Clinical trial NCT01953003
Conditions: Malignant Neoplasm of Breast
Sponsor: Pierre Fabre Medicament
Start date: 2013-09-01; Completion date: 2017-07-01
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Options for the treatment of patients who have progressed after an anthracycline and a taxane are limited. Capecitabine currently has a role in this setting, yet as many as 80% of patients do not respond to this treatment and those who respond eventually develop clinical resistance.

The antitumour activity of vinflunine has been demonstrated in patients with breast cancer after exposure to anthracycline and to taxane.

Vinflunine plus capecitabine has been shown to be a feasible combination for patients previously treated with an anthracycline and a taxane. Each drug in combination can be administered at efficacious doses.

This population has few therapeutic options with established clinical benefit. The development of a new regimen and potential new standard of care for this group is important.

* Primary objective:

  • to compare in patients with advanced breast cancer pretreated with anthracycline and taxane the efficacy of the combination of vinflunine and capecitabine with capecitabine alone, in terms of progression-free survival.
* Secondary objectives:

  * to evaluate the response rate, the time to response and the duration of response in both arms
  * to compare the disease control rate between arms
  * to evaluate the duration of disease control in both arms
  * to evaluate the overall survival in both arms
  * to evaluate safety

Methodology This multicentre, open-label, randomised, Phase III study will enrol a total of 334 patients with advanced breast cancer who have previously been treated with an anthracycline and a taxane. Patients will be randomised in a 1:1 ratio to receive VFL plus capecitabine (Arm A) or capecitabine alone (Arm B).

Detailed description:
RECIST 1.1 will be used for tumor assessment CTC - CAE version 3.0 will be used for safety assessment

Arms: arm 1: Vinflunine dose 280 mg/m² on day 1 of each cycle every 3 weeks, Capecitabine 825 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. arm 2: 1250 mg/m² twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest
Interventions: intervention 1: vinflunine intervention 2: Capecitabine
Intervention descriptions: intervention 1: intravenous administration day 1 once every 3 weeks, 280 mg/m² intervention 2: Arm A : 1650 mg/m² Arm B : 2500 mg/m²

Protocol documents:
Prot_000.pdf: 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
1/144 
 
Sponsor: Pierre Fabre Médicament 
Represented by: 
Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
92654 Boulogne-Billancourt, France 
 
 
 
 
 
 
 
 
L00070 IN 311 B0 


 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
2/144 
 
 
Sponsor: Pierre Fabre Medicament 
Represented by: 
Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
92654 Boulogne-Billancourt, France 
 
 
 
L0070 I.V. Vinflunine 
 
 
Clinical study protocol 
 
 
A multicentre, randomised, phase III study of vinflunine plus 
capecitabine versus capecitabine alone in patients with advanced 
breast cancer previously treated with an anthracycline  
and a taxane 
 
 
Pierre Fabre Study Code:  
 
L00070 IN 311 B0 
 
 
 
Sponsor’s representatives:  
 
Clinical Development Physician: 
 
                        Andrius BACEVICIUS, MD 
Clinical Study Manager:  
 
 
 
 
 
 
Christine PETILAIRE BELLET 
 
Coordinating investigator:   
 
Binghe Xu, MD 
 
 
 
 
 
 
Cancer Institute and Hospital 
 
 
 
 
 
 
Chinese Academy of Medical Sciences (CAMS) 
 
 
 
 
 
 
Beijing, China 
 
Version No.7 
 
 
 
 
Date of version: 29JUL16 
 
The information contained in this document is confidential and is the property of Pierre Fabre Medicament. This information is given for the 
needs of the trial and must not be disclosed without prior written consent of Pierre Fabre Medicament. 
Persons to whom this information is given for the needs of the trial must be informed that it is confidential and must not be disclosed. 


 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
3/144 
 
STUDY SYNOPSIS 
 
Name of SPONSOR:  
Pierre Fabre 
MEDICAMENT 
 
 
Name of finished product: 
JAVLOR® 
 
Name of active substance(s): 
VINFLUNINE DITARTRATE 
 
Title of the study 
A multicenter, randomised, phase III study of vinflunine plus capecitabine versus capecitabine alone in patients with advanced 
breast cancer previously treated with an anthracycline and a taxane (L00070 IN 311 B0). 
Coordinating investigators: Binghe Xu 
Planned number of study centres:  
26 centres have been active in China, Singapore and Taiwan. 
Study rationale 
Options for the treatment of patients who have progressed after an anthracycline and a taxane are limited. Capecitabine currently 
has a role in this setting, yet as many as 80% of patients do not respond to this treatment and those who respond eventually 
develop clinical resistance. 
The antitumour activity of vinflunine has been demonstrated in patients with breast cancer after exposure to anthracycline and to 
taxane. 
Vinflunine plus capecitabine has been shown to be a feasible combination for patients previously treated with an anthracycline 
and a taxane. Each drug in combination can be administered at efficacious doses. 
This population has few therapeutic options with established clinical benefit. The development of a new regimen and potential 
new standard of care for this group is important. 
Period of inclusion  
Q3 2013 to Q4 2014  
Clinical phase Phase III 
Objectives 
- Primary objective: 
• 
To compare in patients with advanced breast cancer pretreated with anthracycline and taxane the efficacy of the 
combination of vinflunine and capecitabine with capecitabine alone, in terms of progression-free survival. 
- Secondary objectives: 
The secondary objectives listed below will be no more evaluated: 
• 
 To evaluate the response rate, the time to response and the duration of response in both arms 
• 
 To compare the disease control rate between arms 
• 
 To evaluate the duration of disease control in both arms 
• 
 To evaluate the overall survival in both arms 
 
Except following secondary objective, which will be evaluated: 
• 
 To evaluate safety 
Study L00070 IN 311 B0 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
4/144 
Name of SPONSOR:  
Pierre Fabre 
MEDICAMENT 
 
 
Name of finished product: 
JAVLOR® 
 
Name of active substance(s): 
VINFLUNINE DITARTRATE 
 
Methodology 
This multicentre, open-label, randomised, Phase III study planned to enrol a total of 334 patients. The sponsor decided to stop the 
recruitment after enrolment of a total of 112 patients with advanced breast cancer who have previously been treated with an 
anthracycline and a taxane. Patients will be randomised in a 1:1 ratio to receive VFL plus capecitabine (Arm A) or capecitabine 
alone (Arm B). 
Randomisation will be stratified according to : 
1. Karnofsky Performance Status (“90-100%” versus “70-80%”), 
2. Visceral involvement (yes versus no), visceral lesions include one of the following : liver, lung, pleura (including pleural 
effusion), heart (including pericardial effusion), peritoneum (including abdominal ascites), spleen and adrenal glands, 
3. Investigator site. 
Number of patients  
 A sample size of 167 patients per arm was planned.  Following the sponsor decision, a total of 112 patients have been enrolled in 
this. The inclusions are now closed. 
Diagnosis and main inclusion criteria 
Inclusion criteria : 
1. 
Patients must give written informed consent 
2. 
Women with histologically or cytologically confirmed Her-2 negative carcinoma of the breast. 
3. 
Documented locally recurrent or metastatic disease not amenable to curative surgery or radiotherapy. 
4. 
Patients must have received either one, two or three prior chemotherapy regimens including those administered in the 
neoadjuvant or adjuvant setting (neoadjuvant chemotherapy followed by adjuvant chemotherapy will count for one line).  
5. 
Prior treatment must have included both an anthracycline (i.e., doxorubicin or pirarubicin or epirubicin) and a taxane (i.e., 
paclitaxel or docetaxel) in any combination or order whatever the setting. 
Note that the patients must have received a minimum cumulative dose of 180 mg/m² of doxorubicin/ pirarubicin or 300 
mg/m² of epirubicin. 
6. 
Documented progression on or within 12 months of the most recent chemotherapy. 
7. 
Prior hormone therapy is allowed either in the neoadjuvant and/or adjuvant setting and in the advanced setting provided 
that the treatment is terminated 2 weeks prior to randomisation.  
8. 
Prior radiation therapy is allowed to < 30% of the bone marrow and must be completed at least 3 weeks before 
randomisation. 
9. 
Must have measurable or non measurable disease according to RECIST (version 1.1). In patients who present with a single 
lesion,  available histological or cytological confirmation is required. 
10. Adequate recovery from recent surgery. At least one week must have elapsed from the time of minor surgery, at least 3 
weeks for major surgery. 
11. Estimated life expectancy ≥ 12 weeks. 
12. Karnofsky performance score ≥ 70%. 
13. Age ≥ 21 years and < 80 years. 
14. Adequate haematological function defined by absolute neutrophil count > 1.5 x 109/L, platelet count > 100 x 109/L  and 
haemoglobin > 10 g/dL. 
Study L00070 IN 311 B0 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
5/144 
Name of SPONSOR:  
Pierre Fabre 
MEDICAMENT 
 
 
Name of finished product: 
JAVLOR® 
 
Name of active substance(s): 
VINFLUNINE DITARTRATE 
 
15. Adequate hepatic function defined by total bilirubin < 1.5 x upper limit of normal (ULN) ; aspartate aminotransferase 
(AST) and alanine aminotransferase (ALT) < 2.5 x ULN (or < 5 x ULN in case of liver metastases) ; alkaline phosphatase 
< 5 x ULN 
16. Adequate renal function defined as calculated creatinine clearance > 50 ml/min according to Cockroft-Gault formula 
17. ECG without clinically relevant abnormality 
18. Patients on coumadin or warfarin must be on stable doses and have an International Normalized Ratio (INR) ≤ 3 at the 
time of screening. 
19. Women of childbearing potential must be using a medically accepted method of contraception (i.e. intrauterine devices, 
condom) to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and 
for up to 3 months after the last dose of study treatment in such a manner that the risk of pregnancy is minimised. Women 
of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to first treatment 
administration. 
20. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the 
study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial. 
Exclusion criteria : 
1. 
Patients with known or with clinical evidence of brain metastasis or leptomeningeal involvement 
2. 
Patients with pulmonary lymphangitis or symptomatic pleural effusion (grade > 2) that results in pulmonary dysfunction 
requiring active treatment. 
3. 
Patients having received any other experimental drug or chemotherapy within 30 days before randomisation. 
4. 
History of second primary malignancy, except: bilateral breast carcinoma, in situ carcinoma of the cervix, adequately 
treated non melanomatous carcinoma of the skin, and other malignancy treated at least 5 years previously with no evidence 
of recurrence. 
5. 
Patients with pre-existing motor/sensory peripheral neuropathy of NCI CTCAE version 3.0 grade > 1. 
6. 
Patients having received > 3 regimens of chemotherapy 
7. 
Prior therapy with capecitabine and/or vinca alkaloids (including vinflunine) 
8. 
History of severe hypersensitivity to vinca alkaloids and/or to fluoropyrimidine or any contra indication to any of the study 
drugs. 
9. 
Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency. 
10. A female is not eligible to enter the study if: pregnant or lactating or with positive pregnancy test at inclusion. 
11. Female of childbearing potential who is unwilling or unable to use a medically accepted method to avoid pregnancy during 
the 2 months preceding the start of study treatment, throughout the study period and at least 3 months following the last 
dose of study treatment. 
12. Known history of HIV infection. 
13. Inability to take and/or absorb oral medication including previous gastric surgery or any evidence of partial oesophageal, 
gastric, small or large bowel obstruction; gastrointestinal disorder that affect the absorption of capecitabine (malabsorption 
syndrome, 2/3 gastric resection and bowel resection). 
14. Patients who have any serious, concurrent uncontrolled medical disorder especially uncontrolled hypercalcaemia, 
congestive heart failure, uncontrolled high-risk hypertension, arrhythmia, angina pectoris or previous history of myocardial 
infarction within 6 months prior to randomisation 
15. Prior bone marrow transplantation or autologous stem cell infusion following high-dose chemotherapy.. 
Study L00070 IN 311 B0 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
6/144 
Name of SPONSOR:  
Pierre Fabre 
MEDICAMENT 
 
