmHg including increasing the 
dose of the current anti-hypertensive 
agent(s) (if appropriate) and/or initiation 
of additional anti-hypertensive agents, if 


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(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose-Modification 
Criteria and 
Toxicity 
Management 
required.  
Allow up to 14 days for BP to be 
controlled.  If BP does not reduce to 
< 140/90 mmHg after 14 days, lucitanib 
should be reduced again by 2.5 mg (to the 
next dose level). 
Allow an additional 14 days for BP to be 
controlled. 
If BP does not reduce to < 140/90 mmHg 
within the additional 14 days, lucitanib 
should be interrupted for up to 14 days.  If 
BP decreases to < 140/90 mmHg in 
14 days, restart lucitanib at the last dose. 
If BP remains at ≥ 140/90 mmHg after 
14 days, sponsor approval is required prior 
to re-initiating lucitanib treatment. 
 
In case of confirmed hypertension 
with SBP equal or above 160 mmHg, 
and/or DBP equal or above 
100 mmHg. 
Patients presenting with no 
hypertension-related symptoms & no 
more than one risk factor1 
Continue lucitanib therapy.  
Immediately start anti-hypertensive 
treatment or optimize current 
anti-hypertensive treatment. 
Allow up to 4 days for BP to be controlled 
(BP < 140/90 mmHg), with close 
follow-up by the treating physician.   
If BP does not reduce to  
≤ 160/100 mmHg within 4 days, lucitanib 
should be reduced by 2.5 mg.   
If BP does not reduce to ≤ 160/100 mmHg 
within 4 additional days despite lucitanib 
dose reduction and optimal 
anti-hypertensive therapy, lucitanib should 
be interrupted.  
If BP decreases to < 140/90 mmHg within 
14 days, resume lucitanib at next lower 
dose. 
If BP is not controlled (< 140/90 mmHg) 
within 14 days after interruption of 
lucitanib and despite optimal 
anti-hypertensive treatment, lucitanib 
should be permanently discontinued. 
 
 
 
 
 


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(continued) 
 
Patients with mildly symptomatic 
hypertension2 (outside of cardiovascular, 
cerebral, or major renal complications) or 
several risk factors1 or already receiving 
two anti-hypertensive agents 
Temporarily interrupt lucitanib therapy.  
Immediate use of two anti-hypertensive 
agents may be considered in patients with 
no history of hypertension.  For patients 
already on two anti-hypertensive agents, 
modification of the current 
anti-hypertensive therapy and/or adding a 
third agent should be considered. 
The patient should be followed by the 
investigator closely to evaluate the 
response to anti-hypertensive treatment. 
Allow up to 14 days for BP to be 
controlled (BP < 140/90 mmHg).   
If BP decreases to < 140/90 mmHg within 
14 days, resume lucitanib at next lower 
dose. 
If BP does not reduce to < 140/90 mmHg 
within 14 days, lucitanib should be 
permanently discontinued.   
 
In case of confirmed hypertensive 
crisis with life-threatening 
consequences. 
Hypertensive crisis is defined as an 
increase in BP (≥ 180 mmHg SBP 
and/or ≥ 120 mmHg DBP) that can 
lead to life-threating consequences 
(e.g., cerebral stroke). 
Lucitanib must be permanently 
discontinued. 
1Risk factors include those comorbidities that in the opinion of the investigator 
would increase the patient’s risk of hypertension-related complications, 
e.g., diabetes, coronary artery disease 
2 Mildly symptomatic hypertension defined as symptoms of headache, facial 
flushing, etc in the absence of additional cardiac or neurological findings 
Pharmacological management should be based on the investigator’s 
judgment and no definite recommendations for an anti-hypertensive agent 
can be made.  However, calcium channel blockers may be preferred as initial 
treatment based on their rapidity of action and safety profile. Angiotensin 
Converting Enzyme (ACE) inhibitors can be considered in case of 
concomitant proteinuria.  In case of rapid elevation of BP, two 
anti-hypertensive agents should be considered.  The use of three 
anti-hypertensive agents such as concomitant use of a renin-angiotensin 
system inhibitor, calcium channel blocker, and diuretic drug may be 
considered based on the investigator’s decision.  In that case, close 
surveillance of kidney function and electrolytes is strongly recommended. 
 


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Dose-Modification 
Criteria and 
Toxicity 
Management 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management of proteinuria 
Patients will be monitored for proteinuria by dipstick every two weeks 
during Cycle 1 and Cycle 2 and every 28 days thereafter.  Patients with early 
signs of proteinuria by dipstick (2+) should be closely monitored and 
proteinuria evaluated quantitatively (24 hours protein excretion or protein-to-
creatinine ratio).  Additional safety monitoring should be performed as 
clinically indicated including tests for the assessment of free/conjugated 
bilirubin, haptoglobin N, schizocytes, or renal biopsy.   
The following treatment and lucitanib dose adjustments algorithm should be 
followed in case proteinuria is encountered:  
In case of first onset of 
proteinuria ≥Grade 2 (i.e., ≥1 g 
in 24 hours by quantitative 
assessments) 
Lucitanib treatment should be 
withheld and proteinuria monitored 
by dipstick twice weekly. Upon 
recovery of proteinuria to Grade ≤1 
(1+ by dipstick or urinary protein 
<1.0 g/24 hours), lucitanib treatment 
should be resumed at the same dose 
and dipstick monitoring should 
continue. 
In case of second onset of 
proteinuria ≥Grade 2 
Withhold the drug and perform a 
quantitative assessment of 24-hour 
urinary protein.  Upon recovery, the 
lucitanib treatment should be 
resumed with a 2.5 mg dose 
reduction (e.g., 10 mg to 7.5 mg) 
In case of third onset of 
proteinuria ≥Grade 2 
Repeat assessments and dose 
modifications as outlined above (e.g., 
7.5 mg to 5 mg) 
In case of fourth onset of 
proteinuria ≥Grade 2 
If proteinuria ≥ Grade 2 recurs 
following dose reductions to 5 mg, or 
if there is no recovery within 30 
days, discontinue treatment 
permanently 
Management of sub-clinical hypothyroidism 
Plasma TSH and thyroid hormones levels should be measured, per protocol.  
Treatment with levothyroxine 50 μg/day is recommended for patients with 
TSH values above 5 mIU/L, even if triiodothyronine (T3) and thyroxine (T4) 
are normal.  The treatment with lucitanib can continue at the same dose. 
Management of LVEF 
LVEF will be assessed by ECHO or MUGA.  It is recommended to use the 
same technique for a given patient throughout the whole study duration.  In 
case of HF symptoms or modification on imaging from baseline the 
following rules must be applied: 
• 
No signs of HF and LVEF ≥45% OR absolute drop from baseline 
≤15 EF % points.  Continue lucitanib at the same dose level and repeat 
LVEF assessment per protocol 
• 
Patient is symptomatic OR LVEF <45% OR absolute drop from baseline 
>15 EF % points.  Hold lucitanib until resolution (LVEF ≥50% and 


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Dose-Modification 
Criteria and 
Toxicity 
Management 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
asymptomatic).  If resolution occurs within 3 weeks, lucitanib can be 
resumed at a reduced dose by 2.5 mg increments, as described above, 
otherwise withdraw lucitanib permanently 
• 
No recovery OR LVEF <20%.  Discontinue lucitanib permanently and 
follow-up the patient 
Management of QTC prolongation 
In case Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 3 prolongation of the QTCF (Fridericia correction) interval >500 msec, 
lucitanib treatment must be withheld. 
Serum calcium, phosphorus, potassium, and magnesium levels should be 
analyzed, and levels should be corrected to within normal limits if needed.  
In all cases a second ECG must be carried out to confirm the QTCF 
prolongation >500 msec within 1 hour of the initial ECG.  Concomitant 
medication list should be reviewed. 
Once QTCF prolongation has resolved, lucitanib may be restarted at a 2.5 mg 
lower dose.  Further dose reductions are permitted, as described above. 
Grade 4 QTC prolongation (QTC >501 msec or >60 msec change from 
baseline and Torsades de Pointes or polymorphic ventricular tachycardia or 
symptoms of serious arrhythmia) should result in permanent discontinuation 
of lucitanib. 
Management of liver toxicities 
In case of Grade 3 increases in ALT and AST, the dose will be withheld until 
recovery to Grade 2.  If recovery occurs within 14 days, treatment will be 
resumed at the same dose level.  If no recovery occurs within 14 days, the 
treatment will be resumed at a 2.5 mg lower dose upon recovery.  Further 
dose reductions are permitted, as described above.  In case of repeated events 
at 5 mg or absence of recovery to Grade 2 within 7 days, lucitanib will be 
stopped permanently. 
Management of Posterior Reversible Encephalopathy Syndrome (PRES) 
If a patient presents with symptoms suggestive of posterior reversible 
encephalopathy syndrome (PRES) (e.g., persisting headache not responsive 
to usual analgesics, confusion, visual symptoms, seizures and coma), 
immediately interrupt lucitanib treatment and consider performing all 
relevant clinical and radiological examinations (e.g., neurological 
consultation, MRI) in order to ensure early diagnosis and treatment of this 
syndrome.  A follow-up MRI should be performed in order to confirm the 
diagnosis of PRES, and if confirmed, lucitanib treatment must be 
permanently discontinued. 
Management of other toxicities 
For other Grade 3 or 4 hematologic and non-hematologic toxicities (except 
for alopecia), lucitanib treatment should be withheld until recovery to 
Grade 2 for hematological or Grade 1 for non-hematological toxicity.  Upon 
recovery, the drug may be resumed at a 2.5 mg lower dose.  Once the dose 
has been reduced within a treatment cycle, treatment continues at that dose 
level; no dose escalation is possible within a cycle.  If a patient continues to 
experience toxicity after all allowed dose reduction steps as described above 
(i.e., after a patient has been dose-reduced from starting dose to 5 mg/day), 
or if dosing with lucitanib is interrupted for >14 consecutive days due to 
toxicity, treatment should be permanently discontinued, unless otherwise 


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Dose-Modification 
Criteria and 
Toxicity 
Management 
(continued) 
 
agreed between the investigator and the sponsor. 
In the event of Grade 3 or 4 nausea and vomiting, antiemetics should be 
used.  If, despite maximal antiemetic use, Grade 3 or 4 nausea or vomiting 
persists, lucitanib treatment should be withheld until recovery and dose 
reduction and discontinuation should follow the same paradigm as 
recommended for other Grade 3 and 4 non-hematologic toxicities. 
Concomitant 
Medications 
Permitted concomitant medication and medication that should be used 
with caution:   
• 
Lucitanib is highly bound to plasma proteins; therefore, use caution with 
warfarin which is also highly bound to plasma protein and with a narrow 
therapeutic window 
• 
Supportive care (e.g., antiemetics, analgesics for pain control) may be 
used at the investigator’s discretion and in accordance with institutional 
procedures   
• 
Drugs with potential to cause prolonged QT interval and/or possible risk 
or conditional risk to cause Torsades de Pointes must be used with 
caution (see Appendix C) 
• 
Considering the risk of drug-drug interactions, concomitant use of 
moderate inhibitors of CYP2C8 or CYP3A4 are not recommended 
during the study (see Appendix E) 
Prohibited concomitant medications: 
• 
Systemic anticancer therapy (e.g., hormonal therapy, immune therapy, 
targeted therapy), except for bisphosphonates and denosumab in patients 
with bone metastases  
• 
Prior treatment with bevacizumab within 3 months prior to the first dose 
of lucitanib 
• 
Radiotherapy during the treatment period is prohibited.  Palliative bone 
radiotherapy at focal sites can be allowed during the screening period, 
before lucitanib intake and providing recovery is achieved before study 
drug initiation 
• 
Drugs known to cause prolonged QT interval and/or known risk of 
causing Torsades de Pointes (see Appendix C) 
• 
Strong inhibitors of CYP2C8 or CYP3A4 are contraindicated during the 
study.  Should acute treatment with a strong inhibitor be deemed 
necessary, lucitanib must be temporarily withheld.  Lucitanib may be 
resumed after a minimum of seven days of ending acute treatment with a 
strong inhibitor of CYP2C8 or CYP3A4. 
• 
Co-administration of strong inducers of CYP3A4 (Appendix E) are not 
permitted at any time during treatment with lucitanib 


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Withdrawal 
Criteria 
 
A patient must be discontinued from protocol-prescribed therapy if any of 
the following apply: 
• 
Consent withdrawal at the patient’s own request or at the request of their 
legally authorized representative 
• 
Progression of patient’s underlying disease, unless in the opinion of the 
investigator, the patient has indolent progression with evidence of 
continued clinical benefit from treatment.  This must be approved by the 
sponsor and reviewed on a case by case basis 
• 
Any event, adverse or otherwise, that, in the opinion of the investigator, 
would pose an unacceptable safety risk to the patient 
• 
An intercurrent illness that, in the opinion of the investigator, would 
affect assessments of the clinical status to a significant degree and 
requires discontinuation of therapy 
• 
A positive pregnancy test at any time during the study 
• 
Major non-compliance that may affect patient safety 
• 
Investigator decision 
After stopping protocol-specified treatment, all patients will remain in the 
study and will be followed for safety (through 28 days after last dose), and 
for survival status by telephone (at approximately two monthly intervals, 
until death). 
Efficacy 
Assessments 
Efficacy measures will include tumor assessments, consisting of clinical 
examination and computed tomography (CT) scans of the chest, abdomen, 
and pelvis with intravenous contrast and appropriate slice thickness per 
RECIST Version 1.1; other alternative studies (magnetic resonance imaging 
[MRI] and X-ray) may be performed if clinically indicated.  Brain imaging is 
required at baseline.  Patients with brain lesions detected at baseline will 
require repeat brain imaging as part of the follow-up tumor assessments.  
The first on-treatment scan should be completed on Cycle 2, Day 1, and 
every 8 ± 1 weeks through Cycle 6 (i.e., C4D1, C6D1).  Thereafter, scans 
should be completed every 12 ± 1 weeks (i.e., C9D1, C12D1, C15D1, etc.) 
until disease progression.  All patients must have scans to confirm 
radiographic progression.  Patients that permanently discontinue lucitanib 
should continue scans until radiographic disease progression.  Copies of 
tumor scans will be collected centrally to facilitate independent evaluation if 
subsequently required.   
Safety 
Assessments 
Safety measures will include:  
• 
AEs 
• 
Hematology, including reticulocyte count, prothrombin time (PT)/partial 
thromboplastin time (PTT); clinical chemistry including TSH, T3, and 
T4; and urinalysis 
• 
12-lead ECGs  
• 
ECHOs 
• 
Vital signs and body weight 
• 
Concomitant medications/procedures 
• 
ECOG performance status 
• 
Lucitanib dose modifications (reductions) 


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Biomarker 
Assessments 
• 
FGFR1 and 11q amplification status in tumor tissue assessed by FISH, 
CISH, and NGS 
• 
RNA expression of various lucitanib-related genes including, but not 
limited to FGFR1, FGF3/4/19, and additional FGF family members 
• 
Protein expression of FGFR1 as determined by IHC 
• 
Genomic analysis of ctDNA 
Pharmacogenomic 
Assessments 
Analysis of inter-patient variation in genes encoding proteins involved in 
drug ADME. 
Sparse PK 
Assessments (All 
Cohorts) 
Plasma levels of lucitanib will be measured on pre-dose samples collected on 
Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, and 5.  An additional sample 
will be collected on Cycle 2, Day 1, 1–3 hours post-dose.  Sparse blood 
sampling for POPPK analyses will be conducted in all patients treated with 
lucitanib.   
PK Sub Study  
Patients in Cohorts A or C may be enrolled in the PK sub study, at 
participating sites, as follows:  
• 
Participation in the PK sub study will be optional for patients 
enrolled into Cohort A 
• 
Participation in the PK sub study will be mandatory for patients 
enrolled into Cohort C until enrollment of the PK sub study is 
complete 
PK sampling will be performed at the specified time points on each on the 
following two days: 
• 
Day –7: lucitanib in tablet formulation* 
• 
Day 1: lucitanib in capsule formulation*  
On Day –7 and Day 1, PK specimens will be collected 5–10 min pre-dose 
and post-dose at 15 min (±2 min), 30 min (±3 min), 1 hr (±5 min), 1.5 hr 
(±5 min), 2.5 hr (±10 min), 4 hr (±15 min), 6 hr (±15 min), 8 hr (±15 min), 
10 hr (±30 min) (optional), and 24 hr (±30 min).   
PK evaluations will be based on determination of the following parameters 
for lucitanib including (but not limited to): AUC0–t, Cmax, tmax, t1/2, VSS/F, and 
Cl/F, if data allow. The PK parameters between the tablet and the capsule 
formulations will be compared.  
A central laboratory will be used for the bioanalysis of lucitanib. 
*The dose assigned for patients participating in the PK sub study will be the 
same for Days –7 and 1 and depends on the version of the amendment 
approved at the time of patient enrollment (Amendment #3: 15 mg; 
Amendment #4: 10 mg). 
Pharmacodynamic 
Assessments 
Measurement of circulating plasma levels of FGF-2, FGF-23, sVEGFR1, 
VEGF-A, sCSF-1R, and CSF-1. 
Patient-Reported 
Outcome 
Assessments 
PROs will be measured using the FACT-B questionnaire. 


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Statistical 
Procedures 
 
Analysis Populations 
• 
Efficacy population: all treated patients who received at least one dose of 
lucitanib and are confirmed as FGFR1- or 11q-amplified per the central 
laboratory  
• 
Safety population:  all patients who have received at least one dose of 
lucitanib 
Sample Size Justification 
Approximately 200 patients will be enrolled to the 10 mg and 15 mg daily 
dosing groups.  A total of at least 80 patients in the 10 mg arm is sufficient to 
reliably estimate the median PFS and 6 month PFS rate in these heavily 
pre-treated patients.  An observed median PFS greater than 4 months or 
similarly a 6-month PFS rate of at least 40% will be sufficient to consider the 
10 mg dose group worthy of further study.  Therefore, with at least 
80 patients treated at 10 mg, the width of the 90% confidence interval for the 
6 month PFS rate will be less than ±10% so that if the observed 6 month rate 
is 50% then the lower limit on the confidence interval will be greater than 
40%. 
Cohort C will enroll up to 40 patients to evaluate whether the PFS of a FGF 
non-amplified population is comparable to patients who are FGFR1- or 11q-
amplified (Cohorts A and B). 
The same target response of 40% will be used to evaluate Cohort C.  With 
40 patients, the width of the 90% confidence interval for the 6 month PFS 
rate will be less than ±15%, so that if the observed 6 month rate is less than 
25% then the upper limit on the confidence interval will be less than 40%, 
which is evidence that subsequent studies of 10 mg should exclude FGF non-
amplified patients. 
Statistical Methods 
The Kaplan-Meier methodology will be used to summarize the primary 
endpoint of PFS.  The 25th, 50th (median), and 75th percentiles will be 
presented along with the Kaplan-Meier estimates of the 6 and 12 month PFS 
rates.   
The ORR and DCR will be summarized with frequencies and percentages.  
The DR and OS will be summarized utilizing Kaplan-Meier methodology.  
Data Monitoring 
Committee 
A data monitoring committee (DMC) consisting of two external investigator 
advisors and specified Clovis personnel will meet approximately quarterly 
after the first patient is enrolled to review the efficacy and safety data.   
A detailed description of the composition, roles and responsibilities, and 
functioning of the DMC is provided in the DMC Charter. 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE 
angiotensin converting enzyme 
ADME 
absorption/distribution/metabolism/excretion 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate transaminase  
AUC 
area under the curve 
AUC0−24 
area under the curve from time zero to 24 hours 
AUC0–t 
area under the curve from time zero to time t 
BMT 
bone marrow transplant 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1, Day 1 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CGH 
comparative genomic hybridization 
CISH 
chromogenic in-situ hybridization 
Cl/F 
total plasma clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response  
CRO 
contract research organization  
CT 
computed tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events (Version 4.03) 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 


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EDC 
electronic data capture 
ER+ 
estrogen receptor positive 
FACT-B 
Functional Assessment of Cancer Therapy-Breast   
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptors 
FISH 
fluorescence in-situ hybridization 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
hERG 
human ether-a-go-go-related gene 
HF 
heart failure 
HIPAA 
Health Information Portability and Accountability Act  
HLP 
hemolymphopoietic 
IB 
investigator’s brochure 
IC50 
Concentration of inhibitor required for 50% inhibition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data and Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board  
ITT 
Intent to treat 
IWRS 
Interactive Web Response System 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MRI 
magnetic resonance imaging 
msec 
millisecond 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next Generation Sequencing 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung carcinoma 
ORR 
objective response rate 
OS 
overall survival 


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PD 
progressive disease 
pharmacodynamic 
PDGF 
platelet-derived growth factor 
PDGFRα/β 
platelet-derived growth factor receptors alpha and beta 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic(s) 
POPPK 
population pharmacokinetics 
PR 
partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PRO 
patient-reported outcomes 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QoL 
quality of life 
qPCR 
quantitative polymerase chain reaction 
QTCF 
QT interval corrected using Fridericia’s method 
RECIST 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SD 
stable disease 
SOP 
standard operating procedure 
ß-hCG 
human chorionic gonadotropin ß 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
T3 
triiodothyronine 
T4 
thyroxine 
TMA 
thrombotic microangiopathy 
tmax 
time to maximum concentration 
TSH 
thyroid stimulating hormone 
UGT 
uridine diphosphate-glucuronyltransferase 
ULN 
upper limit of normal 
US 
United States  
VEGF 
vascular endothelial growth factor  
VEGFR 
vascular endothelial growth factor receptors 
VSS/F 
Volume of distribution at steady state 
WBC 
white blood cell 


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3 
INTRODUCTION 
3.1 Current standard of care for metastatic breast cancer 
Metastatic breast cancer remains an incurable disease, with approximately 41,000 disease-
associated deaths in the United States (US) annually [1].  Breast cancer includes three main 
molecular classes; i.e., estrogen receptor positive (ER+)/human epidermal growth factor 
receptor 2 (HER2)-negative breast cancers, HER2-overexpressing breast cancer, and triple 
negative breast cancers.  ER+/HER2-negative phenotype is the most frequent and accounts 
for around 70% of all breast cancers.  Endocrine therapy is the cornerstone treatment of 
ER+/HER2– metastatic breast cancer [2].  However, most of the patients will relapse after 
several months of treatment.  Once endocrine resistant, prognosis is poor and patients with 
ER+/HER2– metastatic breast cancer are offered chemotherapy.  For patients with HER2-
overexpressing breast cancer, several therapies have been approved that meaningfully 
prolong progression free survival (PFS) and overall survival (OS) in these patients.  With 
newer agents and combinations of existing agents, HER2-overexpressing breast cancer 
patients are experiencing profound and durable responses that can provide years of benefit.  
Lastly, those patients with triple negative breast cancer do not tend to respond to endocrine 
therapy or HER2-directed therapy.  Therefore, these patients are generally offered 
chemotherapy with little hope for significant benefit.  Although these three subtypes of 
metastatic breast cancer are treated with different drugs and have distinct prognoses, all of 
these patients will eventually develop resistance or intolerance to approved drugs.  Therefore, 
there is a medical need for new pharmacological agents that improve outcomes for all 
patients with metastatic breast cancer. 
3.2 Targeting FGF pathway metastatic breast cancer 
The gene coding for fibroblast growth factor receptor 1 (FGFR1) is amplified in roughly 10% 
of breast cancers [3].  Several preclinical studies have suggested that targeting FGFR1 in 
FGFR1-amplified cell lines leads to antitumor effects.  Shi et al [4] have shown that dovitinib 
(targeting FTL3, cKIT, FGFR, vascular endothelial growth factor receptor [VEGFR] 1, 
VEGF2, VEGF3, platelet-derived growth factor receptor [PDGFR], and CSF1R) inhibits 
FGFR1-amplified breast cancer cell lines, but not the FGFR non-amplified ones.  Similar 
results were reported in another study showing that brivanib (VEGFR and FGFR1, 2 
inhibitor) inhibits FGF-induced cell proliferation in FGFR1-amplified cell lines [5].  
Furthermore, FGFR1-knock down was shown to decrease cell proliferation and reverse 
resistance to endocrine therapy in FGFR1-amplified breast cancer cell lines [6].  Currently, 
several FGFR inhibitors are being developed in the setting of metastatic breast cancer.  One 
phase 2 trial has reported that dovitinib demonstrated anti-tumor activity in patients with 
FGFR1-amplified, but not in FGFR1 non-amplified breast cancers [7].  
In addition to FGFR1 amplification, approximately 15% of breast cancers demonstrate 
amplification of an 11q (FGF3, FGF4, Cyclin D1, or FGF19) amplicon, and this change has 
been associated with poor prognosis [8].  This amplicon contains genes for FGF3, FGF4, and 
FGF19 proteins that are ligands of FGFR1.  Amplification of that chromosome region 
(amplicon) may lead to increased signaling in the FGF/FGFR pathway, neo-angiogenesis, 
and mediation of resistance to targeted and endocrine therapies [9]. 


