Conditions: Recurrent or Metastatic Head and Neck Carcinoma
Keywords: Vinflunin Vinflunin + Methotrexate Metastatic Squamous Cell Carcinoma of the Head and Neck
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 459
Healthy volunteers: no

Brief summary:
For patients relapsing after platinum-based therapy, few data are available. The current use of cetuximab associated with radiotherapy in localized disease and associated with platinum-based chemotherapy in the first-line setting stresses the need for new therapeutic options at later stages of SCCHN.Vinca-alkaloids demonstrated activity in SCCHN. Vinflunine demonstrated superior antitumour activity to vinorelbine in preclinical animal models. Recent preliminary phase I results of the vinflunine plus methotrexate combination in SCCHN, based on a clinical review, show encouraging antitumour activity and an acceptable safety profile. Therefore the combination of vinflunine and methotrexate appears a promising salvage regimen after platinum failure.

The present study has been designed as a multicenter, randomised phase III study which will compare the combination of IV vinflunine with methotrexate to methotrexate alone in SCCHN patients having failed platinum-based therapy.

Detailed description:
This study was designed to compare the OS of VFL plus MTX versus MTX alone in patients with SCCHN who had failed platinum-based chemotherapy.

The trial was designed in accordance with current standards used routinely in oncology phase III trials and used established methods of assessment. The RECIST (version 1.1) and NCI CTCAE (version 3.0) guidelines are internationally recognised methods for assessing efficacy and tolerance, respectively.

The patient population was appropriate for this type of phase III study and included adult patients with recurrent and/or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, who had received prior chemotherapy regimens with documented progression. This population of patients was considered appropriate to meet the study objectives.

Recent preliminary phase I results of the VFL plus MTX combination in SCCHN, reported in a clinical review, showed encouraging antitumour activity and an acceptable safety profile A number of chemotherapy agents have been reported as having single-agent activity in SCCHN. However, reliable evidence of efficacy in the second-line setting is lacking, and there is currently no established standard of care. MTX used alone as the reference regimen at a dose of 40 mg/m2/week can be considered as the best available evidence-based option. Also, other trials using this comparator have demonstrated that it is generally accepted as a reasonable choice, and is often used in general practice.

The efficacy and safety assessments employed in this study are standard measures routinely used in studies of this type

Arms:
arm 1: vinflunine IV 280 mg/m² Day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks arm 2: methotrexate IV 40 mg/m² Day 1, 8 and 15 every 3 weeks

Interventions: intervention 1: Vinflunine intervention 2: Methotrexate
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Confidential 
Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
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Sponsor : Pierre Fabre Médicament 
Represented by : 
Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
92654 Boulogne-Billancourt, France 
 
 
 
 
 
 
 
 
 
 
STUDY: L00070 IN 309 F0 


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Sponsor : Pierre Fabre Medicament 
Represented by : 
Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
92654 Boulogne-Billancourt, France 
 
 
 
L0070 / IV vinflunine 
 
 
 
A phase III study of IV vinflunine in combination with methotrexate versus 
methotrexate alone in patients with recurrent or metastatic squamous  
cell carcinoma of the head and neck previously treated with  
platinum-based chemotherapy 
 
 
 
Pierre Fabre Study Code: L00070 IN 309 F0 
 
 
EudraCT number: 2011-005081-38 
 
 
Sponsor’s representatives: 
 
• Clinical Development Physician (Monitor) : Andrius BACEVICIUS, MD (extern) 
• Clinical Study Coordinators: F. EL GHAIB (extern), A. LAURANS (extern), E. PIAT 
(extern) 
 
 
Coordinating investigators: 
- J.B. Vermorken, MD, Belgium (Study Chairman) 
- J. Fayette, MD, France 
 
 
 
 
 
- J.P. Machiels, MD, Belgium  
 
 
 
 
 
- R. Mesia, MD, Spain 
 
 
 
Version No.: 7 
 
 
Date: 5th February 2016 
 
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. 


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STUDY SYNOPSIS 
 
NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
Title of the study: 
Phase III study of IV vinflunine in combination with methotrexate versus methotrexate alone in 
patients with recurrent or metastatic squamous cell carcinoma of the head and neck previously 
treated with platinum-based chemotherapy (study L00070 IN 309 F0) 
 
Planned list of investigators: 117 out of 150 planned centers have been active in Austria, Belarus, Belgium, Brazil, Estonia, 
France, Germany, Italy, Mexico, Poland, Russia, Slovakia, Spain, Taiwan and Ukraine 
 
Study rationale:  
 
For patients with incurable recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-
based chemotherapy is frequently the only available treatment. Recently the addition of cetuximab was shown to 
improve overall survival over platinum-based chemotherapy alone in this setting (Vermorken JB, 2008). However 
recurrent/metastatic SCCHN remains incurable and all patients eventually relapse/progress. Second-line therapy options 
are scarce and single-agent methotrexate is still the standard treatment. 
Vinorelbine proved to be an active drug in SCCHN patients having failed prior platinum-based chemotherapy (Testolin 
A., 1994 ; Porta C., 2001). Vinflunine (VFL) is a novel generation vinca-alkaloid which has been granted a marketing 
authorization approval for the second-line treatment of transitional cell carcinoma of the urothelial tract after platinum 
failure by the EMA. Moreover VFL was shown to be effective in the second line treatment of non-small cell lung cancer 
after platinum failure and in metastatic breast cancer after anthracycline and taxane failure. Therefore IV vinflunine is a 
promising candidate in SCCHN patients after platinum failure. 
Single-agent methotrexate remains the standard second-line treatment although its efficacy is poor. Methotrexate has 
been successfully combined with vinca-alkaloids for the treatment of a variety of solid tumours including bladder cancer 
(Harker W.G., 1985), breast cancer (Elomaa J., 2003), mesothelioma (Hunt K., 1996) and SCCHN (Iop A., 1998). 
Recent preliminary phase I results of the vinflunine plus methotrexate combination in SCCHN (L00070IN117F0), based 
on a clinical review, show encouraging antitumour activity and an acceptable safety profile (Preliminary Clinical 
Evaluation). Based on these premises, the combination of vinflunine and methotrexate is expected to improve on 
methotrexate monotherapy. 
Study period (estimated): Q1 2014-Q4 2016 
Clinical phase: III 
Objectives: 
 
 
- primary : 
to compare the overall survival (OS) of IV vinflunine in combination with methotrexate versus  
 
 
 
methotrexate alone in incurable recurrent / metastatic SCCHN patients who have failed platinum- 
 
 
 
based chemotherapy. 
 
 
- secondary : . to evaluate the response and disease control rate in the 2 study arms 
 
 
 
. to assess the response and disease control duration in the 2 study arms 
 
 
 
. to assess the progression-free survival in the 2 study arms 
 
 
 
. to assess the safety profile in both arms 
 
 
 
. to compare the change in disease-related symptoms in the 2 study arms by using the EORTC quality 
 
 
 
  of life questionnaire 
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NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
Methodology 
 
This is a multicenter, open-label, randomised phase III study of IV VFL in combination with methotrexate versus 
methotrexate alone in incurable recurrent / metastatic SCCHN patients previously treated with platinum-based 
chemotherapy. 
 
Patients will be stratified at inclusion by the following factors :  
- WHO performance status (PS) (0  versus 1) 
- Refractory or resistant to platinum versus other 
- Prior radiotherapy (yes versus no) 
- Prior treatment with any anti-EGFR medication (yes versus no)  
- Center 
 
Patients will be randomly assigned to receive in a 1 : 1 ratio one of the two study treatments : 
- Arm A : vinflunine given at the dose of 280 mg/m² on day 1 and methotrexate administered at the dose of 30 mg/m² on 
days 1 and 8 every 3 weeks. 
- Arm B : methotrexate given at the dose of 40 mg/m²/week. 
 
An Independent Data Monitoring Committee (IDMC) will be charged with reviewing all the safety and efficacy data. 
 
An early safety review will be conducted after 40 patients are randomised (20 in each arm) and treated for at least one 
cycle. The IDMC will review the safety data and make recommendations accordingly. 
 
An interim analysis of efficacy and safety will be performed after the first tumour assessments scheduled at 6 weeks from 
the first 100 patients randomised in the test arm become available. The non progression rate at 6 weeks and the safety in 
the test arm will be reviewed by the IDMC. Based on this interim analysis, the IDMC will determine whether the 
enrolment should continue or not. Because the projected accrual could be slow in the study, the patient enrolment will 
continue while waiting the decision of the IDMC. 
Following this interim analysis, a futility analysis has been carried out. 
The results of this analysis showed that the probability to demonstrate a significant benefit of overall survival at the time 
of the final analysis is very low. 
As a consequence, the sponsor has decided to stop the recruitment of study patients on 16th October 2015. 
Number of patients 
 
A sample size 530 randomised patients (265 randomised patients per arm) was planned, including an anticipated 5% loss 
to follow-up. 
A total of 459 patients (230 randomised patients in the arm A and 229 randomised patients in the arm B) have been enrolled 
in this study. The inclusions are now closed. 


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Diagnosis and main inclusion criteria 
 
Inclusion criteria : 
Patients must satisfy all the following inclusion criteria before they are allowed to participate in the study:  
 
1. Patients must give written informed consent (personally signed and dated) before completing any study-related 
procedure 
 
2. Histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx or larynx 
 
3. Documented progressive disease after chemotherapy for locoregionally advanced or recurrent/metastatic SCCHN 
which included a platinum derivative (cisplatin or carboplatin) that is not suitable for local therapy. Platinum-based 
chemotherapy can have been associated with cetuximab. 
Eligible patients include one of the following categories : 
 - patients who have received induction chemotherapy (ICT) consisting of cisplatin plus 5-fluorouracil or docetaxel 
 plus cisplatin plus 5-fluorouracil followed by radiotherapy alone or chemoradiation (CRT) or radiotherapy 
 concomitant with cetuximab provided that recurrence occurs within 6 months of completing local therapy 
 - patients who have completed cisplatin-based CRT with or without ICT provided that recurrence occurs within 6 
 months of completing local therapy. The minimum cumulative dose of cisplatin during CRT must be 200 mg/m². 
 - patients with recurrent and/or metastatic SCCHN who relapse after platinum-based (cisplatin or carboplatin) 
 chemotherapy given in first-line with an interval < 12 months 
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NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
Diagnosis and main inclusion criteria (ctd) 
 
- patients with metastatic SCCHN at diagnosis who have been treated with platinum-based (cisplatin or carboplatin) 
 
chemotherapy in first-line and relapse with an interval < 12 months.  
 
 
The definition of failure will be as follows : 
 
 
- refractory disease : progression during platinum-based regimen 
 
 
- resistant disease : progression during the time from completion of platinum-based chemotherapy but less than 6  
 
 
months after its completion 
 
 
- other type of failure : progression > 6 months but < 12 months after completion of platinum-based chemotherapy 
 
 
4. No more than one prior chemotherapy regimen for recurrent/metastatic disease. Prior treatments with targeted therapy   
 
used in monotherapy are allowed 
 
 
5. Minimum interval of 4 weeks between the completion of first-line chemotherapy and randomisation 
 
 
6. Measurable or non measurable disease 
 
 
7. WHO performance status < 1 
 
 
8. Age > 18 years and < 80 years 
 
 
9. Adequate haematological function: absolute neutrophil count (ANC) > 1.5 x 109/L, platelets > 100 x 109/L, 
 
haemoglobin > 10g/dL. 
 
 
10. Adequate hepatic function: transaminases < 2.5 x Upper Limit of Normal (ULN), total bilirubin < 1.5 x ULN, 
 
alkaline phosphatase < 5 x ULN 
 
 
11. Adequate renal function: a calculated (Cockroft-Gault) creatinine clearance > 60 ml/min  
 
 
12. Women of childbearing potential must be using a medically accepted method of contraception (barrier methods, oral 
 
contraceptive, intrauterine devices) 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 
 
 
13. Fertile men must be using adequate contraceptive measures throughout the study period and for up to 3 months after 
 
the last dose of study treatment if their partners are women of childbearing potential 
 
 
14. The patient must have access to social insurance if applicable in the local regulations 
 
 
15. 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  
If any of the following apply, the patient must not enter the study:  
 
 
1. Nasopharyngeal carcinoma 
 
 
2. History of brain or leptomeningeal involvement 
 
 
3. History of other cancers except other synchronous head and neck squamous cell carcinomas, adequately treated in situ 
 
carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin or other cancer curatively treated with 
 
surgery and/or radiotherapy (with or without other anti-cancer therapy) and with no evidence of disease for at least 3 
 
years 
 
 
4. Albumin level < 35 g/L 
 
 
5. Patients with weight loss ≥ 5% within the last 3 months 
 
 
6. Recurrent pulmonary or upper airways infections (3 times or more in the last 3 months) requiring antibiotics and/or  
 
any infection requiring antibiotics within the last month before study entry 
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NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
 
Exclusion criteria  
 
 
7. Grade > 2 peripheral neuropathy at study entry according to NCI-CTC AE (version 3.0) 
 
8. Serum potassium < the lower limit of normal 
 
9. ECG demonstrating a QT/QTc interval > 480 msec 
 
 
10. A female is not eligible to enter the study if : 
 
 
. Pregnant or lactating 
 
 
. 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 
 
Male unwilling or unable to use a medically accepted method to avoid pregnancy throughout the study period and at least 
 
3 months following the last dose of study treatment if their partners are women of  
 
childbearing potential. 
 
 
12. Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled  
 
i.e. active serious infection, poorly controlled diabetes mellitus, concurrent heart failure [New York Heart Association 
 
(NYHA) class III-IV] or with progressive or unstable angina, myocardial infarction within 6 months, and/or poorly 
 
controlled hypertension. 
 
 
13. “Third space” fluids (pleural effusion, ascites, massive edema) 
 
 
14. Concomitant treatment with any other anti-cancer therapy and contraindicated medication (see Section 6.1 
 
 
15. Prior treatment with vinca-alkaloids and methotrexate 
 
 
16. Participation into a clinical study of an investigational agent within 30 days before study entry 
Test product, dose and mode of administration: 
Patients randomised in the test arm (arm A) will receive IV vinflunine infused over 20 minutes  at 280 mg/m² on day 1 
and methotrexate administered as a bolus intravenous injection at 30 mg/m² on days 1 and 8 of each three-week cycle. 
Administration of vinflunine requires prophylactic measures as follows:  
- anti-emetic prophylaxis by giving a single dose of dexamethasone 8 mg or an equivalent dose of methylprednisolone 
just before the infusion 
- prophylaxis of constipation combining dietary measures and the administration of laxatives from day 1 to day 5 of each 
cycle 
Reference therapy, dose and mode of administration: 
 
Patients randomised in the control arm (arm B) will receive methotrexate alone administered weekly as a bolus 
intravenous injection at the dose of 40 mg/m²/week. 
One cycle of methotrexate is defined as a three-week period, i.e. 3 weekly administrations of methotrexate (days 1, 8 and 
15). 
Duration of treatment: 
 
Patients will receive at least 2 cycles of study drug unless disease progression or unacceptable toxicity. After 6 weeks of 
study treatment, tumour response will be assessed: patients who respond or have stable disease will receive 2 additional 
cycles and will be reevaluated for tumour response. Patients with progressive disease will be removed while patients who 
respond or have stable disease will continue study treatment until disease progression. 
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Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
8/145 
 
 
 
NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
 
Criteria for evaluation: 
 
 
- Efficacy assessment: 
 
 
The primary efficacy endpoint will be the overall survival defined as time from randomisation to death or last follow-up. 
 
 
Secondary endpoints include the response and disease control rate by using RECIST (version 1.1), the response and  
 
disease control duration and the progression-free survival. 
 
- Safety assessment will be assessed by: 
 
 
 
. physical examination 
 
 
. regular reporting of adverse event by using NCI CTC AE (version 3.0) 
 
 
ECG to be performed on day 1 of cycle 1 before and after drug administration in both arms. Thereafter, ECG will be  
 
 
performed before drug administration every 2 cycles in both arms. After review of safety data including ECG results by 
 
 
the IDMC, the need for repeated ECGs before each cycle can be revised. 
 
 
. complete blood cell counts performed on days 1 and 8 of each cycle in arm A and before each weekly administration  
 
 
 
in arm B 
 
 
. serum biochemistry including AST, ALT, alkaline phosphatase, total bilirubin, urea, creatinine, calculated   
 
 
creatinine clearance, glucose, calcium, sodium, potassium, magnesium, chloride, bicarbonate, total protein and  
 
 
albumin. Tests will be performed every 3 weeks, except glucose, total protein and albumin which will be performed  
 
 
every 6 weeks in both arms. 
 
 
- Patient-reported outcomes will be assessed by using the QLQ-core 30 EORTC questionnaire and the QLQ-Head and  
 
Neck 35 EORTC module. 
Statistical methods:  
 
The primary objective of the study is to show that the combination of IV vinflunine and methotrexate is superior to 
methorexate alone in terms of overall survival. Patients will be randomised in a 1:1 ratio. The final analysis will require at 
least 437 deaths to detect a statistically significant difference in the median OS of 7.5 months in the test arm versus 5.5 
months in the control arm. This number of events gives a 90% power to show a difference between the two treatment arms 
using a two-sided log-rank test at an alpha = 0.05 significance level. 
 
An expected total number of 530 patients randomised were planned. An approximately 19 months accrual period was 
planned.  
Following the decision to stop the recruitment:  
- 
The statistical analysis will actually be conducted on the 459 randomised patients. 
- 
325 events are expected to observe at the end of study allowing a power of 80%. 
Whatever the number of events at the end of study, the final analysis of OS (primary analysis) will be performed on the 
ITT population. 
Only descriptive analyses will be performed on all secondary efficacy analyses for ITT population. 
 