 
Name of finished product: 
JAVLOR® 
 
Name of active substance(s): 
VINFLUNINE DITARTRATE 
 
Test product, dose and mode of administration  
Patients randomised in arm A will receive:  
Vinflunine at the dose of 280 mg/m² on day 1 of each cycle every 3 weeks, over a 20-minute IV infusion.  
In addition, patients will receive capecitabine which will be self administered in the outpatient setting. Patients will take 825 mg/m² 
twice daily orally for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest.  
A cycle of therapy is defined as 3 weeks. 
Reference therapy, dose and mode of administration  
Patients randomised in arm B will receive: 
Capecitabine self administered in the outpatient setting. Patients will take 1250 mg/m² twice daily orally for 14 consecutive days 
beginning on day 1 of each cycle followed by 1 week of rest. A cycle of therapy is defined as 3 weeks. 
Duration of treatment  
Patients will continue the study treatment until : 
• 
disease progression, 
• 
unacceptable toxicity 
• 
patient’s request 
Criteria for evaluation: 
- Efficacy assessment 
Efficacy will be determined by using RECIST (version 1.1). All lesions will be assessed at baseline then every 6 weeks (+/- 3 
working days) from randomisation (regardless of the timing of treatment cycles). 
- Safety assessment 
Clinical safety will be assessed by: 
• 
complete history of malignant and non malignant disease. 
• 
full physical examination including vital signs, weight, PS, and neurological examination 
• 
ECG at baseline and at the end of treatment 
• 
regular reporting of adverse events that will be graded by using NCI CTCAE version 3.0 
• 
complete blood count at baseline then on day 1 of each cycle 
• 
serum chemistry at baseline then on day 1 of each cycle. 
Study L00070 IN 311 B0 
4/5 
 


 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
7/144 
 
Name of SPONSOR:  
Pierre Fabre 
MEDICAMENT 
 
 
Name of finished product: 
JAVLOR® 
 
Name of active substance(s): 
VINFLUNINE DITARTRATE 
 
Statistical methods 
As the final population size is much lower than the population size required to ensure adequate statistical power, , the 
collection of data will be stopped and the analyses will be performed when patients have either completed the end of 
treatment period or completed 35 cycles. As patients are not followed until progression, the results should be not 
representative and they will only be used as exploratory data. 
The primary objective of this study is to show the superiority of the vinflunine plus capecitabine combination (arm A) versus 
capecitabine alone (arm B) in terms of progression-free survival in breast cancer patients after anthracycline and taxane 
failure. 
It is assumed that the median progression-free survival will be 4.0 months for the control arm (arm B). The goal of the study 
is to show a PFS improvement of 1.5 months (HR=0.727) i.e. a median PFS of 5.5 months for the VFL plus capecitabine 
arm.  
Using a two sided log-rank test with a target type I error α = 5%, it is required to observe 310 events (progression or death)  
in order to have a 80% power (1 - β) to show a statistically significant PFS difference when the true hazard ratio is 0.727. 
An approximately 24 months accrual period was planned for the 334 patients. Following the decision to stop the recruitment, 
the statistical analysis will be actually conducted on the 112 randomised patients and only descriptive analyses will be 
performed on the ITT population. 
The primary efficacy analysis will be the description of median PFS in the ITT population.. 
The safety analysis will be performed in the evaluable population for safety. Haematological parameters (WBC, ANC, 
platelets, haemoglobin), febrile neutropenia, biochemical parameters (ALT, AST, alkaline phosphatase, creatinine, total 
bilirubin) and non haematological toxicities will be assessed. The NCI CTCAE version 3.0 will be used except hand-foot-
syndrome which will be graded using Roche Hand-Foot-Syndrome Grading Scale. 
End of study 
The end of study is the date of the last patient study treatment administration plus 30 days (EOT). 
No follow up period assessments will be performed subsequently to the approval of the amendment PA06: 
-Patients under treatment will stop the study at End Of Treatment (EOT) 
-Patients under follow up will stop the study immediately. 
Study L00070 IN 311 B0 
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CONFIDENTIAL 
 
 
 
 
 
 
 
L00070 IN 311 B0 
 
 
Clinical Study Protocol – Version 7 
Date:29JUL16 
8/144 
Table 1: Study flow chart 
Required assessments 
Screening 
period 
Treatment period 
End of 
Treatment (d) 
Follow-Up (f) 
Timing 
Day -21  
to -1 
Day 1 
every cycle 
Day 1 to 
Day 14 
Every 6 
weeks 
 
 
Signed Informed Consent 
X (a) 
 
 
 
 
 
Study treatment 
Vinflunine (Arm A) 
 
X 
 
 
 
 
Capecitabine (Arms A + B) 
 
 
X 
 
 
 
Demographic data 
Demography/Medical History/Diagnosis and prior 
therapy 
X 
 
 
 
 
 
Her-2 status and ER/PgR status 
X (q) 
 
 
 
 
 
Serum/urine pregnancy test in women of childbearing 
potential 
X (j) 
 
 
 
 
 
Physical Examination/Vital signs/Weight 
Neurological examination 
X (b) 
X 
 
 
X 
 
Karnofsky Performance Status 
X (b) 
X 
 
 
X 
 
Safety 
Electrocardiogram (ECG) 
X (b) 
X (o) 
 
 
X 
 
Pretreatment events /  
Adverse events/ SAE 
X (k) 
X 
 
 
X 
X 
Complete blood count 
X (b) 
X (n) 
 
 
X 
 
Blood chemistry (c) 
X (b) 
X (p) 
 
 
X 
 
INR (as clinically indicated) (l) 
X 
 
 
 
 
 
Concomitant medications/blood Products 
X (k) 
X 
 
 
X 
 
Efficacy (i) 
Chest CT-Scan or MRI 
X 
 
 
X 
X (g) 
 
Abdominal/pelvic CT-scan or MRI 
X 
 
 
X 
X (g) 
 
Bone scintigraphy (e) 
X 
 
 
 
X (g) 
 
Bone X-rays or CT scan (bone window) or MRI (h) 
X 
 
 
X (h) 
X (g) 
 
Clinical/biological skeletal parameters/related events 
(m) 
X 
X 
 
 
X (g) 
 
Brain CT scan or MRI if clinical suspicion of CNS 
metastases 
X 
 
 
 
 
 
Other imaging if necessary 
X 
 
 
X 
X (g) 
 
(a): Prior to any study procedure. 
(b): Within 7 days prior to first study drug treatment. 
(c): Transaminases, alkaline phosphatases, total bilirubin, total protein, urea, creatinine and calculated creatinine clearance, calcium, sodium and potassium. 
(d): 30 days + 3 days after study treatment discontinuation. 
(e):  Bone scintigraphy in all patients at baseline. To be repeated in the following cases: 
- In  patients who had bone lesions at study entry to document  an  overall complete response 
- In all patients: at any time during study treatment in case of suspicion of progression due to skeletal related events defined as any observation of the following 
clinical/biological parameters: increase in pain intensity or analgesic consumption or alkaline phosphatase level or  calcium  level; or  new  bone  pain  symptoms  
requiring other palliation therapy i.e. radiotherapy, surgery, bisphosphonates; or spinal cord compression; or pathological bone fracture. 
(f): Only for patients who discontinued study participation before approval of PA06 :until disease progression: every 6 weeks.  After disease progression, every 6 
months until death or end of study. 
(g) Only for patients who discontinued study participation before approval of PA06 ::in case of treatment discontinuation for other reason than PD, all efficacy 
assessments including clinical and biological parameters of bone lesion (described above) must be performed every 6 weeks until disease progression is documented, 
then  survival  information  will  be  collected  approximately  every  6  months  until  death or end of study.  Bone scintigraphy should be performed at any time in case 
of worsening of at least one of the clinical/biological parameters described above. 
(h): If deemed necessary by the investigator ; to be performed on hot spots of bone scintigraphy 
(i): Tumour assessment is to be performed every 6 weeks (+/- 3 working days) from randomisation (regardless of the timing of treatment cycles): all lesions found at 
baseline should be re-investigated at each tumour assessment (for bone lesions, see specific assessment guidelines in Section  8.1.1.2). Additional examinations may be 
performed if appearance of new lesions is suspected. 
(j): Within 72 hours prior to first study drug treatment 
(k) Within 2 weeks prior to first study drug treatment 
(l) Patients on oral coumarin derivative should have their anticoagulant response (INR) monitored closely 
(m) Including evaluation of bone pain, analgesic consumption and assessment of biological  parameters   ( alkaline  phosphatases,  calcaemia) 
(n) to be performed within 24 hours before day 1 of each cycle 
(o) if clinically indicated 
(p) same than (n) except at cycle 1 day 1 
(q) to be known prior to randomisation 

SAP_001.pdf: 
 
PIERRE FABRE MEDICAMENT 
Institut de Recherche Pierre Fabre  
45, Place Abel Gance 
92654 Boulogne-Billancourt 
STATISTICAL ANALYSIS PLAN 
 
Compound Number : L00070 
Name of Test Drug : I.v Vinflunine (Javlor) 
Study code : L00070 IN 311 B0 
Title of the study:  
 
 
A MULTICENTRE, RANDOMISED, PHASE III STUDY OF VINFLUNINE 
PLUS CAPECITABINE VERSUS CAPECITABINE ALONE IN 
PATIENTS WITH ADVANCED BREAST CANCER PREVIOUSLY 
TREATED WITH AN ANTHRACYCLINE  
AND A TAXANE 
 
 
Author Name :   
 
Benjamin POIRIER (Statistician - Axiodis) 
 
 
 
 
   
 
 
Reviewers Names :  
 
Stéphanie JEAN-ALPHONSE (Head of Statistical Department) 
 
 
 
 
Mia COMPERNOLLE (Clinical Study Physician – Kelly Life) 
 
Date of approval :  
 
05/07/2017 
Date of version :  
    
Final version n° 3 (05/07/2017)  
Date of previous version : 
Final version n° 2 (25/06/2014) – Approval (25/06/2014) 
 
Reason(s) for change :  
- 
According to the protocol amendment PA06 (29/07/2016), the 
statistical analysis was reduced to: 
o 
Efficacy: a descriptive summary of the primary efficacy 
variable on the ITT population (i.e. no analysis on 
secondary criteria) 
o 
Safety: a description of safety parameters 
 
 
 
 
 
 
 