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3.3 Targeting angiogenesis in metastatic breast cancer 
It is well established that tumor growth beyond the size of 1–2 mm is angiogenesis-dependent 
[10].  The VEGF plays a central role in tumor angiogenesis.  The biological functions of 
VEGF are mediated upon binding to receptor tyrosine kinases; VEGFR-1 (FLT-1), 
VEGFR-2, and VEGFR–3.  VEGFRs are closely related to KIT and PDGFRs and are 
activated upon ligand-mediated receptor dimerization [11].  VEGF-inhibitors have shown 
activity in patients with metastatic breast cancer [12, 13].  Nevertheless, the magnitude of 
treatment efficacy is low and toxicity remains significant [14].  Based on these 
considerations, VEGF inhibitors are not considered as standard of care, although approved 
and reimbursed in several countries.  Recent studies have suggested that FGFR-1 could play a 
critical role in tumor angiogenesis and tumor growth.  FGFs are potent stimulators of 
angiogenesis in both normal and pathological tissues, having a direct effect on both vessel 
assembly and sprouting [15].  Blockade of the FGF pathway can overcome resistance to 
VEGFR inhibitors, emphasizing the importance of FGFR and specifically the need for 
multi-targeted inhibitors [16, 17]. 
3.4 Lucitanib for the treatment of FGF-aberrant metastatic breast cancer 
Lucitanib is a selective orally available tyrosine kinase inhibitor targeting FGFR1–3, 
VEGFR1–3, and PDGFRα and β, with activity in relevant cell lines and animal models.  
Lucitanib is currently being developed by Clovis Oncology (in the US, and later Japan) and 
Les Laboratoires Servier (in Europe and elsewhere) for the treatment of patients with cancer.  
Considering the key roles of FGF and VEGF in the biology of metastatic breast cancer, 
selective inhibition of FGFR1–3, VEGFR1–3, and PDGFRα and β targets relevant 
pro-angiogenic growth factors, as well as simultaneously targeting proliferation and 
endocrine and/or anti-VEGFR therapy resistance in FGF-driven tumors.  
3.5 Nonclinical Overview 
3.5.1 Nonclinical pharmacology 
3.5.1.1 Pharmacodynamics 
Non-clinical pharmacology studies demonstrated significant anti-proliferative, 
anti-angiogenic, and anti-tumor activity of lucitanib.  In vitro, lucitanib was a highly potent, 
selective inhibitor of the tyrosine kinase activity of FGFR1–3, VEGFR1–3, and PDGFRα/β 
[18].  In human cell line models, lucitanib inhibited the phosphorylation of VEGFR2, 
FGFR1, FGFR2, and PDGFRβ receptors and the proliferation of cancer cell lines dependent 
on FGFR1–3, VEGFR2, and PDGFRα receptor signaling for growth.  
In vivo, the oral administration of lucitanib, over a range of well tolerated doses, to mice or 
rats significantly inhibited tumor growth in subcutaneous xenograft models using a range of 
human tumor cell lines or primary patient-derived tumors (breast, colon, ovarian, 
hepatocellular, renal, lung) [19, 20, 21, 22, 23, 24, 25, 26].  
Lucitanib showed no significant inhibition when evaluated in vitro in a broad screen against 
receptors, ion channels, enzymes, and transporters suggesting that unexpected 
pharmacological activity is unlikely to be based on the concentration of inhibitor required for 
50% inhibition (IC50) obtained or on available tissue distribution data. 


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3.5.1.2 Safety pharmacology 
Lucitanib, administered orally up to 80 mg/kg, is devoid of any notable effect on the central 
nervous system (CNS) and on the respiratory function in rat [27, 28].  
In vitro, lucitanib had no effect on human ether-a-go-go-related gene (hERG) residual tail 
current, up to 10 µM [29].  In vivo, lucitanib increased blood pressure (BP) in rats and dogs 
and slightly decreased heart rate in dogs [30, 31, 32].  A complete recovery from the 
hypertensive effect occurred 2 days after treatment ended in rats.  In dogs, all effects were 
reversible within 48 hours after treatment at a dose of 1 mg/kg/day, but were still present up 
to 72 hours after treatment at the higher doses (25 mg/kg).  In dogs, there were no changes in 
QT corrected for changes in heart rate by Fridericia’s formula.  The dose of 1 mg/kg was the 
no-observed-adverse-effect-level (NOAEL) for cardiovascular variables in the dog.  This 
dose corresponded to a mean Cmax of 377 ng/mL. 
3.5.2 Nonclinical pharmacokinetics and metabolism 
Lucitanib pharmacokinetic (PK) properties were evaluated in nu/nu mice, Sprague Dawley 
rats, beagle dogs, and cynomologus monkeys.  Concentrations of lucitanib in plasma were 
determined by protein precipitation followed by high performance liquid 
chromatography-tandem mass spectrometry [33, 34].  After oral administration, the 
absorption rate of lucitanib was moderate reaching time to maximum concentration (Tmax) 
within 2–3 hours post-dosing [35, 36, 37, 38].  The absolute oral bioavailability was 
intermediate in rats and high in mice, dogs, and monkeys.  Lucitanib was highly distributed in 
mice, rats, and monkeys, and in xenograft tumors implanted in nu/nu nude mice [39, 40].  
Lucitanib is eliminated with a moderate clearance and a long half-life (t1/2). 
In humans, lucitanib is expected to be well absorbed; it showed high permeability in Caco-2 
cell lines with minor impact of an efflux transporter [41].  Lucitanib is moderately 
metabolized by oxidative and conjugation routes.  Recent results from in vitro metabolism 
studies indicated that lucitanib oxidative metabolism was mainly mediated by cytochrome 
P450 (CYP) isoforms 2C8 (∼50%) and 3A4 (∼50%).  No potent inhibition of lucitanib on 
major human CYP isoforms was observed in vitro except for a possible non-competitive 
inhibition of CYP2B6 activity [42]. 
3.5.3 Toxicology 
The toxicity of lucitanib was evaluated in rats and monkeys in repeat-dose studies with up to 
28 days of dosing [43, 44] to support daily oral dose administration of lucitanib to cancer 
patients.  The monkey was selected as the relevant non-rodent species for this toxicology 
program based on severe clinical signs of gastrointestinal (GI) toxicity, exposure variability 
in dogs.  After daily oral administration over 4 weeks, the maximum tolerated dose (MTD) 
was 3.75 mg/kg in the rat and 2.5 mg/kg in the monkey.  The rat was considered more 
sensitive than the monkey based on exposure at the MTD in both species. 
The primary toxicological effects of lucitanib in both species were alterations in the 
hemolymphopoietic (HLP) system, kidneys, and skeletal system as well as circulatory 
disturbances (hemorrhages, angiectasis and/or vasculitis/vascular necrosis) in multiple 
organs/tissues (adrenal glands, GI tract, gall bladder [monkey only], bone marrow, brain 
choroid plexus [monkey only], skin, and liver).  In addition, changes in the incisor teeth, 
ovaries, and male reproductive organs were noted in rats only.  After a 2-week recovery 


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period, complete reversal of the effects was seen in squamous epithelium of the tongue, 
esophagus, and vagina in monkeys, and pancreas and ovaries in rats.  Partial recovery was 
noted in the choroid plexus (monkeys), GI tract, liver, skin, exocrine glands, adipose tissue, 
and HLP system.  Prominent changes were still present in the adrenal glands, kidneys, 
skeletal system, gall bladder (monkeys), male reproductive organs (rats), and teeth (rats). 
Lucitanib was genotoxic and clastogenic in the three genotoxicity studies conducted. 
3.6 Clinical Experience with Lucitanib 
3.6.1 Clinical study #E-3810-I-01/CL1-80881-007 
The ongoing first-in-human (FIH) clinical study with lucitanib (Study #E-3810-I-01) was 
initiated on 30 July 2010 at three clinical sites in Europe.  The study is an open-label, dose-
escalation, Phase 1/2 study to determine the MTD, recommended Phase 2 dose (RP2D), 
safety, efficacy, PK, and pharmacodynamics (PD) of lucitanib in adult patients with advanced 
solid tumors.  The study consists of two phases, a dose-escalation phase followed by a dose-
expansion phase at the identified RP2D [17, 45].  Patients are required to have histologically 
or cytologically confirmed locally advanced or metastatic solid tumors, relapsed or refractory 
to standard therapy.  For the dose-expansion phase, patients were required to have tumors 
bearing FGFR1 or 11q 12–14 amplification (Cohort 1) or tumors sensitive to anti-angiogenic 
treatment (Cohort 2). 
From July 2010 to September 2014, 134 patients were enrolled and 133 patients received at 
least one dose of lucitanib.  The study is now closed to recruitment.  Of the 133 patients, 
24 patients had metastatic breast cancer. 
3.6.1.1 Pharmacokinetics 
The clinical PK properties of lucitanib were evaluated within the FIH study following single 
and multiple daily oral administrations.  Lucitanib exposure exhibited high inter-patient 
variability.  Lucitanib was rapidly absorbed with a maximum plasma concentration (Cmax) 
reached within  
1–3 hours.  In the dose-escalation phase, exposure to lucitanib increased with increasing dose 
with no evidence of non-linearity.  The t1/2 of lucitanib was long (31–40 hours) and in 
agreement with the low apparent clearance and the moderate apparent volume of distribution.  
The moderate apparent volume of distribution is the result of high plasma protein binding 
limiting the distribution but a high permeability.  At steady state, the area under the curve 
from time zero to 24 hours (AUC0–24) was approximately double that on Day 1, consistent 
with daily administration of a compound with a t1/2 of 31–40 hours.   
3.6.1.2 Preliminary clinical efficacy 
In the FIH study, heavily pre-treated patients were enrolled and demonstrated encouraging 
signs of activity. Specifically in dose-escalation: 3 out of 17 treated patients (with thymoma, 
small cell lung, and thymic epidermoid cancers) experienced durable stable disease (SD) 
lasting over 2.5 years: 40, 31, and 33 cycles, respectively. 
During the dose-expansion phase, 21 patients were enrolled in the FGF-amplified cohort 
(Cohort 1); this cohort included 8 patients with FGFR1-amplified breast cancer and 4 patients 
with 11q-amplified breast cancer.  Seven of the 21 patients experienced a partial response 
(PR); 6 breast cancers (4 with FGFR1-amplified breast cancer and 2 with 11q-amplified 


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breast cancer) and 1 bladder cancer.  SD was confirmed in 12 patients (5 breast cancers, 
2 renal cancers).  Two patients experienced a best response of progressive disease (PD) 
(1 breast cancer, 1 squamous non-small cell lung carcinoma [NSCLC]).  An additional 
non-evaluable breast cancer patient with extensive bone lesions had a clear metabolic 
response by positron emission tomography (PET) scan.  PRs were seen in both hormone 
receptor positive and triple negative breast cancer patients.  Most of the responses in the 
FGF+ breast cohort were durable with a mean duration of response (DR) of 7.6 months.  
Importantly, there were responses in the 10, 15, and 20 mg starting dose levels and, upon 
dose reduction to 10 mg/day, the clinical benefit was maintained.  The clinical efficacy of 
lucitanib was further demonstrated by a PFS of 9.4 months in this group of highly pre-treated 
advanced breast cancer patients.  Two out of 3 patients with FGFR1-amplified squamous 
NSCLC experienced PD after two cycles; the third had SD for 8 months. 
Five out of 24 patients in the anti-angiogenic sensitive continuous dosing cohort (Cohort 2) 
experienced a PR; in patients with thyroid (n = 2), hepatocellular, renal, and thymus cancers 
treated at 15 and 20 mg/day.  These patients experienced a median DR of 7.3 months and a 
median PFS of 9.9 months.  One patient who had advanced non-squamous NSCLC 
experienced a best response of PD.  In the anti-angiogenic cohort, there were two breast 
cancer patients evaluated for tumor response; both patients had PD.  
3.6.1.3 Summary of clinical safety 
A combined interim safety analysis was performed inclusive of breast cancer patients 
enrolled to three Servier-sponsored clinical studies (CL1-80881-007, CL2-80881-001, CL1-
80881-002), and 43 patients in this study (CO-3810-025) as of the data cutoff date of 21 May 
2015.  Across the ongoing lucitanib clinical studies of lucitanib in patients with metastatic 
breast cancer, patients were treated with one of six lucitanib doses, ranging between 5 mg and 
30 mg daily administered on a continuous schedule or at 15 mg daily administered on two 
different intermittent schedules (5/2 or 21/7).  A total of 230 patients administered at least 
one dose of lucitanib were included in the combined safety set.  The most frequently reported 
treatment-emergent AEs are hypertension, asthenia, hypothyroidism, proteinuria, and 
anorexia; and GI disorders such as diarrhea, nausea, and vomiting.  Most of these common 
(≥30%) AEs were assessed as Grade 1 or 2, except for hypertension, where the majority of 
subjects with a hypertension event had a Grade 3 event. A small number of patients had a 
Grade 4 event of hypertension.  The AEs most commonly reported as related to study drug 
were similar to the most frequently reported AEs (≥30%), regardless of relationship to study 
drug or severity. 
Approximately 40% of all patients had at least one SAE. Fourteen patients (6.1%) had an 
SAE of thrombotic microangiopathy; all were assessed by the Investigator as related to study 
drug, and 5 patients (2.3%) had an SAE of thrombotic microangiopathy that led to 
withdrawal of study drug.  Although hypertension was reported in over 80% of all patients in 
the pooled analysis, and over 50% with a worst Grade 3, a comparatively low incidence of 
patients (2.6%) had a serious event of hypertension. 
The most common AEs that led to discontinuation were hypertension and thrombotic 
microangiopathy (each 2.3%); for these, all were assessed as related to study drug. 
Of the 230 patients in the pooled analysis, eight patients (3.5%) had an AE with a fatal 
outcome:  disease progression and respiratory failure; general physical health deterioration, 


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tracheal haemorrhage; malignant neoplasm progression, and neoplasm progression. None of 
these fatal AEs were assessed as related to lucitanib. 
One case of Posterior Reversible Encephalopathy Syndrome (PRES) also known as 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in a  
52-year-old female patient treated with lucitanib at the dose of 15 mg daily in Study #CL2-
80881-001/BIG 2-13/FINESSE, sponsored by Institut de Recherches Internationales Servier.  
The diagnosis was confirmed by both the investigator and an external expert with the review 
of a follow-up MRI showing disappearance of the white matter lesions initially observed. 
This is the first diagnosed case of PRES related to lucitanib among approximately 242 
patients treated with lucitanib to date.  This type of event is therefore now recognized as an 
important potential risk of treatment with lucitanib.  
It is described as a class-effect with anti-angiogenic molecules with a rare incidence of < 1%. 
However, several other risks factors have been described such as age, gender, exposure to 
hormone therapies (anti-estrogens) [46] and several chemotherapeutic agents or targeted 
therapies [47, 48, 49].  Clinical symptoms of PRES include confusion (71%), seizures (58%), 
headache (48%), visual disturbances (33%) or focal neurological deficit (10-15%) [48, 50]. 
These symptoms and signs are not specific and can be seen in many other neurological 
disorders.  The clinical and radiological evolution of PRES is usually favorable, but the 
mortality is around 3-6 % and persistent neurological sequelae can be observed in 10-20% of 
cases [50]. 
The role of hypertension is discussed in several publications and it appears that pronounced 
fluctuations of BP, rather than absolute BP increase, might precede the syndrome. However, 
approximately 15-20% of patients with PRES are normotensive or hypotensive. Even among 
patients who are hypertensive, less than 50% have a documented mean arterial BP above the 
usually quoted upper limit of cerebral blood flow autoregulation (≥140-150mmHg) [50]. 
Precautionary measures are included in the protocol (Section 7.4.7) 
The observed toxicity profile of lucitanib is related to its potent anti-VEGF activity and is 
consistent with those reported for other anti-angiogenic drugs.  While lucitanib-associated 
AEs were reported by most patients, they rarely led to treatment discontinuations and when 
dose reductions were required, clinical activity was maintained.  Although AEs were 
common, many patients enrolled in the FIH study (Study #E-3810-I-01) demonstrated 
meaningful clinical benefit from therapy.  The tumor responses combined with the PD 
changes suggest that lucitanib is a clinically active drug in patients with solid tumors in both 
FGF-aberrant and anti-angiogenic cohorts.  
3.7 Rationale for Study 
This study will estimate PFS in patients with FGFR1- and 11q-amplifed, and non-amplified 
metastatic breast cancer.  This endpoint is relevant to demonstrate not only the anti-tumor 
activity, but also the durability and tolerability of lucitanib in these patient populations. 
Based on the phase 1/2, FIH study (Study #E-3810-I-01), 15 mg daily was advanced as the 
RP2D of lucitanib.  However, interim data from ongoing lucitanib studies have shown that 
the daily dose of 15 mg is difficult for many patients to sustain and dose reductions have been 
frequently required.  Further, clinical responses have been observed at both 10 mg and 15 mg 
daily dosing schedules.  Therefore, in mid-2015, the decision was made to implement 
lucitanib at 10 mg daily across the clinical development program.  In line with this change 
across the lucitanib clinical development program, enrollment to the 15 mg cohort (Cohort B) 


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has ended and enrollment to the 10 mg cohort (Cohort A) continues.  Likewise, patients 
without FGFR1 or 11q amplification (Cohort C) are to receive 10 mg of lucitanib daily. 
This study will also evaluate the anti-tumor efficacy, safety, and population pharmacokinetic 
(POPPK)/PD relationships of oral single agent lucitanib, when administered to patients with 
FGFR1- or 11q-amplified and non-amplified breast cancer after failure of currently available 
standard therapies. 
 
 


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4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 Objectives 
4.1.1 Primary Objective 
• 
To estimate the anti-tumor efficacy of oral single-agent lucitanib as measured by 
investigator assessed PFS, when administered to patients with FGFR1- or 11q-amplified 
breast cancer after failure of currently available standard therapies 
 
4.1.2 Secondary Objectives 
• 
To estimate anti-tumor efficacy of oral single-agent lucitanib as measured by ORR, DR, 
disease control rate (DCR), and OS To estimate patient-reported outcomes (PRO) 
following treatment with lucitanib  
• 
To evaluate safety and tolerability of lucitanib  
• 
To assess the comparative PK of the lucitanib tablet formulation with the lucitanib 
capsule formulation  
4.1.3 Exploratory Objectives 
• To explore tumor tissue and blood-based biomarkers that may be predictive of response 
or primary resistance to treatment with lucitanib 
• To explore blood-based PD biomarkers of lucitanib activity 
• To determine PK of lucitanib in this patient population using population PK (POPPK) 
methods and explore correlations between exposure, response, and/or safety findings 
4.2 Endpoints 
4.2.1 Primary Endpoint 
• PFS per RECIST Version 1.1 as determined by the investigator 
4.2.2 Secondary Endpoints 
• ORR according to RECIST Version 1.1  
• DR and DCR according to RECIST Version 1.1 
• OS 
• Change from baseline in PRO using the Functional Assessment of Cancer Therapy-Breast 
(FACT-B) questionnaire 
• Treatment emergent AEs, laboratory abnormalities, physical examinations including vital 
signs and electrocardiogram (ECG) abnormalities 
• PK parameters including area under the concentration (AUC) curve from time zero to 
time t (AUC0–t), Cmax, Tmax, t1/2,  volume of distribution at steady state (VSS/F), and total 
plasma clearance (Cl/F) for lucitanib, if data allow 


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4.2.3 Exploratory Endpoints 
• Concordance of tumor tissue FGFR1 and 11q amplification assessed across different 
technical platforms (FISH, Next Generation Sequencing  [NGS], comparative genomic 
hybridization [CGH], chromogenic in-situ hybridization [CISH], quantitative polymerase 
chain reaction [qPCR], or circulating tumor cells [CTCs/ctDNA]  
• Exploration of different cut-off values for determining FGFR1 and 11q amplification in 
tumor tissue by FISH and correlation with clinical efficacy 
• Ribonucleic acid (RNA) expression of FGFR1, FGF3/4/19, and additional FGF family 
members; correlation with FGFR1 and 11q amplification status and clinical efficacy 
• Protein expression of FGFR1 as determined by immunohistochemistry (IHC) in tumor 
tissue; correlation with FGFR1 amplification status 
• Genomic analysis of circulating tumor DNA (ctDNA) 
• PD biomarker analysis measurement of circulating plasma biomarker levels including but 
not limited to FGF-2, FGF-23, sVEGFR1, VEGF-A, sCSF-1R, and CSF-1 
• Pharmacogenomic analysis of variations in genes encoding proteins involved in 
absorption/distribution/metabolism/excretion (ADME) 
• Plasma PK parameters for lucitanib based on sparse sampling for POPPK analysis 
 


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5 
STUDY DESIGN 
5.1 Overall Study Design and Plan 
This is a phase 2, open-label, multicenter study evaluating the efficacy and safety of lucitanib 
administered orally to patients with metastatic breast cancer.  Patients with FGFR1- or 11q 
(FGF3, FGF4, Cyclin D1, or FGF19)-amplified metastatic breast cancer may be enrolled into 
one of two different cohorts (Cohort A: FGF-amplified or Cohort C: FGF non-amplified, both 
receiving 10 mg daily).    
For patients with local FGFR1 or 11q test results, a central laboratory will confirm the 
presence or absence of the FGFR1 and/or 11q amplification.  Central testing prior to 
enrollment for these patients is not required for study enrollment.  
Patients with local FGFR1 and 11q results for whom the central reading does not confirm the 
amplification status can continue the study at the discretion of the investigator if clinical 
benefit is observed.  If there are a significant number of patients with discordant local and 
central testing results, additional patients may be enrolled. 
For patients without a local FGFR1 or 11q test result, tissue may be submitted for central 
testing under a prescreening process, and a positive central laboratory test result is required 
for screening and subsequent enrollment of these patients.   
FGFR1-amplified and 11q-amplified patients will be enrolled* as follows: 
• Cohort A (10 mg): approximately 80 patients  
FGF non-amplified patients will be enrolled as follows: 
• 
Cohort C (10 mg): up to 40 patients 
The dose assigned to patients enrolled into Cohort C depends on the version of the 
amendment approved at the time of patient enrollment (Amendment #3: 15 mg; Amendment 
#4: 10 mg). 
*Amendment #4 removes the 1:1 randomized treatment assignment (10 mg vs. 15 mg) and 
accrual of patients to Cohort B (15 mg).  Up to 80 patients were expected enrolled into 
Cohort B under the previous versions of this protocol. 
Up to 20 patients enrolled will participate in a PK sub-study to assess the comparative PK of 
the lucitanib tablet formulation taken at Day –7 with the lucitanib capsule formulation taken 
at Day 1.   
Patients in Cohorts A or C will be enrolled in the PK sub study at participating sites, as 
follows:  
• Participation in the PK sub study will be optional for patients participating in  
Cohort A 
• 
Participation in the PK sub study will be required for patients participating in  
Cohort C until enrollment of the PK sub study is completed 


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5.1.1 Screening Period 
FGF-amplified (Cohort A) and FGF non-amplified (Cohort C) patients will undergo 
screening assessments within 28 days of the first dose of lucitanib.  
Cohort A or C patients enrolled into the PK sub-study must undergo screening assessments 
within 21 days of the first dose of lucitanib, i.e., prior to Day –7.   
For all patients, AEs will be assessed from the time of first dose of lucitanib through 28 days 
after the last protocol-specified treatment administration.  Study-procedure-related AEs that 
occur after signing of the Informed Consent Form (ICF) and before administration of 
lucitanib will also be collected as AEs.  AEs that occur after signing of the ICF and before 
lucitanib should be captured on the Medical History eCRF. 
5.1.2 Treatment Period 
Lucitanib will be administered once daily and swallowed with water (see Section 7.3).  
Patients should take lucitanib at approximately the same time each day, on an empty stomach, 
at least 2 hours before and 2 hours after a meal (fasting window is a total of four hours).  
Treatment with lucitanib is continuous but cycles will be defined as 28 days in duration.  
Dosing will be delayed or reduced according to protocol-specified toxicity criteria (See 
Section 7.4).  Protocol-specified treatment will continue until there is clinical tumor 
progression or unacceptable toxicity.   
Patients will undergo serial assessments for anti-tumor efficacy, drug safety, and PROs.  
Tumor scans will be acquired by the investigative site and evaluated locally for patient 
treatment decisions.  Electronic copies of tumor scans will be uploaded to a central 
radiological vendor and held for review, if deemed necessary.  Sparse blood sampling for 
POPPK analyses will be conducted in all patients treated with lucitanib.  Serial blood 
sampling for PD evaluation will be conducted.  Local laboratories will be used for standard 
hematology and chemistry tests.  Echocardiogram (ECHO)/multiple-gated acquisition 
(MUGA) will be done locally.  ECGs will be stored and may be analyzed centrally.  Patients 
will be asked to self-monitor their BP at least two times per week and instructed to contact 
the study site in the event of a BP reading equal or above 160 mmHg systolic and/or greater 
than 100 mmHg diastolic (see Section 9.5.1.3). 
Patients with SD or better after their Cycle 6 scan will continue to have tumor scans every 
12 ± 1 weeks until tumor progression.  After discontinuation of protocol-specified treatment, 
subsequent specific anticancer therapy used at the investigator’s discretion will be recorded.  
Patients will be encouraged to undergo an optional post-treatment tumor biopsy at time of 
progression and before subsequent-line therapy is initiated. 
5.1.3 End-of-Study  
All patients should return to the clinic for end-of-study assessments 28 (±7) days after the last 
dose of lucitanib has been administered.   
The trial will be completed when all enrolled patients have discontinued treatment and 
completed the end-of-study follow-up visit.   