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NAME OF SPONSOR:  
PIERRE FABRE MEDICAMENT 
NAME OF FINISHED PRODUCT:  
JAVLOR® 
NAME OF ACTIVE SUBSTANCE(S):  
VINFLUNINE DITARTRATE 
Statistical methods (ctd):  
 
The primary efficacy analysis will be led on the Overall Survival. The hypothesis of superiority will be accepted if the p-
value from a stratified log-rank test is smaller than 0.05. The stratification factors will be those used at the time of 
randomisation except center because of the high number of participating centers in the study: 
− WHO performance status (0 versus 1), 
− Refractory or resistant to platinum versus other, 
− Prior radiotherapy (yes versus no), 
− Prior treatment with any anti-EGFR medication (yes versus no). 
The primary efficacy population will be the Intent-to-Treat Population (ITT). As a supportive analysis, Overall Survival 
will be also analysed on the Eligible population. 
The Progression-Free Survival (PFS) will be performed on the ITT and eligible populations. A stratified log-rank test will 
be used in order to compare the two treatment arms with the same stratification factors defined above. 
The Objective response Rate (ORR) and Disease control Rate (DCR) will be compared with a Cochran-Mantel-Haenszel 
(CMH) test between the two treatment arms. Furthermore, the ORR and DCR will be estimated and compared between 
the two treatment arms in the subgroups of patients entering the study with measurable disease. These analyses will be 
performed on the ITT and evaluable for response populations. 
The duration of response and disease control will be also analysed on the ITT and evaluable for response populations. A 
stratified log-rank test will be used in order to compare the two treatment arms with the same stratification factors defined 
above. 
Multivariate analyses of Overall Survival, PFS, ORR and DCR will be performed to take account of pronostic factors. A 
stratified Cox proportional hazards and a logistic regression will be used. 
The safety analysis will be performed in the evaluable population for safety. Haematological parameters, febrile 
neutropenia, biochemical parameters and non haematological toxicities will be assessed. For haematological and 
biochemical parameters, the worst NCI CTCAE version 3.0 grade will be presented by patient and by cycle. For non 
haematological toxicities, the worst NCI CTCAE version 3.0 grade will be presented by patient. 
Health-related quality of life will be assessed using the QLQ-core EORTC questionnaire and the QLQ-Head and Neck 
module. 
There will be one early safety review after 40 are randomised (20 in each arm) and treated for at least 1 cycle. 
An interim analysis based on the non progression rate at 6 weeks will be performed after tumour response data from the 
first 100 randomised patients in the test arm become available. The main purpose of this interim analysis is to stop the 
study if result indicating poor efficacy of the test regimen is observed. It is assumed that the test arm will be of no further 
interest in the second-line treatment of SCCHN patients if the observed non-progression rate at 6 weeks (first tumour 
assessment scheduled) is less than the lower limit of the 95% CI of the expected non-progression rate at 6 weeks. 
Assuming that this expected non-progression rate at 6 weeks is equal to 61%, the 95% CI is [51%-71%] and the study 
will be stopped prematurely if > 49 progressions (or deaths for progression) out of 100 evaluable patients for efficacy will 
be observed. 
Safety and efficacy results of the interim analyses will be reviewed by an IDMC. 
End of study 
 
The end of study is the date of the last patient study treatment administration plus 30 days. 
No follow-up visit will be performed. At the time of the amendment PA11: 
- 
Patients under treatment will stop the study at the EOT. 
- 
Patients under follow-up will stop immediately. 
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Table 1: Study flow chart 
Required assessments 
Screening 
period 
Treatment period 
End of 
treatment (f) Follow-up (g) 
Timing 
Day - 21  
to - 1 
Day 1 
every cycle 
Every 
6 weeks 
 
 
Signed informed consent 
X (a) 
 
 
 
 
Demographic data 
Demography/Medical 
History/Diagnosis 
X 
 
 
 
 
Serum or urine pregnancy test in 
women of childbearing potential 
X (j) 
 
 
 
 
Physical Examination/Vital 
signs/Weight 
X (b) 
X 
 
X 
 
WHO Performance Status 
X (b) 
X 
 
X 
X 
Safety 
Electrocardiogram (ECG) 
X (m) 
X (m) 
 
 
 
Pre-treatment events/Adverse 
events/SAE  
X (k) 
X 
 
X 
X 
Complete blood cell count (l) 
X (b) 
X (c) 
(within 24 
hours) 
 
X 
 
Blood chemistry (d) 
X (b) (e) 
X 
X (e) 
X (e) 
 
Concomitant medications/Blood 
Products 
X(k) 
X 
 
X 
 
Efficacy (i) 
Cervical CT-Scan or MRI 
X 
 
X 
X 
X (h) 
Chest/upper abdominal CT-Scan or 
MRI 
X 
 
X 
X 
X (h) 
Other imaging if necessary 
X 
 
X 
X 
X (h) 
Health-related quality of life 
EORTC QLQ-C30 and QLQ-  
H & N 35 
Before 
randomisation 
within 24h 
 
X 
X 
 
 
(a) Prior  to any study procedure. 
(b) Within 7 days prior to first study drug treatment. 
(c) CBCC performed on days 1 and 8 in arm A; on days 1, 8 and 15 in arm B 
(d) Transaminases, alkaline phosphatase, total bilirubin, urea, creatinine, calculated (Cockroft-Gault) creatinine clearance , calcium, sodium, potassium, magnesium, chloride, 
bicarbonate.  
(e) Glucose, total protein and albumin to be performed in addition. 
(f) Within 30 days after study treatment discontinuation. 
(g) Until disease progression: every 6 weeks. After disease progression, every month for the first 6 months and then every 3 months until death. 
 
At the time of the amendment PA11, no more follow-up visit will be performed. 
(h) In case of treatment discontinuation for other reason than PD, all efficacy assessments must be performed every 6 weeks from time of randomisation until disease 
progression is documented, then survival  information will be collected approximately every month for the first 6 months then every 3 months until death. 
 
At the time of the amendment PA11, these assessments will not be performed. 
(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. 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)  To be repeated in the event of fever or infection according to institutional standards and investigator decision. 
(m)  To be performed within 7 days before randomisation and repeated on D1 of the first cycle before and after drug administration in both arms. Thereafter, to be repeated 
before drug administration every two cycles in both arms. After review of safety data including ECG results by the IDMC, the need for repeated ECGs before each cycle 
can be revised 
 
 


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APPROVAL FORM 
STUDY: L00070 IN 309 F0 
PROTOCOL Version No. 7 dated: 5th February 2016 
 
 
 
 
 
 
Sponsor’s representatives 
 
Head of Development Platform 
 
 
Name : François BRACKMAN 
Date :  
Signature : 
 
 
 
 
 
 
Study Chairman 
 
Jan VERMORKEN   
 
 
Date :  
 
          Signature : 
Department of Medical Oncology 
University hospital Antwerp 
Edegem, Belgium 
 
 
 
 
 
 
 
 
 


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COUNTRY COORDINATING INVESTIGATOR 
SIGNATURE FORM* 
STUDY: L00070 IN 309 F0 
PROTOCOL Version No. 7  dated: 5th February 2016 
 
 
 
 
 
 
 
 
Country Coordinating Investigator**: 
Name   
Date:   
  
 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* if required by local regulation 
** if applicable or principal investigator for a national study  


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INVESTIGATOR SIGNATURE FORM 
STUDY: L00070 IN 309 F0 
PROTOCOL Version No. 7 dated: 5th February 2016 
 
 
 
 
 
 
 
 
 
 
By my signature below, I, Dr. ______________________________________________ hereby confirm that I 
agree: 
 to conduct the trial described in the protocol n° L00070 IN 309 F0 Version No. 7 dated 5th February 2016 in 
compliance with GCP, with applicable regulatory requirements and with the protocol agreed upon by the 
sponsor and given approval/favourable opinion by the Ethics Committee ; 
 to document the delegation of significant study related duties and to notify the sponsor of changes in site 
personnel involved in the study ; 
 to comply with procedures for data recording and reporting ; 
 to permit monitoring, auditing and inspection ; 
 to retain the trial-related essential documents until the sponsor informs these documents are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the availability of adequate resources, personnel and 
facilities for the conduct of this trial. 
 
 
Date: 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 


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Sponsor’s personnel 
 
 
Clinical Development Physician (monitor): 
Dr Andrius BACEVICIUS 
Tel: 33 (0)5.34.50.69.24 
 
Fax: 33 (0)5.34.50.65.92 
Clinical Development Department 
E-mail: andrius.bacevicius.externe@pierre-fabre.com 
BP 13562 - 3, Avenue Hubert Curien 
31035 Toulouse Cedex 1, France 
 
Clinical Study Coordinators: 
Fatima EL GHAIB 
Tel: 33 (0)1.49.10.82.13 
 
Fax: 33 (0)1.49.10.83.31 
Clinical Development Department 
 
E-mail: fatima.el.ghaib.externe@pierre-fabre.com 
45, Place Abel Gance 
92654 Boulogne Cedex, France 
 
 
Amandine LAURANS 
Tel: 33 (0)1.49.10.80.32 
 
Fax: 33 (0)1.49.10.83.31 
Clinical Development Department 
 
E-mail: amandine.laurans.externe@pierre-fabre.com 
Same address 
 
Emilie PIAT 
Tel: 33 (0)1.49.10.84.18 
 
Fax: 33 (0)1.49.10.83.31 
Clinical Development Department 
 
E-mail: emilie.piat.externe@pierre-fabre.com 
Same address 
 
 
Study assistant: Ludivine DELAHAYES 
Tel: 33 (0)1.49.10.84.77 
 
 
Fax: 33 (0)1.49.10.83.31 
 
E-mail: ludivine.delahayes.externe@pierre-fabre.com 


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TABLE OF CONTENTS 
 
STUDY SYNOPSIS .......................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................ 22 
1. 
INTRODUCTION ................................................................................................................. 24 
1.1. 
BACKGROUND ON THE STUDY .................................................................................... 24 
1.1.1. 
Background on the disease ................................................................................................ 24 
1.2. 
BACKGROUND ON IV VINFLUNINE ............................................................................. 26 
1.2.1. 
Chemistry and pharmacology ............................................................................................ 26 
1.2.1.1. 
Dose and pharmacokinetics ............................................................................................ 28 
1.2.1.2. 
Overview on clinical development ................................................................................. 29 
1.2.1.3. 
Safety profile of vinflunine as a single agent ................................................................. 30 
1.2.1.4. 
Vinflunine and methotrexate in combination ................................................................. 31 
1.3. 
STUDY RATIONALE ......................................................................................................... 33 
2. 
STUDY OBJECTIVES ......................................................................................................... 34 
3. 
STUDY DESIGN ................................................................................................................... 34 
4. 
STUDY POPULATION ........................................................................................................ 36 
4.1. 
INCLUSION CRITERIA ..................................................................................................... 36 
4.2. 
EXCLUSION CRITERIA .................................................................................................... 38 
4.3. 
NUMBER OF PATIENTS ................................................................................................... 40 
5. 
STUDY TREATMENT ......................................................................................................... 40 
5.1. 
STUDY DRUG ADMINISTRATION ................................................................................. 40 
5.1.1. 
Vinflunine and methotrexate (arm A) ............................................................................... 40 
5.1.1.1. 
Vinflunine ....................................................................................................................... 40 
5.1.1.2. 
Anti-emetic and laxative prophylaxis ............................................................................. 41 
5.1.1.3. 
Methotrexate ................................................................................................................... 42 
5.1.2. 
Methotrexate (arm B) ........................................................................................................ 42 
5.2. 
GUIDELINES FOR TREATMENT MODIFICATIONS .................................................... 43 
5.2.1. 
General considerations ...................................................................................................... 43 
5.2.2. 
Vinflunine (arm A) ............................................................................................................ 43 
5.2.2.1. 
Dose modifications ......................................................................................................... 43 
5.2.2.2. 
Treatment modifications for haematological toxicity .................................................... 44 
5.2.2.3. 
Treatment modifications for non-haematological toxicity ............................................. 45 
5.2.3. 
Methotrexate in Arm A ..................................................................................................... 47 
5.2.3.1. 
Dose modifications ......................................................................................................... 47 


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5.2.3.2. 
Treatment modifications for haematological toxicity .................................................... 47 
5.2.3.3. 
Treatment modifications for non-haematological toxicity ............................................. 49 
5.2.4. 
Methotrexate in Arm B ...................................................................................................... 50 
5.2.4.1. 
Dose modifications ......................................................................................................... 50 
5.2.4.2. 
Treatment modifications for haematological toxicity .................................................... 50 
5.2.4.3. 
Treatment modifications for non haematological toxicity ............................................. 52 
5.2.5. 
Discontinuation of vinflunine or methotrexate in Arm A due to toxicity ......................... 53 
5.3. 
TREATMENT ASSIGNMENT ........................................................................................... 54 
5.4. 
DURATION OF TREATMENT .......................................................................................... 55 
6. 
CONCOMITANT MEDICATIONS .................................................................................... 55 
6.1. 
PROHIBITED TREATMENTS ........................................................................................... 55 
6.1.1. 
Arms A and B .................................................................................................................... 55 
6.1.2. 
Arm A ................................................................................................................................ 56 
6.1.3. 
Arm B ................................................................................................................................ 56 
6.2. 
RESTRICTED TREATMENT ............................................................................................. 56 
6.2.1. 
Arm A ................................................................................................................................ 56 
6.2.2. 
Arm A and B ..................................................................................................................... 57 
6.3. 
AUTHORISED TREATMENTS ......................................................................................... 57 
7. 
PLAN OF THE STUDY ........................................................................................................ 57 
7.1. 
SCREENING PERIOD ........................................................................................................ 58 
7.2. 
ASSIGNMENT OF SCREENING NUMBER ..................................................................... 58 
7.3. 
STUDY ENTRY .................................................................................................................. 59 
7.4. 
EVALUATION DURING THE STUDY PERIOD ............................................................. 60 
7.5. 
END-OF-STUDY PERIOD EVALUATION ....................................................................... 61 
7.6. 
PREMATURE DISCONTINUATION ................................................................................ 62 
7.7. 
FOLLOW-UP PERIOD ASSESSMENT ............................................................................. 64 
8. 
MEASUREMENTS AND EVALUATION ......................................................................... 65 
8.1. 
EFFICACY ASSESSMENT ................................................................................................ 65 
8.1.1. 
Overall survival ................................................................................................................. 65 
8.1.2. 
Evaluation of tumour response .......................................................................................... 65 
8.1.2.1. 
Disease measurability ..................................................................................................... 66 
8.1.2.2. 
Criteria for evaluation ..................................................................................................... 67 
8.1.2.3. 
Best overall response ...................................................................................................... 69 
8.2. 
SAFETY ASSESSMENT .................................................................................................... 70 
8.2.1. 
Clinical safety .................................................................................................................... 70 
8.2.2. 
Laboratory investigations .................................................................................................. 70 
8.3. 
PHARMACOKINETICS ..................................................................................................... 70 


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8.4. 
QUALITY OF LIFE ............................................................................................................. 70 
8.5. 
PHARMACOECONOMICS ................................................................................................ 71 
8.6. 
COMPLIANCE .................................................................................................................... 71 
9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................... 71 
9.1. 
ADVERSE EVENTS ........................................................................................................... 71 
9.1.1. 
Definition ........................................................................................................................... 71 
9.1.2. 
Grading of adverse events ................................................................................................. 72 
9.1.3. 
Reporting of adverse events .............................................................................................. 72 
9.2. 
SERIOUS ADVERSE EVENTS .......................................................................................... 73 
9.2.1. 
Definition of SAE .............................................................................................................. 73 
9.2.2. 
Reporting of SAE .............................................................................................................. 74 
9.2.3. 
Follow-up of SAE.............................................................................................................. 74 
9.2.4. 
SAE occurring after the study............................................................................................ 75 
9.2.5. 
Sponsor’s responsibilities for safety reporting purposes ................................................... 75 
9.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 75 
9.4. 
REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 76 
10. CLINICAL PHARMACY .................................................................................................... 77 
10.1. PHARMACEUTICAL INFORMATION ............................................................................. 77 
10.1.1. Pharmaceutical information of vinflunine ......................................................................... 77 
10.1.1.1. Drug supply .................................................................................................................... 77 
10.1.1.2. Storage ............................................................................................................................ 77 
10.1.2. Pharmaceutical information of methotrexate .................................................................... 78 
10.1.2.1. Drug supply .................................................................................................................... 78 
10.1.2.2. Storage ............................................................................................................................ 78 
10.2. PACKAGING AND LABELLING ...................................................................................... 78 
10.2.1. Packaging and labelling of vinflunine ............................................................................... 78 
10.2.1.1. Packaging ....................................................................................................................... 78 
10.2.1.2. Packaging use ................................................................................................................. 78 
10.2.1.3. Study drug labelling ........................................................................................................ 79 
10.2.2. Packaging and labelling of methotrexate ........................................................................... 79 
10.3. ON SITE DRUG ACCOUNTABILITY AND DISPENSING ............................................. 79 
10.4. RECALL OF INVESTIGATIONAL PRODUCTS .............................................................. 80 
10.5. UNUSED DRUG AND DESTRUCTION ........................................................................... 81 
11. DATA ANALYSIS ................................................................................................................ 81 
11.1. SAMPLE SIZE ..................................................................................................................... 81 
11.2. PROTOCOL DEVIATIONS ................................................................................................ 82 
11.3. POPULATION ANALYSED ............................................................................................... 82 


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11.3.1. Intent-to-treat population (ITT) ......................................................................................... 82 
11.3.2. Eligible population ............................................................................................................ 82 
11.3.3. Evaluable population for tumour response ........................................................................ 82 
11.3.4. Evaluable population for safety ......................................................................................... 83 
11.3.5. Evaluable population for health-related quality of life assessment ................................... 83 
11.4. DEFINITIONS ..................................................................................................................... 83 
11.5. CLINICAL STATISTICAL METHODS ............................................................................. 86 
11.5.1. Statistical methodology ..................................................................................................... 86 
11.5.1.1. Statistical methods for categorical, ordinal and quantitative variables .......................... 87 
11.5.1.1.1. Statistical methods for categorical variables................................................ 87 
11.5.1.1.2. Statistical methods for ordinal variables ...................................................... 87 
11.5.1.1.3. Statistical methods for continuous variables ............................................... 87 
11.5.1.2. Statistical methods for time to event data....................................................................... 87 
11.5.1.3. Statistical methods for health-related Quality of Life data ............................................. 88 
11.5.2. Baseline assessment ........................................................................................................... 88 
11.5.3. Efficacy assessment ........................................................................................................... 88 
11.5.3.1. Efficacy parameters ........................................................................................................ 88 
11.5.3.1.1. Primary efficacy parameter .......................................................................... 88 
11.5.3.1.2. Secondary efficacy parameters .................................................................... 88 
11.5.3.2. Efficacy analyses ............................................................................................................ 89 
11.5.3.2.1. Primary efficacy analysis ............................................................................. 89 
11.5.3.2.2. Supportive analysis of the primary efficacy parameter ................................ 89 
11.5.3.2.3. Sensitivity analyses of the primary parameter ............................................. 89 
11.5.3.2.4. Secondary efficacy analyses ......................................................................... 90 
11.5.4. Safety assessment .............................................................................................................. 93 
11.5.4.1. Safety parameters ........................................................................................................... 93 
11.5.4.2. Safety analyses ................................................................................................................ 93 
11.5.5. Quality of life  assessment ................................................................................................. 94 
11.5.5.1. Health-related quality of life parameters ........................................................................ 94 
11.5.5.2. Health-related quality of life analyses ............................................................................ 95 
11.5.6. Interim analyses ................................................................................................................. 95 
11.5.6.1. Early Safety Review ....................................................................................................... 95 
11.5.6.2. Efficacy and Safety Interim Analysis ............................................................................. 96 
12. STUDY MONITORING AND DATA COLLECTION ..................................................... 97 
12.1. DATA COLLECTION ......................................................................................................... 97 
12.1.1. CRF / eCRF ....................................................................................................................... 97 
12.1.2. Source documents .............................................................................................................. 98 
12.2. STUDY MONITORING ...................................................................................................... 99 
13. DATA MANAGEMENT ..................................................................................................... 100 
13.1. DATA ENTRY ................................................................................................................... 100 
13.2. DATA REVIEW ................................................................................................................ 100 