The information contained in this document is confidential and is the property of the sponsor. This 
information is given for the needs of the trial and must not be disclosed without prior written consent of 
the sponsor. Persons to whom this information is given for the needs of the trial must be informed that it 
is confidential and must not be disclosed.  
 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
Date of approval : Final version n°3 (05/07/2017) 
Folder : V:\02_Department_Activities\03_Direction_Equipe_Pôle_Medical\Redaction_Medicale\_Documents_Soudhir\L00070 IN 
311_CSR\L00070IN311B0_SAP_V3_20170705.doc 
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CONFIDENTIAL 
SIGNATURES 
 
 
Title 
Name 
(First & Last name) 
Consistency 
between SAP 
and study 
protocol  
Date 
Signature 
Author 
Statistician 
Benjamin POIRIER 
(Axiodis) 
NA 
 
 
Reviewer 
Clinical Study 
Physician 
Mia COMPERNOLLE 
(Kelly Life) 
NA 
 
 
Approving 
Officer 
Head of 
Statistical 
Department 
Stéphanie JEAN-
ALPHONSE 
 Confirmed  
 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
Date of approval : Final version n°3 (05/07/2017) 
Folder : V:\02_Department_Activities\03_Direction_Equipe_Pôle_Medical\Redaction_Medicale\_Documents_Soudhir\L00070 IN 
311_CSR\L00070IN311B0_SAP_V3_20170705.doc 
3/41   
CONFIDENTIAL 
 
TABLES OF CONTENTS  
 
1. 
STUDY OBJECTIVES............................................................................................................................ 10 
2. 
STUDY DESIGN ..................................................................................................................................... 10 
3. 
SAMPLE SIZE ........................................................................................................................................ 12 
4. 
EFFICACY PARAMETERS .................................................................................................................... 12 
4.1. 
PRIMARY EFFICACY PARAMETERS ................................................................................................ 13 
4.2. 
SECONDARY EFFICACY PARAMETERS ......................................................................................... 13 
5. 
SAFETY PARAMETERS ....................................................................................................................... 13 
5.1. 
ADVERSE EVENTS ............................................................................................................................ 13 
5.2. 
FEBRILE NEUTROPENIA .................................................................................................................. 15 
5.3. 
HAEMATOLOGICAL PARAMETERS ................................................................................................. 15 
5.4. 
BIOCHEMICAL PARAMETERS .......................................................................................................... 15 
6. 
OTHER PARAMETERS ......................................................................................................................... 16 
6.1. 
CONCOMITANT MEDICATIONS PARAMETERS .............................................................................. 16 
7. 
DEFINITION OF POPULATIONS .......................................................................................................... 16 
7.1. 
INTENT-TO-TREAT POPULATION .................................................................................................... 16 
7.2. 
ELIGIBLE POPULATION .................................................................................................................... 16 
7.3. 
EVALUABLE POPULATION FOR RESPONSE .................................................................................. 16 
7.4. 
EVALUABLE POPULATION FOR SAFETY ........................................................................................ 16 
8. 
STATISTICAL METHODS ..................................................................................................................... 17 
8.1. 
STATISTICAL SOFTWARE AND METHODOLOGY .......................................................................... 17 
8.2. 
STATISTICAL METHODS FOR CATEGORICAL VARIABLES .......................................................... 17 
8.3. 
STATISTICAL METHODS FOR ORDINAL VARIABLES .................................................................... 17 
8.4. 
STATISTICAL METHODS FOR CONTINUOUS VARIABLES............................................................ 17 
8.5. 
STATISTICAL METHODS FOR TIME DEPENDENT DATA .............................................................. 17 
9. 
TREATMENT GROUP DESCRIPTION ................................................................................................. 19 
9.1. 
DESCRIPTION AT BASELINE ............................................................................................................ 19 
9.1.1. 
Overview of the study ....................................................................................................................... 19 
9.1.2. 
Characteristics at baseline ............................................................................................................... 19 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
Date of approval : Final version n°3 (05/07/2017) 
Folder : V:\02_Department_Activities\03_Direction_Equipe_Pôle_Medical\Redaction_Medicale\_Documents_Soudhir\L00070 IN 
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CONFIDENTIAL 
9.2. 
DESCRIPTION DURING THE STUDY ............................................................................................... 22 
9.2.1. 
Actual Dose intensity per cycle ........................................................................................................ 24 
9.2.2. 
Relative dose intensity per cycle ...................................................................................................... 24 
9.2.3. 
Actual Dose intensity per patient ...................................................................................................... 25 
9.2.4. 
Relative dose intensity per patient ................................................................................................... 25 
9.2.5. 
Dose reductions ............................................................................................................................... 26 
9.2.6. 
Treatment cancellation (Capecitabine) ............................................................................................ 26 
9.2.7. 
Vinflunine infusion interruption (Arm A) ............................................................................................ 27 
9.2.8. 
Treatment delay ............................................................................................................................... 27 
9.2.9. 
Route of administration and setting .................................................................................................. 28 
9.2.10. 
Concomitant medications ............................................................................................................... 28 
10. 
EFFICACY ANALYSES ....................................................................................................................... 29 
10.1. 
PRIMARY EFFICACY ANALYSIS ..................................................................................................... 29 
10.2. 
SENSITIVITY ANALYSES OF THE PRIMARY EFFICACY PARAMETER ....................................... 29 
10.3. 
SECONDARY EFFICACY ANALYSES ............................................................................................. 29 
11. 
SAFETY ANALYSES ........................................................................................................................... 29 
11.1. 
OVERVIEW OF THE SAFETY .......................................................................................................... 29 
11.2. 
ADVERSE EVENTS .......................................................................................................................... 30 
11.2.1. 
All adverse events .......................................................................................................................... 30 
11.2.2. 
Serious adverse events .................................................................................................................. 30 
11.2.3. 
Deaths ............................................................................................................................................ 31 
11.3. 
LABORATORY TESTS ..................................................................................................................... 31 
11.3.1. 
Haematological toxicities ................................................................................................................ 31 
11.3.2. 
Biochemical toxicities ..................................................................................................................... 31 
12. 
CHANGES INTERFERED SINCE LAST VERSION ............................................................................ 31 
13. 
REFERENCES ..................................................................................................................................... 33 
14. 
APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS ............................................................ 35 
15. 
APPENDIX 2: STATISTICAL ANALYSIS CONVENTIONS ................................................................ 38 
15.1. 
CALCULATION OF A DURATION .................................................................................................... 38 
15.2. 
CALCULATION OF A DELAY ........................................................................................................... 38 
15.3. 
MISSING DATA ................................................................................................................................. 38 
15.3.1. 
General conventions ...................................................................................................................... 38 
15.3.2. 
Conventions for dates .................................................................................................................... 39 
15.4. 
DOSE MODIFICATIONS................................................................................................................... 39 


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15.5. 
OVERALL RESPONSE OF THE PATIENT ...................................................................................... 39 
15.6. 
DATE OF FIRST RESPONSE AND DATE OF PROGRESSION ..................................................... 39 
15.6.1. 
Date of first response ..................................................................................................................... 39 
15.6.2. 
Date of progression or death .......................................................................................................... 39 
15.7. 
TOXICITY .......................................................................................................................................... 40 
15.7.1. 
Haematological toxicities ................................................................................................................ 40 
15.7.2. 
Biochemical toxicities ..................................................................................................................... 40 
15.7.3. 
Definition of a toxic death ............................................................................................................... 41 
15.7.4. 
Treatment duration ......................................................................................................................... 41 
15.8. 
END OF STUDY ................................................................................................................................ 41 
15.8.1. 
Death for progression ..................................................................................................................... 41 
 


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LIST OF TABLES 
 
Table 9-1 : Categorized dose of vinflunine .................................................................................................... 23 
Table 9-2: Categorized bi-daily dose of capecitabine .................................................................................... 23 
Table 9-3: Planned dose intensity in mg/m²/wk in the vinflunine plus capecitabine arm ............................... 25 
Table 9-4: Planned dose intensity in mg/m²/wk in the capecitabine arm ....................................................... 25 


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LIST OF APPENDICES  
Appendix 1 : LIST OF TABLES, FIGURES AND LISTINGS ....................................................................... 34 
Appendix 2 : STATISTICAL ANALYSIS CONVENTIONS .......................................................................... 34 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridisation 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events  
DCR 
Disease control rate 
DI 
Dose Intensity 
EORTC 
European Organisation for Research and Treatment of Cancer 
FISH 
Fluorescent In Situ Hybridisation 
FN 
Febrile Neutropenia 
HB 
Haemoglobin 
HLGT 
High Level Group Term 
HLT 
High Level Term 
i.v 
Intravenous 
ICH 
Immuniohistochemistry 
IDMC 
Independent Data Monitoring Comitee 
IRRC 
Independent Response Review Comitee 
ITT 
Intent-To-Treat 
LLT 
Lowest Level Term 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progression Disease 
PDI 
Planned Dose Intensity 
PLT 
Platelets 
PR 
Partial Response 
KPS 
Karnofsky Performance Status 
MedDRA 
Medical Dictionary for Regulatory Activities 
PFS  
Progression-Free Survival 
PT 
Preferred Term 
PTS  
Patients 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 


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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
The Statistical Analysis Software 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxalo-acetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SIADH 
Syndrome of Inappropriate Anti-Diuretic Hormone 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
VFL 
Vinflunine 
WBC 
White Blood Cells 
WHO 
Work Health Organization 
Wk(s) 
Week(s) 
 
 
 


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1. STUDY OBJECTIVES 
The primary objective of this study was to compare the progression-free survival (PFS) between the 
test arm (vinflunine + capecitabine) and the control arm (capecitabine alone) in patients with advanced 
breast cancer previously treated with an anthracycline and a taxane. 
As the final population size is much lower than the population size required to ensure adequate 
statistical power, the collection of data was stopped and the analyses will be performed when patients 
have either completed the end of treatment period or completed 35 cycles. As patients are not 
followed until progression, the results should be not representative and they will only be used as 
exploratory data. Following the decision to stop the recruitment, the statistical analysis will be actually 
conducted on the 112 randomised patients and only descriptive analyses will be performed on the ITT 
population  
The primary efficacy analysis will be the description of median PFS in the ITT population.  
The Secondary objective of the study is to evaluate the safety that will be described by the treatment 
arm. 
2. STUDY DESIGN 
This multicentre, open-label, randomised, Phase III study was designed to enrol 334 patients with 
advanced breast cancer who have previously been treated with an anthracycline and a taxane. 
Patients will be randomised in a 1:1 ratio to receive vinflunine plus capecitabine (Arm A) or 
capecitabine alone (Arm B). 
Randomisation was stratified according to the following strata. 
1. Karnofsky performance status (“90-100” versus “70-80”),  
2. Visceral involvement (yes versus no), visceral lesions include one of the following : liver, lung, 
pleura (including pleural effusion), heart (including pericardial effusion), peritoneum (including 
abdominal ascites), spleen and adrenal glands, 
3. Study site. 
using a minimization procedure (Pocock, SJ, 1975) . 
 