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5.1.4 Long Term Follow-Up 
All patients will be followed at approximately two monthly intervals to determine survival 
status, until death or sponsor decision to end the trial, whichever comes first. 
5.2 Study Schema 
The study schema in Figure 1 summarizes the treatment design of the study. 


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Figure 1: 
Study Schema 
 
 
 


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6 
STUDY POPULATION 
6.1 Number of Patients and Sites 
FGFR1-amplified and 11q-amplified patients will be enrolled* as follows: 
• Cohort A (10 mg): approximately 80 patients  
FGF non- amplified patients will be enrolled into Cohort C as follows: 
• Cohort C (10 mg): up to 40 patients 
*1:1 randomization to Cohorts A and B was removed with Amendment #4. 
Up to 20 patients will participate in a PK sub study to assess the comparative PK of the lucitanib 
tablet formulation with the lucitanib capsule formulation.  Additional patients may be added to 
the PK sub-study to account for patients with incomplete PK sampling profiles at either Day –7 
or Day 1, or to account for higher than expected variability in the observed PK profiles. 
Enrollment into the PK sub study may only be opened at a limited number of sites based on 
study requirements and operational feasibility. 
Patients in Cohorts A or C will be enrolled in the PK sub study at participating sites, as follows:  
• Participation in the PK sub study will be optional for patients participating in Cohort A 
• Participation in the PK sub study will be required for patients participating in Cohort C 
until enrollment of the PK sub study is completed 
There will be approximately 30–40 investigative sites in the United States.  All patients enrolled 
in Cohort C are required to participate in the PK sub study.  Accrual to Cohort C will be limited 
to 10-15 sites participating in the PK sub study, until enrollment in the sub study has been filled. 
6.2 Inclusion Criteria 
All patients must meet all of the following inclusion criteria: 
1. Histologically or cytologically confirmed metastatic breast cancer relapsed or refractory to 
approved standard available treatment 
° 
Specifically, patients with HER2-positive disease, as defined by the American 
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 
guidelines [51], must have exhausted approved HER2-directed therapies prior to 
enrollment 
2. Prior treatment with standard first line therapy in the metastatic setting 
3. FGFR1 amplification or 11q amplification status determined on the most recent tumor tissue 
available, or detected in blood using validated methods for detecting circulating tumor cells 
(CTCs) or ctDNA: 
a) Patients in Cohort A: FGFR1- or 11q-amplified 
b) Patients in Cohort C: neither FGFR1- nor 11q-amplified 
Patient amplification status will be based on: 


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° 
local assessment by FISH, NGS, CGH, CISH, or qPCR; or  
° 
local assessment in blood using validated methods for detecting circulating tumor 
cells (CTCs) or ctDNA; or 
° 
central assessment by FISH, as confirmed by a prescreening process 
4. Availability of formalin-fixed paraffin embedded (FFPE) tumor tissue sufficient for the 
central confirmation by FISH of FGFR1 amplification or 11q amplification status.  Detailed 
sample handling instructions are provided in the Laboratory Manual 
5. Demonstrated progression of disease by radiological or clinical assessment 
° 
Measurable disease according to RECIST Version 1.1 is NOT required for 
enrollment 
6. Patient, aged ≥18 years old 
7. Eastern Cooperative Oncology group (ECOG) Performance status 0 or 1 
8. Estimated life expectancy >6 months 
9. Normal left ventricular function defined as a left ventricular ejection fraction (LVEF) ≥50% 
by ECHO or MUGA 
10. Screening for laboratory values within the following parameters: 
° 
Hematology: absolute neutrophil count (ANC) ≥1000/mm3; platelet count 
≥100,000/mm3; hemoglobin ≥9 g/dL 
° 
Renal function:  
− Serum creatinine <1.5 mg/dL or creatinine clearance >45 mL/min 
(Modification of Diet in Renal Disease formula [MDRD])  
− Dipstick protein measurement <2+.  If dipstick ≥2+ then perform 24-hour 
urine protein measurements and if proteinuria <300 mg patient is eligible 
for inclusion 
° 
Liver function tests: total bilirubin ≤1.5 upper limit of normal (ULN; unless 
evidence of Gilbert’s disease confirmed by uridine diphosphate-
glucuronyltransferase [UGT] polymorphism); aspartate transaminase (AST) and 
alanine transaminase (ALT) ≤3 ULN; AST and ALT ≤5 ULN in case of liver 
metastases 
11. For women with childbearing potential, a negative pregnancy test within 7 days prior to 
initiation of the study drug 
12. Willingness to use an effective contraceptive method during the study and up to six months 
after the last dose is administered.  Effective methods include the following: non-hormonal 
intrauterine device, barrier method (condoms, diaphragm) also in conjugation with 
spermicidal jelly, or total abstinence.  Oral, injectable, or implant hormonal contraceptives 
are discouraged 
13. Written consent on an Institutional Review Board (IRB)/Independent Ethics 
Committee(IEC)-approved ICF prior to any study-specific evaluation 


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6.3 Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 
1. Current or recent treatment with biologic anticancer therapies.  Required washout for 
prior biologic anticancer therapies: 
° 
3 months for bevacizumab 
° 
28 days or five half-lives, whichever is shorter, for all other biologic therapies 
2. Ongoing AEs from prior anticancer therapies, including radiation, targeted or cytotoxic 
therapies without resolution of any Grade 2 or greater side effects to Grade ≤1 
3. Current treatment with any prohibited medications associated with prolongation of QT 
interval and known risk of Torsades de Pointes (see Appendix C) 
4. Active CNS metastases, as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth (patients with history of CNS metastases or cord compression are 
eligible if they are clinically stable for at least 4 weeks before first dose of lucitanib and 
do not require high-dose steroid treatment) 
5. History of clinically significant or uncontrolled cardiac disease, including congestive 
heart failure (HF; New York Heart Association functional classification ≥3), angina, 
myocardial infarction within 6 months, or ventricular arrhythmia 
6. QTC prolongation (defined as a QTC interval >470 msec according to Fridericia’s 
correction) 
7. Uncontrolled hypertension (defined as systolic blood pressure [SBP] ≥140 mmHg and/or 
diastolic blood pressure [DBP] ≥90 mmHg with optimized anti-hypertensive therapy) 
° 
The requirement for >2 anti-hypertensives to control hypertension at time of 
enrollment is exclusionary 
8. Active second malignancy, i.e., patient known to have potentially fatal cancer present for 
which he/she may be (but is not necessarily) currently receiving treatment  
° 
Patients with a history of malignancy that has been completely treated, with no 
evidence of that cancer currently, are permitted to enroll in the trial provided all 
chemotherapy was completed >6 months prior and/or bone marrow transplant 
(BMT) >2 years prior 
9. Uncontrolled hypothyroidism defined as serum thyroid stimulating hormone (TSH) 
higher than 5 mIU/mL while receiving optimized thyroid hormone replacement therapy 
10. Patient with history of thrombotic disorders: 
° 
Any history of venous thrombotic events, deep vein thrombosis (with the 
exception of catheter related deep vein thrombosis), or pulmonary embolism 
within 6 months prior to the first dose of lucitanib 
° 
Any history of arterial thrombotic events, cerebrovascular accident, or transient 
ischemic accident within 6 months prior to the first dose of lucitanib 


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° 
Any peripheral vascular disease or vasculitis which required treatment within 
6 months prior the first dose of lucitanib 
° 
Patient with hereditary risk factors of thromboembolic events (e.g., mutation of 
the Factor V of Leiden) 
11. Received administration of strong inhibitors of CYP2C8 or CYP3A4 or strong inducers 
of CYP3A4 ≤7 days prior to first dose of lucitanib or have on-going requirements for 
these medications (Appendix E) 
12. Received investigational treatment within 28 days prior to enrollment in this study 
13. Non-study related minor surgical procedures ≤14 days prior to administration of 
lucitanib.  In all cases, the patient must be sufficiently recovered and stable before 
treatment administration 
14. History of major surgical procedure or significant trauma within 28 days prior to 
lucitanib.  In all cases, the patient must be sufficiently recovered and stable before 
treatment administration 
15. Females who are pregnant or breastfeeding 
16. Presence of any serious or unstable concomitant systemic disorder incompatible with the 
clinical study (e.g., substance abuse, uncontrolled psychiatric condition, uncontrolled 
intercurrent illness including active infection, arterial thrombosis, and symptomatic 
pulmonary embolism) 
17. Foreseeable poor compliance to the study procedures 
18. Any other reason the investigator considers the patient should not participate in the study 
6.4 Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion and women of childbearing potential must not be considering 
getting pregnant, or become pregnant, during the study.  Female patients who are more than 
2 years postmenopausal or have had a hysterectomy will not be considered of childbearing 
potential.  Female patients of childbearing potential must have a negative serum pregnancy less 
than 7 days prior to administration of the first dose lucitanib.  If the serum pregnancy results are 
not available prior to dosing, a urine pregnancy test can be performed to confirm that the patient 
is not pregnant prior to dosing.  Both values should be entered in the electronic case report form 
(eCRF).  Another serum pregnancy test will be performed at the end-of-study visit. 
Patients of reproductive potential (males and females) must practice an effective method of 
contraception during treatment and for 6 months following the last dose of lucitanib.  Adequate 
contraception is defined as double-barrier method (i.e., condom plus spermicide in combination 
with a diaphragm, cervical/vault cap, or intrauterine device).  Oral, injectable, or implant 
hormonal contraceptives are discouraged.  
Patients will be instructed to notify the investigator if pregnancy is discovered either during or 
within 6 months of completing treatment with lucitanib.  This also applies to male patients whose 


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partners become pregnant while the patient is on study, or within the 6-month period after the 
last dose of lucitanib. 
6.5 Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study.   


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7 
DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS 
7.1 Description of Study Treatments  
Lucitanib is supplied as an oral formulation as either hard gelatin capsules or tablets. A brief 
description of the investigational product is provided below (additional information may be 
found in the Investigator’s Brochure and pharmacy manual):  
Drug name: 
CO-3810 
International 
Nonproprietary Name 
(INN): 
lucitanib 
 
Capsules 
Tablets 
Formulation: 
2.5 mg (orange and white size 4), 
5 mg (orange size 4), and  
10 mg (white size 4) 
5 mg (white),  
7.5 mg (pink) 
Excipients: 
lactose monohydrate, sodium 
croscarmellose, and magnesium 
stearate 
glycerol, pregelatinized starch, 
hydroxypropylmethyl 
cellulose, and magnesium 
stearate, polyethylene glycol 
6000, titanium dioxide, iron 
oxide (7.5 mg only) 
Temperature storage 
conditions: 
59 – 77°F / 15 – 25°C 
59 – 86°F / 15 – 30°C 
 
Lucitanib is packaged in child-resistant tamper evident high-density polyethylene (HDPE) 
bottles.  Bottles with capsules will contain desiccant.Lucitanib will be supplied to the study sites 
by the sponsor. Lucitanib supplies should be stored in their original packaging and not 
refrigerated.  Each bottle of study drug will contain the unique identification code and the LOT 
number. 
At the start of each cycle, the patient will receive sufficient lucitanib supplies to complete 
4 weeks of treatment. 
Bottles containing lucitanib will be labeled according to national regulations for investigational 
products. The expiry date will not appear on the labels, but will be controlled by the use of an 
Interactive Web Response System (IWRS). 
7.2 Method of Assigning Patients to Treatment Groups 
After confirming that patients fulfill entry criteria, the Investigator or his/her delegate will enroll 
patients as follows: 


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• Cohorts A and C (non-PK sub study patients): enrollment in IWRS on C1D1 to receive 
lucitanib at 10 mg daily* 
• PK sub study patients: manual enrollment at Day -7 visit to receive single dose of 10 mg 
lucitanib in a tablet formulation, followed by enrollment in IWRS on C1D1 to receive 
lucitanib at 10 mg daily* 
Based on analysis of data from the PK sub study and confirmation of acceptable PK 
comparability, patients may begin lucitanib treatment with the tablet formulation upon 
enrollment and patients who began treatment with capsule formulation may, at the discretion of 
the Sponsor and Investigator, be switched to the tablet formulation. 
*Treatment should be initiated within 3 days of enrollment. 
7.3 Preparation and Administration of Protocol-Specified Treatment 
All patients will be assigned to receive lucitanib 10 mg daily.  The treatment dose may be 
achieved by combining capsules or tablets of different strengths (see Section 7.1).  Patients 
should take lucitanib as directed by the treating physician.  Lucitanib should be taken with water 
(240 mL or 8 ounces).  Patients should take lucitanib at approximately the same time each day, 
on an empty stomach, at least 2 hours before and 2 hours after a meal (fasting window is a total 
of four hours). 
Treatment with lucitanib is continuous, but cycles will be defined as 28 days in duration.  Dosing 
will be delayed or modified according to Dose Modification Criteria and Toxicity Management 
guidelines (See Section 7.4).  Patients are allowed dose reductions by 2.5 mg increments after 
Cycle 1, Day 1 (C1D1).     
Tablets and capsules must be transferred from the bottle to the mouth with minimal 
manipulations.  The investigator will instruct the patient and personnel not to open the capsules; 
however, in the case of accidental release of the powder from the capsules, contaminated 
clothing should be removed and washed separately, rubber gloves should be put on, and all 
contaminated surfaces should be thoroughly cleaned with alcohol, a detergent solution, and then 
wiped clean with water.  Patients should be advised to not suck, chew, or crush the capsules or 
tablets.  Personnel should avoid exposure to crushed and/or broken tablets.  In case of accidental 
skin contact with the content of the capsules or crushed tablets, the area should be flushed with 
large amounts of water for at least 15 minutes and then washed with soap.  Contaminated 
material should be placed in an appropriate container and sealed before disposal. 
If a patient misses a dose but is able to take it within six hours of the intended time, they should 
be instructed to take the missed dose, on an empty stomach as noted above.  However, if the 
patient is not able to take the missed dose within six hours of the scheduled time, they should 
skip the missed dose and resume taking lucitanib at the normal time the following day.  If a 
patient vomits the dose within 15 minutes of taking lucitanib, they should take an additional 
dose.  If vomiting occurs more than 15 minutes after taking lucitanib, they should not take 
another dose until the normal time the following day.   


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Patients in the PK sub study that vomit after taking lucitanib on Day –7 or Day 1 should not take 
an additional dose of lucitanib, and PK sample collections should continue per protocol. 
The investigator or designee will be responsible for distributing the appropriate strength(s) of 
lucitanib capsules to patients.  A sufficient number of capsules will be provided to the patient to 
last until the next scheduled visit.  Patients will be instructed to record daily doses taken or not 
taken in a patient diary and will be instructed to bring their lucitanib capsules and diary to the 
next scheduled visit for reconciliation by site personnel. 
7.4 Dose Modification Criteria and Toxicity Management  
Patients are allowed dose reductions by 2.5 mg increments after C1D1 (with the exception of 
patients in the PK sub-study receiving lucitanib on Day –7 and Day 1).  Patients are permitted to 
re-escalate at the start of a cycle by 2.5 mg as long as the cause of the dose reduction has 
resolved to Grade 1 or better.  Dose escalations above 10 mg daily are not permitted.   
7.4.1 Hypertension 
As observed with other anti-angiogenic anti-cancer therapies, lucitanib can induce or exacerbate 
hypertension (as described in the Investigator’s Brochure).  Rapid increases in BP from pre-
treatment measurements can be observed as early as the first few days following initiation of 
therapy.  Hypertension can also occur later in the course of treatment.  
Hypertension should be closely monitored and treated, if required.  Abnormal BP measurements 
in clinic should be repeated within an hour to confirm findings. 
Additionally, patients should be instructed to self-measure their BP at home at least two times 
per week while receiving lucitanib treatment.  Patient-monitored BP should be followed by the 
investigator at all clinic visits to evaluate the effectiveness of anti-hypertensive treatment. 
The early detection and effective management of hypertension are important to minimize risk for 
the patient and the need for lucitanib dose interruptions and reductions. 
The following treatment and lucitanib dose adjustments algorithm should be followed in case 
hypertension is encountered: 
 
 
 
 


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Table 1:  Hypertension Guidance Algorithm 
Observation 
Action 
Patient experiences hypertension for the first 
time or patient with previously controlled 
hypertension experiences worsening in BP 
values with SBP from 140 to 159 mmHg 
and/or DBP from 90 to 99 mmHg.  
 
 
Patients without pre-existing hypertension 
Initiate anti-hypertensive therapy 
immediately.   
Immediate use of two anti-hypertensive 
agents can be considered in case of rapid 
elevation of BP.  The anti-hypertensive agent 
can be adjusted over a period of 14 days.  The 
patient should be followed by the investigator 
at least once a week to evaluate the response 
to anti-hypertensive treatment.  During this 
period, interruption of lucitanib or dose 
modification is not necessary.  
If BP decreases to < 140/90 mmHg within 
14 days, continue lucitanib at the same dose. 
Patients with pre-existing hypertension 
Intensify/adapt any current anti-hypertensive 
treatment.  Immediate dose and therapeutic 
class optimization should be performed.  Up 
to three anti-hypertensive agents should be 
considered. 
The anti-hypertensive agent can be adjusted 
over a period of 14 days.  The patient should 
be followed by the investigator at least once a 
week to evaluate the response to 
anti-hypertensive treatment.  During this 
period, interruption of lucitanib or dose 
modification is not necessary.  
If BP decreases to < 140/90 mmHg within 
14 days, continue lucitanib at the same dose. 


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Observation 
Action 
In case of persisting hypertension with SBP 
from 140 to 159 mmHg and/or DBP from 
90 to 99 mmHg despite optimized 
anti-hypertensive treatment after 14 days.  
 
 
Reduce lucitanib dose by 2.5 mg.  
Ensure adequate control of BP below 140/90 
mmHg including increasing the dose of the 
current anti-hypertensive agent(s) (if 
appropriate) and/or initiation of additional 
anti-hypertensive agents, if required.  
Allow up to 14 days for BP to be controlled.  
If BP does not reduce to < 140/90 mmHg 
after 14 days, lucitanib should be reduced 
again by 2.5 mg (to the next lower dose). 
Allow an additional 14 days for BP to be 
controlled. 
If BP does not reduce to < 140/90 mmHg 
within the additional 14 days, lucitanib 
should be interrupted for up to 14 days.  If BP 
decreases to < 140/90 mmHg within 14 days, 
restart lucitanib at the last dose. 
If BP remains at ≥ 140/90 mmHg after 
14 days, sponsor approval is required prior to 
re-initiating lucitanib treatment.  
 
 
 
 
 
 
 
 
 


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Observation 
Action 
In case of confirmed hypertension with SBP 
equal or above 160 mmHg, and/or DBP equal 
or above 100 mmHg. 
Patients presenting no hypertension-
related symptoms & no more than one risk 
factor1 
Continue lucitanib therapy.  
Immediately start anti-hypertensive treatment 
or optimize current anti-hypertensive 
treatment. 
Allow up to 4 days for BP to be controlled 
(BP < 140/90 mmHg), with close follow-up 
by the treating physician.   
If BP does not reduce to ≤ 160/100 mmHg 
within 4 days, lucitanib should be reduced by 
2.5 mg.   
If BP does not reduce to ≤ 160/100 mmHg 
within 4 additional days despite lucitanib 
dose reduction and optimal anti-hypertensive 
therapy, lucitanib should be interrupted.  
If BP decreases to < 140/90 mmHg within 
14 days, resume lucitanib at next lower dose. 
If BP is not controlled < 140/90 mmHg) 
within 14 days after interruption of lucitanib 
and despite optimal anti-hypertensive 
treatment, lucitanib should be permanently 
discontinued. 
 