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13.3. DATA CODING................................................................................................................. 100 
13.4. DATA STORAGE.............................................................................................................. 101 
13.5. DATA FREEZING ............................................................................................................. 101 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................. 101 
14.1. ETHICAL CONDITIONS .................................................................................................. 101 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS .............................................. 101 
14.3. SUBJECT’S INFORMATION LEAFLET, CONSENT FORM AND SUBJECT CARD 102 
14.3.1. Subject’s information leaflet and consent form ............................................................... 102 
14.3.2. Subject card ..................................................................................................................... 103 
14.4. PERSONAL DATA PROTECTION .................................................................................. 103 
14.5. INSURANCE POLICY ...................................................................................................... 103 
15. ADMINISTRATIVE PROCEDURES............................................................................... 103 
15.1. PROTOCOL AMENDMENT ............................................................................................ 103 
15.2. SOURCE DOCUMENTS, INVESTIGATORS FILE STORAGE .................................... 104 
15.3. END OF STUDY ............................................................................................................... 104 
15.3.1. End of study ..................................................................................................................... 104 
15.3.2. Early study termination.................................................................................................... 105 
15.3.2.1. Early study termination decided by the sponsor ........................................................... 105 
15.3.2.2. Early study termination decided by the Competent Authorities ................................... 105 
15.4. AUDIT ................................................................................................................................ 105 
15.5. INSPECTION ..................................................................................................................... 106 
15.6. CONFIDENTIALITY ........................................................................................................ 106 
15.7. CLINICAL STUDY REPORT ........................................................................................... 106 
15.8. STUDY RESULTS COMMUNICATION ......................................................................... 106 
15.9. PUBLICATIONS ............................................................................................................... 107 
16. REFERENCES .................................................................................................................... 109 
 


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CONTENTS OF TABLES 
 
 
 
Table 1: Study flow chart ................................................................................................................. 10 
Table 2: Efficacy of methotrexate single agent in SCCHN .............................................................. 25 
Table 3: Haematological results and drug-related adverse events (> 5%) per patient according to 
MedDRA by worst grade (NCI CT version 3.0) ...................................................................... 30 
Table 4: Dose reduction of IV vinflunine ......................................................................................... 43 
Table 5: Dose delay for haematological toxicity on day 1 of each cycle ......................................... 44 
Table 6: Dose modifications for haematological toxicity ................................................................ 44 
Table 7: Dose modifications for non-haematological toxicity ......................................................... 46 
Table 8: Dose reduction of methotrexate in Arm A ......................................................................... 47 
Table 9: Arm A- Dose delay of methothrexate on day 1 for haematological toxicity ...................... 47 
Table 10: Dose delay or cancellation of methotrexate at Day 8 in Arm A ....................................... 48 
Table 11: Dose modifications of methotrexate for haematological toxicity in Arm A .................... 48 
Table 12: Dose modifications of methotrexate in Arm A for non-haematological toxicities .......... 50 
Table 13: Dose reduction of methotrexate in Arm B ....................................................................... 50 
Table 14: Arm B - Dose delay of methotrexate on day 1 for haematological toxicity ..................... 51 
Table 15: Dose cancellation of methotrexate within a cycle in Arm B ............................................ 51 
Table 16: Dose modifications of methotrexate in Arm B for haematological toxicity .................... 52 
Table 17: Dose modifications of methotrexate in Arm B for non-haematological toxicities .......... 53 
Table 18: Study procedures during the screening period ................................................................. 58 
Table 19: Assessments during the treatment period ......................................................................... 60 
Table 20: Assessment at the end of study treatment ........................................................................ 61 
Table 21: Time point response: patients with target (+/- non target) disease ................................... 69 
Table 22: Time point response: patients with non target disease ..................................................... 69 
Table 23: Definitions of ORR and DCR .......................................................................................... 84 
 
 


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APPENDICES 
 
 
Appendix 1: World medical association declaration of Helsinki --------------------------------------- 115 
Appendix 2: Performance status scale ---------------------------------------------------------------------- 124 
Appendix 3: Distribution of active bone marrow in the adult------------------------------------------- 126 
Appendix 4: Treatment labelling ---------------------------------------------------------------------------- 128 
Appendix 5: Serious adverse event report form ----------------------------------------------------------- 132 
Appendix 6: Drug accountability form --------------------------------------------------------------------- 135 
Appendix 7: EORTC questionnaire ------------------------------------------------------------------------- 138 
Appendix 8: Inducers or inhibitors of CYP3A4 ---------------------------------------------------------- 142 
Appendix 9: Diagram of categories of eligible patients according to inclusion criterion no.3 ----- 144 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine amino Transferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate amino Transferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
BSA 
Body Surface Area 
BSC 
Best Supportive Care 
CA 
Competent Authorities 
CBCC 
Complete Blood Cell Count 
CI 
Confidence Interval 
CMV 
Cisplatin-Methotrexate-Vinblastine 
CNS 
Central Nervous System 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRT 
Chemoradiation 
CSC 
Clinical Study Coordinator 
CT 
Chemotherapy 
CT scan  
Computed Tomography Scan 
CVL 
Central Venous Line 
D 
Day 
DCR 
Disease Control Rate 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
DVFL 
4-O-DeacetylVinflunine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermic Growth Factor Receptor 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End Of Treatment 
FDA 
Food and Drug Administration 
5-FU 
5 Fluorouracil 
GCP 
Good Clinical Practice 
Hb 
Haemoglobin 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
ICT 
Induction Chemotherapy 
IDMC 
Independent Data Monitoring Committee 
i.p. 
Intraperitoneal 
IRPF 
Institut de Recherche Pierre Fabre  
IRRC 
Independent Response Review Committee 
ITT 
Intent To Treat 
i.v. 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KPS 
Karnofsky Performance Status 
LD 
Longest Diameter 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximal Tolerated Dose 
M-VAC 
Methotrexate-Vinblastine-Doxorubicin-Cisplatin 
N 
Number 
NC 
No Change 
NCI CTC AE 
National Cancer Institute - Common Toxicity Criteria for Adverse Events 
NS 
Normal Saline 
NSCLC 
Non Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OR 
Overall response 
PD 
Progressive Disease 
PFM 
Pierre Fabre Médicament 
PFS 
Progression-Free Survival  
PLT 
Platelets 
PR 
Partial Response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PS 
Performance Status 
pt (s) 
Patient (s) 
RD 
Recommended Dose 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous-Cell Carcinoma of the Head and Neck 
s.d. 
Standard Deviation 
SD 
Stable disease 
SGOT (AST) 
Serum Glutamic Oxalo-Acetic Transaminase  
SGPT (ALT) 
Serum Glutamic Pyruvic Transaminase 
TCCU  
Transitional Cell Carcinoma of the Urothelial tract 
Tmax 
 
Time to reach the Cmax 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
VFL 
Vinflunine 
WBC 
 
White Blood Cell(s) 
WHO 
 
World Health Organization 
WNL 
 
Within Normal Limits  
 
 


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1. INTRODUCTION 
1.1. 
BACKGROUND ON THE STUDY 
1.1.1. 
Background on the disease 
Squamous cell carcinoma of the head and neck (SCCHN) represents 5% of newly diagnosed 
cancers in adult patients. Worldwide more than 500.000 new cases are projected annually and 
approximately 300 000 deaths are attributed to this disease. 
It is a potentially curable malignancy when diagnosed at an early stage. Unfortunately, patients 
often present with an advanced locoregional disease. Despite aggressive local management, fewer 
than 30% of those patients are cured. The majority will die of locoregional recurrences. 
Approximately, 10% of newly diagnosed patients and up to 30% of relapsed patients will present 
with distant metastases. Locoregional recurrence not suitable for local therapy and metastatic 
disease are incurable and have been managed palliatively with chemotherapy. 
Many single agents have been shown to produce tumour response including methotrexate, cisplatin, 
carboplatin, bleomycin, doxorubicin, taxanes, vinblastin, vinorelbine and 5-fluorouracil (5-FU) 
(Colevas D., 2006). Combination regimens produced statistically higher response rates than single 
agents (Forastiere A., 1992 ; Jacobs C., 1992). The combination of cisplatin and 5-FU emerged as a 
favoured treatment in the 1980s and 1990s. This was based on the higher response rates reported in 
recurrent/metastatic disease (Jacobs C., 1992 ; Clavel M., 1994) but at the expense of greater 
toxicity and without demonstrating improved survival. Triple-agent regimen, usually docetaxel, 
cisplatin and 5FU, was shown to be superior to cisplatin plus 5 FU but increased toxicity limits its 
use to induction chemotherapy (Posner M, 2007, Vermorken JB, 2007c). Cetuximab demonstrated 
significantly prolonged locoregional control and overall survival when used in combination with 
radiotherapy in locally advanced SCCHN (Bonner J.A., 2006). More recently, the addition of 
cetuximab to platinum-based chemotherapy improved overall survival when given as first-line 
treatment in patients with recurrent/metastatic SCCHN (Vermorken JB, 2008). The median overall 
survival was increased from 7.4 months to 10.1 months by the addition of cetuximab. However, 


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approximately one third of patients respond to first-line platinum-based therapy. Thus, there is 
clearly an unmet therapeutic need for the treatment of recurrent/metastatic SCCHN who failed 
platinum-based therapy. 
For patients with incurable recurrent/metastatic SCCHN who failed platinum-based therapy, single 
agent methotrexate remains a standard option (Pivot X., 2001 ; Stewart S., 2009). In this setting, 
the standard regimen of methotrexate is 40 to 60 mg/m² intravenously weekly (Colevas D., 2006). 
Methotrexate is eliminated primarily in the urine whereas hepatic metabolism pathway is limited. 
After intravenous administration, about 60-80% of the dose is excreted in urine as unchanged drug 
within 24 hours post-dosing and biliary elimination remains low (Seideman P., 1993). The 
expected adverse effects of methotrexate are mucositis and myelosuppression, other side effects 
include vomiting, diarrhoea, transient erythematous skin rash and transient elevations of liver 
enzymes. Response rates ranging from 3.9% to 10.8% and median overall survival between 3.7 and 
6.7 months were reported. Differences in efficacy results can be explained by different selection 
criteria and improvement in the management of SCCHN between 1992 and 2010. Efficacy results 
published on the use of methotrexate single agent are shown below. 
Table 2: Efficacy of methotrexate single agent in SCCHN 
Author 
(years) 
Disease setting 
N of 
patients 
Response 
rate  
(%) 
Disease 
control rate 
(%) 
Progression-free 
survival (months) 
[95% CI] 
Overall survival 
(months) [95% CI] 
Forastiere A., 1992 
First-line 
88 
10 
60 
NA 
5.6 [ NA ] 
Schornagel J.H., 1995 
First-line 
133 
16 
47 
NA 
6.0 [ NA ] 
Vermorken JB, 1999 
First-line 
42 
19.5 
- 
2.0 [1.6-3.7] 
6.1 [5.5 - 8.7] 
Pivot X., 2001 
Failure after induction CT or 
chemoradiotherapy / Second-line 
46 
10.8 
41.3 
1.5 [1-18] 
3.7 [0.5-18.0] 
Stewart S., 2009 
Second-line or unsuitable for 
platinum-based CT 
161 
3.9 
48.0 
NA 
6.7 [ NA ] 
Machiels JP, 2011 
Failure of at least one platinum-
based CT 
95* 
1.1 
27.0 
2.0 [2-2.4] 
5.2 [4.1 - 6.4] 
* patients randomised to BSC : 78% of them received methotrexate 
NA : Not Available 
 
Among new agents which were tested in recurrent / metastatic SCCHN patients who failed 
platinum-based therapies, anti-EGFR antibodies have been the most promising (Goerner M., 2010). 
In a retrospective analysis, J. Vermorken (Vermorken JB, 2007a) reported the potential of 
cetuximab to prolong survival. Cetuximab used alone (Vermorken JB, 2007b) or in combination 


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with cisplatin (Herbst R., 2005) or carboplatin (Baselga J., 2005) achieved response rates from 10% 
to 13%, disease control rates of 46% to 56% and overall survival between 5.2 months and 6.1 
months. However zalutumumab failed to demonstrate a significant increase in overall survival over 
best supportive care (78% of patients received methotrexate) despite slight improvement in median 
progression-free survival from 8.4 to 9.9 weeks (Machiels JP, 2011). Cetuximab has now been 
granted marketing authorization approval in combination with radiotherapy for locally advanced 
disease and in combination with platinum-based chemotherapy for recurrent / metastatic disease by 
the EMA and the FDA. 
With the use of cetuximab in earlier stages of SCCHN, new effective therapeutic options are 
urgently needed in patients with incurable recurrent / metastatic disease who failed platinum-based 
chemotherapy. Methotrexate remains an option but its activity is poor as shown in Table 2. 
1.2. 
BACKGROUND ON IV VINFLUNINE 
1.2.1. 
Chemistry and pharmacology 
Vinflunine (VFL) is a novel microtubule inhibitor obtained by semi-synthesis using an original 
chemical approach in order to selectively modify the catharanthine moiety of the Vinca alkaloid 
scaffold (Fahy J, 1997). 
Research was focused on identifying an original chemical approach that induced dramatic changes 
in the skeleton of the molecule and optimise the therapeutic index of these derivatives. This 
investigation has focused on the reactivity of these functionalised compounds in superacidic media. 
A semi-synthetic microtubule-targeting agent, vinflunine, was selected on the basis of its high level 
of in vivo antitumour activity against experimental tumours compared with other agents of the same 
class. The optimal structural modification of this compound is the introduction of 2 fluorine atoms 
at the 20' position, a part of the molecule previously inaccessible by classic chemistry (Jacquesy JC, 
2000). Pharmacological investigations have highlighted the essential contribution of the fluorine 
atoms to this antitumour activity (Duflos A, 2002). 
Classic primary pharmacological screening of a large series of derivatives centred on in vitro 
cytotoxicity tests and in vivo activity assays; vinflunine was selected for detailed preclinical 


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investigations essentially on the basis of its high in vivo antitumour activity compared with other 
compounds of the same class.  
Vinflunine antitumour activity was fully demonstrated against a large and varied panel of murine 
and xenograft models. It was proved to be active against 5 of the 7 murine ‘solid’ tumours tested 
and against 13 human tumour xenografts yielding a response rate of 45%, with marked tumour 
growth inhibition and/or tumour regressions (Hill BT, 1999). This figure meets the current NCI 
criteria for a new agent, predicted to have some degree of clinical activity (Johnson JI, 2001). 
Furthermore, superiority of vinflunine relative to vinorelbine (VRL) was clearly established. 
Among ten experimental human tumour models, VFL proved active in 6 tumours (including 2 with 
a high activity rating) whilst vinorelbine was active against 4 tumours (including only 1 high 
activity rating). This activity was usually achieved in the absence of any significant body weight 
loss (i.e. < 15%) or early deaths, in tumour-bearing animals. The high level of tolerance to VFL and 
its durable antitumour activity provided a favourable profile for further development of this new 
product. (Kruczynski A, 1998b ; Hill BT, 2001). 
Vinflunine interacts with tubulin at the vinca-binding domain and inhibits tubulin assembly by 
perturbing microtubule dynamics and mitotic spindles without affecting assembled microtubules. 
VFL exhibits the weakest overall affinity for tubulin and the most readily reversible interaction 
with tubulin (Kruczynkski A, 1998a ; Kruczynski A, 2001). This characteristic was not considered 
as deleterious for the drug since it has been shown that the strength of the binding of vinca-
alkaloids was not necessarily related to antitumour efficacy (Singer WD, 1989). These data were 
consistent with the hypothesis that VFL was likely to result in reduced neurotoxicity relative to 
vincristine, vinblastine and VRL (Lobert S, 1998) and in vitro safety pharmacology data confirmed 
this hypothesis. This potential for lower neurotoxicity represents another important difference 
compared with classic vinca-alkaloids or other microtubule inhibitors like taxanes or new 
epothilones like ixabepilone. 
Data on the resistance profile of the compound added weight to its potential value as a candidate 
for clinical development. VFL, like the other vinca-alkaloids, participates in Pgp-mediated MDR, 
with tumour cells selected for VFL resistance over-expressing Pgp, yet MDR tumour cell lines 
proved generally less cross resistant to VFL relative to the other vinca-alkaloids (Etievant C, 1998). 


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More importantly, VFL induces drug resistance far less readily than vinorelbine in terms of the 
number of passages required selecting for total resistance and the level of resistance ultimately 
obtained. In vitro full resistance was reached in 8 months versus 2 months after 2-fold IC50 
exposures to VFL and VRL respectively. In another model, in vivo complete resistance to VFL was 
obtained after 36 weeks exposure at sub-therapeutic doses compared to only 11 weeks for VRL 
(Etievant C, 2001). 
1.2.1.1. 
Dose and pharmacokinetics 
Following i.v. administration to patients, vinflunine is eliminated according to a multi-exponential 
decay with a rapid decrease of blood concentrations during the first hour. The terminal half-life is 
approximately 40 hours. The volume of distribution is large, 1,100 to 4,400 litres (about 19 to 
59 L/kg) suggesting important tissue distribution and uptake. Total clearance in blood is large (43.9 
L/h, 0.60 L/h/kg). Vinflunine binding to blood cells is moderate, and that to platelets is negligible. 
The binding of VFL to human serum proteins is moderate; there was no binding to α1-
glycoprotein. Several metabolites are observed in blood, the main one being DVFL, which is also 
active. The terminal half-life of DVFL (approximately 5 days) is longer than that of unchanged 
compound. Excretion of VFL and its metabolites is higher in faeces than in urine (2/3 and 1/3 of 
the recovered radioactivity, respectively (IRPF CSR 103, Focan C, 2002, Bennouna J, 2003, 
Bennouna J, 2008). 
VFL pharmacokinetics (PK) are not affected by liver dysfunction (Paule B, 2007). The VFL 
clearance is reduced in patients with low serum creatinine clearance (20 to 60 ml/min) (  Vinflunine 
Investigator Brochure n° 16.1). Similarly, a phase I study in elderly patients demonstrated that VFL 
clearance was decreased in the oldest patients (80 years and beyond) whereas it was unchanged in 
patients between 70 and < 80 years compared to younger ones (< 70 years) (Tourani JM, 2010). 
Strong CYP3A4 inhibitors have been shown to inhibit the VFL metabolism as CYP 3A4 is the only 
isoform of cytochrome P450 involved in the oxidative metabolism of vinflunine. 
 