 
Patients randomised in Arm A received:  
• 
Vinflunine at the dose of 280 mg/m² on day 1 of each cycle every 3 weeks, over a 20-minute 
i.v. infusion and, 


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• 
Capecitabine which was self-administered by the patient in an outpatient setting. Patients will 
take 825 mg/m² twice daily per os for 14 consecutive days beginning on day 1 of each cycle 
followed by 1 week of rest. A cycle of therapy is defined as 3 weeks. 
For patients randomised in Arm B, capecitabine was self-administered by the patient in an 
outpatient setting. Patients took 1250 mg/m² twice daily per os for 14 consecutive days beginning on 
day 1 of each cycle followed by 1 week of rest. A cycle of therapy is defined as 3 weeks. 
The doses and timing of treatment could be modified based on toxicities experienced by the patient. 
Dose modifications guidelines are described in Section 5.4 of the protocol. 
Patients would continue the study treatment until disease progression, unacceptable toxicity or 
patient’s request. 
• 
Patients showing progressive disease should stop study treatment. 
• 
Patients showing objective response (CR or PR) or stable disease should continue the 
treatment until progression. 
In case of documented progression occurring before the first disease evaluation, the treatment should 
be discontinued and the response to treatment should be registered as early progression. 
After treatment discontinuation, the follow-up period is the time from 30 days after the last study 
regimen administration or new anticancer treatment start until death. 


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3. SAMPLE SIZE  
The primary objective of the protocol was to show that the vinflunine plus capecitabine test arm is 
superior to capecitabine as a single agent arm in terms of progression-free survival. 
The final analysis will require at least 310 events (progression or death); this is the number of events 
needed for a two sided, log-rank test at an alpha = 0.05 significance level and a 80% power to show a 
statistically significant difference when the true hazard ratio is 0.727 i.e., when the median PFS in the 
combination arm is 1.5 months greater than median PFS of 4 months in the control arm. 
An expected total number of 334 patients was to be randomised. As the objective of the study could 
not be achieved, the collection of data was stopped and the analysis will be performed in patients 
either completing the end of treatment period or patients completing 35 cycles. The statistical analysis 
will be conducted on the only 112 patients that have been randomized. 
4. EFFICACY PARAMETERS 
Tumour assessment will be performed according to the revised RECIST guidelines (Eisenhauer E, 
2009). Assessment of all lesions will be carried out at baseline then every 6 weeks (+/- 3 working days) 
regardless of the timing of the treatment cycles until disease progression.  
For patients who discontinued the study treatment before the occurrence of disease progression, 
clinical and radiological assessments of all lesions will be performed every 6 weeks until disease 
progression is documented in addition to the survival information. Bone scintigraphy should be 
performed at baseline and at any time during study in case of suspicion of bone lesions progression 
due to skeletal related events defined as any observation of the following clinical/biological parameters:  
o 
Pain intensity: increase by at least one grade of the bone related pain using the CTCAE 
v 3.0 grading:   
o 
Analgesic consumption (per investigator assessment): increase of the analgesic dose 
by at least 50% or increase of the analgesic level according to the following categories 
of analgesics: level 1: simple non-opioids analgesic e.g. paracetamol; level 2: weak 
opioids e.g. codeine or analogs; level 3: strong opioids e.g. morphine.  
o 
Alkaline phosphatase level: increase by at least one grade from baseline or nadir value 
using the following CTCAE version 3.0 grading. 
o 
Calcaemia: increase by at least one grade from baseline or nadir value using the 
following CTCAE version 3.0 grading: 
o 
New bone pain symptoms requiring other palliation therapy i.e. radiotherapy, surgery, 
bisphosphonates. 
o 
Spinal cord compression. 
o 
Pathologic bone fracture. 


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4.1. 
PRIMARY EFFICACY PARAMETERS 
The primary efficacy parameter is progression-free survival (PFS) according to the investigator. 
RECIST version 1.1 will be used. 
Progression-free survival will be calculated from the date of randomisation until the date of progression 
or death (whatever the reason of death).  
The progression-free survival may be censored at the date of last tumour assessment or the date of 
last contact of a follow-up showing no progression, whichever occurs last, in the following cases: 
• 
On-going patients 
• 
Lost to Follow-Up 
• 
Consent withdrawn 
• 
New Anti Cancer therapy given 
• 
No post baseline assessment 
• 
Adequate assessment no longer available (i.e. non evaluable tumour) 
• 
No baseline assessment. 
4.2. 
SECONDARY EFFICACY PARAMETERS 
Analysis of the following secondary efficacy parameters is no longer applicable in the study: 
 the tumour response and disease control rates in both arms, 
 the duration of response, the duration of  disease control, time to treatment failure and time to 
first response in both arms, 
 the overall survival in both arms. 
5. SAFETY PARAMETERS 
5.1. 
ADVERSE EVENTS 
Each patient will be assessed for occurrence of adverse events. The CTCAE version 3.0 will be used. 
Adverse events not classified by the CTCAE will also be reported and graded according to their 
severity: mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening or disabling (grade 4), 
sudden death (grade 5), not applicable in case of progression or adverse event not gradable according 
to CTCAE and leading to dose modification (NA).  
Treatment Emergent Adverse Event (TEAE) will be considered for analysis of adverse effects. A TEAE 
is defined as any event that first occurred during the treatment period (i.e. from first drug administration 
date up to last administration date + 30 days) or that “worsened” during that study period. The definition 
of “worsening” is described below: 
- 
Any increase in the grade (according to CTCAE) compared to baseline adverse event, 
or 
- 
Any adverse event becoming serious during the study period, or 


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- 
Any adverse event not pre-treated at baseline requiring a corrective treatment during 
study, or 
- 
Any adverse event requiring a modification of the study drug administration, or 
- 
Any adverse event becoming possibly, probably or definitely related to the study drug 
An adverse event that meet one of the criteria described above will be considered as TEAE and 
reported in the analyses for the reminder of the study, even if the TEAE downgrades to baseline 
situation. 
Baseline situation of the pre-treatment adverse events will be determined by using: 
- 
the worst grade of the adverse event during the pre-study period (within 2 weeks prior to 
treatment),  
- 
the seriousness of the event during the pre-study period, 
- 
the use of corrective treatment (even if stopped at the day of first administration) during 
the pre-study period.  
This situation will be used as comparator to determine whether an existing adverse event during study 
period becomes treatment-emergent (i.e. if at least one of these previous parameters gets worst during 
study treatment). 
The adverse events and signs and symptoms will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA). The implementation of this international terminology in the Oracle 
Clinical database will be performed using the avalaible version of MedDRA. Each description of the 
toxicity (verbatim) will be associated with the five following items: 
- 
System Organ Class (SOC), 
- 
High Level Group Term (HLGT), 
- 
High Level Term (HLT), 
- 
Preferred Term (PT), 
- 
Lowest Level Term (LLT). 
The matching of the adverse events reported on the CRF pages with the baseline pre-treatment events 
to determine the qualification for TEAE will be done by using the Lowest Level Term of the MedDRA 
dictionary and the qualification for TEAE will be implemented by the study statistician on a dataset 
provided by the data manager and containing all AEs reported on the CRF pages or derived by the 
study data manager according to CRF completion guidelines.  
Two sets of events will be considered:  
 all adverse events regardless of relationship to treatment, 
 the adverse events that are possibly, probably or definitely related to treatment,  
 If the causality is missing, the AE will be considered as related to study treatment 


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A cycle will be evaluable for non-haematological toxicity if the following criteria are fulfilled: 
 At least one drop or one tablet of any treatment was given, 
 The toxicity has been assessed by the investigator during the cycle. 
A patient will be evaluable for non-haematological toxicity if at least one cycle is evaluable and will be 
analysed in the treatment arm she was effectively treated. 
5.2. 
FEBRILE NEUTROPENIA 
According to CTCAE version 3.0, febrile neutropenia (FN) is defined as ANC <1.0 x 109/L and fever 
 38.5°C of unknown origin without clinically or microbiologically documented infection. (§ 5.4.1. 
“General considerations” of the protocol). 
5.3. 
HAEMATOLOGICAL PARAMETERS 
Haematological toxicity will be assessed by laboratory investigations of haemoglobin, WBC, ANC and 
platelets. Grades will be calculated according to CTCAE version 3.0. 
A cycle will be evaluable for haematological toxicity analysis if the following criteria are fulfilled: 
 At least one drop or one tablet of any treatment, 
 At least one blood cell count between Day 2 and Day 1 of next cycle or end of treatment period for 
the last administered cycle, 
 At least one of the four haematological parameters analyzed has been measured. 
A patient is evaluable for haematological toxicity analysis if at least one cycle is evaluable. 
5.4. 
BIOCHEMICAL PARAMETERS 
Biochemical toxicity will be assessed by laboratory investigations of liver function tests (i.e. bilirubin, 
alkaline phosphatase, SGOT/AST, SGPT/ALT), renal function tests (creatinine) and metabolic function 
tests (sodium, potassium, calcium). Grades will be calculated according to the CTCAE version 3.0. 
A cycle will be evaluable for biochemical toxicity analysis if the following criteria are fulfilled: 
 At least one drop or one tablet of any treatment has been administered, 
 At least one biochemistry test between Day 2 and Day 1 of next cycle or end of treatment period 
for the last administered cycle, 
 At least one of the eight biochemical parameters analysed has been measured. 
A patient will be evaluable for biochemical toxicity analysis if at least one cycle is evaluable. 


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In addition, SGOT/AST, SGPT/ALT and bilirubin will be analyzed acoording to the presence or not of 
liver lesions at baseline in order to assess the relationship between liver metastasis and worst grade 
during study. 
The same analysis will be done for Alkaline Phosphatase according to the presence or not of liver/bone 
metastases. 
6. OTHER PARAMETERS 
6.1. 
CONCOMITANT MEDICATIONS PARAMETERS 
In the same way as the adverse events, concomitant medications will be coded using the specific 
international terminology WHO-Drug Dictionary version 2007, March 1.  
If the start and end dates are both anterior to randomization date will be analysed as prior concomitant 
medication. Otherwise, the treatment will be considered as concomitant medication. 
7. DEFINITION OF POPULATIONS 
 
According to Protocol amendment PA06, all statistical analyses will be performed on the Intent-to-treat 
(ITT) population. Other populations will not be constituted. 
7.1. 
INTENT-TO-TREAT POPULATION 
All randomised patients will be included in the intent-to-treat population. They will be analysed in the 
arm they were assigned by randomisation. 
7.2. 
ELIGIBLE POPULATION 
 
No longer applicable for the study. 
7.3. 
EVALUABLE POPULATION FOR RESPONSE 
 
No longer applicable for the study. 
7.4. 
EVALUABLE POPULATION FOR SAFETY 
 
All treated patients will be included in the safety analysis. They will be analysed in the treatment arm 
they actually received. 