 
 
 
 
 
 
 


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Observation 
Action 
Patients with mildly symptomatic 
hypertension2 (outside of cardiovascular, 
cerebral, or major renal complications) or 
several risk factors1 or already receiving 
two anti-hypertensive agents 
Temporarily interrupt lucitanib therapy. 
Immediate use of two anti-hypertensive 
agents may be considered in patients with no 
history of hypertension.  For patients already 
on two anti-hypertensive agents, modification 
of the current anti-hypertensive therapy 
and/or adding a third agent should be 
considered. 
The patient should be followed by the 
investigator closely to evaluate the response 
to anti-hypertensive treatment. 
Allow up to 14 days for BP to be controlled 
(BP < 140/90 mmHg).  
If BP decreases to < 140/90 mmHg within 
14 days, resume lucitanib at next lower dose. 
If BP does not reduce to < 140/90 mmHg 
within 14 days, lucitanib should be 
permanently discontinued.    
In case of confirmed hypertensive crisis with 
life-threatening consequences. 
Hypertensive crisis is defined as an increase 
in BP (≥180 mmHg SBP and/or ≥120 mmHg 
DBP) that can lead to life-threating 
consequences (e.g., cerebral stroke). 
Lucitanib must be permanently discontinued. 
1Risk factors include those comorbidities that in the opinion of the investigator would increase the patient’s risk of 
hypertension-related complications, e.g., diabetes, coronary artery disease 
2Midly symptomatic hypertension defined as symptoms of headache, facial flushing, etc in the absence of additional 
cardiac or neurological findings 
Pharmacological management should be based on the investigator’s judgment and no definite 
recommendations for an anti-hypertensive agent can be made.  However, calcium channel 
blockers may be preferred as initial treatment based on their rapidity of action and safety profile.  
Angiotensin Converting Enzyme (ACE) inhibitors can be considered in case of concomitant 
proteinuria [52, 53, 54].  In case of rapid elevation of BP, two anti-hypertensive agents should be 


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considered.  The use of three anti-hypertensive agents, such as concomitant use of a renin-
angiotensin system inhibitor, calcium channel blocker, and diuretic drug may be considered 
based on the investigator’s decision.  In that case, close surveillance of kidney function and 
electrolytes is strongly recommended.  
Cardiologist and nephrologist advice should be sought when appropriate and especially in the 
context of associated AEs (i.e., proteinuria, as described below).  
Sites should counsel patients on limiting salt intake to less than 4 g/day.  
The patient must be educated before the first intake of lucitanib on the importance of BP 
self-monitoring, trained to recognize signs of hypertension, and to contact the site if BP is greater 
than 160/100 mmHg at any time. 
For purposes of medical history reporting and AE reporting, it is important to strictly follow the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
grading scale, taking into account not only the BP levels, but also the number of 
anti-hypertensive therapies. 
After the withdrawal of lucitanib, the BP must continue to be monitored in order to adjust and 
progressively stop anti-hypertensive treatments that were started during the study (as 
appropriate). 
Table 2:   Grading scale for hypertension (NCI CTCAE Version 4.0) 
 
Grade 1 Prehypertension (SBP 120−139 mmHg or DBP 80−89 mmHg) 
Grade 2 Stage 1 hypertension (SBP 140−159 mmHg or DBP 90−99 mmHg); medical 
intervention indicated; recurrent or persistent (≥24 hours); symptomatic increase 
by >20 mmHg (DBP) or to >140/90 mmHg if previously within normal limits; 
monotherapy indicated 
Grade 3 Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg); medical 
intervention indicated; more than one drug or more intensive therapy than 
previously used indicated 
Grade 4 Life-threatening consequences (e.g., malignant hypertension, transient or 
permanent neurologic deficit, hypertensive crisis); urgent intervention indicated  
Grade 5 Death 


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7.4.2 Proteinuria 
Patients will be monitored for proteinuria by dipstick every two weeks during Cycle 1 and 
Cycle 2 and every 28 days thereafter.  Patients with early signs of proteinuria by dipstick (2+) 
should be closely monitored and proteinuria evaluated quantitatively (24 hours protein excretion 
or protein-to-creatinine ratio).  Additional safety monitoring should be performed as clinically 
indicated including tests for the assessment of free/conjugated bilirubin, haptoglobin N, 
schizocytes, or renal biopsy.   
The following treatment and lucitanib dose adjustments algorithm should be followed in case 
proteinuria is encountered:  
Table 3:   Proteinuria Management Algorithm 
In case of first onset of 
proteinuria ≥Grade 2 (i.e., ≥1 g in 
24 hours by quantitative 
assessments) 
Lucitanib treatment should be withheld and proteinuria 
monitored by dipstick twice weekly.  Upon recovery of 
proteinuria to Grade ≤1 (1+ by dipstick or urinary 
protein <1.0 g/24 hours), lucitanib treatment should be 
resumed at the same dose and dipstick monitoring 
should continue 
In case of second onset of 
proteinuria ≥Grade 2 
Withhold the drug and perform a quantitative 
assessment of 24-hour urinary protein.  Upon recovery, 
the lucitanib treatment should be resumed with a 2.5 
mg dose reduction (e.g., 10 mg to 7.5 mg) 
In case of third onset of 
proteinuria ≥Grade 2 
Repeat assessments and dose modifications as outlined 
above (e.g., 7.5 mg to 5 mg) 
In case of fourth onset of 
proteinuria ≥Grade 2 
If proteinuria ≥ Grade 2 recurs following dose 
reductions to 5 mg, or if there is no recovery within 30 
days, discontinue treatment permanently 
In case of Grade 3 proteinuria or of additional risk factors (e.g., microhematuria, arterial 
hypertension), assessment of free/conjugated bilirubin, haptoglobin N, schistocytes, and/or renal 
biopsy may be indicated in consultation with a nephrologist. 
Proteinuria will be graded as follows (CTCAE Version 4.0): 
 
 
 
 
 
Grade 1: 1+ proteinuria; urinary protein < 1.0 g/24 hours 
Grade 2: 2+ proteinuria; urinary protein ≥ 1.0–3.4 g/24 hours 
Grade 3: Urinary protein ≥ 3.5 g/24 hours 


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7.4.3 Sub-clinical hypothyroidism 
Plasma TSH and thyroid hormones levels should be measured, per protocol.  Treatment with 
levothyroxine 50 μg/day is recommended for patients with TSH values above 5 mIU/L, even if 
triiodothyronine (T3) and thyroxine (T4) are normal.  The treatment with lucitanib can continue 
at the same dose. 
7.4.4 Decrease in LVEF 
LVEF will be assessed by ECHO or MUGA.  It is recommended to use the same technique for a 
given patient throughout the whole study duration.  In case of HF symptoms or modification on 
imaging from baseline the following rules must be applied: 
• No signs of HF and LVEF ≥45 % OR absolute drop from baseline ≤15 EF % points.  
Continue lucitanib at the same dose level and repeat LVEF assessment per protocol 
• Patient is symptomatic OR LVEF <45% OR absolute drop from baseline >15 EF % 
points.  Hold lucitanib until resolution (LVEF ≥50% and asymptomatic).  If resolution 
occurs within 3 weeks, lucitanib can be resumed at a reduced dose by 2.5 mg increments, 
as described above, otherwise withdraw lucitanib permanently 
• No recovery OR LVEF <20 %.  Discontinue lucitanib permanently and follow-up the 
patient 
7.4.5  QTC prolongation 
In case of CTCAE Grade 3 prolongation of the QTCF (Fridericia correction) interval >500 msec, 
lucitanib treatment must be withheld. 
Serum calcium, phosphorus, potassium, and magnesium levels should be analyzed, and levels 
should be corrected to within normal limits if needed.  In all cases a second ECG must be carried 
out to confirm the QTCF prolongation >500 msec within 1 hour of the initial ECG.  A review of 
concomitant medications that could cause QT prolongation and/or Torsades de Points should be 
performed (see Section 8 and Appendix C).  
Once QTCF prolongation has resolved, lucitanib may be restarted at a 2.5 mg lower dose.  
Further dose reductions are permitted, as described above. 
Grade 4 QTC prolongation (QTC >501 msec or >60 msec change from baseline and Torsades de 
Pointes or polymorphic ventricular tachycardia or symptoms of serious arrhythmia) should result 
in permanent discontinuation of lucitanib. 
7.4.6 Liver function test abnormalities 
In case of Grade 3 increase in ALT and AST, the dose will be withheld until recovery to 
Grade 2.  If recovery occurs within 14 days, treatment will be resumed at the same dose level.  If 
no recovery occurs within 14 days, the treatment will be resumed at a 2.5 mg lower dose upon 
recovery.  Further dose reductions are permitted, as described above.  In case of repeated events 
at 5 mg or absence of recovery to Grade 2 within 7 days, lucitanib will be stopped permanently. 


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In case of patient presenting with ALT >3 times the ULN concurrent with a total bilirubin 
>2 times the ULN with no evidence of hemolysis, and an alkaline phosphatase < 2 times the 
ULN or not available, lucitanib must be stopped permanently. 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin, in 
the absence of other causes of liver injury, are considered potential cases of drug-induced liver 
injury (potential Hy’s Law cases) and as such, should always be considered important medical 
events.  Patients who present that combination of laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values. 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, physical assessment, and the possibility of hepatic 
neoplasia (metastases) should be considered.  In addition to repeating AST and ALT, laboratory 
tests should include albumin, total bilirubin, direct bilirubin, prothrombin time (PT) and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
recreational drug and supplement consumption, family history, sexual history, travel history, 
history of contact with a jaundiced subject, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or C 
infection and liver imaging (e.g., biliary tract) may be warranted.  All cases confirmed on repeat 
testing as meeting the criteria mentioned above with no other cause for liver function test (LFT) 
abnormalities identified at the time should be considered potential Hy’s Law cases irrespective 
of availability of all the results of the investigations performed to determine etiology of the 
abnormal LFTs. 
7.4.7 Management of Posterior Reversible Encephalopathy Syndrome (PRES) 
If a patient presents with symptoms suggestive of PRES (e.g., persisting headache not responsive 
to usual analgesics, confusion, visual symptoms, seizures and coma), immediately interrupt 
lucitanib treatment and consider performing all relevant clinical and radiological examinations 
(e.g., neurological consultation, MRI) in order to ensure early diagnosis and treatment of this 
syndrome.  A follow-up MRI should be performed in order to confirm the diagnosis of PRES, 
and if confirmed, lucitanib treatment must be permanently discontinued. 
7.4.8 Other toxicities 
For other Grade 3 or 4 hematologic and non-hematologic toxicities (except for alopecia), 
lucitanib treatment should be withheld until recovery to Grade 2 for hematological or Grade 1 for 
non-hematological toxicity.  Upon recovery, the drug may be resumed at a 2.5 mg lower dose.  
Once the dose has been reduced within a treatment cycle, treatment continues at that dose level; 
no dose escalation is possible within a cycle.  If a patient continues to experience toxicity after 
all allowed dose reduction steps as described above (i.e., after a patient has been dose-reduced 
from starting dose to 5 mg/day), or if dosing with lucitanib is interrupted for >14 consecutive 
days due to toxicity, treatment should be permanently discontinued, unless otherwise agreed 
between the investigator and the sponsor.   


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In the event of Grade 3 or 4 nausea and vomiting, antiemetics should be used.  If, despite 
maximal antiemetic use, Grade 3 or 4 nausea or vomiting persists, lucitanib treatment should be 
withheld until recovery and dose reduction and discontinuation should follow the same paradigm 
as recommended for other Grade 3 and 4 non-hematologic toxicities. 
7.4.9 Planned Surgery 
In the case of planned surgeries, lucitanib should be temporarily withheld at least 7 days prior to 
and 7 days after a minor surgery (e.g., line placement, exploratory laparoscopy).  Lucitanib 
should be temporarily withheld at least 14 days prior to and 14 days after a major surgery 
(e.g., bowel resection, cardiac bypass).  
In all cases, lucitanib treatment should not be resumed until the surgical wound is fully healed.  
7.5 Accountability of Protocol-Specified Treatment 
Study personnel will maintain accurate records of lucitanib shipments/receipts, administration, 
and drug reconciliation.  The study site is responsible for the return or destruction of lucitanib as 
required.  With the exception of lucitanib bottles issued for the PK sub study, a drug 
management system (IWRS) will manage lucitanib inventory at all sites.  Bottles of lucitanib for 
the PK sub study may be managed locally. For management of all other lucitanib requests and 
shipments, the IWRS is required. Any lucitanib accidentally or deliberately destroyed must be 
accounted for.  All bottles must be accounted for prior to their destruction at the study center.  
Unused bottles should be destroyed locally.  If destruction at the site is not possible, supply 
should be returned to the drug depot.  During the course of the study and at completion of the 
study, the number of bottles of lucitanib shipped, destroyed, and returned must be reconciled.  
7.6 Blinding/Masking of Treatment 
This is an open-label study; the investigational product will not be blinded or masked.  All 
patients enrolled will receive lucitanib. 
7.7 Treatment Compliance 
Documentation of dosing will be recorded in a study specific diary provided by the sponsor (or 
designee).  Study site personnel will review the dosing information with the patient (or legally 
authorized representative) on scheduled clinic visit days.  Patients (or legally authorized 
representative) will be asked to record dosing information for lucitanib taken at home in the 
diary and to bring the diary and all unused lucitanib supplies with them to scheduled clinic visits.  
A compliance check and lucitanib count will be performed by study personnel.  Study site 
personnel will record compliance information in the eCRF and retain the diary in the patient’s 
medical record. 


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Lucitanib will be permanently discontinued for patients that fail to take 14 or more doses due to 
non-compliance (not related to toxicity or planned surgery) within any two consecutive cycles, 
unless otherwise agreed between the investigator and the sponsor. 


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8 
PRIOR AND CONCOMITANT THERAPIES 
8.1.1 Permitted Concomitant Medication and Medications that Should be Used 
with Caution 
All concomitant medications will be recorded in the eCRF.  The following concomitant 
medications are permitted during the study or should be used with caution:  
• Lucitanib is highly bound to plasma proteins; therefore, use caution with warfarin, which is 
also highly bound to plasma protein and has a narrow therapeutic window 
• Supportive care (e.g., antiemetics, analgesics for pain control) may be used at the 
investigator’s discretion and in accordance with institutional procedures 
• Drugs with possible risk to cause prolonged QT interval and/or possible risk or conditional 
risk to cause Torsades de Pointes must be used with caution (see Appendix C) 
• Transfusion of blood and blood products 
• Treatment with antibiotics, anti-emetics, anti-diarrheals, analgesics, thyroid replacement 
therapy 
• Bisphosphonates and denosumab in patients with bone metastases and for which the 
treatment was initiated prior to the initiation of study drug Considering the risk of drug-drug 
interactions, concomitant use of moderate inhibitors of CYP2C8 or CYP3A4 are not 
recommended during the study (see Appendix E) 
• Any other medication as appropriate, except for prohibited medications as described in 
Section 8.1.2 below 
8.1.2 Prohibited Concomitant Medications 
The following concomitant medications are not permitted during the study: 
• Systemic anticancer therapy (e.g., hormonal therapy, immune therapy, targeted therapy), 
except for bisphosphonates and denosumab in patients with bone metastases  
• Prior treatment with bevacizumab within 3 months prior to the first dose of lucitanib 
• Radiotherapy during the treatment period is prohibited.  Palliative bone radiotherapy at focal 
sites can be allowed during the screening period, before lucitanib intake and providing 
recovery is achieved before study drug initiation 
• Drugs known to cause prolonged QT interval and/or know risk of causing Torsades de 
Pointes (see Appendix C) 
• Strong inhibitors of CYP2C8 or CYP3A4 are contraindicated during the study.  Should acute 
treatment with a strong inhibitor be deemed necessary, lucitanib must be temporarily 
withheld.  Lucitanib may be resumed after a minimum of seven days of ending acute 
treatment with a strong inhibitor of CYP2C8 or CYP3A4 


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• Co-administration of strong inducers of CYP3A4 (Appendix E) are not permitted at any time 
during treatment with lucitanib 
 
 


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9 
STUDY PROCEDURES 
Table 4 summarizes the procedures and assessments to be performed for patients in Cohorts A, B 
and C with exception of patients in the PK sub study; Table 5 summarizes the procedures and 
assessments to be performed for patients in the PK sub study.  
Unless specified, all procedures and assessments are to be completed within ±2 days of the 
scheduled time point and are synchronized with administration day of lucitanib. 
 


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Table 4: 
Schedule of Assessments (All Cohorts) 
Treatment Period (Daily Dosing)A 
 
 
Cycle 1 
Cycle 2 
and 
Beyond 
Cycle 2 
Only 
ProcedureB 
Screening 
Day 1C 
Day 4 
Day 15 
Day 1 
Day 15 
End-of-
Study 
Two 
Monthly 
Follow-Up 
Informed Consent 
X 
Medical/Oncology History 
X 
Brief History 
X 
X 
X 
Complete Physical Examination 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
Vital Signs, Height, WeightD 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medications and Procedures 
X 
X 
X 
X 
Contraceptive CounselingE 
X 
X 
Serum Pregnancy TestF 
X 
X 
Hematology, Including ReticulocytesG 
X 
X 
X 
X 
X 
Serum ChemistryH 
X 
X 
X 
X 
X 
UrinalysisI 
X 
X 
X 
X 
X 
X 
X 
Tumor Scans (Including brain imaging for patients 
with known CNS metastases or when clinically 
indicated)J 
X 
 
 
 
X 
 
X 
 
Submit FFPE Tumor TissueK 
X 
X 
Adverse EventsL 
X 
X 
X 
X 
X 
X 
X 
Lucitanib Dispensation/Administration 
X 
X 
ECG AssessmentsM 
X 
X 
X 
X 
LVEF (ECHO or MUGA)N 
X 
X 
X 
Plasma for ctDNA AnalysisO 
X 
X 
X 
X 
X 
Plasma PD Biomarker SamplingP 
X 
X 
X 
X 
X 


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Treatment Period (Daily Dosing)A 
 
 
Cycle 1 
Cycle 2 
and 
Beyond 
Cycle 2 
Only 
ProcedureB 
Screening 
Day 1C 
Day 4 
Day 15 
Day 1 
Day 15 
End-of-
Study 
Two 
Monthly 
Follow-Up 
Blood for Sparse PK SamplingQ 
X 
X 
Pharmacogenomic Blood Sampling 
X 
Quality of Life QuestionnaireR 
X 
X 
X 
Review and Collection of BP and Dosing Diary 
X 
X 
X 
X 
Survival Status 
X 
X 
Subsequent Therapies for Breast Cancer 
X 
X 
 
A Lucitanib will be administered daily, at least 2 hours before and 2 hours after a meal (on an empty stomach) with water (240 mL or 8 ounces).  The total fasting period is 
4 hours. 
B Unless specified, procedure is completed ±2 days of scheduled time point.  Procedures for C1D4 must be completed ±1 day of scheduled time point. 
C Procedures required prior to lucitanib administration on C1D1 may be omitted if completed ≤3 days earlier during the screening period. 
D Vital signs (BP, pulse, and temperature) taken pre-dose on drug administration days; height is only required once at screening.  BP self-monitoring, two times per week, is 
requested from patients (see Section 9.5.1.3).   
E Patients are to continue using effective contraception for 6 months after the last dose of lucitanib and report any pregnancies during this period. 
F Serum ß-hCG (evaluated by local labs) will be performed only on women of childbearing potential ≤7 days prior to C1D1 and End -of-Study.  If the serum pregnancy test 
results are not available on Day 1, a urine pregnancy test can be performed on Day 1 to confirm that the patient is not pregnant prior to dosing. 
G Includes hemoglobin, hematocrit, WBC and differential (with ANC), platelet count, PT/PTT, and reticulocyte count ≤14 days prior to the first day of dosing.  Blood will 
be sent for analysis at a local laboratory and must be reviewed by the investigator prior to start of lucitanib administration.  Additional tests may be performed at the 
investigator’s discretion. 
H Includes TSH, T3, T4, total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium, potassium, chloride, CO2, 
calcium, magnesium, and phosphorus, ≤28 days prior to first day of dosing.  Total cholesterol will be completed during screening only.  Blood will be sent for analysis at a 
local laboratory and must be reviewed by the investigator prior to start of lucitanib administration. 
I Includes dipstick for protein, glucose, blood, pH, and ketones.  If dipstick findings are abnormal, then a microscopic evaluation will be performed to assess the abnormal 
findings. 


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J Tumor scans obtained within 28 days prior to C1D1, may be used as the baseline scans.  Scans should preferably be CT scans of the chest, abdomen, and pelvis with 
intravenous contrast and appropriate slice thickness per RECIST Version 1.1, using the same methods throughout the study that were used to detect lesions at baseline.  
Other alternative studies (MRI, X-ray) may be performed if clinically indicated.  Brain imaging is required at baseline and must be repeated at follow-up tumor assessments 
for patients with brain lesions.  The first on-treatment scan should be completed on C2D1, and every 8 ± 1 weeks through Cycle 6 (i.e., C4D1, C6D1).  Thereafter, scans 
should be completed every 12 ± 1 weeks (i.e., C9D1, C12D1, C15D1, etc.) until disease progression.  Tumor scans do not need to be repeated at End-of-Study if <2 weeks 
since last scan or the patient had disease progression at the last scan.  Scans will be evaluated locally for patient treatment decisions.  Scans will be sent to a central 
radiological laboratory. 
K For patient selection, FGFR1 and 11q amplification status may be determined based on local assessment, or based on central assessment as confirmed by a prescreening 
process.  FFPE tumor tissue is required for all enrolled patients.  The post-treatment biopsy is optional and requires additional consent.  Detailed sample handling 
instructions are provided in the Laboratory Manual. 
L AEs will be assessed from the time of first dose of lucitanib through 28 days after the last dose.   
M ECGs will be taken in triplicate anytime during screening, pre-dose (5–10 mins prior to dosing), and approximately 2 hrs (±5 mins) post-dose on Day 1 of each Cycle, 
and at End-of-Study, any time after treatment is discontinued.   
N LVEF will be assessed by ECHO or MUGA.  It is recommended to use the same technique for a given patient throughout the study.  ECHO should be performed at 
Screening, on C2D1, and every 8 weeks thereafter, and at the End-of-Study. 
O Whole blood will be collected pre-dose and processed locally for plasma ctDNA.  Collections occur at screening, C1D1, C1D15, Day 1 of all subsequent Cycles, and 
End-of-Study.  Refer to the Laboratory Manual for sample handling instructions. 
P Whole blood will be collected pre-dose and processed locally for plasma for PD biomarkers.  Refer to the Laboratory Manual for sample handling instructions. 
Q Plasma levels for sparse PK of lucitanib will be measured on pre-dose samples collected on C1D15 and Day 1 of Cycles 2, 3, and 5.  An additional sample will be 
collected on C2D1, 1–3 hours post-dose.   
R Quality of Life Questionnaire (FACT-B) should be collected from the patient prior to dosing at C1D1; then on Day 1 of Cycles 3, 5, and 7.  After Cycle 7, questionnaires 
will be collected every 3 cycles (on Day 1 Cycles 10, 13, 16, etc.) and at End-of-Study. 
 
 


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Table 5: 
Schedule of Assessments (PK Sub Study) 
 
Screening 
 
Treatment Period (Daily Dosing)A 
 
 
Cycle 1 
Cycle 2 
and 
Beyond 
Cycle 2 
Only 
ProcedureB 
Day –28 
to Day –8 
Day –7 
Day 1C 
Day 4 
Day 15 
Day 1 
Day 15 
End-of-
Study 
Two 
Monthly 
Follow-Up 
Informed Consent 
X 
 
Medical/Oncology History 
X 
 
Brief History 
 
X 
X 
X 
Complete Physical Examination 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Vital Signs, Height, WeightD 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medications and 
Procedures 
X 
X 
X 
X 
X 
Contraceptive CounselingE 
X 
 
X 
Serum Pregnancy TestF 
X 
 
X 
Hematology, Including ReticulocytesG 
X 
X 
X 
X 
X 
X 
Serum ChemistryH 
X 
X 
X 
X 
X 
X 
UrinalysisI 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Scans (Including brain imaging 
for patients with known CNS metastases 
or when clinically indicated)J 
X 
 
X 
X 
Submit FFPE Tumor TissueK 
X 
 
X 
Adverse EventsL 
X 
X 
X 
X 
X 
X 
X 
X 
Single Dose Lucitanib Tablet 
AdministrationM 
 
X 
 
 
 
 
 
 
 
Lucitanib Dispensation/AdministrationM 
 
X 
X 
ECG AssessmentsN 
X 
X 
X 
X 
X 


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Screening 
 
Treatment Period (Daily Dosing)A 
 
 
Cycle 1 
Cycle 2 
and 
Beyond 
Cycle 2 
Only 
ProcedureB 
Day –28 
to Day –8 
Day –7 
Day 1C 
Day 4 
Day 15 
Day 1 
Day 15 
End-of-
Study 
Two 
Monthly 
Follow-Up 
LVEF (ECHO or MUGA)O 
X 
 
X 
X 
Plasma for ctDNA AnalysisP 
X 
 
X 
X 
X 
X 
Plasma PD Biomarker SamplingQ 
X 
 
X 
X 
X 
X 
Blood for Sparse PK SamplingR 
 
X 
X 
Pharmacogenomic Blood Sampling 
 
X 
Quality of Life QuestionnaireS 
 
X 
X 
X 
Review and Collection of  
BP and Dosing Diary 
X 
X 
X 
X 
X 
Survival Status 
 
X 
X 
Subsequent Therapies for Breast Cancer 
 
X 
X 
Intensive PK SamplingT 
 
X 
X 
 
 
 
 
 
 
 
A Lucitanib will be administered daily, at least 2 hours before and 2 hours after a meal (on an empty stomach) with water (240 mL or 8 ounces).  The total fasting period is 
4 hours. 
B Unless specified, procedure is completed ±2 days of scheduled time point.  Procedures for C1D4 must be completed ±1 day of scheduled time point. 
C Procedures required prior to lucitanib administration on C1D1 may be omitted if completed ≤3 days earlier during the screening period.  The total time from the Day –7 
visit to the Cycle 1 Day 1 visit must not be fewer than 7 days, but may be greater than 7 days, if necessary. 
D Vital signs (BP, pulse, and temperature) taken pre-dose on drug administration days and post-dose following collection of the 24 hr PK samples on Day –7 and Day 1; 
height is only required once at screening.  BP self-monitoring, two times per week, is requested from patients, including between Day –7 and Day 1 (see Section 9.5.1.3).   
E Patients are to continue using effective contraception for 6 months after the last dose of lucitanib and report any pregnancies during this period. 
F Serum ß-hCG (evaluated by local labs) will be performed only on women of childbearing potential ≤7 days prior to C1D1 and End-of-Study.  If the serum pregnancy test 
results are not available on Day 1, a urine pregnancy test can be performed on Day 1 to confirm that the patient is not pregnant prior to dosing. 
G Includes hemoglobin, hematocrit, WBC and differential (with ANC), platelet count, PT/PTT, and reticulocyte count ≤14 days prior to the first day of dosing.  Blood will 
be sent for analysis at a local laboratory and must be reviewed by the investigator prior to start of lucitanib administration.  Additional tests may be performed at the 
investigator’s discretion. 