Vinflunine clinical development started in December 1998. Three Phase I trials were conducted in 
order to determine the maximum tolerated dose (MTD) and the recommended dose according to 


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three different schedules of vinflunine administration: on day 1 every 3 weeks, weekly 
administration, on day 1 and day 8 every 3 weeks (Bennouna J, 2003; Delord JP, 2001, Puozzo C, 
2001, Vermorken JB, 2003; Johnson P, 2006). 
Based on safety, pharmacokinetic and antitumour activity data from these three phase I trials, 
vinflunine every 3 weeks schedule was considered optimal. Following a preliminary safety survey 
performed on the first 28 patients treated in the early phase II studies, a dose adjustment to 
vinflunine 320 mg/m² was used over a 20 minutes infusion for all subsequent patients included in 
clinical trials (  Vinflunine Investigator Brochure n° 16.1). 
1.2.1.2. 
Overview on clinical development 
An international program of phase II studies with vinflunine as a single agent has been carried out 
in chemonaive patients, and also as salvage therapy in order to determine the tumour response in a 
large spectrum of solid tumours: melanoma, renal carcinoma, ovarian cancer (after 1st line 
paclitaxel/platinum), mesothelioma (1st line), colon carcinoma (after oxaliplatin/irinotecan-
containing regimens), non-small cell lung cancer (2nd line after platinum-containing regimen), in 
transitional cell carcinoma of the urothelium (2nd line after platinum-containing regimen) and breast 
carcinoma (after anthracyclines/taxane exposure). 
Phase III studies were completed in advanced transitional cell carcinoma of the urothelial tract 
(TCCU) and in advanced non-small cell lung cancer (NSCLC). In both trials VFL was given as 
second-line after failure of prior platinum-based chemotherapy. In advanced TCCU, VFL 
demonstrates a survival advantage over best supportive care (Bellmunt J., 2009) and was granted a 
marketing authorization approval in this indication by the EMA. In advanced NSCLC, VLF 
showed similar efficacy results to docetaxel (Krzakowski M., 2010). 
Three phase III studies are carried out in advanced breast cancer (  Vinflunine Investigator 
Brochure n° 16.1). 


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1.2.1.3. 
Safety profile of vinflunine as a single agent 
Safety data from 1076 patients treated at the initial dose of 320 mg/m² and 483 patients treated at 
the initial dose of 280 mg/m² were collected and analysed in the clinical studies sponsored by PFM. 
The table below gives the incidences of drug-related adverse events reported in at least 5% of 
patients. Detailed information is provided in the Investigator Brochure no. 16.1 (November 2013). 
 
Table 3: Haematological results and drug-related adverse events (> 5%) per patient 
according to MedDRA by worst grade (NCI CT version 3.0) 
 
System Organ Class / 
VFL 320 mg/m² 
(n = 1076) 
VFL 280 mg/m² 
(n = 483) 
Preferred term 
Any grade 
Grade 3 - 4 
Any grade 
Grade 3 - 4 
 
N 
% 
N 
% 
N 
% 
N 
% 
Haematological Laboratory Test Results  
Haematological Laboratory Test Results 
(1064 pts : 12 not evaluable) 
Haematological Laboratory Test Results 
(476 pts : 7 not evaluable) 
Anemia 
898 
84.4 
80 
7.5 
398 
83.6 
35 
7.4 
Leucopenia 
754 
70.9 
326 
30.6 
206 
43.3 
58 
12.2 
Neutropenia 
742 
69.7 
487 
45.8 
187 
39.3 
59 
12.4 
Thrombocytopenia 
361 
33.9 
29 
2.7 
107 
22.5 
11 
2.3 
Febrile neutropenia 
53 
5.0 
53 
5.0 
15 
3.1 
15 
3.2 
Gastrointestinal disorders 
Abdominal pain 
265 
24.6 
54 
5.0 
100 
20.7 
23 
4.8 
Abdominal pain upper 
64 
5.9 
5 
0.5 
16 
3.3 
0 
0 
Constipation 
567 
52.7 
121 
11.2 
210 
43.5 
44 
9.1 
Diarrhoea 
124 
11.5 
9 
0.8 
44 
9.1 
9 
1.0 
Nausea 
446 
40.3 
28 
2.6 
150 
31.1 
15 
3.4 
Stomatitis 
326 
29.4 
22 
2.0 
98 
20.3 
5 
1.0 
Vomiting 
310 
28.0 
29 
2.7 
93 
19.3 
13 
2.7 
General disorders and administration site conditions 
Chest pain 
55 
5.1 
14 
1.3 
14 
1.3 
1 
0.2 
Fatigue 
583 
54.2 
133 
12.4 
107 
22.2 
34 
7.0 
Injection site reaction 
190 
17.7 
4 
0.4 
71 
14.7 
0 
0 
Pyrexia 
98 
9.1 
3 
0.3 
33 
6.8 
2 
0.4 
Investigations 
Weight decreased 
211 
19.6 
3 
0.3 
66 
13.7 
2 
0.4 
Metabolism and nutrition disorders 
Decreased Appetite 
281 
26.1 
23 
2.1 
101 
20.9 
11 
2.3 
Musculoskeletal and connective tissue disorders 
Arthralgia 
83 
7.7 
11 
1.0 
37 
7.7 
2 
0.4 
Myalgia 
208 
19.3 
38 
3.5 
61 
12.6 
6 
1.2 
Pain in jaw 
78 
7.2 
7 
0.7 
19 
3.9 
0 
0 
Nervous system disorders 
Headache 
90 
8.4 
6 
0.6 
15 
3.1 
1 
0.2 
Paraesthesia 
89 
8.3 
4 
0.4 
14 
2.9 
1 
0.2 
Peripheral sensory neuropathy 
65 
6.0 
2 
0.2 
28 
5.8 
3 
0.6 
Skin and subcutaneous tissue disorders 
Alopecia 
31 
2.9 
NA 
NA 
72 
14.9 
NA 
NA 


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The majority of patients treated at the initial dose of 280 mg/m² were TCCU patients who presented 
with WHO performance status of 1 and/or underwent prior pelvic irradiation. As a consequence, 
the safety profiles observed in patients treated at 320 mg/m² and in those treated at 280 mg/m² are 
similar. This finding justifies starting VFL at the lower dose of 280 mg/m² in patients with 
decreased PS. 
The main adverse events were neutropenia with grade 3-4 neutropenia in 45.8% of patients at 320 
mg/m² and 12.4% at 280 mg/m² and constipation reported in 52.7% of patients at 320 mg/m² and 
43.5% of these at 280 mg/m². It is noteworthy that no systematic prophylaxis with laxatives was 
recommended at this stage of VFL clinical development. 
Clinical data demonstrated a moderate, frequent but reversible neurotoxicity (peripheral 
neuropathy, headache, dizziness, neuralgia). 
1.2.1.4. 
Vinflunine and methotrexate in combination 
A phase I study has been designed to determine the recommended dose of the combination of VFL 
plus methotrexate in patients with recurrent or metastatic SCCHN previously treated with a 
platinum-based chemotherapy and also to assess the safety, the pharmacokinetics profile and the 
antitumour activity of the combination. Preliminary clinical results are available (Preliminary 
Clinical Evaluation).  
VFL was given at a fixed dose of 280 mg/m² on day 1 in combination with methotrexate 20, 30 or  
40 mg/m² administered on days 1 and 8 of every three-week cycle. 
Cohorts of a minimum of 3 to 6 evaluable patients per dose level were intended to be enrolled.  
The criteria of MTD were met at the first DL (VFL 280 mg/m² + MTX 30 mg/m²) due to the 
occurrence of one DLT in 2 out of 3 evaluable patients treated at this DL (one grade 3 constipation 
and one grade 3 febrile neutropenia). The DL -1 (VFL 280 mg/m² + MTX 20 mg/m²) was thus 
investigated and determined to be the RD and thus tested in 10 patients: DLT was observed in 2 out 
of 10 evaluable patients treated at this DL (one grade 3 neutropenic infection and one grade 3 
ileus).  


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The study protocol was then amended to restrict the population to fit patients (serum albumin ≥ 
35g/L; weight loss < 5% within the last 3 months and absence of recurrent, i.e. ≥ 3 times 
pulmonary or upper airway infections, requiring antibiotics in the last 3 months). In this population 
of fit patients, two DLs were tested: VFL 280 mg/m² + MTX 30 mg/m² (DL1bis) and VFL 280 
mg/m² + MTX 40 mg/m² (DL2bis). At DL1bis, 3 evaluable patients, among 4 treated patients, were 
treated without any dose limiting toxicity (DLT). The higher DL2bis was then investigated and 
identified as the MTD due to the occurrence of DLT in 2 out of 6 patients (one grade 3 and one 
grade 4 febrile neutropenia). The RD was VFL 280 mg/m² on D1 + MTX 30 mg/m² on D1 and D8, 
every 3 weeks. 
At the RD, determined in fit patients, having received 1 to 3 cycles, the main haematological 
toxicity was neutropenia: grade 3 neutropenia in 1 patient and grade 4 neutropenia in 3 patients. 
Only one grade 4 non-haematological toxicity was observed in one patient (asthenia) and the most 
common grade 1-2 non-haematological toxicities included constipation, fatigue, abdominal pain, 
nausea, and alopecia.  
A total of 31 patients were enrolled in the study (pre- and post-amendment), 20 of whom having 
been considered evaluable for response. 
Clinical activity was shown as evidenced by 3 responses: one confirmed complete response and 2 
confirmed partial responses reported in the 20 patients evaluable for response (15%) and additional 
stable disease in 8 patients (40 %). Therefore, disease control was achieved in 11 patients (55%). 
Vinflunine pharmacokinetics were investigated on day 1 of cycle 1 when VFL was combined with 
methotrexate (MTX) and on day 1 of cycle 2 when VFL was administered alone and MTX given 
two days later. Methotrexate pharmacokinetics was also assessed on day 1 of cycle 1 when both 
drugs were combined and on day 8 of cycle 1 when MTX was administered alone.  
Preliminary PK analysis showed no obvious mutual drug-drug interaction between vinflunine and 
methotrexate. 


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1.3. 
STUDY RATIONALE 
For patients relapsing after platinum-based therapy, few data are available. Nolatrexed, a new 
synthase inhibitor demonstrated a similar activity to methotrexate in this setting (Pivot X., 2001). 
Cetuximab, a monoclonal antibody designed to block human EGFR, was investigated in 
recurrent/metastatic SCCHN patients refractory to cisplatin-based chemotherapy. In this setting, the 
combination of cetuximab and cisplatin achieved response rates of 10% with median overall 
survival of 5.2 and 6.1 months in 2 phase II studies (Baselga J., 2005 ; Herbst R., 2005). As a single 
agent, cetuximab showed a 13% response rate with median overall survival of 5.9 months in 
another phase II study carried out in the same population (Vermorken JB, 2007b). The current use 
of cetuximab associated with radiotherapy in localized disease and associated with platinum-based 
chemotherapy in the first-line setting stresses the need for new therapeutic options at later stages of 
SCCHN. 
Vinca-alkaloids demontrated activity in SCCHN (Colevas D., 2006). Single agent vinorelbine 
showed activity after first-line cisplatin-based chemotherapy (Testolin A., 1994 ;  Porta C., 2001). 
Vinflunine demonstrated superior antitumour activity to vinorelbine in preclinical animal models. 
This translates into a well-established efficacy of vinflunine in the second-line treatment of TCCU 
and NSCLC after platinum failure. 
Vinca-alkaloids have been successfully combined with methotrexate in a variety of solid tumours. 
In the first-line treatment of advanced TCCU, M-VAC is still considered the most effective 
regimen despite its toxicity (Calabro F., 2007) ; CMV is generally considered similar in efficacy 
although no direct comparison has been made (Harker W.G., 1985). In metastatic breast cancer, the 
combination of vinorelbine, methotrexate and 5-FU used as first-line therapy produced a 50% 
response rate (Elomaa J., 2003). Methotrexate plus vinblastine with or without platinum achieved a 
53% response rate and median overall survival of 14 months in malignant mesothelioma (Hunt K., 
1996). In SCCHN relapsing after cisplatin plus 5-fluorouracil, a regimen combining vinorelbine, 
bleomycin and methotrexate showed activity with a response rate of 27% and acceptable toxicity 
(Iop A., 1998). Recent preliminary phase I results of the vinflunine plus methotrexate combination 
in SCCHN, based on a clinical review, show encouraging antitumour activity and an acceptable 
safety profile (Preliminary Clinical Evaluation). 


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Therefore the combination of vinflunine and methotrexate appears a promising salvage regimen 
after platinum failure. 
The present study has been designed as a multicenter, randomised phase III study which will 
compare the combination of IV vinflunine with methotrexate to methotrexate alone in SCCHN 
patients having failed platinum-based therapy. 
2. STUDY OBJECTIVES 
• Primary objective: to compare the overall survival of IV vinflunine in combination with 
methotrexate versus methotrexate alone in incurable recurrent/metastatic SCCHN patients 
having failed platinum-based chemotherapy. 
• Secondary objectives:  
- to evaluate the response and disease control rate in the 2 study arms. 
- to assess the response and disease control duration in the 2 study arms 
- to assess the progression-free survival in the 2 study arms. 
- to assess the safety profile in both arms 
- to compare the change in disease-related symptoms by using the EORTC quality of life 
questionnaire. 
3. STUDY DESIGN 
This is a multicenter, open-label, randomised phase III study of IV vinflunine in combination with 
methotrexate versus methotrexate alone in incurable recurrent/metastatic SCCHN patients having 
failed prior platinum-based chemotherapy. 
Randomisation will be stratified according to a minimisation procedure (Pocock SJ, 1975) on the 
following baseline factors:  
 
- WHO performance status (0 versus 1) 
 
- Refractory or resistant to platinum versus other 
 
- Prior radiotherapy (yes versus no) 


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- Prior treatment with any anti-EGFR medication (yes versus no) 
 
- Center 
Patients will be randomly assigned to receive in a 1 : 1 ratio one of the study arms : 
- Arm A: IV vinflunine given at the dose of 280 mg/m² on day 1 and methotrexate administered at 
the dose of 30 mg/m² on days 1 and 8 of every three-week cycle. 
- Arm B: methotrexate given at the dose of 40 mg/m²/week. 
Overall survival will be the primary endpoint of the study. The final analysis will require at least 
437 deaths. The study has been powered at 90 % to show an improvement of survival from 5.5 
months in the control arm ( Machiels JP, 2011) to 7.5 months in the test arm. 
Throughout the study, patients will be closely monitored for safety evaluation and will be assessed 
for tumour response every 6 weeks (every 2 cycles). Patients will receive at least 2 cycles unless 
they experienced unacceptable toxicity or early disease progression. Patients who respond or have 
stable disease will receive 2 additional cycles and will be reevaluated for tumour response. Patients 
with progressive disease will be removed while patients who respond or have stable disease may 
continue study treatment until disease progression. 
Tumour responses and date of progression will be evaluated for all randomised patients. After 
documentation of disease progression, patients were followed every month during the first 6 
months and then every 3 months until death. 
At the time of the amendment PA11, patients will be followed only 30 days after the last 
treatment administration. 
An Independent Data Monitoring Committee (IDMC) which purpose is to protect the safety of trial 
participants, the credibility and validity of data, will be charged of reviewing the results of :  
- an early safety review which will be conducted after 40 patients are randomised (20 in each 
arm) and treated for at least one cycle. The IDMC will review the safety data and make 
recommendations accordingly. 
- an interim analysis which will take place when 100 randomised patients in the test arm have 
undergone the first tumour assessment scheduled 6 weeks from randomisation. This interim 


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analysis will evaluate the observed non-progression rate at 6 weeks and the safety in the test 
arm. Based on this interim analysis, the IDMC will determine whether the enrolment should 
continue or not. Because the projected accrual in the study can be slow, the patient enrolment 
will continue while waiting the decision of the IDMC. 
Following this interim analysis, a futility analysis has been carried out. 
The results of this analysis showed that the probability to demonstrate a significant benefit of 
overall survival at the time of the final analysis is very low. 
As a consequence, the sponsor has decided to stop the recruitment of study patients on 16th 
October 2015. 
4. STUDY POPULATION 
4.1. 
INCLUSION CRITERIA 
Patients must satisfy all the following inclusion criteria before they are allowed to participate in the 
study:  
1. Patients must give written informed consent (personally signed and dated) before completing any 
study-related procedure 
2. Histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of 
the oral cavity, oropharynx, hypopharynx or larynx 
3. Documented progressive disease after chemotherapy for locoregionally advanced or recurrent / 
metastatic SCCHN which included a platinum derivative (cisplatin or carboplatin) that is not 
suitable for local therapy. Platinum-based chemotherapy can have been associated with cetuximab. 
Eligible patients include one of the following categories (see Appendix 9 for diagram): 
 
- patients who have received induction chemotherapy (ICT) consisting of cisplatin plus 5-
 
fluorouracil or docetaxel plus cisplatin plus 5-fluorouracil followed by radiotherapy alone 
 
or chemoradiation (CRT) or radiotherapy concomitant with cetuximab provided that 
 
recurrence occurs within 6 months of completing local therapy 
 
- patients who have completed cisplatin-based CRT with or without ICT provided that 


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recurrence occurs within 6 months of completing local therapy. The minimum cumulative 
 
dose of cisplatin during CRT must be 200 mg/m². 
 