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8. STATISTICAL METHODS 
8.1. 
STATISTICAL SOFTWARE AND METHODOLOGY 
Most analyses will be carried out with 9.3 version of SAS for Windows (or later version if available). 
All statistical tests will be two-sided at a 5% level of significance unless specified otherwise. 
All baseline descriptive statistics will be presented in summary tables by treatment arm and overall.  
Continuous data will be summarized with the following items: frequency, median (if n 3), min, max, 
mean and standard deviation if relevant. 
Categorical data will be presented in contingency tables with frequencies and percentages of each 
modality (including missing data modality). 
8.2. 
STATISTICAL METHODS FOR CATEGORICAL VARIABLES 
The ² test will be performed to compare proportions or replaced by Fisher’s exact test if the expected 
frequency in one cell of the contingency table is less than 5. The 95% confidence interval for 
proportions will be computed following the exact method. If a stratified analysis is required a Cochran-
Mantel-Haenszel (CMH) test will be used (option CMH in the TABLES statement of the FREQ 
procedure in SAS). 
8.3. 
 STATISTICAL METHODS FOR ORDINAL VARIABLES 
Comparisons between the two treatment arms will be provided for ordinal data using the non-
parametric Wilcoxon rank sum test. 
8.4. 
STATISTICAL METHODS FOR CONTINUOUS VARIABLES 
The distributions of quantitative data will be examined by the Kolmogorov-Smirnov test in order to test 
for normality. In case of Gaussian distribution, the comparison between the 2 treatment arms will be 
made with a Student t-test. If the distribution is not considered as Gaussian then the non-parametric 
Wilcoxon test will be performed. 
8.5. 
STATISTICAL METHODS FOR TIME DEPENDENT DATA 
To describe time dependent parameters, Kaplan-Meier curves and life tables by treatment arm will be 
provided. Confidence intervals on the median will be calculated using the Brookmeyer and Crowley 


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method. Hazard ratio and 95% confidence intervals will be reported. A stratified Cox proportional 
model will be performed to compare the two treatment arms taking into account the stratification 
factors (except centre) used at the time of randomisation. 


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9. TREATMENT GROUP DESCRIPTION 
9.1. 
DESCRIPTION AT BASELINE 
Analysis of baseline characteristics and demography will be performed on the ITT population, by 
treatment arm. 
9.1.1. 
Overview of the study  
The reasons for treatment discontinuation will be reported. Study discontinuation will be described 
according to the following reasons: adverse event (related or not), death (related or not), progressive 
disease, lost to follow up, protocol deviation and other reasons.  
The patient status (dead, alive, lost to follow-up ) at the cut-off date will be displayed together with each 
reason of death (progressive disease, adverse event, other). 
The number of patients randomised, treated will be presented by treatment group and overall.  
Time between randomisation and first administration will be tabulated by treatment arm. 
The duration of follow-up is defined as the time elapsed between the date of randomisation and the 
date of last news or death, death being a censored observation.  
9.1.2. 
Characteristics at baseline 
Demographic and baseline characteristics of patients will be displayed. The following variables will be 
analysed on the ITT population according to the arm assigned at randomisation: 
Demographic data   
 Age at the time of randomisation 
 Categorized groups of age :< 35, [35 – 50[, [50 – 65[, [65 – 75[, [75 – 80[ and > 80 years, 
 Karnofsky performance status at baseline in categorical data, 
 Body weight, 
 Body surface area. 
 Menopausal status (defined by the presence of the term “Menopause” in the Medical History) 
Last available value will be used for baseline analysis. 
Stratification data Extract from the IVRS database   
 Categorized groups of performance status (“70-80” vs. “90-100”) at randomisation, 
 Visceral disease (“yes” vs. “no”) at randomisation. 
Disease history: 


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Characteristics at diagnosis: 
 Primary site of cancer: right / left / bilateral 
 Histological type: carcinoma / ductal/  lobular  /inflammatory/ other (with specification) 
 TNM classification, 
 SBR grade. 
Characteristics at study entry: 
 Hormonal receptors at study entry: hormonal receptor ER+/- (positive/negative/unknown or not 
done), hormonal receptor PR+/- (positive/negative/unknown or not done), 
 HER-2 status at study entry (ICH method): 0/1+/2+/3+/missing/not done, 
 HER-2 status at study entry (FISH/CISH method): negative/positive/missing/not done, 
 Hormone receptors and HER-2 status (triple negative* versus HR positive* and HER-2 negative 
versus HR positive or negative*), 
 Extent of the disease at study entry (locoregional disease/metastatic disease), 
 Measurable disease  
 Categorized groups of number of organs involved: 1, 2 and  3 organs, 
 Detail of organs involved. 
 Time from initial diagnosis to study entry, 
 Progression-free interval, 
 Categorized groups of progression-free interval: ≤ 4 months / > 4 months, 
 Disease-free interval, 
 Categorized groups of disease-free interval:  ≤12 months / > 12 months 
 Treatment free interval, 
 
* : Triple negative patients are those presenting with HER2-, PgR- and ER- 
     HR positive patients are those presenting with PgR+/- and ER+ or PgR+ and ER+/- 
     HR negative patients are those presenting with PgR- and ER- 
     HR positive or negative patients are those presenting with PgR+/- and ER+/- 
 
Measurable disease defined as: 
• 
Yes if the number of targeted lesions is > 0,  
• 
No if number of targeted lesions is not > 0 and the number of non-targeted lesions is > 0 
• 
No disease in other cases  
The progression free interval is the time interval elapsed between the date of end of the last prior 
chemotherapy given in the metastatic setting and the date of relapse or progression after this last line 
of chemotherapy. This progression free interval of patients relapsing or progressing during the last line 
treatment will be estimated to last one day. 
The disease free interval is the time interval elapsed between the date of end of the last prior 
chemotherapy according to intents neo-adjuvant/adjuvant and the date of relapse or progression.  


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The treatment free interval is the time elapsed between the date of end of the last treatment (prior 
chemotherapy, prior hormone therapy…, whichever occurs last) and the first administration of study 
treatment.  
 
Prior therapy 
An overview of prior therapies for Breast carcinoma will be provided giving: 
 Number of patients with at least one prior therapy 
 Number of patients treated by medication 
 Number of patients treated by chemotherapy 
 Number of patients treated by hormonotherapy 
 Number of patients treated by other antineoplastic drug 
 Number of patients who underwent a surgery 
 Number of patients who underwent a radiotherapy 
 For the last Medication (including chemotherapy, hormone therapy, antineoplastic therapy): intent, 
time between stop date of medication and date of relapse/progression (expressed in weeks). 
 For surgeries: number of surgeries 
 For the last radiotherapy: intent 
 
Chemotherapy 
 Number of patients who underwent a chemotherapy with intents and intent of last chemotherapy, 
 Number of lines, 
 Prior anthracycline-based chemotherapy by intent, 
 Categorized group of prior cumulative dose of anthracyclines, by type of anthracyclines:  
No Anthracyclines,  
Epirubicin ≥ 300 mg/m²,  
Epirubicin < 300 mg/m²,  
Epirubicin dose unknown,  
Doxorubicin/Pirarubicin ≥ 180 mg/m²,  
Doxorubicin/Pirarubicin < 180 mg/m²,  
Doxorubicin/Pirarubicin dose unknown,  
Epirubicin ≥ 300 mg/m² / Doxorubicin/Pirarubicin ≥ 180 mg/m²,  
Other (Liposomal Doxorubicin). 
 Prior taxane-based chemotherapy by intent,  
 Categorized group of prior taxanes: 
Docetaxel at any dose,  
Paclitaxel at any dose. 
 Class of prior adjuvant/neo-adjuvant chemotherapy (if both in the same time):  
 anthracyclines-based, 
 anthracyclines-taxanes 
 anthracyclines-other 
 anthracyclines single agent 
 taxanes-based, 
 taxanes-anthracyclines, 
 taxanes-other, 
 taxanes single agent, … 


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 Class of prior advanced disease chemotherapy: anthracyclines-based, anthracyclines-taxanes, 
anthracyclines-other, 
anthracyclines 
single 
agent, 
taxanes-based, 
taxanes-anthracyclines, 
taxanes-other, taxanes single agent   
 Best response of the last chemotherapy by intent and by class of chemotherapy, 
 Best response of the last chemotherapy by HER status (0/1+/2+/3+/missing/not done) 
 
Hormone therapy 
 Number of patients who underwent a hormone therapy with intents and intent of last hormone 
therapy, 
 Details of hormone therapy treatments received. 
 Number of patients who underwent a castration, 
 
Clinical examination 
 Electrocardiogram (normal/abnormal but not clinically significant/abnormal clinically significant),  
 Temperature, Blood Pressure, Pulse, 
 Baseline biological abnormalities,  
 Baseline haematological abnormalities. 
Last available baseline value will be used for baseline analysis. 
 
Concomitant medications at baseline 
 Concomitant medications whatever the intent, 
 Concomitant medications with a tumour related intent,  
 Concomitant medications with a prophylactic intent, 
 Concomitant medications with pre-treatment event indication, 
 Concomitant medications with a medical history, 
 
Prior medical history 
 Prior medical or surgical history according to MedDRA Preferred Term (PT) and System Organ 
Classification (SOC). 
 
Pre-treatment events 
 Pre-treatment events according to MedDRA Preferred Term (PT) and System Organ Classification 
(SOC), 
 
9.2. 
DESCRIPTION DURING THE STUDY 
In arm A, a cycle is defined as 1 administration of vinflunine (day 1) and 14 consecutive days (starting 
from day 1) of capecitabine doses bi-daily with treatment rescheduled every 3 weeks.  
In arm B, a cycle is defined as 14 consecutive days of capecitabine doses bi-daily, with treatment 
rescheduled every 3 weeks. 


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Duration of exposure is defined as the time elapsed between the date of 1st intake and the date of last 
capecitabine (if given) administration + 7 days or day 1 (administration of vinflunine) + 21 days if 
capecitabine not given.  
A summary table will provide by treatment arm, the following items: 
 Duration of exposure, 
 Number of patient with at least one dose permanently discontinued, 
 Number of patient with at least one dose temporarily cancelled, 
 Number of patients with at least one dose reduced (including dose delayed and reduced), 
 Number of patients with at least one dose delayed (including dose delayed and reduced). 
The total number of cycles given during the study, the median number of cycles as well as the number 
of patients by cycle will be given. The categorized groups of vinflunine and capecitabine doses by cycle 
will be presented.  
The actual dose (mg/m²) will be calculated from the total dose administered (mg) divided by the BSA. 
The BSA will be recalculated at each cycle. 
The following categories of vinflunine and capecitabine doses will be used: 
Table 9-1 : Categorized dose of vinflunine 
Dose category  
in mg/m² 
 
Dose of vinflunine  
in mg/m² 
>320  
] 335 - ] 
320  
] 300 – 335 ] 
280  
] 265 - 300 ] 
250  
] 237.5 - 265 ] 
225 
] 212.5- 237.5  ] 
< 225 
] 0 - 212.5 ] 
Table 9-2: Categorized bi-daily dose of capecitabine 
Dose category  
in mg/m² 
 
Dose of capecitabine in 
mg/m² 
Arm A 
> 1250 
]1400 – [ 
1250  
]1100–1400] 
950 
]887.5–1100]   
825 
] 742.5–887.5] 
660 
 ]642.5–742.5] 
625 
 ]562.5–642.5] 
500 
] 437.5–562.5] 
<500 
] 0–437.5]  
Arm B 
> 1250 
]1400 – [ 
1250 
] 1100-1400] 
950 
] 787.5–1100] 
625 
] 462.5–787.5] 
<625 
] 0–462.5] 
 