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H Includes TSH, T3, T4, total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium,  magnesium, potassium, 
chloride, CO2, calcium, and phosphorus ≤21 days prior to first day of dosing.  Total cholesterol will be completed during screening only.  Blood will be sent for analysis at 
a local laboratory and must be reviewed by the investigator prior to start of lucitanib administration. 
I Includes dipstick for protein, glucose, blood, pH, and ketones.  If dipstick findings are abnormal, then a microscopic evaluation will be performed to assess the abnormal 
findings. 
J Tumor scans obtained within 21 days prior to C1D1, may be used as the baseline scans.  Scans should preferably be CT scans of the chest, abdomen, and pelvis with 
intravenous contrast and appropriate slice thickness per RECIST Version 1.1, using the same methods throughout the study that were used to detect lesions at baseline.  
Other alternative studies (MRI, X-ray) may be performed if clinically indicated.  Brain imaging is required at baseline and must be repeated at follow-up tumor 
assessments for patients with brain lesions.  The first on-treatment scan should be completed on C2D1, and every 8 ± 1 weeks through Cycle 6 (i.e., C4D1, C6D1).  
Thereafter, scans should be completed every 12 ± 1 weeks (i.e., C9D1, C12D1, C15D1, etc.) until disease progression.  Tumor scans do not need to be repeated at 
End-of-Study if <2 weeks since last scan or the patient had disease progression at the last scan.  Scans will be evaluated locally for patient treatment decisions.  Scans will 
be sent to a central radiological laboratory. 
K For patient selection, FGFR1 and 11q amplification status may be determined based on local assessment, or based on central assessment as confirmed by a prescreening 
process.  FFPE tumor tissue is required for all enrolled patients.  The post-treatment biopsy is optional and requires additional consent.  Detailed sample handling 
instructions are provided in the Laboratory Manual. 
L AEs will be assessed from the time of first dose of lucitanib through 28 days after the last dose.  
M On Day –7 a dose of the lucitanib tablet formulation will be given followed by a dose of the lucitanib capsule formulation on Day 1.      
N ECGs will be taken in triplicate anytime during screening, pre-dose (5–10 mins prior to dosing), and approximately 2 hr (±5 min) post-dose on Day –7 (Cohort C) and 
Day 1 (All Cohorts) of each Cycle, and at End-of-Study, any time after treatment is discontinued. 
O LVEF will be assessed by ECHO or MUGA.  It is recommended to use the same technique for a given patient throughout the study.  ECHO should be performed at 
Screening, on C2D1, and every 8 weeks thereafter, and at the End-of-Study. 
P Whole blood will be collected pre-dose and processed locally for plasma ctDNA.  Collections occur at screening, C1D1, C1D15, Day 1 of all subsequent Cycles, and 
End-of-Study.  Refer to the Laboratory Manual for sample handling instructions. 
Q Whole blood will be collected pre-dose and processed locally for plasma for PD biomarkers.  Refer to the Laboratory Manual for sample handling instructions. 
R Plasma levels for sparse PK of lucitanib will be measured on pre-dose samples collected on C1D15 and Day 1 of Cycles 2, 3, and 5.  An additional sample will be 
collected on C2D1, 1–3 hours post-dose.   
S Quality of Life Questionnaire (FACT-B) should be collected from the patient prior to dosing at C1D1; then on Day 1 of Cycles 3, 5, and 7.  After Cycle 7, questionnaires 
will be collected every 3 cycles (on Day 1 Cycles 10, 13, 16, etc.), and at End-of-Study. 
T  PK specimens will be collected at the following time points on Day –7 and Day 1: 5–10 min pre-dose, post-dose at 15 (±2) min, 30 (±3) min, 1 hr (±5 min), 1.5 hr 
(±5 min), 2.5 hr (±10 min), 4 hr (±15 min), 6 hr (±15 min), 8 hr (±15 min), 10 hr (±30 min) (optional), and 24 hr (±30 min).   


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9.1 Screening Period  
Following written informed consent, and unless otherwise specified, the following assessments 
should be performed during the 28-day period prior to the first dose of lucitanib.  Assessments 
performed prior to patient signing informed consent are acceptable only if confirmed to have 
been standard of care. 
Up to 20 patients enrolled in Cohort A and Cohort C will participate in a PK sub study at select 
sites.  These patients should have all screening assessments performed within the 21-day period 
prior to the first dose of lucitanib, i.e., between Day –28 and Day –8 (Table 5).  
• Medical history, including demographic information (birth date, race, gender, etc.), smoking 
status, and oncology history including date of cancer diagnosis, prior cancer treatment, and 
any surgical procedures 
• Documentation of tumor tissue results demonstrating FGFR1 or 11q amplification 
(Cohorts A and B) or FGFR1 and 11q non-amplification (Cohort C) by established 
laboratory methods (e.g., FISH, NGS, CGH, CISH, or qPCR); or local assessment in blood 
using validated methods for detecting CTCs or ctDNA 
− For patients without local test results of FGFR1 or 11q amplification, or FGFR1 and 11q 
non-amplification, a separate prescreening consent will be available to enable testing 
before initiating additional CO-3810-025 specific screening.  Patients must read and sign 
a separate prescreening consent form to undergo testing of tissue by the central 
laboratory.  Upon central confirmation of FGFR1 or 11q amplification, or FGFR1 and 
11q non-amplification, patients may consent for and begin screening for the study.  
• Complete physical examination by body system, height, and weight 
• ECOG performance status 
• Vital signs (BP, pulse, and temperature) 
• Prior and concomitant medications and procedures 
• Contraceptive counseling 
• Serum pregnancy test (by local laboratory) ≤7 days prior to the first day of dosing for women 
of childbearing potential.  If the serum pregnancy test results are not available prior to 
dosing, a urine pregnancy test can be performed to confirm that the patient is not pregnant 
prior to dosing.  Both values should be entered in the eCRF 
• Hematology (hemoglobin, hematocrit, white blood cell [WBC] and differential [with ANC], 
platelet count, PT/partial thromboplastin time (PTT), and reticulocyte count) ≤14 days prior 
to the first day of dosing 
• Serum chemistry (TSH, T3, T4, total protein, albumin, creatinine, blood urea nitrogen [BUN] 
or urea, total bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium, potassium, 
chloride, CO2, calcium, magnesium,  phosphorus, and total cholesterol)  


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• Urinalysis performed on freshly voided clean sample (dipstick for protein, glucose, blood, 
pH, and ketones).  If dipstick findings are abnormal based on investigator judgment, then a 
microscopic evaluation will be performed to assess the abnormal findings 
• Tumor assessments.  Assessments should consist of clinical examination and computed 
tomography (CT) scans of the chest, abdomen, and pelvis with intravenous contrast and 
appropriate slice thickness per RECIST Version 1.1; other alternative studies (magnetic 
resonance imaging [MRI] and X-ray) may be performed if clinically indicated.  The same 
methods used to detect lesions at baseline are to be used to follow the same lesions 
throughout the clinical study 
• Brain imaging is required at baseline.  Patients with brain lesions detected at baseline require 
repeat brain imaging as part of the follow-up tumor assessments.  The same methods used to 
detect brain lesions at baseline are to be used to follow the same lesions throughout the 
clinical study 
• Archival FFPE tumor specimen for central laboratory confirmation of FGFR1 or 11q 
amplification status and companion diagnostic development is required.  Detailed sample 
handling instructions are provided in the Laboratory Manual 
• Blood sampling for ctDNA analysis.  Detailed sample handling instructions are provided in 
the Laboratory Manual 
• Blood sampling for biomarker analysis.  Detailed sample handling instructions are provided 
in the Laboratory Manual 
• 12-lead ECG (in triplicate, 10-sec tracings >2 min apart) 
• LVEF (ECHO or MUGA) 
At the end of screening, patients may be enrolled to receive daily treatment with lucitanib 10 mg 
(see Section 7.2).    
9.2 Treatment Period  
Before enrolling a patient, all eligibility criteria must be satisfied.   
Patients will receive lucitanib 10 mg daily.  Beginning on Day 1, lucitanib will be administered 
once daily to be swallowed with water (240 mL or 8 ounces).  Patients should take lucitanib at 
approximately the same time each day, on an empty stomach, at least 2 hours before and 2 hours 
after a meal.  Patients will record the dose and timing of administration of oral lucitanib in their 
daily dosing diary.  Treatment with lucitanib is continuous but cycles will be defined as 28 days 
in duration.   
BP self-monitoring should be completed at least twice a week by patients and measurements 
should be recorded in their diaries and brought to the clinic visits for review (see 
Section 9.5.1.3). 
Unless otherwise specified, all patients will undergo the following procedures and assessments. 


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9.2.1 Day –7 PK Sub Study 
The following pre-dose and post-dose assessments will be performed at Day –7 for patients 
participating in the PK sub study: 
Pre-dose Assessments 
Post-dose Assessments 
• Complete physical examination 
• Weight 
• ECOG performance status 
• Vital signs (BP, pulse, and temperature) 
• Concomitant medications 
• Hematology (including reticulocyte 
count) and serum chemistry  
• Urinalysis 
• AE monitoring 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart) 5–10 min prior 
to dosing  
• PK blood sample (5–10 min prior to 
dosing)  
 
• 12-lead ECG (in triplicate, 10-sec tracings 
>2 min apart), 2 hours (±5 min) following 
dosing with lucitanib 
• AEs experienced by the patient since 
dosing will be documented 
• Concomitant medications administered 
since dosing will be recorded 
• PK blood sampling collected at the 
following time points: 15 (±2) min, 30 
(±3) min, 1 hr (±5 min), 1.5 hr (±5 min), 
2.5 hr (±10 min), 4 hr (±15 min), 6 hr 
(±15 min), 8 hr (±15 min), 10 hr (±30 
min) (optional), and 24 hr (±30 min) 
• Vital signs (BP, pulse, and temperature) 
taken after last PK sample 
 
 
 
 
 
 
 
 
 
 


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9.2.2 Day 1 of Cycle 1 (C1D1:PK sub study patients) 
The following procedures will be performed at C1D1 for patients participating in the PK sub 
study:  
Pre-dose Assessments 
Post-dose Assessments 
• Complete physical examination 
• Weight 
• ECOG Performance status 
• Vital signs (BP, pulse, and temperature) 
• Concomitant medications 
• Hematology (including reticulocyte 
count) and serum chemistry  
• Urinalysis 
• Blood sampling for ctDNA analysis 
• Blood sampling for biomarker analysis 
• Blood sampling for pharmacogenomics 
analysis 
• AE monitoring 
• Lucitanib will be dispensed to the 
patient 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart) 5–10 min prior to 
dosing  
• QoL Questionnaire (FACT-B) 
• PK blood sample (5–10 min prior to 
dosing) 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart), 2 hours (±5 min) 
following dosing with lucitanib 
• AEs experienced by the patient since 
dosing will be documented 
• Concomitant medications administered 
since dosing will be recorded 
• PK blood sampling collected at the 
following time points: 15 (±2) min, 30 
(±3) min, 1 hr (±5 min), 1.5 hr (±5 min), 
2.5 hr (±10 min), 4 hr (±15 min), 6 hr 
(±15 min), 8 hr (±15 min), 10 hr (±30 
min) (optional), and 24 hr (±30 min) 
• Vital signs (BP, pulse, and temperature) 
after last PK sample 
 
 
 
 
 
 
 


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9.2.3 Day 1 of Cycle 1 (C1D1; all patients with exception of PK sub study) 
Patients will be required to take their first dose of lucitanib at the clinic and within 3 days of 
enrollment.  The following procedures will be performed on C1D1 for all patients with exception 
of those in the PK sub study:  
Pre-dose Assessments 
Post-dose Assessments 
• Complete physical examination 
• Weight 
• ECOG performance status 
• Vital signs (BP, pulse, and temperature) 
• Concomitant medications 
• Hematology (including reticulocyte 
count) and serum chemistry  
• Urinalysis 
• Blood sampling for ctDNA analysis 
• Blood sampling for biomarker analysis  
• Blood sampling for pharmacogenomics 
analysis 
• AE monitoring 
• Lucitanib will be dispensed to the 
patient 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart) 5–10 mins prior 
to dosing  
• Quality of Life (QoL) Questionnaire 
(FACT-B) 
 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart), 2 hours (±5 min) 
following dosing with lucitanib 
• AEs experienced by the patient since 
dosing will be documented 
• Concomitant medications administered 
since dosing will be recorded 
•  
 
 
 


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9.2.4 Day 4 of Cycle 1 (C1D4; all patients) 
The following procedures will be performed during the visit. 
Assessments 
• Brief history and review of AEs 
• Weight 
• Vital signs (BP, pulse, and temperature) 
• Urinalysis 
• AE monitoring 
• Review and collection of BP diary  
 
9.2.5 Day 15 of Cycle 1 (C1D15; all patients) 
The following procedures will be performed during the visit.  Patients will be instructed to 
refrain from taking their dose of lucitanib at home on the day of their clinic visit. 
Assessments 
• Brief history and complete physical 
examination 
• Weight 
• Vital signs (BP, pulse, and temperature) 
• Hematology (including reticulocyte 
count) and serum chemistry 
• Urinalysis 
• AE monitoring 
• Pre-dose blood sampling for ctDNA 
analysis 
• Pre-dose blood sampling for PD 
analysis 
• Pre-dose blood for sparse PK sampling 
 
 
 
 


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9.2.6 Day 1 of Cycle 2 (C2D1) and Subsequent Cycles (all patients) 
Patients will be instructed to refrain from taking their dose of lucitanib at home on the day of 
their clinic visit because the dose will be taken during the clinic visit.   
The following procedures will be performed pre-dose and post-dose at C2D1 and subsequent 
visits: 
Pre-dose Assessments 
Post-dose Assessments 
• Complete physical examination 
• Weight 
• ECOG performance status 
• Vital signs (BP, pulse, and temperature) 
• Concomitant medication since last visit 
• Hematology (including reticulocyte count) 
and serum chemistry  
• Urinalysis 
• Blood sampling for ctDNA analysis  
• Blood sampling for biomarker analysis  
• AE monitoring 
• 12-lead ECG (in triplicate, 10-sec tracings 
>2 min apart) 5–10 mins prior to dosing  
• LVEF (ECHO or MUGA) − every 8 weeks 
post-C2D1 
• Blood for sparse PK sampling (Day 1 of 
Cycles 2, 3, and 5) 
• QoL Questionnaire (FACT-B) on Day 1 of 
Cycles 3, 5, and 7.  After Cycle 7, 
questionnaires will be collected every 3 
cycles (on Day 1, Cycles 10, 13, 16 etc.) 
• Lucitanib will be dispensed to the patient 
• 12-lead ECG (in triplicate, 10-sec 
tracings >2 min apart), 2 hours (±5 min) 
following dosing with lucitanib 
• AEs experienced by the patient since 
dosing will be documented 
• Concomitant medications administered 
since dosing will be recorded 
• PK sample 1–3 hours post-dose on Day 
1 of Cycle 2  
 
Other assessments required during the visit and irrespective of dosing are: 
• Tumor assessments will be performed at Cycle 2, Day 1 and thereafter every 8 ± 1 weeks 
until Cycle 6 and thereafter every 12 ± 1 weeks until tumor progression (see Section 9.5.2.1) 
• Review and Collection of BP and dosing diary  


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9.2.7 Day 15 of Cycle 2 (C2D15; all patients) 
The following procedures will be performed during the visit. 
Assessments 
• Brief history and review of AEs  
• Weight 
• Vital signs (BP, pulse, and temperature) 
• Urinalysis 
• AE monitoring 
9.3 End-of-Study Visit (all patients) 
The following procedures will be performed for all patients 28 days (±7 days) after the last dose 
of protocol-specified treatment: 
• Complete physical examination 
• Weight 
• ECOG performance status 
• Vital signs (BP, pulse, and temperature) 
• Concomitant medications since last visit 
• Contraceptive counseling 
• Serum pregnancy test for women of childbearing potential 
• Hematology (including reticulocyte count), and serum chemistry 
• Urinalysis 
• Tumor scans (using the same methodology as was used at screening), including brain scans 
for patients with brain lesions at baseline, unless it has been <2 weeks since last scan or 
disease progression was noted on the last scan 
• Blood sampling for ctDNA analysis 
• Blood sampling for biomarker analysis  
• AE monitoring (until 28 days after last dose of protocol-specified treatment; all ongoing 
SAEs should be followed until resolution or stabilization.  After the 28-day window, only 
new SAEs assessed as related to study drug should be recorded) 
• Review and collection of BP and dosing diary  
• 12-lead ECG (in triplicate, 10-sec tracings >2 min apart)  


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• LVEF (ECHO or MUGA) 
• QoL questionnaire (FACT-B) 
• Survival status 
• Subsequent therapies for breast cancer 
• Optional post-treatment biopsy for PD analyses, at time of disease progression and before 
subsequent anti-line therapy is initiated 
9.4 Two Monthly Follow-Up (All Cohorts) 
• Survival status 
• Subsequent therapies for breast cancer 
9.5 Methods of Data Collection 
9.5.1 Safety Evaluations 
9.5.1.1 Adverse Event Assessment 
The investigator has the responsibility for assessing the safety of the patients and for compliance 
with the protocol to ensure study integrity.  Patients will be monitored for AEs from the time of 
first dose of lucitanib through 28 days after the last dose of protocol-specified treatment.  
Study-procedure-related AEs that occur after signing of the ICF and before administration of 
lucitanib will also be collected.  Any ongoing SAEs will be followed until resolution or 
stabilization.  AEs and laboratory abnormalities will be graded according to the NCI CTCAE 
Version 4.03 [55] grading system and recorded in the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 10. 
9.5.1.2 Clinical Laboratory Investigations 
Certified local laboratories will perform study-related clinical laboratory tests according to 
institutional procedures, and the results will be reviewed by the investigator.  The panels of 
laboratory tests to be performed are shown below: 
Hematology:  Hemoglobin, hematocrit, WBC and differential (with ANC), platelet count, 
PT/PTT, and reticulocyte count per the schedule of evaluation at screening, during treatment, and 
at the end-of-study visit.  Hematology results must be reviewed by the investigator prior to the 
start of treatment with lucitanib. 
Clinical Chemistry:  TSH, T3, T4, total protein, albumin, creatinine, BUN or urea, total 
bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium, potassium, chloride, CO2, calcium, 
magnesium, and phosphorus per the schedule of evaluations at screening, during treatment, and 
at the end-of-study visit.  Total cholesterol will be performed at screening only. 


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Urinalysis:  Performed on freshly voided clean sample by dipstick for protein, glucose, blood, 
pH, and ketones per the schedule of evaluations.  If dipstick findings are abnormal, then a 
microscopic evaluation will be performed to assess the abnormal findings.  Urinalysis will be 
performed at screening, during treatment, and at the end-of-study visit.   
Serum Human Chorionic Gonadotropin ß (ß-hCG) Pregnancy Test:  Performed on women 
of childbearing potential ≤7 days prior to administration of the first dose of lucitanib, and at the 
end-of-study visit.  If the serum pregnancy test results are not available prior to the first dose of 
lucitanib, a urine pregnancy test can be performed to confirm that the patient is not pregnant 
prior to dosing.  Both values should be entered in the eCRF.  A negative result must be 
confirmed by a physician before the first dose of lucitanib can be administered. 
Laboratory reports will be reviewed by the investigator or delegated physician to assess clinical 
significance.  Clinically significant abnormalities should be documented in the eCRF as an AE as 
defined in Section 10.4. 
9.5.1.3 Vital Signs 
Vital signs will include BP, pulse, and body temperature.  All vital signs will be obtained after 
the patient has been resting for at least 5 minutes.  Vital signs will be performed at screening and 
at each study visit, including the end-of-study visit.   
BP self-monitoring should be completed at least twice a week by patients and measurements 
should be recorded in their diaries and brought to the clinic visits for review.  For the week 
following the first dose of lucitanib, patients are encouraged to record BP in their diary at least 
once, but preferably twice, prior to their C1D4 visit.  After review, the investigator will consider 
whether the readings require medical treatment or reporting as an AE.  Patients are instructed to 
contact the investigator, if  BP values equal or above 160 mmHg systolic and/or equal or above 
100 mmHg diastolic.  Equipment and guidance to the patients on how to self-monitor their BP 
will be provided by the sponsor. 
9.5.1.4 12-Lead Electrocardiograms 
Serial 12-lead ECGs (10-sec ECG tracings collected in triplicate [>2 minutes apart]) will be 
taken at the following time points and as clinically indicated: 
All cohorts: 
• Screening:  anytime during the screening period  
• Day 1 of each treatment cycle:  Pre-dose (5–10 minutes prior to dosing) and 2 hours 
(± 5 min) following dosing with lucitanib 
• End-of-Study:  Any time after dosing has been discontinued, but within 28 days of last dose 


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PK Sub Study: 
• Day –7:  Pre-dose (5–10 minutes prior to dosing) and 2 hours (± 5 min) after dosing with the 
lucitanib tablet formulation 
ECGs should be performed after the patient has been resting for at least 5 minutes.  The 12-lead 
ECGs collected will be analyzed at a central ECG laboratory.  Details on recording ECGs and 
preparation for central interpretation will be included in the investigator’s file.  
9.5.1.5 LVEF 
LVEF will be assessed by ECHO or MUGA at screening, on Day 1 of Cycle 2 and every 
8 weeks thereafter, and at the End-of-Study.  It is recommended to use the same technique for a 
given patient throughout the whole study duration.  ECHO/MUGA results will be analyzed 
locally. 
9.5.1.6 Body Weight and Height 
Height will be measured during the screening visit only.  Weight will be measured at all clinic 
visits (the patient should be in light indoor clothes).   
9.5.1.7 Physical Examinations 
Physical examinations will include an assessment of all the major body systems.  Complete 
physical examinations will be performed at screening, Day –7 (PK sub study only), Day 1 of 
each cycle, C1D15, Day 1 of each cycle, and at the end-of-study visit. 
9.5.1.8 ECOG Performance Status 
ECOG performance status (Appendix B) will be assessed at screening, Day –7 (for patients 
participating in the PK sub study only), and on Day 1 of each cycle during treatment, and at the 
end-of-study visit.  ECOG performance status should be assessed by the same study personnel at 
each visit, if possible.  Care will be taken to accurately score performance status, especially 
during screening for study eligibility purposes.  Additional consideration should be given to 
borderline ECOG performance status to avoid enrolling patients with significant impairment. 
9.5.2 Efficacy Evaluations 
9.5.2.1 Tumor Assessments 
The first on-treatment scan should be completed on Cycle 2, Day 1, and every 8 ± 1 weeks 
through Cycle 6 (i.e., C4D1, C6D1).  Thereafter, scans should be completed every 12 ± 1 weeks 
(i.e., C9D1, C12D1, C15D1, etc.) until disease progression.  All patients must have scans to 
confirm radiographic progression.  Tumor scans do not need to be repeated at end-of-study if 
<2 weeks since last scan or the patient had disease progression at the last scan.  Patients that 
permanently discontinue lucitanib should continue scans until radiographic disease progression.  
Scans will be evaluated locally for patient treatment decisions.  Copies of tumor scans will be 


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collected centrally to facilitate independent evaluation if subsequently required.  Tumor response 
will be interpreted using RECIST Version 1.1 (Appendix A). 
Tumor assessments should consist of clinical examination and CT scans of the chest, abdomen, 
and pelvis with intravenous contrast and appropriate slice thickness per RECIST Version 1.1; 
other alternative studies (MRI and X-ray) may be performed if clinically indicated.  The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 
the clinical study. 
Brain imaging is required at baseline.  Patients with brain lesions detected at baseline require 
repeat brain imaging as part of the follow-up tumor assessments.  The same methods used to 
detect brain lesions at baseline are to be used to follow the lesions throughout the clinical study. 
9.5.3 Biomarker Assessments  
The following biomarker assessments will be done: 
• FGFR1 and 11q amplification status in tumor tissue assessed by FISH, CISH, NGS, and 
qPCR 
• RNA expression of various genes related to signaling pathways inhibited by lucitanib 
including, but not limited to FGFR1, FGF3/4/19, and additional FGF family members 
• Protein expression of FGFR1 as determined by IHC 
FFPE tumor tissue will be used for FGFR1 and/or 11q amplification confirmatory central 
laboratory testing.  Detailed sample handling instructions are provided in the Laboratory Manual.  
Tumor samples may be used to develop a tissue-based diagnostic test.  
Following disease progression, patients will be encouraged to undergo an optional post-treatment 
tumor biopsy before subsequent-line therapy is initiated.   
Sample handling instructions will be provided in a separate Laboratory Manual.    
9.5.4 Population PK Assessments 
Plasma levels of lucitanib will be measured on pre-dose samples collected on Day 15 of Cycle 1 
and Day 1 of Cycles 2, 3, and 5.  An additional sample will be collected on Cycle 2, Day 1,  
1–3 hours post-dose.  Sparse blood sampling for POPPK analyses will be conducted in all 
patients treated with lucitanib.  Refer to the Laboratory Manual for sample handling instructions. 
9.5.5 PK Sub Study 
Up to 20 patients will participate in the PK sub study.  PK sampling will be performed at 
specified time points on each on the following two days: 
• Day –7: lucitanib in tablet formulation 
• Day 1: lucitanib in capsule formulation 


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The dose assigned for patients participating in the PK sub study will be the same for Days –7 
and 1 and depends on the version of the amendment approved at the time of patient enrollment 
(Amendment #3: 15 mg; Amendment #4: 10 mg). 
The total time from the Day -7 visit to the Cycle 1 Day 1 visit must not be fewer than 7 days, 
but may be greater than 7 days, if necessary.  Lucitanib will not be taken between Day -7 and 
Cycle 1, Day 1.  
PK specimens will be taken on Day –7 and Day 1 PK specimens will be collected 5–10 min pre-
dose, and post-dose at 15 (±2) min, 30 (±3) min, 1 hr (±5 min), 1.5 hr (±5 min), 2.5 hr (±10 
min), 4 hr (±15 min), 6 hr (±15 min), 8 hr (±15 min), 10 hr (±30 min) (optional), and 24 hr (±30 
min).  Refer to the Laboratory Manual for sample handling instructions. 
9.5.6 Pharmacogenomic Assessment 
Blood draw for pharmacogenomic assessment will be drawn either during Screening or on C1D1 
prior to dosing. 
9.5.7 Pharmacodynamic Evaluations 
For all patients PD evaluations will be performed  at screening, pre-dose on Day 1 of each 
treatment cycle, on Day 15 of Cycle 1, and at the End-of-Study visit for analysis of ctDNA and 
measurement of circulating plasma levels of, including but not limited to, FGF-2, FGF-23, 
sVEGFR1, VEGF-A, sCSF-1R, and CSF-1. 
Blood samples collected for ctDNA analysis will be processed locally to yield plasma (ctDNA 
fraction) and buffy coats (genomic DNA fraction).  Genomic DNA extracted from the buffy coat 
or whole blood may be compared to tumor DNA so that molecular alterations unique to the 
tumor that may modulate response or resistance to study-assigned therapy can be unambiguously 
identified. 
Analysis may be performed on a subset of patients if it becomes clear that the analysis will have 
limited scientific value in some patients (e.g., because of a very low titer of ctDNA), or if there 
are not enough serially collected samples from individual patients to allow for adequate 
biomarker evaluation. 
Samples may be used for the development of a blood-based diagnostic test.  
Please refer to the Laboratory Manual for details on collecting and processing of PD blood 
samples. 
9.5.8 Quality-of-Life Assessments 
QoL will be measured using the FACT-B questionnaire (Appendix D), which will be 
administered on Day 1 of Cycles 1, 3, 5, and 7.  After Cycle 7, questionnaires will be collected 
every 3 cycles (on Day 1 Cycles 10, 13, 16, etc.), and at End-of-Study. 