- patients with recurrent and/or metastatic SCCHN who relapse after platinum-based 
 
(cisplatin or carboplatin) chemotherapy given in first-line with an interval < 12 months 
 
- patients with metastatic SCCHN at diagnosis who have been treated with platinum-based 
 
(cisplatin or carboplatin) chemotherapy in first-line and relapse with an interval < 12 
months. 
The definition of failure is as follows: 
 
- refractory disease: progression during platinum-based regimen 
 
- resistant disease: progression during the time from completion of platinum-based 
 
chemotherapy but < 6 months after its completion 
 
- or other type of failure: progression > 6 months but < 12 months after completion of  
 
platinum-based chemotherapy 
4. No more than one prior chemotherapy regimen for recurrent/metastatic disease. Prior treatments 
with targeted therapy used in monotherapy are allowed 
5. Minimum interval of 4 weeks between the completion of first-line chemotherapy and 
randomisation 
6. Measurable or non measurable disease 
7. WHO performance status < 1  
8. Age > 18 years and < 80 years 
9. Adequate haematological function: absolute neutrophil count (ANC) > 1.5 x 109/L, platelets > 
100 x 109/L, haemoglobin > 10g/dL.  
10. Adequate hepatic function: transaminases < 2.5 x Upper Limit of Normal (ULN), total bilirubin 
< 1.5 x ULN, alkaline phosphatase < 5 x ULN 
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12. Women of childbearing potential must be using a medically accepted method of contraception 
(barrier methods, oral contraceptives, intrauterine devices) 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 
13. Fertile men must be using adequate contraceptive measures throughout the study period and for 
up to 3 months after the last dose of study treatment if their partner are women of childbearing 
potential 
14. The patient must have access to social insurance if applicable in the local regulations 
15. 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. 
4.2. 
EXCLUSION CRITERIA 
If any of the following apply, the patient must not enter into the study:  
1. Nasopharyngeal carcinoma 
2. History of brain or leptomeningeal involvement 
3. History of other cancers except other synchronous head and neck squamous cell carcinomas, 
adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the 
skin or other cancer curatively treated with surgery and/or radiotherapy (with or without other anti-
cancer therapy) and with no evidence of disease for at least 3 years 
4. Albumin level < 35 g/L 
5. Patients with weight loss ≥ 5% within the last 3 months 


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6. Recurrent pulmonary or upper airways infections (3 times or more in the last 3 months) requiring 
antibiotics and/or any infection requiring antibiotics within the last month before study entry 
7. Grade > 2 peripheral neuropathy at study entry according to NCI-CTC AE (version 3.0) 
8. Serum potassium < the lower limit of normal 
9. ECG demonstrating a QT/QTc interval > 480 msec 
10. A female is not eligible to enter the study if : 
 
. Pregnant or lactating 
 
. 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 
Male unwilling or unable to use a medically accepted method to avoid pregnancy throughout the 
study period and at least 3 months following the last dose of study treatment if their partners are 
women of childbearing potential 
12. Patients with any underlying medical condition that might be aggravated by treatment or which 
cannot be controlled i.e. active serious infection, poorly controlled diabetes mellitus, concurrent 
heart failure [New York Heart Association (NYHA) class III-IV] or with progressive or unstable 
angina, myocardial infarction within 6 months, and/or poorly controlled hypertension. 
13. “Third space” fluids (pleural effusion, ascites, massive edema) 
14. Concomitant treatment with any other anti-cancer therapy and contraindicated medication (see 
Section 6.1) 
15. Prior treatment with vinca-alkaloids and methotrexate 
16. Participation into a clinical study of an investigational agent within 30 days before study entry 


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4.3. 
NUMBER OF PATIENTS 
An estimated sample size of 265 randomized patients in each arm was expected, i.e. a total of 530 
randomised patients. The required number of events to observe at the final analysis is 437 deaths. 
An approximately 19 months accrual period was planned. 
Following the decision to stop the recruitment, 459 patients have actually been enrolled in this 
study with a 1:1 ratio for randomization. 
The details of the original sample size are given in Section 11.1. 
5. STUDY TREATMENT 
5.1. 
STUDY DRUG ADMINISTRATION 
5.1.1. 
Vinflunine and methotrexate (arm A) 
Descriptions  of  study  drugs,  storage,  packaging,  labelling and  drug accountability are given in 
Section 10. 
Patients randomised to arm A will receive vinflunine on day 1 as a 20 minute IV infusion at 280 
mg/m² and methotrexate on days 1 and 8 as a bolus intravenous injection at 30 mg/m² of every 
three-week cycle. 
The total dose to be given will be calculated according to body surface area (BSA). In calculating 
BSA, actual heights and weights should be used. BSA should be recalculated prior to the next cycle 
dosing. 
5.1.1.1. 
Vinflunine 
The calculated dose of vinflunine will be administered as follows: 
1. Mix vinflunine in a 100 mL bag of normal saline (NS) or 5% glucose solution. 
2. Establish venous access on a large vein preferably in the upper part of the forearm or 
using a central venous line (CVL). 


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The veins of the dorsum of the hand and veins close to joints should be avoided. 
3. Start a venous infusion of 500 mL bag of NS or 5% glucose solution at a free-flowing rate to 
assess the patency of the vein. 
4. Infuse the vinflunine over 20 minutes. Piggy-back the vinflunine infusion to the side injection 
port closest to the 500 mL NS or 5% glucose solution bag. This allows the vinflunine to be 
further diluted during administration. 
5. Assess for patency frequently during the infusion, 
6. Maintain extravasation precautions throughout the infusion. 
7. After vinflunine infusion is completed (the line must be totally drained), run the remaining NS 
or 5% glucose solution bag at a flowing rate of 300 mL/hour (volume of at least 100 ml) for 
flushing the vein. 
5.1.1.2. 
Anti-emetic and laxative prophylaxis 
- Antiemetic prophylaxis will consist of a single dose of dexamethasone 8 mg or an equivalent dose 
of methylprednisolone just before each infusion. 
- Administration of vinflunine requires addition of dietary measures and laxatives, to avoid 
potentially serious constipation, starting the day of each vinflunine administration (day 1) to 
day 5 as follows: 
 Dietary measures including proper dietary fluid and fibre intake: 
- Oral hydration: at least 1.5 litres of water per day. 
- Diet containing high fibre foods (10 to 20 g of bran, whole-wheat breads and cereals 
or 5 fresh or cooked vegetables or fruits) 
 Administration of laxatives listed below : 
- predominantly stool softener : lactulose, polyethylene glycol, docusate sodium, milk of 


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magnesium or mineral oil (paraffin) 
- or predominantly stimulant : senna derivatives, cascara or bisacodyl. 
Dose for laxatives are per investigator discretion. Use of other laxative treatment is allowed upon 
prior sponsor approval. 
For patients considered at increased risk of serious constipation, defined as: 
 History of chronic or refractory constipation, 
 Concomitant treatment with opioids, 
 Peritoneal carcinomatosis or abdominal tumour masses, 
 Persistent symptoms under vinflunine despite the days 1 to 5 dietary measures and 
laxatives administration, 
the use of a stool softener and a stimulant is recommended to maximise efficacy (Droney J, 2008). 
Mouthwash is recommended as prophylaxis of stomatitis. 
5.1.1.3. 
Methotrexate 
Mouthwash is recommended as prophylaxis of stomatitis. 
On day 1, methotrexate will be administered by direct bolus injection through the side arm of the 
remaining NS or 5% glucose solution bag after completion of vinflunine infusion. 
On day 8, methotrexate will be administered though the side arm of a freely running NS or 5% 
glucose solution IV infusion. 
5.1.2. 
Methotrexate (arm B) 
Descriptions of study drug, storage, packaging, labelling and drug accountability are given in 
section 10. 
Patients randomised to arm B will receive methotrexate on a weekly basis as a bolus intravenous 
injection at the dose of 40 mg/m²/week. The drug will be administered by direct injection through 
the side arm of a freely running NS or 5% glucose solution IV infusion. 


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One cycle of methotrexate is defined as a three-week period, i.e. 3 weekly administrations of 
methotrexate (days 1, 8, and 15). 
5.2. 
GUIDELINES FOR TREATMENT MODIFICATIONS 
Treatment will be modified in case of dose limiting haematological and/or non haematological 
toxicity. Dose adjustment and/or treatment delay are to be made according to the body system 
showing the greatest degree of toxicity. Toxicities will be graded according to the NCI Common 
Terminology criteria for Adverse Events (version 3.0). 
5.2.1. 
General considerations 
After any dose reduction, this dose is then maintained with no re-escalation of doses in 
subsequent cycles. 
Re-treatment may be delayed by one week up to 2 weeks pending recovery. Any patient who 
requires a delay of more than 2 weeks, for whatever reason, will be taken off study. 
In case of toxicity, all dosing adjustment or delay should be applied to both drugs of arm A unless 
there is another specific recommendation. 
5.2.2. 
Vinflunine (arm A) 
5.2.2.1. 
Dose modifications 
Guidelines which have to be applied for dose modifications are detailed in Table 4. 
The dose of i.v. vinflunine may be decreased depending on how well the patient tolerates the study 
drug. Dose of i.v. vinflunine will be reduced as described below. 
Table 4: Dose reduction of IV vinflunine 
Dose Level 
Vinflunine 
0 (starting dose) 
280 mg/m² 
-1 
250 mg/m² 
-2 
225 mg/m² 


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Patients requiring dose reductions below dose level -2 must discontinue study drug with the 
following exception: patients with responding disease after consultation and approval by the 
sponsor. 
5.2.2.2. 
Treatment modifications for haematological toxicity 
Complete blood cell counts will be performed on days 1 and 8 of each cycle during the treatment 
period. If a patient experienced fever (temperature ≥ 38°C) and/or developed infection, blood cell 
count should be immediately performed. 
Cycle delay 
Cycle is considered delayed if Day 1 treatment has been performed: 
- 
either ≥ 21 + 4 days since last Day 1 study drug administration (i.e., Day 26 or more). 
- 
or ≥ 14 + 4 days since last Day 8 study drug administration 
Neutrophil count should be > 1.5 x 109/L (grade 1) and platelet count > 100 x 109/L before each 
new cycle. 
Table 5 details haematological toxicity which must result in cycle delay. 
Table 5: Dose delay for haematological toxicity on day 1 of each cycle 
Haematological toxicity on scheduled day 1 
Day 1 administration of study treatment 
Absolute neutrophils 
 
Platelets 
 
ANC ≥ 1.5 x 109/L 
And 
≥ 100  x 109/L 
No dose modification. Treat on time 
ANC < 1.5 x 109/L 
And/Or 
< 100  x 109/L 
Delay one week and reassess 
If recovery has not occurred after a 2-week delay, the treatment will be discontinued unless 
approved by the sponsor. 
Dose modifications 
Table 6 details haematological toxicity which must result in dose reduction. 
Table 6: Dose modifications for haematological toxicity 
Haematological toxicity during the previous cycle 
Dose adjustment for next cycle 


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Grade 3 thrombocytopenia 
(platelets > 25 x 109/L and  < 50 x 109/L) with 
significant bleeding or requiring transfusion 
 
Grade 4 thrombocytopenia 
(platelets < 25 x 109/L) 
First appearance : decrease one dose level 
Grade 4 neutropenia  
(ANC < 0.5 x 109/L) lasting ≥ 5 days 
Second appearance : decrease one dose level 
Neutropenic infection (grade > 3 neutropenia 
concomitant with grade > 3 infection) 
Third appearance : stop treatment 
Febrile neutropenia of any grade 
 
5.2.2.3. 
Treatment modifications for non-haematological toxicity 
Based on prior clinical experience of i.v. vinflunine, non-haematological adverse events which may 
require treatment modification include : 
- nausea and vomiting 
- constipation 
- stomatitis 
- and peripheral neuropathy. 
Therefore, specific recommendations for treatment modifications for each of these adverse events 
are provided in this section. 
Rare cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been observed after 
administration of vinflunine. The typical clinical symptoms and signs are, with various degrees: 
neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and 
gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the 
posterior regions of the brain. Clinical and radiological features usually resolved rapidly without 
sequelae after treatment discontinuation.  
Vinflunine must be discontinued in patients who develop neurological signs of PRES. 
Cycle delay 
Rules defining the cycle delay are the same as outlined in section 5.2.2.2. 


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All non-haematological toxicity, except alopecia and fatigue should be resolved to grade < 1 prior 
to starting a new cycle of treatment. 
If grade > 3 toxicity persists for more than 2 weeks, the study drug should be permanently 
discontinued. 
Dose modifications 
The table below outlines dose modifications for non-haematological toxicity. 
Table 7: Dose modifications for non-haematological toxicity 
Non haematological toxicity during the 
previous cycle 
Dose adjustment for next cycle 
Constipation 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
Grade 4 
 
 
Maintain treatment at the same dose 
Adjust laxative therapy* 
 
Decrease one dose level 
Adjust laxative therapy* 
 
Discontinue treatment 
Stomatitis 
 
 
Grade 2 
 
 
Grade > 3 
 
 
Maintain treatment at the same dose 
 
Decrease one dose level 
Peripheral neuropathy 
 
 
Grade 2 
 
 
Grade > 3 
 
 
Decrease one dose level 
 
Discontinue treatment 
Other grade > 3** toxicities 
To be adjusted as medically indicated after discussion between 
investigator and sponsor 
Hyperbilirubinemia 
 
Grade 2 (> 1.5 x ULN ***and ≤ 3.0 x ULN) 
 
Grade 3 (>3.0 x ULN) 
 
Decrease dose to 250 mg/m² 
Delay treatment until recovery to grade 2 and resume at 250 mg/m² 
Decreased creatinine clearance (Cockroft-
Gault) 
 
< 40 ml/min and ≥ 20 ml/min 
 
< 20 ml/min 
 
Decrease dose to 250 mg/m² 
Discontinue treatment 
* Give a stimulant and a stool softener 
** Except grade 3 fatigue 
*** Upper limit of normal 


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5.2.3. 
Methotrexate in Arm A 
5.2.3.1. 
Dose modifications 
The following dose levels will be used in modifying the dose of methotrexate in arm A: 
 
Table 8: Dose reduction of methotrexate in Arm A 
Dose level 
Methotrexate 
0 (starting dose) 
30 mg/m² 
- 1 
20 mg/m² 
Patients requiring dose reductions to less than 20 mg/m² must be discontinued with the exception 
of responding patients after consultation and approval by the sponsor. 
5.2.3.2. 
Treatment modifications for haematological toxicity 
Complete blood cell counts will be performed before each administration of methotrexate. 
Cycle delay 
Cycle is considered delayed if Day 1 treatment has been performed: 
- 
either ≥ 21 + 4 days since last Day 1 study drug administration (i.e., Day 26 or more). 
- 
or ≥ 14 + 4 days since last Day 8 study drug administration 
Neutrophil count should be > 1.5 x 109/L (grade 1) and platelet count > 100 x 109/L before each 
new cycle (day 1 administration) as shown below. 
 
Table 9: Arm A- Dose delay of methothrexate on day 1 for haematological toxicity 
Haematological toxicity before day 1 administration 
Day 1 administration of study treatment 
Absolute neutrophils 
 
Platelets 
 
ANC ≥ 1.5 x 109/L 
and 
≥ 100  x 109/L 
No dose modification. Treat on time 
ANC < 1.5 x 109/L 
and / or 
< 100  x 109/L 
Delay cycle and reassess one week later 
 


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Dose delay / cancellation of methotrexate at day 8 
If neutrophils count are < 1.5 x 109/L and/or platelets count < 100 x 109/L, the day 8 administration 
should be delayed 1 week, to day 15. If no recovery after reassessment one week later, the dosing 
should be cancelled (Table 10). 
This protocol does not allow other cases of dosing delay of methotrexate. Any delay of a 
methotrexate dosing done outside of this above rule (also shown in Table 10) will be recorded as a 
delay and as a protocol deviation, (≥ 4 days with respect to the planned day). 
Table 10: Dose delay or cancellation of methotrexate at Day 8 in Arm A 
Haematological toxicity before administration 
Absolute Neutrophils 
 
Platelets 
Day 8 
ANC > 1.5 X 109/L 
and 
> 100 X 109/L 
Treat on time 
ANC < 1.5 x 109/L 
and / or 
< 100 x 109/L 
Delay 1 week and reassess. If no 
recovery, dose must be cancelled 
Dose modifications 
Table 11 details severe haematological toxicity which must lead to dose reduction. 
Table 11: Dose modifications of methotrexate for haematological toxicity in Arm A 
Haematological toxicity after the previous 
administration 
Dose adjustment for next administration 
Grade 3 thrombocytopenia 
(platelets > 25 x 109/L and  < 50 x 109/L) with 
significant bleeding or requiring transfusion 
 
Grade 4 thrombocytopenia 
(platelets < 25 x 109/L) 
First appearance : reduce one dose level 
Grade 4 neutropenia  
(ANC < 0.5 x 109/L) lasting  ≥ 5 days 
 
Neutropenic infection (grade > 3 neutropenia 
concomitant with grade > 3 infection) 
Second appearance: stop MTX 
Febrile neutropenia of any grade 
 


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5.2.3.3. 
Treatment modifications for non-haematological toxicity 
The non haematological adverse events which may require treatment modifications include: 
- stomatitis 
- increased transaminases 
- and less often, nausea, vomiting, diarrhoea and skin rash. 
Cycle delay 
Rules defining the cycle delay are the same as outlined in section 5.2.3.2. 
Day 1 administration must be delayed in case of grade > 1 stomatitis or grade > 1 increase of 
transaminases (> 2.5 x ULN). Methotrexate must not be readministered before total recovery. 
If recovery requires more than 2 weeks, methotrexate should be permanently discontinued. 
Dose cancellation  
Administration on day 8 must be cancelled in case of grade > 1 stomatitis or grade > 1 increase of 
transaminases (> 2.5 x ULN). 
The protocol does not allow Day 8 dosing delay of methotrexate in case of non-haematological 
toxicity. Any delay of a methotrexate Day 8 dosing will be recorded as a delay and as a protocol 
deviation if it has been performed ≥ 7 + 4 days since last Day 1 study drug administration (i.e., Day 
11 or more).


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Dose modifications 
The table below outlines dose reduction for non-haematological toxicity. 
Table 12: Dose modifications of methotrexate in Arm A for non-haematological toxicities 
Non haematological toxicity after the previous administration 
Dose adjustment for next 
administration 
Stomatitis 
 
Grade 1 
 
Grade 2 
 
Grade > 3 
 
Maintain the same dose 
Decrease one dose level 
Discontinue MTX 
Transaminases 
 
> 2.5 x ULN and < 5.0 x ULN 
 
> 5.0 x ULN and < 20 x ULN 
 
Decrease one dose level 
Discontinue MTX 
Decreased creatinine clearance (Cockroft-Gault) 
 
≤ 60 mL/min and ≥ 20 mL/min  
 
< 20 mL/min 
 
Decrease one dose level 
Discontinue treatment 
Other grade > 3* toxicities 
To be adjusted as medically indicated 
* except grade 3 fatigue 
5.2.4. 
Methotrexate in Arm B 
5.2.4.1. 
Dose modifications 
The following dose levels will be used in modifying the dose of methotrexate: 
Table 13: Dose reduction of methotrexate in Arm B 
Dose level 
Methotrexate 
0 (starting dose) 
40 mg/m² 
- 1 
30 mg/m² 
- 2 
20 mg/m² 
Patients requiring dose reductions to less than 20 mg/m² must be discontinued with the exception 
of responding patients after consultation and approval by the sponsor. 
5.2.4.2. 
Treatment modifications for haematological toxicity 
Complete blood cell counts will be performed before each administration of methotrexate. 