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Actual dose intensity (mg/m²/wk) and relative dose intensity (%) will be calculated per cycle and per 
patient for the vinflunine plus capecitabine and the capecitabine alone arms. Cumulative dose (mg/m²) 
will also be given. Descriptive statistics such as median and range will be provided.  
The number and percentage of cycles/patients with a RDI  90%, in ]90%;100%] or > 100% will also be 
given.  
The actual dose received (mg/m²) at cycle i will be equal to the actual dose received (mg) at cycle i 
divided by the body surface area at the beginning of the cycle i. 
The body surface area will be calculated as follows: 


10000
84
.
71
725
.0
*
*
425
.0
*
*
BSA



H
W
 
where: 
 W = Weight (kg) at the beginning of cycle i, or last weight available if missing at cycle i, 
 H = Height (cm) at the beginning of the study. 
BSA as per investigator will be used as an estimate when height has not been provided at baseline.  
9.2.1. 
Actual Dose intensity per cycle 
Actual dose intensity per cycle will be defined as follows: 



7
/]
i  
cycle
at 
 
date
 
Course
1
i  
cycle
at 
 
date
 
Course
[
i  
cycle
at  
  
(mg/m²)
  
recieved
  
dose
  
Actual
(wk)
  i  
cycle
 
of
duration 
  
Actual
i  
cycle
at  
  
(mg/m²)
  
recieved
  
dose
  
Actual
i  
cycle
at 
 
DI




 
The duration of the last cycle will be estimated to be 3 weeks. 
9.2.2. 
Relative dose intensity per cycle 
Relative dose intensity (%) at cycle n° i will be the ratio of the actual dose intensity (mg/m²/wk) at cycle 
i to the planned dose intensity (mg/m²/wk) that is to say: 
 
100
(mg/m²/wk)
 
intensity 
  
dose
  
Planned
(mg/m²/wk)
  i  
cycle
at  
 
intensity 
  
dose
  
Actual
100
PDI
i  
cycle
at  
  
DI
i  
cycle
at  
  
RDI
















 
where : 
3
(mg/m²)
 
dose
  
Planned
(wk)
 i  
cycle
  
of
duration  
  
Theorical
(mg/m²)
 
dose
  
Planned
i 
cycle
at 
 
PDI


 
 


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Tables 9-3 and 9-4 give for each treatment arm of the study the PDI : 
 
Table 9-3: Planned dose intensity in mg/m²/wk in the vinflunine plus capecitabine arm 
Treatment  
Administration 
Dose (mg/m²) 
Planned Dose 
(mg/m²) per 
cycle 
 
P.D.I 
(mg/m²/wk) 
vinflunine 
Day 1 
280 
280 
93.33 
capecitabine 
Bid from day 1 to 14 
825 
23100 
7700 
 
 
Table 9-4: Planned dose intensity in mg/m²/wk in the capecitabine arm 
Treatment  
Administration 
Dose (mg/m²) 
Planned Dose 
(mg/m²) per 
cycle 
P.D.I 
(mg/m²/wk) 
capecitabine 
Bid from day 1 to 14 
1250 
35000 
11666.67 
 
 
9.2.3. 
Actual Dose intensity per patient 
Actual dose intensity per patient will be defined as follows : 






n
i
duration
n
i
dose
i
i
1
1
(wk)
duration 
Treatment 
(mg/m²)
 
dose
 
Cumulative
DI
 
where : 
 dosei = actual dose received (mg/m²) at cycle i, 
 durationi = actual duration (wks) of cycle i, 
 n = total number of cycle(s) per patient. 
9.2.4. 
Relative dose intensity per patient 
Relative dose intensity (%) will be the ratio of the actual dose intensity (mg/m²/wk) to the planned dose 
intensity (mg/m²/wk) that is to say : 
 
 
100
(mg/m²/wk)
 
intensity 
  
dose
  
Planned
(mg/m²/wk)
 
intensity 
  
dose
  
Actual
100
PDI
DI
RDI
















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where : 
3
(mg/m²)
 
dose
  
Planned
cycles
 
of
number 
 
(wk)
 
cycle
 a 
of
duration  
  
Theorical
cycles
 
of
number 
 
(mg/m²)
 
dose
  
Planned
PDI




 
 
 
9.2.5. 
Dose reductions  
Dose reductions are allowed by the study protocol for vinflunine and capecitabine in both arms. The 
number of patients and cycles with a dose reduction will be presented as well as the reasons. 
9.2.5.1.Vinflunine dose reduction at day 1 (Arm A) 
 Number of patients with at least one dose of vinflunine in arm A reduced at day 1 
 Number of cycles with a dose of vinflunine in arm A reduced at day 1 
 Reasons for vinflunine dose reduction at day 1 (as per protocol): 
Reason for dose reduction of vinflunine 
Dose reduction as per protocol 
N cycles 
From 280 to 250 
mg/m² 
From 250 to  225 
mg/m² 
 
N 
% 
N 
% 
N 
% 
Non-study drug related adverse event 
 
 
 
 
 
 
Study drug related haematological AE 
 
 
 
 
 
 
Study drug related non-haematological AE 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 Total number of haematological and non-haematological toxicities and nature, as per protocol or 
not, which have led to a dose reduction,  
 Detail of the haematological and non-haematological toxicities which have led to a dose reduction, 
9.2.5.2.Capecitabine dose reductions  
 Number of patients with at least one dose of capecitabine reduced: 
 Number of cycles with at least dose of capecitabine reduced: 
 Reasons for capecitabine dose reductions (as per protocol)  
 Total number of haematological and non-haematological toxicities, which have led to a dose 
reduction of capecitabine,  
 Detail of the haematological and non-haematological toxicities which have led to a dose reduction 
of capecitabine, 
9.2.6. 
Treatment cancellation (Capecitabine) 
Capecitabine dosing may be cancelled as per protocol (§ 5.4.3.2 of the protocol). 


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The number of cycles with at least one day (morning and afternoon doses both not taken for 
capecitabine) cancelled and number of patients with at least one day of dosing cancelled will also be 
displayed. Reasons for treatment cancellation will be provided. 
 Number of patients with at least one capecitabine dose cancelled, 
 Number of cycles with at least one capecitabine dose cancelled, 
 Reasons for capecitabine dose cancellation. 
 Total number of toxicities, as per protocol or not, which have led to a capecitabine dose 
cancellation,  
 Detail of the haematological and non-haematological toxicities which have led to a capecitabine 
dose cancellation, 
9.2.7. 
Vinflunine infusion interruption (Arm A) 
Vinflunine infusion interruption may occur. The number of patients and cycles with a infusion 
interruption will be presented as well as the reasons. 
 Number of patients with at least infusion of vinflunine in arm A interrupted at day 1, 
 Number of cycles with a infusion of vinflunine in arm A interrupted at day 1, 
 Reasons for vinflunine infusion interruption at day 1, 
 Total number of toxicities, as per protocol or not, which have led to a infusion interruption,  
 Detail of the haematological and non-haematological toxicities which have led to a infusion 
interruption, 
9.2.8. 
Treatment delay 
The number of patients and cycles delayed will be presented with reason for treatment delay.  
A treatment cycle will be considered as delayed if administered  4 days after the planned date with a 
three weeks interval from day 1 of previous cycle. In arm A, the date of vinflunine administration will 
determine the day 1 of the cycle; in arm B (and for patients continuing capecitabine alone in arm A), 
the first day of capecitabine intake will determine the day 1 of the cycle, whatever the first dose has 
been taken in the morning or the afternoon. Only delay for Day 1 will be calculated. 
The delays will be categorized as follows: 
 [4 – 7 days[, 
 [7 – 14 days[, 
  14 days. 
 
The following parameters will be described by arm: 
 Number of patients with at least one cycle delayed by four days or more, 
 Number of cycles delayed, 
 Categorized groups of cycle delay, 


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 Reasons for cycle delay of four days or more, 
 Total number of haematological and non-haematological toxicities, and nature, as per protocol or 
not, which have led to a dose delay,  
 Detail of the haematological and non-haematological toxicities which have led to a delay, 
9.2.9. 
Route of administration and setting 
The route of vinflunine administration and setting in arm A will be presented by patient and by cycle. 
 Route of administration and setting by patient and by treatment arm: 
 
 
Arm A 
N 
% 
Route of administration 
 
 
  Central venous line 
 
 
  Peripheral vein 
 
 
Change in route of administration 
 
 
  No 
 
 
  Yes 
 
 
Setting 
 
 
  Out-patient clinic 
 
 
  In-patient clinic 
 
 
Change in setting 
 
 
  No 
 
 
  Yes 
 
 
Number of patients 
 
 
 
 Route of administration by cycle: 
Courses  
Arm A 
Central 
venous 
line 
N (%) 
Peripheral 
vein 
N (%) 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
 
 
… 
 
 
Number of 
cycles 
 
 
 
9.2.10. Concomitant medications 
Medications administered concomitantly with the study treatment will be summarized according to the 
prophylactic indication, tumour related indication, pre-treatment events or medical history indication 
and whatever the indication, by patient and by cycle.  


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10. EFFICACY ANALYSES  
10.1. PRIMARY EFFICACY ANALYSIS 
 
The primary efficacy population will be the intent-to-treat (ITT) population.  
As the final population size is much lower than the population size required to ensure adequate 
statistical power, no statistical test will be performed.  
PFS will be described by treatment arm. Hazard ratio and 95% confidence interval of the hazard ratio 
will be computed using the SAS® procedure «PHREG». The treatment arm will be entered as a 
covariate in the Cox proportional hazard model and the variables of stratification at randomisation 
(except centre) will be entered as stratification factors in the model. Kaplan-Meier curves will also be 
provided by treatment arm. 
10.2. SENSITIVITY ANALYSES OF THE PRIMARY EFFICACY PARAMETER 
No sensitivity analyses of the primary efficacy parameter will be performed. 
10.3. SECONDARY EFFICACY ANALYSES 
Not Applicable. 
 
 
11. SAFETY ANALYSES 
Safety analysis will be performed on the evaluable population for safety described in section 7.4 for 
each treatment arm. 
11.1. OVERVIEW OF THE SAFETY 
The adverse events incidence, overall and per CTCAE grade, will be presented. The worst CTCAE 
grades or maximum severity grades (for non haematological adverse events not classified by the 
CTCAE) will be analysed by cycle and by patient, and by treatment arm, regardless or not to the 
relationship to treatment. 
For definition of evaluable cycle/patient for non-haematological and haematological toxicity, see § 5.1 
and § 5.3, respectively. 