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9.5.9 Patient Diary  
Patient diaries will be provided to patients and should be brought to the site at each visit for 
review.  Patient will use the diary to note the date and dose of lucitanib administration.  BP 
measurements (see Section 9.5.1.3) will also be recorded in the dairy. 


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10 ADVERSE EVENT MANAGEMENT 
10.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment.  An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not related to the investigational medicinal product.  This includes an exacerbation of 
pre-existing conditions or events, intercurrent illnesses, drug interaction, or the significant 
worsening of the indication under investigation that is not recorded elsewhere in the eCRF under 
specific efficacy assessments.  Anticipated fluctuations of pre-existing conditions, including the 
disease under study, that do not represent a clinically significant exacerbation or worsening are 
not considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study.  AEs 
should be elicited by asking the patient a nonleading question (e.g., “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”).  AEs will be reported on 
the AE eCRF.  Symptoms reported spontaneously by the patient during the physical examination 
will also be documented on the AE eCRF (not on the physical examination eCRF, which is 
reserved for physical signs or findings). 
10.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose that: 
• Results in death.  Death may occur as a result of the underlying disease process.  
Nevertheless, any event resulting in death during the reporting period must be treated as an 
SAE and reported as such.  All deaths occurring within 28 days of the last administration of 
lucitanib should be reported as SAEs 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, PRES, or 
seizures that do not result in in-patient hospitalization, or the development of drug dependency or 
drug abuse. 


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10.3 Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and do not need to be reported to the sponsor: 
• Pre-planned or elective hospitalization including social and/or convenience situations 
(e.g., respite care) 
• Overdose of either Clovis study drug or concomitant medication unless the event meets SAE 
criteria (e.g., hospitalization).  However, the event should still be captured as a non-serious 
AE on the appropriate eCRF page 
• Events of progression of the patient’s underlying cancer as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as an SAE unless the outcome is fatal during the study or within the safety reporting 
period.  If the event has a fatal outcome during the study or within the safety reporting 
period, then the event of Progression of Disease must be recorded as an AE and as a SAE 
with CTCAE Grade 5 (fatal outcome) indicated 
• Diagnosis of progression of disease or hospitalization due to signs and symptoms of disease; 
progression alone should not be reported as SAEs 
10.4 Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory.  In some cases, significant 
changes in laboratory values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• An action on the study drug is made as a result of the abnormality 
• Intervention for management of the abnormality is required 
• At the discretion of the investigator should the abnormality be deemed clinically significant 
10.5 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the study the investigator is to stop dosing with lucitanib 
immediately. 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to the sponsor 
using the Pregnancy Report Form within the same timelines as an SAE (Section 10.8).  This 
applies to female patients as well as female partners of male patients. 
A pregnancy should be followed through to outcome, whenever possible.  Once the outcome of 
the pregnancy is known, the Pregnancy Outcome Report Form should be completed and reported 
to the sponsor. 


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AEs or SAEs that occur during pregnancy will be assessed and processed according to the AE or 
SAE processes using the appropriate AE or SAE forms.   
10.6 Recording of Adverse Events and Serious Adverse Events 
AEs will be assessed from the time of first dose of lucitanib through 28 days after the last 
protocol-specified treatment administration.  Study-procedure-related events that occur after 
signing of the ICF and before administration of lucitanib will also be collected as AEs.  
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words.  Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome.  For example, fever, shortness of breath, and cough may be reported as pneumonia, if 
that is a suspected or final diagnosis. 
The existence of an AE may be concluded from a spontaneous report of the patient; from the 
physical examination; or from special tests such as the ECG, laboratory assessments, or other 
study-specified procedure (source of AE). 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
SAEs that occur during the study or within 28 days after receiving the last dose of 
protocol-specified treatment, whether or not related to study drug, must be reported to the 
sponsor/designee within 24 hours of knowledge of the event (Section 10.8).  After the 28-day 
specified window, only SAEs considered to be treatment-related should be reported. 
10.6.1 Intensity of Adverse Events 
The severity of the AE will be graded according to the NCI CTCAE Version 4.03 grading scale.  
For AEs not covered by NCI CTCAE Version 4.03, the severity will be characterized as mild, 
moderate, severe, or life-threatening according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and may 
interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or prolongation 
of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
10.6.2 Causal Relationship of Adverse Events to Investigational Medicinal Products 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, and dechallenge or rechallenge. 


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Not Related  
• An AE that is clearly due to extraneous causes (e.g., concurrent disease, concomitant 
medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of study drug 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted 
• An alternative explanation is likely but not clearly identifiable 
 
Related  
• An AE that is difficult to assign to alternative causes 
• It follows a strong or reasonable temporal sequence from administration of study drug 
• It could not be reasonably explained by the patient’s clinical state, concurrent disease, or 
other concomitant therapy administered to the patient 
• It follows a known response pattern to study drug 
• It is confirmed with a positive rechallenge or supporting laboratory data 
10.6.3 Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug 
• None 
• Dose reduced/delayed 
• Lucitanib temporarily interrupted 
• Lucitanib permanently discontinued 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Improved 
• Ongoing 
• Death 


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• Lost to follow-up 
10.7 Follow-Up of Adverse Events and Serious Adverse Events 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until resolved; judged no longer clinically significant; or, if a chronic condition, until 
fully characterized through 28 days after the last dose of protocol-specified treatment.  Any 
SAEs must be followed until resolution or stabilization. 
10.8 Regulatory Aspects of Serious Adverse Event Reporting 
All SAEs, regardless of relationship to study drug, must be reported to the sponsor/designated 
safety contact within 24 hours of knowledge of the event, according to the procedures below.  It 
is important that the investigator provides an assessment of the relationship of the SAE to study 
treatment at the time of the initial report.  The Clinical Trial Serious Adverse Event Report Form 
must be used for reporting SAEs.   
While not considered an SAE, pregnancy occurring in a female patient or in the female partner 
of a male patient must also be reported to the sponsor/designated safety contact as soon as the 
event is known by the clinical site.  If the pregnancy occurs in a female patient, study drug 
should be stopped immediately.  Notification to the sponsor/designee should take place via 
facsimile or email utilizing the Pregnancy Report Form.   
Further details on SAE/pregnancy reporting can be found in the investigator’s file.   
Clovis or its designee is responsible for submitting reports of AEs associated with the use of the 
drug that are both serious and unexpected to the U.S. Food and Drug Administration (FDA), 
according to 21 Code of Federal Regulations (CFR) 312.32 and to the European regulatory 
authorities according to the European Commission Clinical Trials Directive (2001/20/EC); and 
to other regulatory authorities, according to national law and/or local regulations, as applicable.  
All investigators participating in ongoing clinical studies with the study medication will receive 
copies of these reports for prompt submission to their IRB or IEC. 
Clovis or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements.  


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11 STATISTICAL METHODS  
11.1 Analysis Populations 
The following analysis populations are defined for the study: 
Efficacy Population – all patients who have received at least one dose of lucitanib and are 
confirmed as FGFR1-, 11q-amplified, or FGF non-amplified per the central laboratory.  
Safety Population – all patients who have received at least one dose of lucitanib. 
11.2 Statistical Methods 
11.2.1 General Considerations 
Patients randomized prior to implementation of Amendment #4 were stratified by FGF aberrancy 
(FGFR1- or 11q-amplified) and prior anti-angiogenic therapy (yes or no) status at baseline.  
Comparisons of the 15 mg and 10 mg dose groups may be stratified by these same factors.  
Patients that have amplification of both FGFR1 and 11q are categorized as FGFR1-amplified for 
purposes of analysis.  Since patients will no longer be randomized to the 15 mg dose group, the 
comparisons of the FRGR1-amplified, 11q-amplified, and FGF non-amplified subgroups will be 
made for the patients initially treated at 10 mg and for both dose groups.  
Quantitative variables will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum, and maximum) and/or frequency and percentages for medically 
relevant categories.  Categorical variables will be presented using frequencies and percentages.  
Exact 95% confidence intervals may be presented for frequencies.   
All data will be used to their maximum possible extent but without any imputations for missing 
data. 
All statistical analyses will be conducted with the statistical analysis software (SAS®) system. 
11.2.2 Patient Disposition  
The frequency and percentage of patients in each analysis population will be presented.  The 
primary reason for discontinuation of lucitanib will be summarized.   
11.2.3 Baseline Characteristics  
Baseline characteristics and demographic data will be summarized for the safety population. 
11.2.4 Efficacy Analyses  
Kaplan-Meier methodology will be used to summarize the time to event variables.  The 25th, 
50th (median), and 75th percentiles will be presented along with the Kaplan-Meier estimates of 
the 6 and 12 month rates.  The efficacy results may be presented separately by cohort or the three 
cohorts together. 


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11.2.4.1 Progression Free Survival (PFS) 
PFS is defined as 1+ the number of days from the date of first dose of study drug to disease 
progression or death due to any cause, whichever occurs first.  Patients without a documented 
event of progression will be censored on the date of their last adequate tumor assessment (i.e., 
radiologic assessment), or the date of first dose if no tumor assessments have been performed.  
Progression events will be determined by the investigator.  PFS will be summarized utilizing 
Kaplan-Meier methodology. 
11.2.4.2 Objective Response Rate (ORR) 
ORR is the proportion of patients with a best response of CR or PR according to RECIST 
Version 1.1.  The best response is recorded from the start of treatment (Day 1) until disease 
progression or recurrence.  The ORR will be summarized with frequencies and percentages. 
11.2.4.3 Duration of Response (DR) 
DR for CR and PR will be measured from the date that any of these best responses is first 
recorded until the first date that PD is objectively documented.  DR will be summarized utilizing 
Kaplan-Meier methodology.   
11.2.4.4 Disease Control Rate (DCR) 
The DCR is defined as the percentage of patients with a best response rate of CR, PR, or SD for 
at least 12 weeks.  The DCR will be summarized with frequencies and percentages. 
11.2.4.5 Overall Survival (OS) 
OS is defined as 1+ the number of days from the date of first dose of study drug to death due to 
any cause.  Patients without a documented date of death will be censored on the last date the 
patient was known to be alive.  OS will be summarized utilizing Kaplan-Meier methodology.    
11.2.4.6 PK Sub-Study  
Comparative PK parameters will include AUC0–t, Cmax, Tmax, T1/2, VSS/F, and Cl/F for lucitanib 
and will be determined using noncompartmental methods.  AUC0–t will be calculated using the 
trapezoid rule.  The PK parameters will be compared between the tablet and the capsule 
formulations. 
11.2.5  Safety Analyses  
The safety analyses will be performed using the safety population (all patients who have received 
at least one dose of lucitanib).   


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11.2.5.1 Extent of Exposure 
The following will be summarized by individual dose group and by dose group combined:  
• Number of cycles initiated 
• Number of dose reductions, or interruptions  
The number of cycles initiated will be investigated by summarizing the number of cycles started 
by each patient.  The number of patients with at least one dose reduction/delay or interruption 
will be summarized with frequencies and percentages.    
11.2.5.2 Adverse Events 
AE coding will be performed using the Medical Dictionary for Drug Regulatory Activities.  The 
severity of the toxicities will be graded according to the NCI CTCAE Version 4.03 criteria 
whenever possible.  Treatment-emergent AEs are defined as AEs with an onset date on or after 
the date of first dose of lucitanib until the date of the last dose of protocol-specified treatment 
plus 28 days.  AEs will be considered treatment-emergent if all or part of the date of onset of the 
AE is missing and it cannot be determined if the AE meets the definition for treatment-emergent. 
The number and percentage of patients who experienced treatment-emergent AEs for each 
system organ class and preferred term will be presented by individual dose group and by dose 
groups combined.  Multiple instances of the treatment-emergent AEs in each system organ class 
and multiple occurrences of the same preferred term are counted only once per patient.  The 
number and percentage of patients with at least one treatment-emergent AE will also be 
summarized by individual dose group and by dose groups combined.   
Separate tables will present the following by cohort: 
• All treatment-emergent AEs 
• Treatment-emergent AEs by CTCAE Version 4.03 grade 
• Grade 3 or greater treatment-emergent AEs 
• Treatment-related, treatment-emergent AEs 
• Serious treatment-emergent AEs 
• Serious treatment-related AEs 
• Treatment-emergent AEs with an outcome of death 
• Treatment-emergent AEs leading to discontinuation of lucitanib 
• Treatment-emergent AEs resulting in interruption, reduction, or delay of lucitanib 
The incidence of treatment-emergent AEs will be summarized by relationship to lucitanib using 
“treatment-related” and “not treatment-related” categories.  If a patient experiences multiple 
occurrences of the same AE with different relationship categories, the patient will be counted 
once as a relationship category of treatment-related.   


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If a patient experiences multiple occurrences of the same AE with different intensity toxicity 
grades, the patient will be counted once for the maximum (most severe) toxicity grade.  AEs with 
a missing intensity will be presented in the summary table with a toxicity grade of “Missing.”  
For each toxicity grade, the number and percentage of patients with at least one 
treatment-emergent AE of the given grade will be summarized.    
Non-treatment-emergent AEs (pre-treatment and post-treatment) will be presented in the data 
listings.  
11.2.5.3 Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis.  Laboratory values will be presented in Systeme International units.  
The baseline laboratory value will be defined as the last value prior to or on the day of the first 
dose of lucitanib.  The on-treatment period will be defined as the day after the first dose of 
lucitanib to 28 days after the last dose of lucitanib.  Laboratory values collected during the 
on-treatment period will be included in the summary tables.  The laboratory values collected 
after the on-treatment period will only be presented in the data listings.   
The summary of laboratory data will include descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum) of the maximum, minimum, and last value during the 
on-treatment period by dose group.  Summaries using descriptive statistics of the change from 
baseline to the maximum, minimum, and last value during the on-treatment period will also be 
given by dose group.  Separate listings will be produced for clinically significant laboratory 
abnormalities (i.e., those that meet Grade 3 or 4 criteria according to CTCAE Version 4.03) by 
individual dose group and by dose groups combined.   
11.2.5.4 Vital Signs Measurements 
The baseline vital signs measurement will be defined as the last value prior to or on the day of 
the first dose of lucitanib.  The on-treatment period will be defined as the day after the first dose 
of lucitanib to 28 days after the last dose of protocol-specified treatment.  Vital signs 
measurements collected during the on-treatment period will be included in the summary tables.  
The vital signs measurements collected after the on-treatment period will only be presented in 
the data listings.   
The summary of vital signs data will include descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum) of the maximum, minimum, and last value during the 
on-treatment period by dose group.  Summaries using descriptive statistics of the change from 
baseline to the maximum, minimum, and last value during the on-treatment period will also be 
given by dose group.  
11.2.5.5 12-Lead Electrocardiograms  
ECG intervals will be stratified into categories indicative of potential clinical significance.  Each 
patient’s maximum QT and QTC intervals from the pre-treatment visit and treatment period visits 
will be classified as ≤450 msec, >450 to ≤480 msec, >480 to ≤500 msec, and >500 msec.  For 


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each patient’s maximum change from the pre-treatment ECG visit for QT and QTC, intervals will 
be classified into <30 msec, ≥30 to <60 msec, and ≥60 msec.  The number and percentage of 
patients in each classified category will be presented.   
Descriptive statistics will be used to summarize other ECG parameters of PR, QRS, QT, and RR 
interval, and the corresponding changes from pre-treatment ECG visit at each time point.  Plots 
of the mean QT/QTC over time for C1D1 and End-of-Study/pre-treatment ECG day 
measurements will be provided.   
11.2.5.6 Other Safety Measurements 
Body weight and ECOG performance status will be summarized with descriptive statistics 
(N, mean, standard deviation, median, minimum, and maximum) and frequencies and 
percentages for relevant categories.  Concomitant medications/procedures will be tabulated and 
summarized. 
11.2.6 Patient Reported Outcomes  
PROs will be measured using the FACT-B questionnaire in all patients with both a baseline 
assessment and at least one post-baseline assessment.  
The baseline PRO measurement will be defined as the last value prior to or on the day of the first 
dose of lucitanib.  The on-treatment period will be defined as the day after the first dose of 
lucitanib to 28 days after the last dose of protocol-specified treatment.  PRO measurements 
collected during the on-treatment period will be included in the summary tables. 
The summary of PRO data will include descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum) of the maximum, minimum, and last value during the 
on-treatment period.  Summaries using descriptive statistics of the change from baseline to the 
maximum, minimum, and last value during the on-treatment period will also be given by relevant 
cohort. 
11.2.7 Population PK Analyses 
A separate POPPK data analysis plan will be developed and will outline the detailed approach to 
data handling, model development and diagnostics, individual model parameter estimation, 
exploration of covariate effects, and final model evaluation techniques.  POPPK analyses and 
results will be reported separately. 
11.2.8 Exploratory Analyses 
The exploratory endpoints will be summarized descriptively. 
11.3 Sample Size Considerations 
Up to 200 patients will be enrolled.   


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A total of at least 80 patients in the 10 mg arm is sufficient to reliably estimate the median PFS 
and 6 month PFS rate in these heavily pre-treated patients.  An observed median PFS greater 
than 4 months or a 6-month PFS rate of at least 40% will be sufficient to consider the 10 mg dose 
group worthy of further study.  Therefore, with at least 80 patients treated at 10 mg, the width of 
the 90% confidence interval for the 6 month PFS rate will be less than ±10%, so that if the 
observed 6 month rate is 50% then the lower limit on the confidence interval will be greater than 
40%. 
The treatment effect in Cohort C (biomarker negative sub-group) is not expected to be as large as 
in Cohorts A and B; however, the same target of 40% will be used to evaluate Cohort C.  With 
40 patients, the width of the 90% confidence interval for the 6 month PFS rate will be less than 
±15%, so that if the observed 6 month rate is less than 25% then the upper limit on the 
confidence interval will be less than 40%, which is evidence that subsequent studies of 10 mg 
should exclude biomarker negative patients.     
11.4 Interim Analysis 
A data monitoring committee (DMC) consisting of two external investigator advisors and 
specified Clovis personnel will meet approximately quarterly after the first patient is enrolled to 
review the efficacy and safety data.   
A detailed description of the composition, roles and responsibilities, and functioning of the DMC 
is provided in the DMC Charter. 


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12 PATIENT DISPOSITION 
12.1 Patient Discontinuations 
A patient must be discontinued from protocol-prescribed therapy if any of the following apply: 
• Consent withdrawal at the patient’s own request or at the request of their legally authorized 
representative 
• Progression of patient’s underlying disease, unless in the opinion of the investigator and 
approved by the sponsor, the patent has indolent progression with evidence of continued 
clinical benefit from treatment.  This must be approved by the sponsor and reviewed on a 
case by case basis 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient 
• An intercurrent illness that, in the opinion of the investigator, would affect assessments of the 
clinical status to a significant degree and requires discontinuation of therapy 
• A positive pregnancy test at any time during the study 
• Major non-compliance that may affect patient safety 
• Investigator decision 
In addition, the sponsor may discontinue the trial early for any of the reasons noted in 
Section 13.6.  
The sponsor (or designee) should be notified of all study terminations as soon as possible.  The 
date and reason for cessation of lucitanib must be documented in the eCRF and source 
documents. 
To the extent possible, end-of-study procedures should be performed on all patients who receive 
lucitanib.  The end-of-study visit should occur 28 ± 7 days following the last dose of lucitanib.  
After stopping protocol-specified treatment, all patients will remain in the study and will be 
followed for safety (through 28 days after last dose; those with ongoing SAEs will be followed 
until either resolution or stabilization has been determined), and for survival status by telephone 
(at approximately two monthly intervals, until death). 


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13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol; Good Clinical Practices (GCPs), 
including International Conference on Harmonization (ICH) Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements; and 
in accordance with the ethical principles of the Declaration of Helsinki.   
13.1.1 Regulatory Authority Approvals 
The sponsor or designee will submit the study protocol plus all relevant study documents to 
concerned regulatory agencies for approval prior to the study start.  No patient will be admitted 
to the study until appropriate regulatory approval of the study protocol has been received. 
Each investigator must complete a Form FDA 1572 and provide the completed form according to 
written instructions to the sponsor (or designee).  Each investigator must submit to the sponsor 
(or designee) financial disclosure information according to national law and/or local regulations. 
US-generated data will be handled in accordance with the Health Information Portability and 
Accountability Act (HIPAA).  The trial will be registered at www.clinicaltrials.gov using the 
Protocol Registration System. 
13.1.2 Independent Ethics Committee/Institutional Review Board 
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, or descriptions of the study used to obtain informed consent) will be 
submitted by the investigator to an IEC/IRB.  This also applies to protocol amendments.   
Clovis will supply relevant data for the investigator to submit the study protocol and additional 
study documents to the IEC/IRB.  The principal investigator will submit the study protocol for 
review and approval by an IEC/IRB, according to national law and/or local regulations, and will 
provide the IEC/IRB with all appropriate materials.   
Verification of the IEC’s/IRB’s unconditional approval of the study protocol and the written ICF 
will be transmitted to Clovis.  This approval must refer to the study by exact study protocol title 
and number, identify the documents reviewed, and state the date of the review. 
No patient will be admitted to the study until appropriate IEC/IRB approval of the study protocol 
has been received, the investigator has obtained the signed and dated ICF, and the sponsor is 
notified.   
The principal investigator will submit appropriate reports on the progress of the study to the 
IEC/IRB at least annually in accordance with applicable national law and/or local regulations 
and in agreement with the policy established by the IEC/IRB and sponsor.   