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Cycle delay 
Dosing is considered delayed if Day 1 treatment has been performed: 
- 
either ≥ 21 + 4 days since last Day 1 study drug administration (i.e., Day 26 or more). 
- 
or ≥ 14 + 4 days since last Day 8 study drug administration 
- 
or ≥ 7 + 4 days since last Day 15 study drug administration 
Neutrophil count should be > 1.5 x 109/L (grade 1) and platelet count > 100 x 109/L before each 
new cycle (day 1 administration) as shown below. 
Table 14: Arm B - Dose delay of methotrexate on day 1 for haematological toxicity 
Haematological toxicity before day 1 administration 
Day 1 administration of study treatment 
Absolute neutrophils 
 
Platelets 
 
ANC ≥ 1.5 x 109/L 
and 
≥ 100  x 109/L 
No dose modification. Treat on time 
ANC < 1.5 x 109/L 
and / or 
< 100  x 109/L 
Delay cycle and reassess one week later 
If recovery has not occurred after a 2-week delay, the treatment will be discontinued unless 
approved by the sponsor. 
Dose delay / cancellation of methotrexate at days 8 and 15  
This protocol does not allow other cases of dosing delay of methotrexate. Any delay of a 
methotrexate dosing done outside of this above rule (also shown in Table 10) will be recorded as a 
delay and as a protocol deviation, (≥ 4 days with respect to the planned day). 
The days 8 and 15 administrations should be cancelled if neutrophils count are < 1.5 x 109/L and/or 
platelet count < 100 x 109/L as shown below. 
Table 15: Dose cancellation of methotrexate within a cycle in Arm B 
Haematological toxicity before administration 
Arm B 
Absolute Neutrophils 
 
Platelets 
Day 8 
Day 15 
ANC > 1.5 X 109/L 
and 
> 100 X 109/L 
Treat on time 
Treat on time 
ANC < 1.5 x 109/L 
and / or 
< 100 x 109/L 
Dose cancellation 
Dose cancellation 
 


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Dose modifications 
Table 16 details severe haematological toxicity which must lead to dose reduction. 
Table 16: Dose modifications of methotrexate in Arm B for haematological toxicity 
Haematological toxicity after the previous 
administration 
Dose adjustment for next administration 
Grade 3 thrombocytopenia 
(platelets > 25 x 109/L and  < 50 x 109/L) with 
significant bleeding or requiring transfusion 
 
Grade 4 thrombocytopenia 
(platelets < 25 x 109/L) 
First appearance : reduce one dose level 
Grade 4 neutropenia  
(ANC < 0.5 x 109/L) lasting ≥ 5 days 
Second appearance : reduce two dose levels 
Neutropenic infection (grade > 3 neutropenia 
concomitant with grade > 3 infection) 
Third appearance : stop treatment 
Febrile neutropenia of any grade 
 
5.2.4.3. 
Treatment modifications for non haematological toxicity 
The non haematological adverse events which may require treatment modifications include : 
- stomatitis 
- increased transaminases 
- and less often, nausea, vomiting, diarrhoea and skin rash. 
Cycle delay 
Rules defining the cycle delay are the same as outlined in section 5.2.4.2. 
Day 1 administration must be delayed in case of grade > 1 stomatitis or grade > 1 increase of 
transaminases (> 2.5 x ULN). Methotrexate must not be readministered before total recovery. 
If recovery requires more than 2 weeks, methotrexate should be permanently discontinued. 


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Dose cancellation (days 8 and 15) 
Administration on days 8 and 15 in arm B must be cancelled in case of grade > 1 stomatitis or 
grade > 1 increase of transaminases (> 2.5 x ULN). 
This protocol does not allow other cases of dosing delay of methotrexate. Any delay of a 
methotrexate dosing done outside of this above rule (also shown in Table 10) will be recorded as a 
delay and as a protocol deviation, (≥ 4 days with respect to the planned day). 
Dose modifications 
The table below outlines dose reduction for non-haematological toxicity. 
Table 17: Dose modifications of methotrexate in Arm B for non-haematological toxicities 
Non haematological toxicity after the previous administration 
Dose adjustment for next 
administration 
Stomatitis 
 
Grade 1 
 
Grade 2 
 
Grade > 3 
 
Maintain the same dose 
Decrease one dose level 
Decrease two dose levels 
Transaminases 
 
> 2.5 x ULN and < 5.0 x ULN 
 
> 5.0 x ULN and < 20 x ULN 
 
Decrease one dose level 
Decrease two dose levels 
Decreased creatinine clearance (Cockroft-Gault) 
 
≤ 60 mL/min and ≥ 20 mL/min  
 
< 20 mL/min 
 
Decrease one dose level 
Discontinue treatment 
Other grade > 3* toxicities 
To be adjusted as medically indicated 
* except grade 3 fatigue 
 
 
5.2.5. 
Discontinuation of vinflunine or methotrexate in Arm A due to toxicity 
Patients in arm A who require discontinuation of methotrexate may remain on vinflunine alone for 
the remainder of the study. Likewise, patients who require discontinuation of vinflunine may 
remain on methotrexate alone for the remainder of the study. 


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The patients who require discontinuation of methotrexate must continue with vinflunine at the 
current dose level for at least one more cycle. For patients who require discontinuation of 
vinflunine, methotrexate dosing must be increased to 40 mg/m² for at least one more cycle. 
Thereafter,  
• if toxicity subsequently occurs, that requires treatment modifications of methotrexate, rules 
described in Arm B should  apply (Table 16, Table 17). 
5.3. 
TREATMENT ASSIGNMENT 
Patients will be randomised after written informed consent is obtained, all screening assessments 
(see 
Table 18, Section 7.1) are performed and the health-related quality of life questionnaire is 
completed. 
The investigator will determine a patient to be eligible and will enroll him/her by contacting the 
independent central registration center (either Interactive Voice Response System, IVRS, or 
Interactive Web Response System, IWRS). 
Randomisation will be stratified according to a minimisation procedure (Pocock SJ, 1975) set up 
by the independent central registration centre, on the following factors: 
 - WHO performance status (0 versus 1) 
 - Refractory or resistant to platinum versus other 
 - Prior radiotherapy (yes versus no) 
 - Prior treatment with any anti-EGFR medication (yes versus no) 
 - Center 
Randomisation and registration procedures are described in Section 7.2. 


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Patients withdrawn from the study retain their number. New patients must always be allotted a new 
patient number. 
5.4. 
DURATION OF TREATMENT 
Patients will receive at least 2 cycles of study drug unless there is disease progression or 
unacceptable toxicity. After the first 6 weeks of study treatment, tumour response will be assessed : 
patients who respond or have stable disease will receive 2 additional cycles and will be reevaluated 
for tumour response. Patients with progressive disease will be removed while patients who respond 
or have stable disease will continue study treatment until disease progression. 
In case of documented progression occurring before the first disease evaluation (6 weeks), the 
treatment will be discontinued and the response to treatment will be defined as early progression. 
6. CONCOMITANT MEDICATIONS 
All treatments given in addition to the study treatment at baseline and/or during the study are 
regarded as concomitant treatments and will be documented on the appropriate forms of the CRF / 
eCRF. 
6.1. 
PROHIBITED TREATMENTS 
6.1.1. 
Arms A and B 
• Concomitant use of yellow fever vaccine is contraindicated due to the risk of fatal 
generalized vaccinal disease. Concomitant use of live attenuated vaccines is not 
recommended due to the risk of systemic, possible fatal disease. 
• Patients must not receive any other anticancer treatment while on study. 
• During the study and within 30 days following the last study drug dosing the patient will not 
participate in another study. 
• In combination with methotrexate, the following medications are prohibited : 


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- phenylbutazone 
 
- indometacine 
 
- phenytoine 
 
- salicylates (used at antalgic, anti-pyretic or anti-inflammatory doses) 
 
- trimethoprim 
 
- and probenecid 
6.1.2. 
Arm A 
Strong inhibitors of the cytochrome P450 isoform 3 A4 (CYP3A4) are prohibited during study 
treatment, especially ketoconazole and ritonavir. A non-exhaustive list of inducers or inhibitors of 
CYP3A4 is provided in Appendix 8. Concomitant use of CYP3A4 inhibitors or inducers should be 
avoided during the treatment period since they could alter systemic exposure to vinflunine (IRPF 
CSR CA 18 3009). 
6.1.3. 
Arm B 
Cross-over to vinflunine is prohibited. 
6.2. 
RESTRICTED TREATMENT 
6.2.1. 
Arm A 
Caution is warranted when administering vinflunine to patients taking drugs that are highly 
dependent on CYP3A4 for metabolism and have a narrow therapeutic index. Systemic exposure to 
these medications could be increased while receiving vinflunine. 
Even if no data is available, the opposite impact to that from inhibitors (that is decrease in 
vinflunine blood levels) may be anticipated. Concomitant CYP3A4 inducers should be avoided 
(list provided in Appendix 8), if possible, since they could alter the systemic exposure to 
vinflunine. 


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The use of concomitant medications that prolong the QT/QTc interval should be avoided (list 
provided in http://crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=All). 
6.2.2. 
Arm A and B 
The concomitant use of non steroidal antiflammatory drugs including selective inhibitors of 
cyclooxygenase 2 and penicillin is not recommended because those drugs can decrease the renal 
clearance of methotrexate. 
6.3. 
AUTHORISED TREATMENTS 
• In the two study arms : 
- ancillary treatments will be given as medically indicated: antiemetics, antidiarrhoeals, 
antibiotics etc 
- analgesics (if opioids are given, laxative prophylaxis should be adapted in the vinflunine 
arm (arm A) according to section 5.1.1.2) 
- localized palliative radiotherapy will be allowed if the irradiation concerns less than 10% 
of the bone marrow reserve (see Appendix 3) 
- prophylactic or therapeutic use of G-CSF will be permitted according to institutional 
guidelines. 
- erythopoietin according to institutional practice 
- nutritional support 
7. PLAN OF THE STUDY 
Written informed consent will be obtained from the patient before any study specific procedure is 
undertaken. Patients will be informed about the study, both verbally and by reviewing the patient 
information sheet and consent form. The patient must be given the opportunity to ask questions and 
be given time to consider his/her participation. The investigator and the patient will both sign and 
personally date the consent form as confirmation of consent. 
Following the amendment PA11, the addendum to the informed consent will be signed by all 
patients (under treatment or in follow-up). 


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7.1. 
SCREENING PERIOD 
The screening period is the time preceding randomization and includes the 21-day period for 
performing screening assessments. 
Table 18: Study procedures during the screening period 
Study screening procedure 
Timing – Comments 
Written informed consent 
To be obtained and signed both by the patient and the investigator 
prior to any study specific procedure 
Demography, medical history,  diagnosis and 
prior therapy 
To be done once at baseline 
Serum or urine pregnancy test in women of 
childbearing potential 
Test within 72 hours prior to the first study treatment. 
TUMOUR ASSESSMENT 
- Cervical CT-Scan or MRI (1) 
- Chest / upper abdominal CT-Scan or MRI (1) 
- Other imaging if necessary (3) 
Mandatory assessments are to be performed within 21 days prior to 
the first study treatment. 
SAFETY ASSESSMENTS 
- Electrocardiogram 
- Laboratory test (2) 
Within 7 days prior to first study treatment 
PHYSICAL EXAMINATION 
Height, weight, blood pressure and pulse, 
temperature, performance status (WHO score) 
Within 7 days prior to first study treatment 
SYMPTOMS / CONCOMITANT 
TREATMENTS 
Within 2 weeks  prior to first day of treatment 
Health-related QUALITY OF LIFE (EORTC 
QLQ-C30 and QLQ H & N 35 questionnaires) 
To be obtained before randomisation (within 24 hours) 
(1) Chest CT-scan must include the supraclavicular area 
(2) Haematology: complete blood count. Serum chemistry: transaminases, alkaline phosphatase, total bilirubin, total 
protein, albumin, urea, creatinine and calculated (Cockroft-Gault) creatinine clearance, glucose, calcium, sodium, 
potassium, magnesium, chloride, bicarbonate 
(3) Bone scintigraphy, brain CT-scan or MRI, etc 
7.2. 
ASSIGNMENT OF SCREENING NUMBER 
For any patient screened, the site will assign a unique screening number which cannot be reused for 
any reason. Patient who have completed all specified baseline screening procedures and satisfy all 
the inclusion/exclusion criteria may be proposed for randomisation. For each site, a patient 
screening log is to be completed with the patient's screening number and the registration number, 
assigned by the randomisation if the patient is registered. If a patient is not registered, the reason for 
exclusion from the study will be recorded in this log. 


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7.3. 
STUDY ENTRY 
Randomisation will be performed by using Interactive Voice Response System (IVRS) or 
Interactive Web Response System (IWRS). 
Once written consent has been given by the patient, all inclusion/exclusion criteria must be checked 
by the investigator in order to confirm eligibility, prior to IVRS (or IWRS) randomisation 
procedure. The following information will be required when the investigator calls the IVRS or logs 
in IWRS for patient enrolment: 
• study code, 
• personal user access number and secret code 
• institution name, investigator's name and country 
• patient's birth date (day/month/year) 
• answers to the questions relating to the stratification factors 
• patient’s eligibility. 
The IVRS / IWRS will randomly assign the patient to one of the two treatment arms and will 
allocate the patient a registration number that will be communicated to the investigator. In parallel, 
the sponsor will receive this registration number as well as any information submitted by the 
investigator during the randomisation procedure. 
The patient number will have six digits. The first two digits identify the country; the third and 
fourth, the centre; and the last two digits the patient within the centre. This patient registration 
number must be reported on all CRF pages and in any study document. A patient who has not been 
randomised and registered before the first administration will not be accepted for the study at a later 
date. 
 


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Randomisation is the starting point of the study, it is mandatory not to exceed an interval of 1 
week between the date of registration and the start of the study treatment. In any case, all 
events occurring after registration must be recorded in the CRF /eCRF and will be taken into 
account in the analysis, whether the patient received the study treatment or not. 
7.4. 
EVALUATION DURING THE STUDY PERIOD 
The treatment period begins on the day of randomisation and continues until 30 days after the last 
study treatment administration. 
The following assessments need to be completed throughout the treatment period: 
Table 19: Assessments during the treatment period 
Assessments 
Timing - Comments 
PHYSICAL EXAMINATION including 
weight, blood pressure and pulse, 
temperature, performance status (WHO 
score) 
To be performed at day 1 of each cycle. 
REVIEW OF SYMPTOMS, TOXICITY 
AND TREATMENTS 
To be performed at day 1 of each cycle. 
All clinical findings and results from any complementary examination 
should be recorded in the CRF / eCRF. 
LABORATORY TESTS (1) 
 
Haematology 
- To be performed within 24 hours on days 1 and 8 of each cycle in arm 
A and before each weekly administration in arm B 
- In case of fever or infection according to institutional standards and 
investigator decision. 
Serum chemistry 
- To be performed within 24 hours before day 1 of each cycle in both 
arms (except glucose, total protein and albumin every 6 weeks) 
ECG  
- To be performed on D1 of the first cycle before and after drug 
administration in both arms and then every two cycles in both arms 
TUMOUR ASSESSMENT (2) 
To be performed every 6 weeks (+/- 3 working days) from 
randomisation (regardless of the timing of treatment cycles). 
All sites identified at baseline must be evaluated at each tumour 
assessment. 
Health-related QUALITY OF LIFE (EORTC 
QLQ-C30 and QLQ H & N 35)  
To be assessed every 6 weeks 
 
(1) 
Haematology: complete blood cell count. 
 
 
Serum chemistry: transaminases, alkaline phosphatase, total bilirubin, total protein, albumin, urea, creatinine and  
 
 
calculated (Cockroft-Gault) creatinine clearance, glucose, calcium, sodium, potassium, magnesium, chloride,  
 
 
bicarbonate 
 
(2) 
Tumour assessment: all target lesions (measurable disease) and non-target lesions (non-measurable disease) 
 
 
found at baseline should be re-investigated at each tumour assessment. Additional examinations may be  
 
 
performed if appearance of new lesions is suspected. 


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- 
Only the lesions found at baseline must be re-investigated. The same methods of assessment 
used at baseline should be used throughout the study to ensure comparability (i.e. scans performed 
immediately following bolus contrast administration using a standard volume of contrast, the 
identical contrast agent and preferably the same scanner). 
- 
Lesions on chest X-rays are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. 
- 
Ultrasound is not an acceptable method to measure disease. 
- 
All adverse events which occurred during the cycle must be assessed and documented using the 
CTCAE version 3.0. 
- 
ECG to be performed on day 1 of cycle 1 before and after drug administration in both arms. 
Thereafter, ECG will be performed before drug administration every 2 cycles in both arms. After 
review of safety data including ECG results by the IDMC, the need for repeated ECGs before each 
cycle can be revised. In case of QT/QTc > 500 msec (grade 3), patients should be hospitalized for a 
close and continuous ECG monitoring until cardiology consultation. 
- 
Concurrent prescriptions, blood products, palliative radiotherapy must be documented. 
7.5. 
END-OF-STUDY PERIOD EVALUATION 
Clinical workup to be performed within 30 days after last administration of study drug as detailed 
below. 
Table 20: Assessment at the end of study treatment 
Assessments 
End of study treatment evaluation 
PHYSICAL EXAMINATION: including 
weight, blood pressure, pulse, temperature, 
performance status (WHO score) 
To be performed within 30 days after discontinuation of study drug. 
REVIEW OF SYMPTOMS, TOXICITIES 
AND TREATMENTS 
To be performed within 30 days after discontinuation of study drug(1). 
All clinical findings and results from any complementary examination should be 
recorded in the CRF / eCRF. 
LABORATORY TESTS 
 
Haematology(2) and serum chemistry(3)  
To be performed within 30 days after discontinuation of study drug. 
TUMOUR ASSESSMENT(4) 
Patients who discontinued protocol treatment for other reason than disease 
progression have had tumour assessments every 6 weeks from time of 
randomisation until revised RECIST guideline (version 1.1) criteria for 


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progressive disease have been met. 
All sites identified at baseline had to be evaluated at each tumour assessment. 
At the time of the amendment PA11, no further assessments will be 
performed after the end of study treatment evaluation period. 
Health-related QUALITY OF LIFE (EORTC 
QLQ-C30 and QLQ H & N 35)  
To be performed within 30 days after discontinuation of study drug. 
(1) All AEs (except alopecia and fatigue) related to the study drug will be followed until recovery or return to the baseline status  
 
or grade 1 or until start day of a new anticancer therapy. 
(2) Haematology: complete blood cell count. 
(3) Serum chemistry: transaminases, alkaline phosphatase, total bilirubin, total protein, albumin, urea, creatinine, and calculated 
 
(Cockroft-Gault) creatinine clearance, glucose, calcium, sodium , potassium, magnesium, chloride, bicarbonate. 
(4) Additional examination may be needed if appearance of new lesions is suspected. 
 