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Some laboratory toxicities will be presented when reported as adverse events according to the study 
completion guidelines.  
Listings of adverse events not graded and those one occurring during follow up will be provided. The 
pre-treatment events will also be presented. 
11.2. ADVERSE EVENTS 
 
11.2.1. All adverse events 
The incidences of the treatment-emergent adverse events (TEAE) as defined in 5.1, graded according 
to NCI-CTCAE version 3.0 will be presented using the MedDRA SOC and PT defined during the 
MedDRA coding process.  
A summary table will provide by treatment arm the following: 
 On treatment deaths 
 Patients with at least one AE  
 Patients with at least one TEAE (overall and by grade) 
 Patients with at least on SAE 
 Patients with at least one TEAE leading to discontinuation 
 Patients with at least one TEAE requiring dose interruption and/or adjustment 
 Patients with at least one TEAE requiring dose interruption 
 Patients with at least one TEAE requiring dose adjustment 
 Patients with at least one TEAE requiring additional therapy 
 Cycles with at least one AE 
 Cycles with at least one TEAE (overall and by grade) 
Overall incidences per patient and per cycle will be depicted as well as the incidence of non related and 
related toxicities only. An analysis will also present the CTCAE grade presented for each SOC and PT 
per patient and cycle according to the relationship with study treatment. 
11.2.2. Serious adverse events 
The number of patients with at least one SAE, one related (suspected and insufficiently documented) 
SAE, number of SAEs, number of related SAEs will be tabulated. Incidences of SAEs by SOC and PT 
will be presented according to the relationship with study treatment. 
A listing of the serious adverse events will be also provided with the following variables: patient 
number, cycle number, seriousness, CTCAE grade, date of onset, date ceased, action taken with 
study drug, corrective treatment and causality 


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11.2.3. Deaths 
The number and percent of patients dead will be tabulated by treatment arm, including number and 
percent of dead related to AE/SAE, due to progression or other reasons. 
A listing of the deaths within 30 days after last administration or more than 30 days after last 
administration will be provided with the following variables: patient number, cycle number, date of 
death, reason of death, source of information. 
11.3. LABORATORY TESTS 
11.3.1. Haematological toxicities 
Leukocytes, ANC, haemoglobin and platelets data will be analysed for haematological toxicity. 
A first analysis will present the worst grade (overall / grade 3/4) by patient and the worst grade (overall / 
grade 3/4) experienced during a cycle. In a second analysis, the worst grade of patients according to 
the grade at baseline will be tabulated. 
11.3.2. Biochemical toxicities 
Liver, renal and metabolic function tests will be analysed with a focus on bilirubin, alkaline 
phosphatase, SGOT/AST and SGPT/ALT, creatinine, creatinine clearance, sodium, potassium and 
calcium.  
In order to examine the evolution of biochemical toxicities, worst CTCAE grade (hypo and hyper for 
metabolic function tests) will be analysed in relation to the grade presented by the patient at baseline. 
In addition, the relationship between liver involvement at baseline and the worst CTCAE grade during 
study will be studied for SGOT/AST, SGPT/ALT and bilirubin. The same analysis will be done for the 
worst CTCAE grade of alkaline phosphatase and liver and/or bone metastases at baseline. 
A listing of patients having at least one LDH>IU/L, giving treatment arm, all LDH values and the 
visceral status at randomisation will be provided. 
12. CHANGES INTERFERED SINCE LAST VERSION 
 
According to the protocol amendment PA06 (29/07/2016), the statistical analysis was reduced to: 
• 
Efficacy: a descriptive summary of the primary efficacy variable (PFS) on the ITT population 
(i.e. no analysis on secondary criteria), 
• 
Safety: a description of safety parameters. 


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As a consequence, the following analyses have been deleted: 
• 
Adverse events of special interest and specific analysis of constipation, because exhaustive 
tables of AE will be produced, 
• 
Description over time of values and changes from baseline for laboratory date, because 
CTCAE grades will be provided, 
• 
Some detailed tables of disease history, prior therapies and concomitant medications, limiting 
the analyses to an overview of the safety and patients characteristics. 
 
Summary tables of adverse events, prior therapies for breast carcinoma and exposure have been 
added. Analyses of laboratory values have been specified, such as LBH or Creatinine Clearance. 
All data will be provided in individual data listings in appendix 16.2 of the Clinical Study Report. 


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CONFIDENTIAL 
  
13. REFERENCES 
 
Pocock SJ, Simon R. 
Sequential treatment assignment with balancing for prognosis factors in the controlled 
clinical trial. 
Biometrics. 1975; 31 (1): 103-115.  
Xeloda, Summary of Product Characteristics 
http://www.emea.europa.eu/humandocs/Humans/EPAR/xeloda/xeloda.htm 
Date of last update 27/03/2008 
Eisenhauer E, Therasse P, Bogaerts J et al. 
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) 
Eur J Cancer. 2009;45(1):228-247 
Raghunatan TE, Lepkowski JM, Van Hoewyk J, Solenberger P 
A multivariate technique for multiply imputing missing values using a sequence of regression 
models Survey Methodology. 2001;27(1):85-95


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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 LIST OF APPENDICES 
 
Appendix 1 : LIST OF TABLES, FIGURES AND LISTINGS 
Appendix 2 : STATISTICAL ANALYSIS CONVENTIONS 
 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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14. APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS 
SECTION 
Title 
RTF reference 
10.1 
Number of Patients enrolled, randomized and treated [All patients] 
10_1a.RTF 
10.1 
Patient disposition [ITT] 
10_1b.RTF 
11.2 
Demographic data [ITT] 
11_2_1.RTF 
11.2 
Statification factors [ITT] 
11_2_2.RTF 
11.2 
Disease History[ITT] 
11_2_3.RTF 
11.2 
Triple negative versus HR positive [ITT] 
11_2_4.RTF 
11.2 
HER-2 negative versus HR [ITT] 
11_2_5.RTF 
11.2 
Summary of Prior therapies for Breast Carinoma [ITT] 
11_2_6.RTF 
11.2 
Prior therapies: chemotherapy [ITT] 
11_2_7.RTF 
11.2 
Prior therapies: hormone therapy [ITT] 
11_2_8.RTF 
11.2 
Clinical examinations at baseline [ITT] 
11_2_9.RTF 
11.2 
Haematological CTCAE grades at study entry [ITT] 
11_2_10.RTF 
11.2 
Biochemical CTCAE grades at study entry [ITT] 
11_2_11.RTF 
11.4.1.1 
Progression-Free Survival (months) [ITT] 
11_4_1_1.RTF 
11.4.1.1 
Progression-Free Survival (months) [ITT] 
11_4_1_1_FIG.RTF 
12.1 
Summary of exposure [ITT] 
12_1_1.RTF 
12.1 
Route of administration and settings by patient [ITT] 
12_1_2.RTF 
12.1 
Route of administration and settings by cycle [ITT] 
12_1_3.RTF 
12.1 
Exposure: Description of cycles [ITT] 
12_1_2.RTF 
12.1 
Exposure: Cumulative dose, actual dose intensity and relative dose intensity by 
patient [ITT] 
12_1_3.RTF 
12.1 
Exposure: Cumulative dose, actual dose intensity and relative dose intensity by 
cycle [ITT] 
12_1_4.RTF 
12.1 
Dose delayed and reasons [ITT] 
12_1_5.RTF 
12.1 
Dose reduction of Vinflunine and reasons [ITT] 
12_1_6a.RTF 
12.1 
Reasons by dose reduction of vinflunine [ITT] 
12_1_6b.RTF 
12.1 
Dose reduction of Capecitabine and reasons [ITT] 
12_1_6c.RTF 
12.1 
Reasons by dose reduction of Capecitabine [ITT] 
12_1_6d.RTF 
12.1 
Capecitabine cancellation and reasons [ITT] 
12_1_7.RTF 
12.1 
Vinflunine infusion interruption and reasons [ITT] 
12_1_8.RTF 
12.2.1 
Summary of Adverse Events [Safety set] 
12_2_1.RTF 
12.2.2 
Adverse events whatever their relationship to study drug – Worst grade events per 
patient by SOC and PT [Safety set] 
12_2_2_1a.RTF 
12.2.2 
Adverse events whatever their relationship to study drug – Worst grade events per 
cycle by SOC and PT [Safety set] 
12_2_2_1b.RTF 
12.2.2 
Drug-related adverse events  – Worst grade events per patient by SOC and PT 
[Safety set] 
12_2_2_2a.RTF 
12.2.2 
Drug-related adverse events  – Worst grade events per cycle by SOC and PT 
[Safety set] 
12_2_2_2b.RTF 
12.2.2 
Serious adverse events whatever their relationship to study drug  – Worst grade 
events per patient by SOC and PT [Safety set] 
12_2_2_3a.RTF 
12.2.2 
Drug-related Serious adverse events – Worst grade events per patient by SOC and 
PT [Safety set] 
12_2_2_3b.RTF 
12.2.2.4 
Worst CTCAE grade of haematological parameters by patient [Safety set] 
12_2_2_4_1a.RTF 