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The IEC/IRB must be informed by the principal investigator of all subsequent study protocol 
amendments and of SAEs or suspected unexpected serious adverse events (SUSARs) occurring 
during the study that are likely to affect the safety of the patients or the conduct of the study. 
13.2 Confidentiality of Information 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient initials and an identification code 
(i.e., not names) should be recorded on any form submitted to the sponsor and the IEC/IRB.  The 
investigator must keep logs on screened and enrolled patients.  In addition, the investigator must 
have a list where the identity of all treated patients can be found. 
The investigator agrees that all information received from Clovis, including, but not limited to, 
the Investigator’s Brochure, this protocol, eCRFs, the protocol-specified treatment, and any other 
study information, remain the sole and exclusive property of the sponsor during the conduct of 
the study and thereafter.  This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
prior written consent from the sponsor.  The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study center to any third 
party or otherwise into the public domain. 
13.3 Patient Informed Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from each patient participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study and prior to undertaking any study-related procedures.   
The ICF, prepared by the investigator with the assistance of the sponsor, must be approved along 
with the study protocol by the IEC/IRB and be acceptable to the sponsor. 
The patient must be provided with the patient information and ICF consistent with the study 
protocol version used and approved by the relevant IEC/IRB.  The ICF must be in a language 
fully comprehensible to the prospective patient.  Patients (and/or relatives, guardians, or legal 
representatives, if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss and decide on their participation in the study with the 
investigator concerned.  The patient and the person explaining about the study and with whom 
they discuss the informed consent will sign and date the ICF.  A copy of the signed ICF will be 
retained by the patient and the original will be filed in the investigator file unless otherwise 
agreed.   


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13.4 Study Monitoring 
On behalf of Clovis, a CRO monitor will contact and visit the investigator at the study center 
prior to the entry of the first patient and at predetermined appropriate intervals during the study 
until after the last patient has completed.  The monitor will also perform a study closure visit.   
In accordance with ICH GCP guidelines, the investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits.  The visits are 
for the purpose of verifying adherence to the study protocol and the completeness, consistency, 
and accuracy of data entered in the eCRF and on other documents.   
The investigator will make all source data (i.e., the various study records, the eCRFs, laboratory 
test reports, other patient records, drug accountability forms, and other pertinent data) available 
for the monitor and allow access to them throughout the entire study period.  Monitoring is done 
by comparing the relevant site records of the patients with the entries on the eCRF (i.e., source 
data verification).  It is the monitor’s responsibility to verify the adherence to the study protocol 
and the completeness, consistency, and accuracy of the data recorded in the eCRFs.   
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved.  Contact 
information for the study monitor is located in the investigator file.  Representatives from Clovis 
may also contact and visit the investigators and monitor data during the study.   
13.5 Case Report Form 
The data will be collected using an electronic data capture (EDC) system by remote data entry on 
eCRFs.  Sites will receive training on the EDC system.  All users will be supplied with unique 
login credentials. 
Prior to study start, the investigator will prepare a list showing the signature and handwritten 
initials of all individuals authorized to make or change entries on eCRFs.  This “study center 
personnel and delegation list” must be kept current throughout the study. 
For each patient enrolled, an eCRF must be completed and reviewed by the principal investigator 
or co-investigator within a reasonable time period (<2 weeks) after data collection.  This also 
applies to records for those patients who fail to complete the study.  If a patient withdraws from 
the study, the reason must be noted in the eCRF.  If a patient is withdrawn from the study 
because of a treatment-limiting AE, thorough efforts should be made to clearly document the 
outcome. 
All laboratory data and investigator observations on the results and any other clinically 
significant test results must be documented on eCRFs. 
Full information regarding EDC and completing eCRFs is included in the investigator files.  All 
questions or comments related to electronic capture should be directed to the assigned monitor. 


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13.6 Study Termination and Site Closure 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  Should 
this be necessary, both parties will arrange discontinuation procedures.  In terminating the study, 
Clovis and the investigator will assure that adequate consideration is given to the protection of 
the patients’ interests. 
Clovis reserves the right to discontinue the study at any time for medical or administrative 
reasons.  When feasible, a 30-day written notification will be given. 
The entire study will be stopped if: 
• The protocol-specified treatment is considered too toxic to continue the study 
• Evidence has emerged that, in the opinion of the sponsor or the investigator(s), makes the 
continuation of the study unnecessary or unethical 
• The stated objectives of the study are achieved 
• The sponsor discontinues the development of lucitanib 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.   
13.7 Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, must 
be made only with the prior approval of Clovis.  Agreement from the investigator must be 
obtained for all protocol amendments and amendments to the informed consent document.  The 
IEC/IRB must be informed of all amendments and give approval prior to their implementation.  
The sponsor will submit any study protocol amendments to the concerned regulatory authorities 
for approval and keep the investigator(s) updated as detailed in the ICH GCP guidelines. 
13.8 Retention of Study Documents 
The study site will maintain a study file, which should contain, at minimum, the Investigator’s 
Brochure, the protocol and any amendments, drug accountability records, correspondence with 
the IEC/IRB and Clovis, and other study-related documents. 
The investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and Clovis or its designees. 
The investigator shall retain records required to be maintained for a period of 5 years following 
the date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated or, if no application is to be filed or if the application is not 


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approved for such indication, until at least 5 years after the investigation is discontinued.  
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by Clovis.  In addition, the investigator must make 
provision for the patients’ medical records to be kept for the same period of time. 
No data should be destroyed without the agreement of Clovis.  Should the investigator wish to 
assign the study records to another party or move them to another location, Clovis must be 
notified in writing of the new responsible person and/or the new location.  Clovis will inform the 
investigator, in writing, when the trial-related records are no longer needed. 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
13.9 Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of Clovis and 
signed by the sponsor’s chief medical officer, thereby indicating their agreement with the 
analyses, results, and conclusions of the clinical study report.   
13.10 Study Publication 
All data generated from this study are the property of Clovis and shall be held in strict 
confidence along with all information furnished by Clovis.  Independent analysis and/or 
publication of these data by the investigator(s) or any member of their staff are not permitted 
without the prior written consent of Clovis.  Written permission to the investigator will be 
contingent on the review by Clovis of the statistical analysis and manuscript, and will provide for 
nondisclosure of Clovis confidential or proprietary information.  In all cases, the parties agree to 
submit all manuscripts or abstracts to all other parties 30 days prior to submission.  This will 
enable all parties to protect proprietary information and to provide comments based on 
information that may not yet be available to other parties. 
13.11 Quality Assurance Audits 
An audit visit to clinical centers may be conducted by a quality control auditor appointed by 
Clovis.  The purpose of an audit, which is independent of and separate from routine monitoring 
or quality control functions, is to evaluate trial conduct and compliance with the protocol, 
standard operating procedure (SOPs), ICH GCPs, and the applicable regulatory requirements.  
The investigator and the sponsor may also be subject to an inspection by FDA, European 
Regulatory authorities, or other applicable regulatory authorities at any time.  The auditor and 
regulatory authorities will require authority from the investigator to have direct access to the 
patients’ medical records.  It is important that the investigator(s) and their staff cooperate with 
the auditor or regulatory authorities during this audit or inspection.  


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15 APPENDICES 
Appendix A. Response Evaluation Criteria in Solid Tumors Criteria 
Appendix B. Eastern Cooperative Oncology Group Performance Status Scale 
Appendix C. List of Concomitant Medications that Can Prolong the QT Interval 
Appendix D. FACT-B Version 4.0 
Appendix E. Inhibitors and Inducers of CYP2C8 and CYP3A4 


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Appendix A  
Response Evaluation Criteria in Solid Tumors Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)56 and at 
http://www.eortc.be/Recist/Default.htm.  A short summary is given below. 
Measurability of tumor at baseline 
Measurable Disease: 
Tumor lesions:  measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with the following: 
1. A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
2. A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable). 
3. A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes:  to be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be not greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.   
Non-measurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as truly non-measurable 
lesions, are considered non-measurable disease.  Lesions considered truly non-measurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.   
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular 
comment.   
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 


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measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are non-measurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) because they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above.  However, if noncystic lesions are 
present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
Tumor response evaluation  
Assessment of overall tumor burden and measurable disease  
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  Measurable disease is defined by the presence of at least one 
measurable lesion.  In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable disease 
only are also eligible.  
Baseline documentation of ‘target’ and ‘non-target’ lesions  
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  


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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 two 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, saggital, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  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) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow).  In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
Response criteria 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment. 


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Evaluation of Target Lesions 
Table 6: 
Evaluation of Target Lesions 
Complete Response 
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 
At least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum longest diameter since 
the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the longest diameter 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.  The appearance of one or more new lesions is also considered 
progression. 
 
 
Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm.  Case report forms or other 
data collection methods may therefore be designed to have target nodal lesions recorded in a 
separate section where, in order to qualify for CR, each node must achieve a short axis < 10 mm.  
For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions.  
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’.  When this occurs it is important that a value be recorded on the case 
report form.  If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT scan slice thickness (but should not be changed with varying CT scan slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 


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however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm.  
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group 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. 
Table 7: 
Evaluation of Target Lesions 
Complete Response 
Disappearance of all non-target lesions and normalization of tumor marker 
level. 
Stable Disease/Incomplete 
Response 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to 
be considered a complete responder.   
Special notes on assessment of progression of non-target disease  
The concept of progression of non-target disease requires additional explanation as follows:  
When the patient also has measurable disease.  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.  
When the patient has only non-measurable disease.  This circumstance arises in some phase 3 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 


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are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increased diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial. 
New lesions  
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or CR.  For example, necrosis of a 
liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.  
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the patient who has visceral disease at baseline and while on study has a CT scan or MRI brain 
ordered which reveals metastases.  The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease).  New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET (a ‘positive’ FDG-PET scan lesion 
means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on 
the attenuation corrected image) at follow-up is a sign of PD based on a new lesion.  
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT 
scan, this is PD.  


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If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT scan, 
additional follow-up CT scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT scan 
that is not progressing on the basis of the anatomic images, this is not PD. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation.  On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response.  
Protocols must specify how any new therapy introduced before progression will affect best 
response designation.  The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions.  Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement.  Specifically, in nonrandomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’.  
Time point response  
It is assumed that at each protocol specified time point, a response assessment occurs. Table 8 
below provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 


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Table 8: Evaluation of best overall response: patients with measurable and non-measurable disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE 
= 
Not evaluable. 
 
 
 
When patients have non-measurable disease only (therefore non-target), the following table is to 
be used.  
Table 9: Evaluation of best overall response: patients with non-measurable disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
On-CR/non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
NE = not evaluable.  
1 = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions can 
be measured is not advised. 
 
Missing assessments and inevaluable designation  
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  


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Best overall response: all time points  
The best overall response is determined once all the data for the patient is known.  
Best response determination in trials where confirmation of CR or PR is not required:  Best 
response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR).  When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline.  If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments.  For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD.  The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable.  
Best response determination in trials where confirmation of CR or PR is required:  CRs or PRs 
may be claimed only if the criteria for each are met at a subsequent time point as specified in the 
protocol (generally 4 weeks later).  In this circumstance, the best overall response can be 
interpreted as in the following table. 
Table 10: Best overall response when confirmation of CR and PR is required 
Overall response first time 
point 
Overall response 
subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, OR PR1 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
1 = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 


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Special notes on response assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the eCRF.  
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PRNE-PR as a confirmed response.  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in the 
tables above.  
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity).  
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-
PET in this circumstance should be prospectively described in the protocol and supported by 
disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
Frequency of tumor re-evaluation  
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment.  However, in the context of phase 2 studies where the 
beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the 
end of a cycle) is reasonable.  Smaller or greater time intervals than these could be justified in 


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specific regimens or circumstances.  The protocol should specify which organ sites are to be 
evaluated at baseline (usually those most likely to be involved with metastatic disease for the 
tumor type under study) and how often evaluations are repeated.  
Normally, all target and non-target sites are evaluated at each assessment.  In selected 
circumstances certain non-target organs may be evaluated less frequently.  For example, bone 
scans (scintigraphy) may need to be repeated only when CR is identified in target disease or 
when progression in bone is suspected.  
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death).  If ‘time to an 
event’ (e.g., time to progression, disease-free survival, PFS) is the main endpoint of the study, 
then routine scheduled re-evaluation of protocol specified sites of disease is warranted.  In 
randomized comparative trials in particular, the scheduled assessments should be performed as 
identified on a calendar schedule (for example: every 6–8 weeks on treatment or every  
3–4 months after treatment) and should not be affected by delays in therapy, drug holidays, or 
any other events that might lead to imbalance in a treatment arm in the timing of disease 
assessment. 
Confirmatory Measurement/Duration of Response 
Confirmation  
As ORR is not the primary endpoint, confirmation of response is not required. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started (if the baseline sum is the smallest, this is the reference for calculation 
of PD). 


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Appendix B  
Eastern Cooperative Oncology Group Performance Status Scale 
ECOG Performance Status 
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 (e.g., light house work or 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. 
 


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Appendix C  
List of concomitant medications that can prolong the QT interval and increase the 
risk of causing Torsades de Pointes 
Medications linked to prolongation of the QT interval and association with Torsade de Pointes 
can be accessed at: http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=All 
 
 
 
 
 
 


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Appendix D  
FACT-B Version 4.057 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
Not 
at all 
A 
little 
bit 
Some
-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ...............................................
0 
1 
2 
3 
4 
GP2 
I have nausea .............................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain .................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment.................
0 
1 
2 
3 
4 
GP6 
I feel ill .......................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ...............................
0 
1 
2 
3 
4 


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SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends ...........................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ....................
0 
1 
2 
3 
4 
GS3 
I get support from my friends ....................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness............................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about 
my illness ...................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) .............................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer not 
to answer it, please mark this box           and go to the 
next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ...................................
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad .....................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness .........................................................................
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness.........
0 
1 
2 
3 
4 
GE4 
I feel nervous .............................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ....................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...................
0 
1 
2 
3 
4 
 
 
 


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FUNCTIONAL WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-
what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) .................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ...........
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness .........................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ......................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .............
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ....
0 
1 
2 
3 
4 
 
 
 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
B1 
I have been short of breath .........................................
0 
1 
2 
3 
4 
B2 
I am self-conscious about the way I dress .................
0 
1 
2 
3 
4 
B3 
One or both of my arms are swollen or tender ..........
0 
1 
2 
3 
4 
B4 
I feel sexually attractive .............................................
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss ..........................................
0 
1 
2 
3 
4 
B6 
I worry that other members of my family might 
someday get the same illness I have ..........................
 
0 
 
1 
 
2 
 
3 
 
4 
B7 
I worry about the effect of stress on my illness .........
0 
1 
2 
3 
4 
B8 
I am bothered by a change in weight .........................
0 
1 
2 
3 
4 
B9 
I am able to feel like a woman ...................................
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience 
pain .............................................................................
0 
1 
2 
3 
4 
 
 
 
 
 


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Clinical Protocol 
Lucitanib 
 
CO-3810-025 
 
27 January 2016 
 
 
 
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Appendix E.  
Inhibitors and Inducers of CYP2C8 and CYP3A4 
CYP Enzyme 
Strong Inhibitor (Contraindicated) 
Moderate Inhibitor 
(Use with Caution) 
CYP2C8 
gemfibrozil 
teriflunomide 
CYP3A4 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice1 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
amprenavir 
aprepitant 
atazanavir 
ciprofloxacin 
darunavir/ritonavir 
diltiazem 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit juice1 
imatinib 
verapamil 
 
CYP Enzymes 
Dual Inhibitor 
(Contraindicated) 
Dual Inhibitor 
(Use with Caution) 
CYP3A4 & 
CYP2C8 
clopidogrel 
verapamil 
teriflunomide 
 
trimethoprim 
ticargrelor 
 
CYP Enzyme 
Strong Inducer (Contraindicated) 
CYP3A4 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s Wort 
 
1 The effects of grapefruit juice vary widely among brands, thus can be classified as both a strong and moderate 
inhibitor depending on concentration, quantity consumed, and preparation. Patients should be advised to avoid. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm#classInhibit 
 

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STATISTICAL ANALYSIS PLAN 
A Phase 2, randomized, open-label, multicenter, safety and efficacy study of 
oral lucitanib in patients with FGF aberrant metastatic breast cancer 
 
 
STUDY DRUG: 
 Lucitanib 
 
PROTOCOL NUMBER: 
 CO-3810-025 
DATE FINAL: 
 15 February 2017 
SPONSOR: 
 Clovis Oncology 
5500 Flatirons Pkwy 
Boulder, CO 80301 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 




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TABLE OF CONTENTS 
APPROVAL PAGE ...................................................................................................................2 
1 
INTRODUCTION ...........................................................................................................7 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................7 
2.1 
Study Objectives and Endpoints ..............................................................................7 
2.2 
Table 2. Overall Study Design Plan .........................................................................9 
2.2.1 
Screening Period ..........................................................................................10 
2.2.2 
Treatment Period .........................................................................................10 
2.2.3 
End-of-Study ................................................................................................11 
2.2.4 
Long Term Follow-Up .................................................................................11 
2.2.5 
Study Schema ...............................................................................................11 
2.2.6 
Number of Patients and Sites .......................................................................12 
3 
SAMPLE SIZE ..............................................................................................................13 
4 
GENERAL ANALYSIS CONSIDERATIONS ............................................................13 
5 
ANALYSIS POPULATIONS .......................................................................................14 
6 
PATIENT DISPOSITION .............................................................................................14 
7 
INCLUSION / EXCLUSION VIOLATIONS ..............................................................14 
8 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................14 
8.1 
Demographics ........................................................................................................14 
8.2 
Baseline Clinical Characteristics ...........................................................................15 
8.3 
Medical History .....................................................................................................15 
9 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................15 
10 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................15 
11 
EFFICACY VARIABLES ............................................................................................16 
11.1 
Primary Efficacy Variable .....................................................................................16 
11.2 
Secondary Efficacy Variables ................................................................................16 
12 
EFFICACY ANALYSIS ...............................................................................................16 
12.1 
Primary Efficacy Analysis .....................................................................................16 
12.1.1 
Progression Free Survival (PFS).................................................................16 
12.1.2    Objective Response Rate (ORR) ....................................................................16 
12.2 
Key Secondary Efficacy Analyses .........................................................................17 
12.2.1 
Duration of Response (DR) ..........................................................................17 
12.2.2 
Disease Control Rate (DCR) .......................................................................17 
12.2.3 
Overall Survival (OS) ..................................................................................17 
12.2.4 
PK Sub Study (Cohort C) .............................................................................17 
13 
POPULATION PK ANALYSES ..................................................................................17 
14 
EXPLORATORY ANALYSES ....................................................................................17 
15 
PATIENT REPORTED OUTCOMES ..........................................................................18 


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16 
STATISTICAL / ANALYTICAL ISSUES ..................................................................18 
16.1 
Handling of Dropouts or Missing Data ..................................................................18 
16.2 
Interim Analysis .....................................................................................................18 
17 
SAFETY ANALYSIS ...................................................................................................18 
17.1 
Adverse Events ......................................................................................................18 
17.2 
Clinical Laboratory Evaluations ............................................................................20 
17.3 
Vital Signs ..............................................................................................................20 
17.4 
12-Lead Electrocardiograms ..................................................................................20 
17.5 
Other Safety Measurements ...................................................................................20 
18 
REFERENCES ..............................................................................................................21 
 LIST OF IN-TEXT TABLES 
Table 1. Primary, Secondary, and Exploratory Objectives and Endpoints .............................7 
 


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ABBREVIATIONS AND SPECIALIST TERMS 
ADME   
 absorption/distribution/metabolism/excretion 
AE  
 adverse event 
AUC0–t 
 area under the curve from time zero to time t 
BP  
 blood pressure 
CGH  
 comparative genomic hybridization 
CI  
 confidence interval 
CISH  
 chromogenic in situ hybridization 
Cmax 
 maximum concentration 
CR  
 complete response 
CRF  
 case report form 
CSR 
 clinical study report 
CTCAE  
 common terminology criteria for adverse events 
CTCs 
 circulating tumor cells 
DMC 
 data monitoring committee 
DNA  
 deoxyribonucleic acid 
DCR 
 disease control rate 
DR 
 duration of response 
ECG  
 electrocardiogram 
ECHO  
 echocardiogram 
ECOG  
 Eastern Cooperative Oncology Group 
eCRF 
 electronic case report form 
e.g.  
 exempli gratia (for example) 
EOS 
 end of study 
ER+ 
 estrogen receptor positive 
FACT-B 
 Functional Assessment of Cancer Therapy-  Breast  
FGF  
 fibroblast growth factor 
FGFR  
 fibroblast growth factor receptor 
FISH  
 fluorescence in situ hybridization 
HER2 
 human epidermal growth factor receptor 2 
i.e.  
 id est (that is) 
ICF 
 informed consent form 
kg  
 kilogram 
MUGA  
 multi gated acquisition scan 
mg  
 milligram 
NA  
 not applicable 
NCI 
 National Cancer Institute 
NE  
 not evaluable 
NGS 
 next generation sequencing 
ORR  
 objective response rate 
OS 
 overall survival 
qPCR 
 quantitative polymerase chain reaction 


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QTCB 
QT interval corrected using Bazette’s method 
QTCF 
QT interval corrected using Fridericia’s method 
PD  
 progressive disease 
PFS  
 progression free survival 
PK  
 pharmacokinetics 
POPPK 
 population pharmacokinetics 
PR  
 partial response 
PRO 
 patient reported outcomes 
RECIST  
 response evaluation criteria in solid tumours 
SAE  
 serious adverse event 
SAP 
 statistical analysis plan 
SAS  
 statistical analysis system (company) 
SD 
 stable disease 
SI 
 Systeme International 
t1/2 
 elimination half-life 
tmax 
 time to maximum concentration 
VEGF  
 vascular endothelial growth factor 
VEGFR  
 vascular endothelial growth factor receptor 
WHO 
 World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
INTRODUCTION 
This document describes the statistical analyses and data presentations to be performed for 
Clovis Oncology protocol CO-3210-025 “A Phase 2, randomized, open-label, multicenter, 
safety and efficacy study of oral lucitanib in patients with FGF aberrant metastatic breast 
cancer”. This statistical analysis plan (SAP) provides a comprehensive and detailed 
description of the strategy, rationale, and statistical techniques to be used to assess the 
efficacy and safety of lucitanib administered orally to patients with metastatic breast cancer. 
 