The patient must not participate into another study of an investigational drug during the 30 days 
after study drug discontinuation. 
7.6. 
PREMATURE DISCONTINUATION 
A patient may voluntarily discontinue his/her participation in this study at any time. The 
investigator may also, at his or her discretion, discontinue the patient from participating in this 
study at any time. If a patient is prematurely discontinued for any reason, the investigator must 
make every effort to perform the assessments as outlined in Section 7.5 end-of-study treatment 
evaluation. These data should be recorded, as they comprise an essential evaluation that should be 
done prior to discharging any patient from the study. 
In the event that a patient is prematurely discontinued from the study at any time due to an adverse 
event (AE) (as defined in Section 9.1) or a serious adverse event (SAE) (as defined in Section 9.2), 
the procedures stated in Sections 9.1 and 9.2 must be followed. 
The primary reason for withdrawal will be clearly documented in the subject’s medical record and 
recorded in the CRF / eCRF. A final evaluation will be completed at the time of discontinuation for 
the study (see Section 7.5). Study treatment must be immediately discontinued for the following 
reasons: 
• Disease progression: any patient who experiences disease progression. The patient will be 
withdrawn from the study and reported as a progression for the final evaluation. 
• The investigator’s decision in the patient’s interest. Particularly, if a serious adverse event 
occurs and is considered by the investigator liable to threaten the health of the patient or if a 


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serious disease occurs and necessitates the prescription of a medication incompatible with the 
pursuit of the study. The study clinical manager (monitor) will be informed by phone or fax 
and the investigator will complete the SAE notification form (Appendix 5) to be forwarded 
to the monitor as soon as possible. 
• An erroneous inclusion according to the protocol. The decision to maintain or not the patient 
in the study will be taken jointly by the investigator and the sponsor. 
• Patient compliance: any significant non-medical deviation from the protocol 
• Investigator non-compliance: any significant medical or non-medical deviation from the 
protocol 
•  A patient who wishes to stop the study treatment may do so at any time but must inform the 
investigator. In this case, the investigator should attempt to contact the patient as soon as 
possible for a final assessment in order to: i) evaluate the patient's clinical condition, ii) if 
necessary, take the appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• A patient who wishes to withdraw his/her consent from the study participation for any reason 
may do so at any time but must inform the investigator. In this case, the investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: i) have 
the patient's decision written in the consent form, ii) obtain the reason for withdrawal and 
report it in the CRF / eCRF, iii) evaluate the patient's clinical condition, iiii) if necessary, 
take the appropriate therapeutic measures: management of an adverse effect or concomitant 
disease, prescription of another treatment. 
• Any other reason to be documented. 
All patients who have received at least one dose of study drug will be evaluable for safety analysis. 
In all cases, available data will be retained for the safety analysis. 


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7.7. 
FOLLOW-UP PERIOD ASSESSMENT 
The follow-up period was initially defined as the time from 30 days after the last study treatment 
administration (last administration of the last study drug administered) until death. 
For patients randomised to arm B (methotrexate), cross-over to vinflunine was prohibited. 
1- For patients who discontinued the study treatment before the occurrence of disease 
progression. 
Clinical and radiological assessments of all lesions had to be performed every 6 weeks from time of 
randomisation until disease progression was documented in addition to survival information listed 
below. 
2- For patient who discontinued the study treatment due to PD. 
Survival information had to be collected approximately every month for the first 6 months and then 
every 3 months until death. 
Had to be recorded: 
• Date last known to be alive and WHO score. 
• If deceased, date, place and cause of death, source of information and performance or not of 
an autopsy. 
• Date and type of subsequent anti-cancer therapy and best response to this therapy. 
At the time of the amendment PA11, there will be no more follow-up period for this study. 


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8. MEASUREMENTS AND EVALUATION 
8.1. 
EFFICACY ASSESSMENT 
8.1.1. 
Overall survival 
The main endpoint of this study is overall survival defined as the time from randomisation to the 
date of death or last follow-up. For patients who have not died, survival duration will be censored 
at the date of last contact or last follow-up. 
8.1.2. 
Evaluation of tumour response 
The same methods of assessment and the same technique should be used at baseline and throughout 
the study to ensure comparability (i.e. scans performed immediately following bolus contrast 
administration using a standard volume of contrast, the identical contrast agent and preferably the 
same scanner). Imaging-based evaluation is preferred to evaluation by physical examination when 
both methods can be used to assess a lesion. CT-scan and MRI are preferred. If not available, 
sequential CT-scan could be used. IV contrast should be used for all patients, unless 
contraindicated. All anonymised images (coded identification of patients) must be duplicated, 
either as CD rom or original films performed at the same time as those performed for the 
investigator, in order to be made available for the sponsor only upon request. They could be used 
for an independent review. 
Ultrasound should not be used to measure tumour lesions. 
The clinical response will be determined using the revised RECIST guideline version 1.1 (Therasse 
P, 2000, Eisenhauer E, 2009). 
Lesions are categorised into one of the two following groups for the purposes of response analysis 
measurable and non-measurable lesions. All the measurable lesions up to a maximum of 2 
lesions per organ and 5 lesions in total will be measured every 6 weeks and will be considered as 
“target lesions”. All the other lesions (non target measurable lesions and non-measurable lesions) 
will be regularly assessed as present or absent or unequivocal progression. 


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8.1.2.1. 
Disease measurability 
♦ Measurable lesions 
Tumour lesions must be accurately measured in at least one dimension (longest diameter to be 
recorded) with a minimum size of : 
 
- 10 mm by CT-scan (CT-scan slice thickness no greater than 5 mm) 
 
- 10 mm caliper measurement by physical examination 
 
- 20 mm by chest x-rays, sequential CT-scan or MRI 
Lymph nodes are defined as measurable if their short axis is > 15 mm by CT-scan. (CT-scan slice 
thickness recommended to be no greater than 5 mm). 
These lesions will be identified as target lesions and will be recorded and measured at baseline. 
CT-scan is the best currently available and most reproducible method for measuring target lesions. 
Irradiated tumour lesions will not be eligible for measurable disease while lesions appearing in a 
previously irradiated area will be considered as measurable lesions. 
"Cystic lesions" thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However if non-cystic lesions are 
present in the same patient, they will be preferred as target lesions. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, that can 
be evaluated by cross sectional imaging techniques such as CT-scan or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
♦ Non-measurable lesions 
Non-measurable lesions are all the lesions other than measurable lesions, including small tumour 
lesions (longest diameter < 10 mm with CT-scan or < 20 mm with conventional techniques and 


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MRI), pathological lymph nodes with short axis > 10 mm but < 15 mm by CT-scan as well as truly 
non-measurable lesions. 
Lesions that are considered as truly non-measurable include the following : 
• 
Lytic bone lesions or mixed lytic-blastic lesions without identifiable soft tissue 
components and blastic bone lesions 
• 
Leptomeningeal disease 
• 
Ascites 
• 
Pleural / pericardial effusion 
• 
Lymphangitis cutis / pulmonis 
• 
Abdominal masses / organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques 
All these lesions will be identified as non-target lesions. Their measurements are not required and 
these lesions will be followed as "present" or "absent", or in rare cases "unequivocal 
progression". 
8.1.2.2. 
Criteria for evaluation 
♦ Target lesions 
The evaluation of target lesions will be performed using the sum of the diameters (longest for 
tumour lesions, short axis for lymph nodes) for all these lesions. If lymph nodes are to be 
included in the sum, then, as noted above, the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterise the objective tumour response of 
the measurable dimension of the disease as follows : 
• Complete Response (CR) : disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 


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• Partial Response (PR) : at least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters. 
• Progression (PD) : at least a 20% increase in the sum of diameters of target lesions 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. Note that the appearance of one or 
more lesions is also considered as a progression. 
• Stable Disease (SD) : neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum diameters while on study. 
♦ Non target lesions 
The evaluation of non-target lesions will be as follows : 
• Complete Response (CR): disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
• Non-CR / Non-PD: persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
• Progression (PD): appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions such as increase in a pleural effusion from “trace” to “large”, 
increase in lymphangitic disease from localised to widespread. 
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden on the basis of non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease, i.e. an increase in tumour burden 
representing an additional 73% increase in volume (which is equivalent to a 20% increase diameter 
in a mesurable lesion). 


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8.1.2.3. 
Best overall response 
The best overall response is determined once all the data for the patient are known. 
Best overall response is defined as the best response across all time points. 
Determination of the overall response in case of presence of target lesions with or without non-
target lesions is detailed in Table 21. For patients with non-target lesions only, determination of the 
overall response is given in Table 22. 
Table 21: Time point response: patients with target (+/- non target) disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-target tumour lesions including pleural effusion, ascites, lymphangitis and/or bone lesions 
which are not associated with symptom appearance or symptom worsening will not disqualify a 
response reported on target lesions if they are not evaluated. 
Non target lymph nodes must be evaluated to document a response reported on target lesions.  
In those patients who had bone lesions at study entry, non target bone metastases must be evaluated 
(bone scintigraphy) to document an overall complete response. 
Table 22: Time point response: patients with non target disease 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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8.2. 
SAFETY ASSESSMENT 
8.2.1. 
Clinical safety 
The following tests will be performed prior to and on specified days during and following therapy: 
• Complete history of malignant and non-malignant diseases, 
• Full physical examination including vital signs, weight, assessment of performance 
status, 
• ECG at baseline, and throughout the study treatment: on day 1 of cycle 1 before and 
after drug administration in both arms and then before drug administration every 2 
cycles in both arms. After review of safety data including ECG results by the IDMC, the 
need for repeated ECGs before each cycle can be revised. 
• Regular collection of adverse events and graded according to CTCAE version 3.0. 
8.2.2. 
Laboratory investigations 
The following tests will be performed according to study flow chart: 
• Complete blood cell counts, 
• Serum chemistry: transaminases, alkaline phosphatase, total bilirubin, total protein, 
albumin, urea, creatinine and calculated (Cockroft-Gault) creatinine clearance, glucose, 
calcium, sodium, potassium, magnesium, chloride, bicarbonate. 
8.3. 
PHARMACOKINETICS 
Not applicable in this study. 
8.4. 
QUALITY OF LIFE 
- During the course of the study, the patients will be asked to complete the QLQ-C30 
questionnaire and the QLQ-H & N 35 module to measure the health-related quality of life. 


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Support for the reliability and validity of the QLQ-C30 questionnaire and the QLQ H & N 35 
module has been reported in the published literature. 
- The QLQ-C30 questionnaire and the QLQ-H & N 35 module will be completed prior to 
randomisation (within 24 hours), every 6 weeks and at the end of treatment evaluation. 
- Patients will be considered evaluable for health-related quality of life analysis if they have 
completed at least 2 questionnaires (including the questionnaire completed within 24 hours prior 
to randomisation). Of note, if local language is not available the patient will not be evaluable. 
8.5. 
PHARMACOECONOMICS 
Data concerning chemotherapy (cycle, dose etc…), setting for chemotherapy, antiemetics, 
concomitant medication, material used (central venous line), adverse events, hospitalisations, 
consultations during chemotherapy, will be collected in order to perform a pharmaco-economic 
assessment (as a piggy-back study) of study treatments. Data will be collected in the CRF / eCRF. 
8.6. 
COMPLIANCE 
The administration of study treatment must be done in the investigational centre and supervised by 
a physician or a nurse of the department. For each patient, the investigator is responsible for 
dispensing the study medication delivered by the Institut de Recherche Pierre Fabre or its 
representative in accordance with the protocol (see Section 10.3). 
9. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
9.1. 
ADVERSE EVENTS 
9.1.1. 
Definition 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign 


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(including an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH-Guideline for GCP).  
All laboratory tests for which abnormal results are collected after the initiation of study treatment 
should be repeated until the values return to normal or to stable status. Abnormal results are 
defined as those falling out of the laboratory normal range that are clinically significant. The 
frequency with which such checks should be made will be defined at the investigator’s opinion 
depending on the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and the sponsor notified. 
9.1.2. 
Grading of adverse events  
The severity of adverse events should be determined using NCI CTC AE version 3.0. 
9.1.3. 
Reporting of adverse events 
Any adverse or intercurrent event occurring during the study period, spontaneously reported by the 
patient or observed by others, will be recorded in the CRF, either in paper or electronic version. 
Haematology and biochemistry adverse events will be extracted from the laboratory forms of the 
CRF. However, in case they result in seriousness and/or corrective treatment, and/or study drug 
treatment modifications and/or discontinuation, they will also be reported in the Pre-treatment or 
Adverse Events Form of the CRF.  
The records will describe the nature (diagnosis, signs and symptoms), severity, date/time of onset, 
date/time of end, outcome and actions taken, and relationship to study treatment (according to the 
investigator’s opinion). 
It will be specified whether the event is serious or not. 
AEs already recorded and designated as "continuing", should be reviewed at each subsequent 
assessment. If resolved, the details in the CRF / eCRF are completed. If any AE changes for the 
worse, in frequency of attacks/symptoms or in severity, a new record of the event must be started 


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(i.e. distinct reports are required for differing frequencies and/or severity of the same event to 
enable comprehensive safety reports and later analysis). 
9.2. 
SERIOUS ADVERSE EVENTS 
9.2.1. 
Definition of SAE 
A serious adverse event (SAE) includes, but is not necessarily restricted to, any event which:  
• results in death (whatever may be the cause), 
• is life-threatening, 
• results in persistent or significant disability/incapacity, 
• requires patient hospitalisation or prolongation of existing hospitalisation, 
• is a congenital anomaly or birth defect, 
• other events including cancer, overdosage, pregnancy and any additional adverse experience 
or abnormal laboratory values occurring during the study period defined by the protocol as 
serious or which the investigator considers significant enough or that suggests a significant 
hazard, contraindications, side effect or precaution will be handled as a serious adverse 
event. 
 
Any overdosage meeting a seriousness criteria should be reported as a SAE as described in § 9.3. 
Any pregnancy occurring after patient exposure to study drug, should be reported on the SAE 
notification form as described in Section 9.4. 
Any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below, will 
not be reported as SAE : 
- Planned (as per protocol) medical/surgical procedure, including central venous line (CVL) 
setting 
- Preparation for routine health assessment/procedure (e.g. routine colonoscopy), 


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- Planned medical/surgical admission (planned prior to entry into study trial, appropriate 
 documentation required), 
- Administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver respite, 
 family circumstances), 
- New treatment of the disease within 30 days after the last study drug administration 
All deaths occurring while the patient is on study including deaths due to disease progression and 
deaths within 30 days of last administration of study drug should be notified as SAE. 
Unexpected adverse drug reaction is defined as:  
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product) (see the ICH Guideline for 
Clinical Safety Data Management: definitions and standards for Expedited Reporting). 
9.2.2. 
Reporting of SAE  
All serious adverse events occurring during treatment and 30 days after the last study drug 
administration, according to the above-mentioned definitions, regardless of treatment or 
relationship to study drug, must be recorded by the investigator as soon as he/she is informed of the 
event.  
The investigator must notify the sponsor of this event by sending within 24 hours the "Notification 
of serious adverse event" form (initial report Appendix 5) with all the available information 
concerning the event, including the causality assessment, to : Pierre Fabre Corporate Vigilances 
Division, by email to: HQ.pharmacovigilance@pierre-fabre.com or by fax: + 33 (0) 1.49.10.80.90. 
9.2.3. 
Follow-up of SAE 
Any serious and/or unexpected adverse event should be medically well documented and the 
information should be available as soon as possible. 


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The investigator must draw-up a special clinical report and use the "Notification of serious adverse 
event" form ("follow-up") and collect the results of the carried out examinations and the reports of 
hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
9.2.4. 
SAE occurring after the study  
Any SAE occurring during 30 days following the last study drug administration for the subject 
should be notified to the sponsor. 
Should also be notified to the sponsor any event occurring at any time after the end of the study 
treatment for the subject that may be related to the study treatment according to the investigator’s 
opinion.  
9.2.5. 
Sponsor’s responsibilities for safety reporting purposes 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 2001/20/EC 
taking into account local specific requirements. The reference documents for each study drug will 
be last version in force (IB, SPC). Indeed, these reference documents are likely to be updated 
during the study. 
9.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. 
The main toxic effect due to an overdose of vinflunine is bone marrow suppression with a risk of 
severe infection. 
Medical management of overdose should include customary therapeutic and supportive medical 
interventions aimed at correcting the presenting clinical manifestations and preventing their 
possible complications. 


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In the absence of seriousness criteria, the overdosage and associated adverse event if any are only 
reported on the AE page of the CRF / eCRF. If the definition of seriousness criteria is met, the SAE 
notification form must be completed and transmitted to the sponsor. 
9.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the sponsor unless associated to a seriousness criteria 
(e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, the women 
must not be administered the study drug(s) and be withdrawn immediately from the study. 
If pregnancy is suspected while the subject is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner. The 
investigators must report to the sponsor any pregnancy which occurs during or after the patient 
exposure to the study drug and until 3 months after the last study drug administration. The 
investigator must immediately notify the monitor using the SAE notification form and also report 
the pregnancy on the AE page of the CRF / eCRF. 
Women who become pregnant during or after exposure to the study drug must be followed by the 
investigator until the completion / termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the sponsor (baby’s healthy status) as a follow-up using the 
SAE notification form. 
 