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SECTION 
Title 
RTF reference 
12.2.2.4 
Worst CTCAE grade of haematological parameters by cycle [Safety set] 
12_2_2_4_1b.RTF 
12.2.2.4 
Shift table of Worst CTCAE grade by patient according to grade at baseline for 
haematological parameters [Safety set] 
12_2_2_4_1c.RTF 
12.2.2.4 
Worst CTCAE grade of biochemical parameters by patient [Safety set] 
12_2_2_4_2a.RTF 
12.2.2.4 
Worst CTCAE grade of biochemical parameters by cycle [Safety set] 
12_2_2_4_2b.RTF 
12.2.2.4 
Shift table of Worst CTCAE grade by patient according to grade at baseline for 
biochemical parameters [Safety set] 
12_2_2_4_2c.RTF 
12.2.2.4 
Worst value of creatinine clearance by patient according to value at baseline 
[Safety set] 
12_2_2_4_2d.RTF 
12.2.2.4 
Worst CTCAE grade of SGOT/AST by patient according to the presence of liver 
metastases at baseline [Safety set] 
12_2_2_4_2e.RTF 
12.2.2.4 
Worst CTCAE grade of SGPT/ALT by patient according to the presence of liver 
metastases at baseline [Safety set] 
12_2_2_4_2f.RTF 
12.2.2.4 
Worst CTCAE grade of bilirubin by patient according to the presence of liver 
metastases at baseline [Safety set] 
12_2_2_4_2g.RTF 
12.2.2.4 
Worst CTCAE grade of alkaline phosphatase by patient according to the presence 
of liver and/or bone metastases at baseline [Safety set] 
12_2_2_4_2h.RTF 
12.2.2.4 
Listing of LBH values >500 IU/L [Safety Set] 
12_2_2_4_2i.RTF 
12.3.1.1 
Summary of deaths [Safety set]  
12_3_1_1a.RTF 
12.3.1.1 
Listing of dead patients within 30 days  after last administration or more than 30 
days after last administration, reason of death, relationship to treatment [Safety set]  12_3_1_1b.RTF 
12.3.1.2 
Listing of Serious Adverse Events [Safety set] 
12_3_1_2.RTF 
14.1.1 
Prior medications whatever the indication per patient at baseline [ITT] 
14_1_1.RTF 
14.1.2 
Prior medications with a tumour related indication per patient at baseline [ITT] 
14_1_2.RTF 
14.1.3 
Prior medications with a prophylactic indication per patient at baseline [ITT] 
14_1_3.RTF 
14.1.4 
Prior medications with pre-treatment event indication per patient at baseline [ITT] 
14_1_4.RTF 
14.1.5 
Prior medications with medical history indication per patient at baseline [ITT] 
14_1_5.RTF 
14.1.6 
Prior medical history by patient according to MedDRA System Organ Class and 
Preferred Term [ITT] 
14_1_6.RTF 
14.1.7 
Pre-treatment events by patient according to MedDRA System Organ Class and 
Preferred Term [ITT] 
14_1_7.RTF 
14.3.1a 
Concomitant medications whatever the indication per patient [ITT] 
14_3_1a.RTF 
14.3.1b 
Concomitant medications whatever the indication per cycle [ITT] 
14_3_1b.RTF 
14.3.2a 
Concomitant medications with a tumour related indication per patient [ITT] 
14_3_2a.RTF 
14.3.2b 
Concomitant medications with a tumour related indication per cycle [ITT] 
14_3_2b.RTF 
14.3.3a 
Concomitant medications with a prophylactic indication per patient [ITT] 
14_3_3a.RTF 
14.3.3b 
Concomitant medications with a prophylactic indication per cycle [ITT] 
14_3_3b.RTF 
14.3.4a 
Concomitant medications with pre-treatment event indication per patient  [ITT] 
14_3_4a.RTF 
14.3.4b 
Concomitant medications with pre-treatment event indication per cycle [ITT] 
14_3_4b.RTF 
14.3.5a 
Concomitant medications with medical history indication per patient  [ITT] 
14_3_5a.RTF 
14.3.5b 
Concomitant medications with medical history indication per cycle [ITT] 
14_3_5b.RTF 
16.2.1 
Discontinued patients 
16_2_1_1.RTF 
16.2.1 
Follow-Up data 
16_2_1_2.RTF 
16.2.3 
Analysis sets 
16_2_3_1.RTF 
16.2.3 
Eligibility criteria 
16_2_3_2.RTF 
16.2.3 
Randomization criteria 
16_2_3_3.RTF 
16.2.4 
Patients’ characteristics 
16_2_4_1.RTF 
16.2.4 
Disease characteristics  
16_2_4_2.RTF 
16.2.4 
Prior surgery for breast carcinoma 
16_2_4_3a.RTF 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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SECTION 
Title 
RTF reference 
16.2.4 
Prior radiotherapy for breast carcinoma 
16_2_4_3b.RTF 
16.2.4 
Prior chemotherapy for breast carcinoma 
16_2_4_3c.RTF 
16.2.4 
Prior treatment for breast carcinoma (Prior Hormonal Treatment or Castration) 
16_2_4_3d.RTF 
16.2.4 
Medical and Surgical History, Concomitant disease 
16_2_4_4.RTF 
16.2.4 
Pre-treatment events 
16_2_4_5.RTF 
16.2.4 
Blood and Platelet transfusion 
16_2_4_6.RTF 
16.2.5 
Treatment administration per cycle 
16_2_5_1.RTF 
16.2.5 
Treatment administration of Vinflunine 
16_2_5_2.RTF 
16.2.5 
Treatment administration of Capecitabine 
16_2_5_3.RTF 
16.2.5 
Cumulative dose, dose intensity and relative dose intensity per arm and per cycle  
16_2_5_4.RTF 
16.2.5 
Treatment modifications  
16_2_5_5.RTF 
16.2.6 
Tumour assessments 
16_2_6_1.RTF 
16.2.6 
Work-Up 
16_2_6_2.RTF 
16.2.6 
Efficacy parameters (PFS) 
16_2_6_3.RTF 
16.2.7 
Adverse Events by patient (Reported Term, Preferred Term and Dates) 
16_2_7_1.RTF 
16.2.7 
Adverse Events by System Organ Class and Preferred Term 
16_2_7_2.RTF 
16.2.7 
Drug-related Adverse Events by patient (Reported Term, Preferred Term and 
Dates) 
16_2_7_3.RTF 
16.2.7 
Drug-related Adverse Events by System Organ Class and Preferred Term 
16_2_7_4.RTF 
16.2.7 
Serious Adverse Events by patient (Reported Term, Preferred Term and Dates) 
16_2_7_5.RTF 
16.2.7 
Serious Adverse Events by System Organ Class and Preferred Term 
16_2_7_6.RTF 
16.2.7 
Patient deaths 
16_2_7_7.RTF 
16.2.8 
Individual haematological laboratory measurements by patient - grades and values 16_2_8_1.RTF 
16.2.8 
Individual biochemical laboratory measurements by patient - grades and values 
16_2_8_2.RTF 
16.2.8 
Blood products 
16_2_8_3.RTF 
16.2.8 
Pregnancy test results 
16_2_8_4.RTF 
16.2.8 
Tumour Markers 
16_2_8_5.RTF 
16.2.9 
Temperature, vital signs, weight 
16_2_9_1.RTF 
16.2.9 
Neurological examination, physical examinatioin 
16_2_9_2.RTF 
16.2.9 
ECG results 
16_2_9_3.RTF 
16.2.10 
Prior and Concomitant medications 
16_2_10_1.RTF 
16.2.10 
Concomitant Radiotherapy 
16_2_10_2.RTF 
16.2.10 
Concomitant surgery 
16_2_10_3.RTF 
 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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15. APPENDIX 2: STATISTICAL ANALYSIS CONVENTIONS 
15.1. CALCULATION OF A DURATION  
Duration in years or months (i.e. treatment duration, follow-up  time, disease and treatment free 
intervals, time from diagnosis to study entry, time to first response, duration of response, stabilisation 
and disease control, PFS and overall survival)  will be calculated as follows : 
30.4375
1
1 
Date
 - 2 
Date
months)
(in  
Duration  






 
with Date 2    Date 1. 
365.25
1
1 
Date
 - 2 
Date
years)
(in  
Duration  






 
For example, age of the patients will be calculated as follows : 
365.25
1
birth
 
of
 
Date
 -
on 
registrati
 
of
 
Date
years)
(in  
  
Age






 
15.2.  CALCULATION OF A DELAY 
 
Delays, usually in days, (i.e. number of days of delay in a cycle, delay between randomisation and first 
administration, number of days between last administration or visit and death, delay between diagnosis 
and study entry, delay between diagnosis and progression, time from randomisation to first 
concomitant radiotherapy) will be calculated as follows : 
1 
Date
 - 2 
Date
days)
(in  
Delay  

 
with Date 2  Date 1. 
 
15.3. MISSING DATA 
15.3.1. General conventions 
Following internal biometry conventions are used: 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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 “A” stands for a non-applicable information, 
 “M” stands for an information not present on CRF form, 
 “D” is indicating that the mention “Not done” was ticked on the page, 
 “O” is a code for a date ongoing, 
 “K” is an abbreviations for unknown information. 
15.3.2. Conventions for dates 
For dates, if the day is missing then convention is to put the day to the value of 15 (half of the month). 
If the day and the month are missing then convention is to put the day to the value of 01 and the month 
to the value of 07 (half of the year). This convention allows to approximate some delays (mostly delays 
analysed at baseline). 
15.4. DOSE MODIFICATIONS 
Dose modifications will be determined between two subsequent cycles. Variation will be calculated by 
comparing actual dose received. 
15.5. OVERALL RESPONSE OF THE PATIENT 
According to the revised RECIST, no confirmation of the response will be required in this phase III 
study to qualify the patient as CR or PR. 
15.6. DATE OF FIRST RESPONSE AND DATE OF PROGRESSION 
15.6.1. Date of first response 
The date of first response is the first date where CR, or PR is assessed. It can be found in the CTA 
module of the CRF. If for the same tumour evaluation, the assessments where made at different dates, 
the maximum of all the dates of assessment of the cycle will be taken into account. 
15.6.2. Date of progression or death 
The date of progression is the first date where PD is assessed. The date used for PFS calculation will 
be the date of progression or the date of death. Date of first progression or death can be found: 
 In CTA module of the CRF, 
 In ETA module of the CRF (in case of assessment during the follow-up, i.e. after the end of the 
treatment period), 
 In DRF module of the CRF in case of death without “objective” progression assessed before. 
If for a tumour evaluation, several assessments show a PD at different dates and the global response 
of the cycle is PD, the minimum of all the dates of assessment of the cycle showing PD (including 
appearance of new lesions) will be taken into account.  


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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15.7. TOXICITY 
15.7.1. Haematological toxicities 
The following units for HGB, WBC, PLT and ANC will be used for the analysis of haematological 
toxicity : 
Parameters 
Units 
HGB 
g/L 
WBC 
109/L 
PLT 
109/L 
ANC 
109/L 
If values were expressed in different units in the CRF, the data management department will be in 
charge of the conversion to SI units. 
Calculation of grades will be done using the following boundaries : 
Grade 
HGB 
WBC 
PLT 
ANC 
Grade 0 
]200 – 120] 
]15 – 4] 
]500 – 150] 
]10 – 2] 
Grade 1 
]120 – 100] 
]4 – 3] 
]150 – 75] 
]2 – 1.5] 
Grade 2 
]100 – 80] 
]3 – 2] 
]75 – 50] 
]1.5 – 1] 
Grade 3 
]80 – 65] 
]2 – 1] 
]50 – 25] 
]1 – 0.5] 
Grade 4 
< 65 
< 1 
< 25 
< 0.5 
Of note, the study data manager calculates grades of haematological toxicities before database is 
made available to the study statistician on a read-only basis. 
15.7.2. Biochemical toxicities 
The following units for SGOT/SGPT, bilirubin, alkaline phosphatase and creatinine will be used for the 
analysis of biochemical toxicity : 
Parameters 
Units 
SGOT/SGPT 
IU/l 
Bilirubin 
µmol/l 
Alkaline phosphatase 
IU/l 
Creatinine 
µmol/l 
If values were expressed in different units in the CRF, the data management department will be in 
charge of the conversion to SI units. 


Statistical Analysis Plan / L00070 IN 311 B0                                                          
 
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Calculation of grades will be done using the following boundaries: 
Grade 
SGOT/SGPT 
Bilirubin 
Alkaline 
phosphate 
Creatinine 
Grade 0 
[LLN – UNL] 
[LLN – UNL] 
[LLN – UNL] 
[LLN – UNL] 
Grade 1 
]UNL – 2.5 x UNL] 
]UNL – 1.5 x UNL] 
]UNL – 2.5 x UNL] 
]UNL – 1.5 x UNL] 
Grade 2 
]2.5 – 5 x UNL] 
]1.5 – 3 x UNL] 
]2.5 – 5 x UNL] 
]1.5 – 3 x UNL] 
Grade 3 
]5 – 20 x UNL] 
]3 – 10 x UNL] 
]5 – 20 x UNL] 
]3 – 6 x UNL] 
Grade 4 
> 20 x UNL 
> 10 x UNL 
> 20 x UNL 
> 6 x UNL 
Of note, the study data manager calculates grades of biochemical toxicities before database is made 
available to the study statistician on a read-only basis. 
For creatinine clearance, the worst values will be analysed according to the following classes: 
<50ml/mn or ≥50ml/mn. 
15.7.3. Definition of a toxic death 
A toxic death is defined as a death caused by a related adverse event either during the treatment 
period or in the 30 days following the last administration. 
15.7.4. Treatment duration  
Treatment duration is calculated for each patient from the date of randomisation to the date of last day 
1 administration + 21 days. 
15.8. END OF STUDY 
15.8.1. Death for progression 
In case of death for progression (so PD documented in the tumour assessment form and death 
documented in death report form are at the same date), the reason for treatment discontinuation is 
Progression.