The purpose of the SAP is to ensure the credibility of the study findings by specifying the 
statistical approaches to the analysis of study data prior to database lock for the final analysis.  
This SAP provides additional details concerning the statistical analyses that were originally 
outlined in the protocol.   
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.3 or 
higher. 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Objectives and Endpoints 
From the original protocol through amendment 5 of the protocol, there were three cohorts 
planned for which objectives and endpoints where defined.  Cohort A was to have a starting 
dose of 10 mg daily of lucitanib; Cohort B was to have a starting dose of 15 mg daily of 
lucitanib; and  Cohort C was added in amendment 2 and was to initially receive 15 mg daily 
of lucitanib.  However, the major protocol amendment #4 discontinued the use of 15 mg as an 
initial starting dose thereby changing the initial starting dose for all subsequently enrolled 
patients in Cohort C to 10 mg of lucitanib as well as advising all investigators with patients 
receiving 15 mg lucitanib to dose reduce to 10 mg. Due to the significant changes to the 
protocol defined Cohorts and corresponding objectives and endpoints throughout the study, 
Table 1 below will only indicate those objectives and endpoints outlined in  
amendment #5 of the protocol.  
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To estimate the anti-tumor efficacy of oral 
single-agent lucitanib as measured by 
investigator assessed PFS, when administered to 
patients with FGFR1- or 11q-amplified breast 
cancer after failure of currently available 
standard therapies 
Progression-free Survival (PFS) per RECIST 
Version 1.1 as determined by the investigator 
 


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Secondary Objectives 
Secondary Endpoints 
To estimate the anti-tumor efficacy of oral 
single-agent lucitanib as measured by 
investigator assessed PFS, when administered to 
patients with FGFR1- or 11q-amplified breast 
cancer after failure of currently available 
standard therapies 
 
ORR according to RECIST Version 1.1 
 
DR and DCR according to RECIST 
Version 1.1 
 
OS 
To estimate patient-reported outcomes (PRO) 
following treatment with lucitanib  
Change from baseline in PRO using the 
Functional Assessment of Cancer Therapy-
Breast (FACT-B) questionnaire 
To evaluate the safety and tolerability of 
lucitanib 
 
Treatment emergent AEs, laboratory 
abnormalities, physical examinations 
including vital signs and electrocardiogram 
(ECG) abnormalities 
To assess the comparative pharmacokinetics 
(PK) of the lucitanib tablet formulation with the 
lucitanib capsule formulation  
PK parameters including area under the 
concentration curve from time zero to time t 
(AUC0–t), maximum concentration (Cmax), 
time to maximum concentration (tmax), 
elimination half-life (t1/2), volume of 
distribution at steady state (VSS/F), and total 
plasma clearance (Cl/F) for lucitanib, if data 
allow 
Exploratory Objectives 
Exploratory Endpoints 
To explore tumor tissue and blood-based 
biomarkers that may be predictive of response 
or primary resistance to treatment with lucitanib 
 
 
Concordance of tumor tissue FGFR1 and 
11q amplification   assessed across 
different technical platforms (fluorescence 
in-situ hybridization [FISH], Next 
Generation Sequencing [NGS], 
comparative genomic hybridization 
[CGH], chromogenic in-situ hybridization 
[CISH],  quantitative polymerase chain 
reaction [qPCR], or circulating tumor 
cells [CTCs/ctDNA]) 
 
Exploration of different cut-off values for 
determining FGFR1 and 11q 
amplification in tumor tissue by FISH and 
correlation with clinical efficacy 
 
Ribonucleic acid (RNA) expression of 
FGFR1, FGF3/4/19, and additional FGF 
family members; correlation with FGFR1 
and 11q amplification status and clinical 
efficacy 


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 
Protein expression of FGFR1 as 
determined by immunohistochemistry 
(IHC) in tumor tissue; correlation with 
FGFR1 amplification status 
 
Genomic analysis of circulating tumor 
DNA (ctDNA) 
To explore blood-based pharmacodynamics 
(PD) biomarkers of lucitanib activity 
 
 
PD biomarker analysis measurement of 
circulating plasma biomarker levels 
including but not limited to FGF-2, FGF-
23, sVEGFR1, VEGF-A, sCSF-1R, and 
CSF-1 
 
Pharmacogenomic analysis of variations 
in genes encoding proteins involved in 
absorption/distribution/ 
metabolism/excretion (ADME) 
 
2.2 
Table 2. Overall Study Design Plan 
The following is the study design plan information contained in amendment 5 of the protocol. 
Please see the original protocol and amendments 1 through 4 to see the changes made to the 
design and plan throughout the course of the study.  
 
This is a phase 2, open-label, multicenter study evaluating the efficacy and safety of lucitanib 
administered orally to patients with metastatic breast cancer.  Patients with FGFR1- or 11q 
(FGF3, FGF4, Cyclin D1, or FGF19)-amplified metastatic breast cancer may be enrolled into 
one of two different cohorts (Cohort A: FGF-amplified or Cohort C: FGF non-amplified, both 
receiving 10 mg daily).    
For patients with local FGFR1 or 11q test results, a central laboratory will confirm the 
presence or absence of the FGFR1 and/or 11q amplification.  Central testing prior to 
enrollment for these patients is not required for study enrollment.  
Patients with local FGFR1 and 11q results for whom the central reading does not confirm the 
amplification status can continue the study at the discretion of the investigator if clinical 
benefit is observed.  If there are a significant number of patients with discordant local and 
central testing results, additional patients may be enrolled. 
For patients without a local FGFR1 or 11q test result, tissue may be submitted for central 
testing under a prescreening process, and a positive central laboratory test result is required 
for screening and subsequent enrollment of these patients.   
FGFR1-amplified and 11q-amplified patients will be enrolled* as follows: 
 Cohort A (10 mg): approximately 80 patients  


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FGF non-amplified patients will be enrolled as follows: 
 
 
Cohort C (10 mg): up to 40 patients 
The dose assigned to patients enrolled into Cohort C depends on the version of the 
amendment approved at the time of patient enrollment (Amendment #3: 15 mg; Amendment 
#4: 10 mg). 
*Amendment #4 removed the 1:1 randomized treatment assignment (10 mg vs. 15 mg) and 
accrual of patients to Cohort B (15 mg).  Up to 80 patients were expected enrolled into Cohort 
B under the previous versions of this protocol. 
Up to 20 patients enrolled will participate in a PK sub-study to assess the comparative PK of 
the lucitanib tablet formulation taken at Day –7 with the lucitanib capsule formulation taken at 
Day 1.   
Patients in Cohorts A or C will be enrolled in the PK sub study at participating sites, as 
follows:  
 
 Participation in the PK sub study will be optional for patients participating in  
Cohort A 
Participation in the PK sub study will be required for patients participating in  
Cohort C until enrollment of the PK sub study is completed 
 
2.2.1 
Screening Period 
FGF-amplified (Cohort A) and FGF non-amplified (Cohort C) patients will undergo screening 
assessments within 28 days of the first dose of lucitanib.  
Cohort A or C patients enrolled into the PK sub-study must undergo screening assessments 
within 21 days of the first dose of lucitanib, i.e., prior to Day –7.   
For all patients, AEs will be assessed from the time of first dose of lucitanib through 28 days 
after the last protocol-specified treatment administration. Study-procedure-related AEs that 
occur after signing of the Informed Consent Form (ICF) and before administration of lucitanib 
will also be collected as AEs. AEs that occur after signing of the ICF and before lucitanib 
should be captured on the Medical History eCRF. 
 
2.2.2 
Treatment Period 
Lucitanib will be administered once daily and swallowed with water. Patients should take 
lucitanib at approximately the same time each day, on an empty stomach, at least 2 hours 
before and 2 hours after a meal (fasting window is a total of four hours). Treatment with 
lucitanib is continuous but cycles will be defined as 28 days in duration. Dosing will be 
delayed or reduced according to protocol-specified toxicity criteria. Protocol-specified 
treatment will continue until there is clinical tumor progression or unacceptable toxicity.   
 
Patients will undergo serial assessments for anti-tumor efficacy, drug safety, and PROs.  
Tumor scans will be acquired by the investigative site and evaluated locally for patient 
treatment decisions. Electronic copies of tumor scans will be uploaded to a central 


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radiological vendor and held for review, if deemed necessary. Sparse blood sampling for 
POPPK analyses will be conducted in all patients treated with lucitanib. Serial blood sampling 
for PD evaluation will be conducted. Local laboratories will be used for standard hematology 
and chemistry tests. Echocardiogram (ECHO)/multiple-gated acquisition (MUGA) will be 
done locally. ECGs will be stored and may be analyzed centrally. Patients will be asked to 
self-monitor their BP at least two times per week and instructed to contact the study site in the 
event of a BP reading equal or above 160 mmHg systolic and/or greater than 100 mmHg 
diastolic. 
 
Patients with SD or better after their Cycle 6 scan will continue to have tumor scans every 
12 ± 1 weeks until tumor progression. After discontinuation of protocol-specified treatment, 
subsequent specific anticancer therapy used at the investigator’s discretion will be recorded.  
Patients will be encouraged to undergo an optional post-treatment tumor biopsy at time of 
progression and before subsequent-line therapy is initiated. 
 
2.2.3 
End-of-Study 
All patients should return to the clinic for end-of-study assessments 28 (±7) days after the last 
dose of lucitanib has been administered. 
 
The trial will be completed when all enrolled patients have discontinued treatment and 
completed the end-of-study follow-up visit. 
 
2.2.4 
Long Term Follow-Up 
All patients will be followed at approximately two monthly intervals to determine survival 
status, until death or sponsor decision to end the trial, whichever comes first. 
 
2.2.5 
Study Schema 
The study schemas in Figure 1 summarizes the updated treatment design of the study. 
 
 
 


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Figure 1: Study Schema 
 
 
 
2.2.6 
Number of Patients and Sites 
FGFR1-amplified and 11q-amplified patients will be enrolled* as follows: 
 Cohort A (10 mg): approximately 80 patients  
FGF non- amplified patients will be enrolled into Cohort C as follows: 
 Cohort C (10 mg): up to 40 patients 
*1:1 randomization to Cohorts A and B was removed with Amendment #4. 
Up to 20 patients will participate in a PK sub study to assess the comparative PK of the 
lucitanib tablet formulation with the lucitanib capsule formulation.  Additional patients may 
be added to the PK sub-study to account for patients with incomplete PK sampling profiles at 
either Day –7 or Day 1, or to account for higher than expected variability in the observed PK 
profiles. 
Enrollment into the PK sub study may only be opened at a limited number of sites based on 
study requirements and operational feasibility. 
Patients in Cohorts A or C will be enrolled in the PK sub study at participating sites, as 
follows:  
 Participation in the PK sub study will be optional for patients participating in Cohort A 
 Participation in the PK sub study will be required for patients participating in Cohort C 
until enrollment of the PK sub study is completed 
There will be approximately 30–40 investigative sites in the United States.  All patients 
enrolled in Cohort C are required to participate in the PK sub study.  Accrual to Cohort C will 


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be limited to 10-15 sites participating in the PK sub study, until enrollment in the sub study 
has been filled. 
 
3 
SAMPLE SIZE 
Under the original protocol, approximately 160 patients were to be randomized 1:1 to the 10 
mg and 15 mg daily dosing groups (Cohorts A and B). 
 
Under protocol amendment 5, the following are the revised sample size considerations. 
 
Up to 200 patients will be enrolled.   
 
A total of at least 80 patients in the 10 mg arm is sufficient to reliably estimate the median 
PFS and 6 month PFS rate in these heavily pre-treated patients.  An observed median PFS 
greater than 4 months or a 6-month PFS rate of at least 40% will be sufficient to consider the 
10 mg dose group worthy of further study.  Therefore, with at least 80 patients treated at 
10 mg, the width of the 90% confidence interval for the 6 month PFS rate will be less than 
±10%, so that if the observed 6 month rate is 50% then the lower limit on the confidence 
interval will be greater than 40%. 
 
The treatment effect in Cohort C (biomarker negative sub-group) is not expected to be as large 
as in Cohorts A and B; however, the same target of 40% will be used to evaluate Cohort C.  
With 40 patients, the width of the 90% confidence interval for the 6 month PFS rate will be 
less than ±15%, so that if the observed 6 month rate is less than 25% then the upper limit on 
the confidence interval will be less than 40%, which is evidence that subsequent studies of 
10 mg should exclude biomarker negative patients. 
 
4 
GENERAL ANALYSIS CONSIDERATIONS 
Due to significant changes to the study design throughout the study, all summaries of data will 
be presented by initial study drug dose level (10 mg, 15 mg) regardless of a patient’s 
enrollment into study cohorts A, B, and C. Initial dose groups will be referred to as treatment 
groups (10 mg, 15 mg). An overall column combining all patients from both treatment groups 
will be included in the data summaries, where applicable.  
 
Quantitative variables will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum, and maximum) and/or frequency and percentages for medically 
relevant categories. Categorical variables will be presented using frequencies and percentages. 
Exact 95% confidence intervals may be presented for frequencies. 
 
All data will be used to their maximum possible extent but without any imputations for 
missing data. 
 
All statistical analyses will be conducted with the statistical analysis software (SAS®) System, 
Version 9.3 or higher. 


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5 
ANALYSIS POPULATIONS 
Per Amendment #5 of the protocol, the following analysis populations were defined for the 
study: 
Efficacy Population – all patients who have received at least one dose of lucitanib and are 
confirmed as FGFR1-, 11q-amplified, or FGF non-amplified per the central laboratory.  
 
Safety Population – all patients who have received at least one dose of lucitanib. 
 
For the final statistical analyses to be conducted in support of the clinical study report, the 
Efficacy Population is redefined as all patients who have received at least one dose of 
lucitanib and have at least one post-baseline tumor scan. 
 
6 
PATIENT DISPOSITION 
The frequency and percentage of patients in each analysis population will be presented.  The 
primary reason for discontinuation of lucitanib will be summarized.   
 
7 
INCLUSION / EXCLUSION VIOLATIONS 
The number of patients that violate each inclusion or exclusion criteria will be listed. 
8 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline characteristics and demographic data will be summarized for the safety population. 
 
8.1 
Demographics 
The demographic variables will be summarized with frequency tabulations.  Descriptive 
statistics may also be used to summarize age, height, and weight.  The categorical variables 
presented will include age, weight, sex, race, and ethnicity. Variable categorizations will be as 
follows:  
• Age (years): ≤ 40, 41-60, 61-80, > 80; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150; 
• Sex: Male, Female 
• Race:  American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other 
• Ethnicity: Hispanic or Latino, not Hispanic or Latino 
 
These categorizations may be adjusted if the majority of the data lies in only 2 or 3 of the 
categories.   


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8.2 
Baseline Clinical Characteristics 
Baseline characteristics variables to be summarized will include ECOG performance status, 
Hormone Receptor and Human Epidermal Growth Factor Receptor Status at diagnosis, 
location of metastatic disease, FGF status, breast cancer stage at diagnosis, number of prior 
anticancer therapies, number of prior adjuvant anticancer therapies, number of prior 
neoadjuvant anticancer therapies, and number of prior metastatic anticancer therapies, and 
time since diagnosis. Categorizations are provided below: 
• ECOG: 0, 1, 2 
• HR/HER2 Status at Diagnosis: HER 2-positive, ER-positive (and not HER 2-positive), 
PR-positive (and not HER 2-positive and not ER-positive), Triple Negative (note the 
hierarchical nature of these four categories) 
• FGF status: 11q, FGFR1, FGFR1 & 11q, Negative 
• Breast cancer stage: Occult, 0, I, IIA, IIB, IIIA, IIIB, IIIC, IV 
• Number of prior metastatic anticancer therapies: <3, 3-6, >6 
• Location of metastatic disease: bone only, visceral only, bone and visceral 
• Time since diagnosis (months):  ≤12, >12-24, >24;  
 
8.3 
Medical History 
Medical history data will be summarized using frequency tabulations by system organ class 
and preferred term. 
9 
STUDY DRUG EXPOSURE AND COMPLIANCE 
The following analyses will be provided as a summary of study drug exposure and 
compliance: 
• Duration of exposure (days): number of days from first dose of study drug to the last dose 
of study drug. 
• Total study drug taken (mg): Number of milligrams of study drug taken during the study. 
• Mean daily dose (mg): Total study drug taken / duration of exposure   
 
The number of days on which drug was actually taken will also be summarized. 
 
10 PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant treatments documented during the study period will be summarized in 
frequency tabulations.  Prior/concomitant medication coding will utilize the World Health 
Organization (WHO) Drug Dictionary 
Any prior medications not considered prior anticancer medications will be listed along with 
concomitant medications.  Prior medications will be defined as those medications with both a 
start and a stop date that is before the day of the first dose of study drug administration.   If 
either the start date and/or the stop date of the medication is missing so that it is unclear 


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whether the medication was stopped prior to first dose of study drug administration then the 
medication will be included in the summary of the concomitant medications.  Concomitant 
medications will be tabulated and summarized. 
11 EFFICACY VARIABLES 
The following are the efficacy variables of interest: 
11.1 Primary Efficacy Variable 
The primary efficacy variable is the investigator determined PFS per RECIST Version 1.1. 
11.2 Secondary Efficacy Variables 
Secondary variables include: 
• Objective Response Rate (ORR) according to RECIST Version 1.1 
• Duration of Response (DR) according to RECIST Version 1.1 
• Disease Control Rate (DCR) 
• Overall Survival (OS) 
• Change from baseline in PRO using the Functional Assessment of Cancer Therapy-Breast 
(FACT-B) questionnaire 
• Treatment emergent AEs, laboratory abnormalities, physical examinations including vital 
signs and electrocardiogram (ECG) abnormalities 
• Plasma PK parameters for lucitanib based on sparse sampling for POPPK analysis  
 
12 EFFICACY ANALYSIS 
12.1 Primary Efficacy Analysis 
Kaplan-Meier methodology will be used to summarize the time to event variables including 
the estimated 50th (median) percentile by treatment group.  
 
12.1.1 
Progression Free Survival (PFS) 
PFS is defined as 1+ the number of days from the date of first dose of study drug to disease 
progression or death due to any cause, whichever occurs first. Patients without a documented 
event of progression will be censored on the date of their last adequate tumor assessment (i.e., 
radiologic assessment), or the date of randomization if no tumor assessments have been 
performed. Progression events will be determined by the investigator. 
 
12.1.2    Objective Response Rate (ORR) 
ORR is the proportion of patients with a best response of CR or PR according to RECIST 
Version 1.1. The best response is recorded from the start of treatment (Day 1) until disease 


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progression or recurrence. The ORR will be summarized with frequencies and percentages. 
The number and frequency of confirmed responses (CR+PR) will also be tabulated. 
 
12.2 Key Secondary Efficacy Analyses 
12.2.1 
Duration of Response (DR) 
DR for CR and PR will be measured from the date that any of these best responses is first 
recorded until the first date that PD is objectively documented. DR will be summarized using 
descriptive statistics (N, mean, standard deviation, median, minimum, and maximum). 
 
12.2.2 
Disease Control Rate (DCR) 
The DCR is defined as the percentage of patients with a best response rate of CR, PR, or SD 
for at least 12 weeks. The DCR will be summarized with frequencies and percentages. 
 
12.2.3 
Overall Survival (OS) 
OS is defined as 1+ the number of days from the date of first dose of study drug to the date of 
death due to any cause. Patients without a documented date of death will be censored on the 
last date the patient was known to be alive. 
 
12.2.4 
PK Sub Study (Cohort C) 
Comparative PK parameters will include AUC0–t, Cmax, Tmax, T1/2, VSS/F, and Cl/F for 
lucitanib and will be determined using noncompartmental methods.  AUC0–t will be calculated 
using the trapezoid rule. The PK parameters will be compared between the tablet and the 
capsule formulations. 
 
13 POPULATION PK ANALYSES 
A specific POPPK data analysis plan will be developed and will outline the detailed approach 
to data handling, model development and diagnostics, individual model parameter estimation, 
exploration of covariate effects, and final model evaluation techniques. Results will be 
presented in a separate PK report to be appended to the clinical study report (CSR). 
14 EXPLORATORY ANALYSES 
The exploratory endpoints will be summarized descriptively. 


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15 PATIENT REPORTED OUTCOMES 
PROs will be measured using the FACT-B questionnaire in all patients with both a baseline 
assessment and at least one post-baseline assessment.  
 
The baseline PRO measurement will be defined as the last value prior to or on the day of the 
first dose of lucitanib. The on-treatment period will be defined as the day after the first dose of 
lucitanib to 28 days after the last dose of protocol-specified treatment. PRO measurements 
collected during the on-treatment period will be included in the summary tables. 
 
The summary of PRO data will include descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum) of the maximum, minimum, and last value during the 
on-treatment period. Summaries using descriptive statistics of the change from baseline to the 
maximum, minimum, and last value during the on-treatment period will also be given by 
relevant cohort. 
 
16 STATISTICAL / ANALYTICAL ISSUES 
16.1 Handling of Dropouts or Missing Data 
All data will be used to their maximum possible extent but without any imputations for 
missing data. 
 
16.2 Interim Analysis 
A data monitoring committee (DMC) consisting of two external investigator advisors and 
specified Clovis personnel was to meet approximately quarterly after the first patient was 
enrolled to review the efficacy and safety data. 
 
A detailed description of the composition, roles and responsibilities, and functioning of the 
DMC is provided in the DMC Charter. 
  
17 SAFETY ANALYSIS 
The safety analyses will be performed using the Safety Population.  
 
17.1 Adverse Events 
The severity of the toxicities will be graded according to the NCI CTCAE whenever possible.  
Treatment-emergent AEs are defined as AEs with an onset date on or after the date of first 
dose of lucitanib until the date of the last dose of protocol-specified treatment plus 28 days.  
AEs will be considered treatment-emergent if all or part of the date of onset of the AE is 
missing and it cannot be determined if the AE meets the definition for treatment-emergent. 
 
The number and percentage of patients who experienced treatment-emergent AEs for each 
system organ class and preferred term will be presented by treatment group.  Multiple 
instances of the treatment-emergent AEs in each system organ class and multiple occurrences 


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of the same preferred term are counted only once per patient.  The number and percentage of 
patients with at least one treatment-emergent AE will also be summarized by treatment group.   
Separate tables will present the following by cohort: 
 
 All treatment-emergent AEs 
 Treatment-emergent AEs by CTCAE grade 
 Treatment-related, treatment-emergent AEs by CTCAE grade 
 Grade 3 or greater treatment-emergent AEs 
 Treatment-related, treatment-emergent AEs 
 Serious treatment-emergent AEs 
 Serious treatment-related, treatment-emergent AEs 
 Treatment-emergent AEs of Grade 3 or higher 
 Treatment-related, treatment-emergent AEs of Grade 3 or higher 
 Treatment-emergent AEs with an outcome of death 
 Treatment-related, treatment-emergent AEs with an outcome of death 
 Treatment-emergent AEs leading to discontinuation of study drug 
 Treatment-related, treatment-emergent AEs leading to discontinuation of study drug 
 Treatment-emergent AEs resulting in interruption of study drug  
 Treatment-related, treatment-emergent AEs resulting in interruption of study drug 
 Treatment-emergent AEs resulting in study drug dose reduction  
 Treatment-related, treatment-emergent AEs resulting in study drug dose reduction 
 Treatment-emergent AEs resulting in interruption or reduction/delay of study drug 
 Treatment-related, treatment-emergent AEs resulting in interruption or reduction/delay of 
study drug  
 Treatment-emergent AEs resulting in interruption, reduction, or discontinuation of study 
drug 
 Treatment-related, treatment-emergent AEs resulting in interruption, reduction, or 
discontinuation of study drug 
The incidence of treatment-emergent AEs will be summarized by relationship to lucitanib 
using “treatment-related” and “not treatment-related” categories.  If a patient experiences 
multiple occurrences of the same AE with different relationship categories, the patient will be 
counted once in the relationship category of treatment-related.   
If a patient experiences multiple occurrences of the same AE with different intensity toxicity 
grades, the patient will be counted once for the maximum (most severe) toxicity grade.  AEs 
with a missing intensity will be presented in the summary table with a toxicity grade of 
“Missing.”  For each toxicity grade, the number and percentage of patients with at least one 


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treatment-emergent AE of the given grade will be summarized.  
   
Non-treatment-emergent AEs (pretreatment and post treatment) will be presented in the data 
listings.  
 
17.2 Clinical Laboratory Evaluations 
Clinical laboratory evaluations include variables for hematology, serum chemistry, and 
urinalysis.  Laboratory values will be presented in Systeme International (SI) units.  The 
baseline laboratory value will be defined as the last value prior to or on the day of the first 
dose of oral lucitanib.  The on-treatment period will be defined as the day after the first dose 
of oral lucitanib to 28 days after the last dose of lucitanib.  Laboratory values collected during 
the on-treatment period will be included in the summary tables.  The laboratory values 
collected after the on-treatment period will only be presented in the data listings.   
 
The summary of laboratory data will include descriptive statistics (N, mean, standard 
deviation, minimum, median, and maximum) of the maximum, minimum, and last value 
during the treatment period by treatment group.  Summaries using descriptive statistics of the 
change from baseline to the maximum, minimum, and last value during the on-treatment 
period will also be presented by treatment group.     
 
17.3 Vital Signs 
The baseline vital sign measurement will be defined as the last value prior to or on the day of 
the first dose of lucitanib. The on-treatment period will be defined as the day after the first 
dose of lucitanib to 28 days after the last dose of protocol-specified treatment.  Vital sign 
measurements collected during the on-treatment period will be included in the summary 
tables.  The vital sign measurements collected after the on-treatment period will only be 
presented in the data listings.   
 
The summary of vital sign data will include descriptive statistics (N, mean, standard 
deviation, minimum, median, and maximum) of the maximum, minimum, and last value 
during the on-treatment period by treatment group and study phase. Summaries using 
descriptive statistics of the change from baseline to the maximum, minimum, and last value 
during the on-treatment period will also be presented by treatment group. Shift tables and 
graphical representations of vital signs parameters may be provided. 
  
17.4 12-Lead Electrocardiograms 
Descriptive statistics will be used to summarize all ECG parameters of heart rate, PR, QRS, 
QT (QTcF, QTcB), and RR interval, at each nominal collection time point. 
  
17.5 Other Safety Measurements 
Shifts from baseline in body weight by CTCAE criteria will be summarized. 
 


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18 REFERENCES