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10. CLINICAL PHARMACY 
10.1. 
PHARMACEUTICAL INFORMATION 
10.1.1. 
Pharmaceutical information of vinflunine 
10.1.1.1. Drug supply 
"Pierre Fabre Medicament" represented by "Institut de Recherche Pierre Fabre" will supply i.v. 
vinflunine to each investigational centre. 
Drug substance name 
• Recommended INN : vinflunine ditartrate 
• Chemical name (4’R) - 20’, 20’-difluoro 3'4’-dihydrovinorelbine L -(+) - tartrate (1 : 2) 
Drug product name 
• Commercial name: JAVLOR. 
Pharmaceutical forms 
Presentation: type I colourless glass vial containing concentrate for solution for infusion of 
vinflunine: 
• 50 mg / 2mL 
• 250 mg / 10 mL. 
Vinflunine must be diluted for administration. 
Composition: vinflunine ditartrate 68.35 mg corresponding to vinflunine (base) 50.00 mg and water 
for injection q.s.f. 2 mL or vinflunine ditartrate 341.75 mg corresponding to vinflunine (base) 
250.00 mg and water for injection q.s.f. 10 mL. 
10.1.1.2. Storage  
• The expiry date is indicated on the labels of the container and vials. 
• Store in a refrigerator (+2° C to +8° C) protected from light in original closed container. 


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• Do not freeze. 
• The stability study allows shipment (not more than 7 days) at temperature up to 30° C 
protected from light in the original closed container. 
• After dilution of product in polyethylene or polyvinyl chloride infusion bag, administration 
has to be undertaken within 24 hours when stored in the refrigerator (+2°C/+8°C) protected 
from light. If the product is exposed to light, administration has to be undertaken within one 
hour. 
10.1.2. 
Pharmaceutical information of methotrexate 
10.1.2.1. Drug supply 
Methotrexate will be supplied directly by “Pierre Fabre Medicament” represented by “Institut de 
Recherche Pierre Fabre” to each investigational centre. 
10.1.2.2. Storage 
See on the outer packaging. The expiry date is indicated on the labels of the container. 
10.2. 
PACKAGING AND LABELLING 
10.2.1. 
Packaging and labelling of vinflunine 
10.2.1.1. Packaging  
Vinflunine concentrate for solution for infusion is available in sealed polystyrene box with 
10 single-dose vials of vinflunine 50 mg / 2ml or 250 mg / 10 ml each. 
10.2.1.2. Packaging use 
Vinflunine must be used vial per vial for all patients according to dosage as given in Section 5.1.1. 
Each vial is for single use only. 


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10.2.1.3. Study drug labelling 
The labels will be in accordance with European Good Manufacturing Practices and the local 
requirements where the study is to be conducted. 
• Each box and each vial are labelled with information shown in Appendix 4 (i.v. vinflunine 
50 mg / 2ml and 250 mg / 10 ml). 
• One tear-off part label of each vial has to be stuck by the person in charge of dispensing 
(hospital pharmacist or investigator) on the appropriate drug accountability form (Appendix 6). 
• Additional documentation will be added in accordance with regulatory requirements if 
necessary. 
10.2.2. 
Packaging and labelling of methotrexate 
The labels will be in accordance with European Good Manufacturing Practices and the local 
requirements where the study is to be conducted. 
Methotrexate is available in vials of 50 mg / 2 ml. 
Methotrexate must be used vial per vial for all patients according to the dose given in section 5.1.2. 
Each vial is for single use only. 
Each box and each vial are labelled with information shown in Appendix 4. 
One tear-off label of each vial has to be stuck by the person in charge of dispensing (hospital 
pharmacist or investigator) on the appropriate drug accountability form (Appendix 6). 
Additional documentation will be added in accordance with regulatory requirements if necessary. 
10.3. 
ON SITE DRUG ACCOUNTABILITY AND DISPENSING 
Study drug supply will be performed by the IVRS (or IWRS) according to the procedures described 
in a user manual which will be given to the investigational centre personnel. Each person accessing 


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the IVRS / IWRS system will be assigned an individual unique access number as detailed in a 
specific charter (see section 5.4). 
The hospital pharmacist or investigator are responsible for adequate storage of the study medication 
according to the manufacturer recommendations and for dispensing the treatment to the patients. 
The study medication must be used in accordance with the protocol and only by the Investigator. 
The investigator and/or pharmacist must maintain adequate and accurate records, showing the 
receipt, storage and distribution of all supplies of the study medication delivered by the Institut de 
Recherche Pierre Fabre. 
These records include:  
• All the accompanying letters, which list the batch number of the medication, the quantities 
received, and the date of reception; 
• The Drug Accountability Forms (see Appendix 6) which include the patient’s identification, 
the date of dispensation, each quantity dispensed, and the identification of the dispenser. 
The original will be kept by the Sponsor and the copies will be left on site: one in the 
pharmacist’s file and one in the investigator’s file; 
• A summarized document entitled “Accountability of investigational products on site” which 
describes all the movements of investigational products during the trial. The original will be 
left in the pharmacist’s file and the copies in the study file, and in the investigator’s file. 
When necessary, study drug can be ordered by calling the IVRS (or logging in the IWRS). 
10.4. 
RECALL OF INVESTIGATIONAL PRODUCTS 
In case of recall of investigational products (decided by the Competent Authorities or the sponsor), 
the investigator will be immediately informed by the sponsor. 
The investigator, in collaboration with the sponsor representatives (monitor, CSC) must urgently 
stop the delivery of the concerned investigational products to the patients. 


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The monitor / CSC in collaboration with the Clinical Pharmacy Department organizes the return of 
the recalled products to the sponsor drug supply unit, according to the sponsor procedures. 
10.5. 
UNUSED DRUG AND DESTRUCTION 
Unused trial medications have to be kept by the investigator or returned to pharmacist. All unused 
drugs must be either destroyed or returned to the sponsor. Destruction will be performed according 
to both sponsor and investigator centre procedures and after checking by the local CRA. It is the 
Investigator’s or pharmacist’s responsibility to insure that the study medication used by the subjects 
plus the left over unused study medication equal the total amount received from the Sponsor. Any 
discrepancy should be explained. 
11. DATA ANALYSIS 
A complete statistical analysis plan (SAP) will be written before the database lock. 
11.1. 
SAMPLE SIZE 
The primary objective of the study is to show that the combination of IV vinflunine and 
methotrexate is superior to methotrexate alone in terms of overall survival. Patients will be 
randomised in a 1:1 ratio.  
The final analysis required at least 437 deaths to detect a statistically significant difference in the 
median OS of 7.5 months in the test arm versus 5.5 months in the control arm. This number of 
events gives a 90% power to show a difference between the two treatment arms using a two-sided 
log-rank test at an alpha = 0.05 significance level. An expected total number of 530 randomised 
patients was planned. 
Following the sponsor’s decision to stop the accrual, 459 patients have been randomised. The 
statistical analysis will be conducted on these 459 patients. 
325 events are expected to observe at the end of study allowing a power of 80%. 


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Whatever the number of events at the end of study, the final analysis of OS (primary analysis) will 
be performed on the ITT population. 
11.2. 
PROTOCOL DEVIATIONS 
No eligibility review will be performed. Eligibility population and evaluable population for tumor 
response will not be defined. 
11.3. 
POPULATION ANALYSED 
11.3.1. 
Intent-to-treat population (ITT) 
All randomised patients will be included in the Intent-To-Treat (ITT) population. They will be 
analysed in the arm they were assigned by randomisation. 
11.3.2. 
Eligible population 
The eligible population is a subset of the ITT population. To be eligible a patient should not have 
any major protocol deviations from inclusion and exclusion criteria. The major protocol deviations 
will be described in the SAP. The eligible patients will be analysed in the arm they were assigned 
by randomisation. 
11.3.3. 
Evaluable population for tumour response 
The evaluable population for tumour response is a subset of the Eligible population. To be included 
in the evaluable population, the patients have to be eligible, evaluable and treated in the arm 
assigned by randomisation. 
To be evaluable a patient must satisfy the following conditions: 
− Patients must have received a minimum of one study treatment administration and 
have tumour assessment at baseline and during study (after week 6) unless progression 
or death from progression is documented before the first on-study tumour assessment at 
week 6. In this case, the patient will be considered as evaluable with early progression, 


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− In patients with measurable disease, all baseline target lesions must have been 
assessed at least once 6 weeks after randomisation, with the same method of 
measurement as baseline, 
− In patients with only non-measurable disease, non-target lesions must have been 
assessed at least once 6 weeks after randomisation, with the same method of 
measurement as baseline. 
11.3.4. 
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. 
11.3.5. 
Evaluable population for health-related quality of life assessment 
To be evaluable for health-related quality of life assessment, patients should have completed one 
questionnaire (at least two third of the questions) within seven days prior to randomisation, and at 
least one questionnaire (at least two third of the questions) during the study period. To be 
considered evaluable, the questionnaires should be available in the native language of the patient, 
otherwise, the patient will not be evaluable for quality of life. 
11.4. 
DEFINITIONS 
• Survival time 
Survival time is measured from the date of randomisation up to death or last follow-up. For patients 
who have not died, survival duration will be censored at the date of last contact if the patient is lost 
to follow-up or at the date of last news. 
• Objective Response Rate 
The Objective Response Rate (ORR) will be calculated as follows: 
(
)
N
PR
CR
ORR ∑
+
=
#
#
 


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with:  
- 
# CR = number of patients whose best response is CR, 
- 
# PR = number of patients whose best response is PR, 
- 
N = number of patients qualified for efficacy analysis. 
• Disease Control Rate 
The Disease Control Rate (DCR) will be calculated as follows: 
(
)
N
SD
PR
CR
DCR ∑
+
+
=
#
#
#
 
with:  
- 
# CR = number of patients whose best response is CR, 
- 
# PR = number of patients whose best response is PR, 
- 
# SD = number of patients whose best response is SD (SD does not include non 
CR/non PD), 
• N = number of patients qualified for efficacy analysis. 
Table 23: Definitions of ORR and DCR 
Type of population 
analysed 
Observed number of best responses 
Measurable and/or non-
measurable disease 
CR 
PR 
ORR =(CR + PR)/N 
SD 
DCR = (CR + PR + SD)/N 
Non CR/Non PD* 
PD 
NE 
Total (N) 
Measurable disease only 
CR 
PR 
ORR = (CR + PR)/N 
SD 
DCR = (CR + PR + SD)/N 
PD 
NE 
Total (N) 
* For patients with only non measurable disease 


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• Duration of objective response 
The duration of objective response will be measured for responders (confirmed CR + PR) from the 
time that measurement criteria are met for complete or partial response (whichever status is 
recorded first) later confirmed, until the date of progression or the date of death due to any cause. 
Patients who are lost to follow-up or reach the time point of analysis without a known record of 
progression or death will have the duration of response censored at the date of last tumour 
assessment or last contact date of a follow-up showing no progression, whichever occurred last. For 
patients who receive a new anti-cancer treatment in the absence of progression, the duration of 
response will be censored at the date of first administration of the new anti-cancer treatment. 
• Duration of disease control 
The duration of disease control will be measured for patients with objective response or stable 
disease, from the date of randomisation until the date of progression or the date of death whatever 
the cause. Patients who are lost to follow-up or reach the time point of analysis without a known 
record of progression or death will have the duration of disease control censored at the date of last 
tumour assessment or last contact date of a follow-up showing no progression, whichever occurred 
last. For patients who received a new anti-cancer treatment in the absence of progression, the 
duration of disease control will be censored at the date of first administration of this new anti-
cancer treatment. 
• Progression-free survival 
Progression-free survival will be calculated from the date of randomisation until the date of 
progression or death (whatever the reason of death). Patients lost to follow-up, or without a known 
record of progression or death at time of analysis will have the progression-free survival censored 
at the date of last tumour assessment or the date of last contact of a follow-up showing no 
progression, whichever occurs last. 


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• Time to treatment failure 
Time-to-treatment failure will be calculated from the date of randomisation up to the date of failure 
(progression, relapse, death or withdrawal due to adverse event, patient’s refusal to continue, lost to 
follow-up or start of new anti-cancer therapy). Patients who reach the time point of analysis without 
failure as defined above will have the time to treatment failure censored at the date of last tumour 
assessment or last contact of a follow-up not showing progression. Patients who discontinued 
treatment for other reason and who are lost to follow-up will be censored at the date of last contact. 
• Time to response 
Time to response will be calculated from the date of randomisation up to the first report of 
documented response. 
11.5. 
CLINICAL STATISTICAL METHODS 
11.5.1. 
Statistical methodology 
The statistical analysis will be performed by Institut de Recherche Pierre Fabre. Data will be 
analysed using the SAS system software version 8.2 (or later if available) for Windows. All 
statistical tests will be two-sided at a 5% level of significance unless otherwise specified. 
Summary tables will be provided according to the standard format of Institut de Recherche Pierre 
Fabre developed for the vinflunine chemotherapy. 
Continuous data will be summarized with the following items: frequency, median, (if n≥ 3), range 
and mean and standard error if relevant. 
Categorical data will be presented in contingency tables with frequencies and percentages of each 
modality (including missing data modality). 
Whatever the number of events at the end of study, the final analysis of OS (primary analysis) will 
be performed on ITT population. 


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Only descriptive analyses will be performed on all secondary efficacy analyses for ITT population 
(secondary analyses on primary and secondary parameters, subgroup analyses, QoL). 
Safety analyses will be performed as planned. 
11.5.1.1. Statistical methods for categorical, ordinal and quantitative variables 
11.5.1.1.1. Statistical methods for categorical variables 
The χ² 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. 
11.5.1.1.2. 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. 
11.5.1.1.3. 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 two 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. 
11.5.1.2. Statistical methods for time to event 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 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 center) used at the time of randomisation. 


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Multivariate analyses will be performed to take account of prognostic factors. A stratified Cox 
proportional hazards model and a logistic regression will be applied to the Overall Survival, 
Progression-Free Survival, and tumour response, respectively. A stepwise procedure, with p = 8% 
to enter variables in the model and p = 10% to remove variables from the model, will be used to 
select the best model. 
11.5.1.3. Statistical methods for health-related Quality of Life data 
Repeated measures data will be analysed with a mixed effect model with change from baseline as 
the response. The most suitable covariance structure will be chosen according to Akaike’s 
Information Criterion and Schwartz’ Bayesian Criterion, between unstructured, compound 
symmetric and autoregressive of order 1. 
11.5.2. 
Baseline assessment 
All baseline data will be tabulated on the intent to treat population: 
• Demographic data, 
• Characteristics of the disease at diagnosis, 
• Prior anti-cancer treatment, 
• Clinical and biological parameters 
11.5.3. 
Efficacy assessment 
11.5.3.1. Efficacy parameters 
11.5.3.1.1. Primary efficacy parameter 
The primary efficacy parameter is overall survival. 
11.5.3.1.2. Secondary efficacy parameters 
The secondary efficacy parameters are:  
• The Progression-Free survival in both arms, 


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• The Objective Response and Disease Control rates in both arms, 
• The duration of response, disease control and time to first response in both arms. 
11.5.3.2. Efficacy analyses 
11.5.3.2.1. Primary efficacy analysis 
The primary efficacy analysis will be led on the Overall Survival. The hypothesis of superiority will 
be accepted if the p-value from a stratified log-rank test is smaller than 0.05. 
The stratification factors will be those used at the time of randomisation except center because of 
the high number of participating centers in the study : 
− WHO performance status (0 versus 1), 
− Refractory or resistant to platinum versus other, 
− Prior radiotherapy (yes versus no), 
− Prior treatment with anti-EGFR medication (yes versus no). 
The primary efficacy population will be the intent-to-treat population. 
11.5.3.2.2. Supportive analysis of the primary efficacy parameter 
To ensure the consistency of the primary endpoint, an additional OS analysis will be conducted on 
the Eligible population. A stratified log-rank test will be used to compare the two treatment arms. 
The stratification factors will be those defined above (see §11.5.3.2.1). 
11.5.3.2.3. Sensitivity analyses of the primary parameter 
In order to determine the role of the study treatments on survival, a sensitivity analysis will be 
done. In this analysis, the overall survival time will be censored at the time of the first further 
chemotherapy. As for the primary efficacy analysis, a stratified log-rank test will be used to 
compare the two treatment arms. The stratification factors will be those defined above (see 
§11.5.3.2.1). This analysis will be done on the ITT and Eligible population. 


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11.5.3.2.4. Secondary efficacy analyses 
11.5.3.2.4.1. Overall survival 
A multivariate analysis using a stratified Cox proportional hazard model for overall survival will be 
performed on the ITT and Eligible population. The stratification factors will be those defined above 
(see §11.5.3.2.1). The following prognostic factors will be taken into account : 
− Age (< 50 years versus ≥ 50 years), 
− Primary tumour site (oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, other), 
− Extent of disease (locoregional recurrence versus metastatic disease with or without 
locoregional recurrence, 
− Tumour grade (well or moderately differentiated, poorly differentiated). 
In case of missing data in some covariates of the multivariate analysis, in addition of the complete 
case analysis (listwise selection approach) consisting in omit those cases with missing data and to 
run the analysis on what remains, a multiple imputation based approach where complete data sets 
are drawn will be used to perform the multivariate analysis. The imputation model will be defined 
in the SAP. 
11.5.3.2.4.2. Progression-Free Survival 
The analysis of Progression-Free Survival (PFS) will be conducted on the ITT population and on 
the eligible population. A stratified log-rank test will be used to compare the two treatment arms. 
The stratification factors will be those defined above (see §11.5.3.2.1). In addition, the time interval 
between tumour assessments will be compared between the two arms. Median and range of time 
elapsed between two consecutive evaluations will be provided in both arms, overall and by cycle 
number. 
Sensitivity analyses of PFS will be performed in the ITT population and in the eligible population. 
Firstly, an analysis will be conducted in which patients who did not show evidence of PD before 
starting new anti cancer therapy will be censored at the date of initiation of new anti-cancer 
therapy. Secondly, the analysis will be repeated considering the start of new anti-cancer therapy as 


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an event. These two analyses aim at ruling out the bias that could arrive from the potential 
imbalance of further anti-cancer therapy between the two arms. 
Another sensitive analysis will consider the patient in progression the day after the last tumor 
assessment showing no progression. For patients who progressed early or were assessed as PD at 
the first evaluation, they will be considered as progressing at the day after the date of 
randomisation. This analysis aims at ruling out potential ascertainment bias and taking into account 
the potential imbalance of early progressors between the two treatment arms.  
A multivariate analysis using a stratified Cox proportional hazard model for Progression-Free 
Survival will be performed on the ITT and Eligible population with the same stratification factors 
as described above (see §11.5.3.2.1). The following prognostic factors will be taken into account : 
− Age (< 50 years versus ≥ 50 years), 
− Primary tumour site (oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, other), 
− Extent of disease (locoregional recurrence versus metastatic disease with or without 
locoregional recurrence, 
− Tumour grade (well or moderately differentiated, poorly differentiated). 
In case of missing data in some covariates of the multivariate analysis, in addition of the complete 
case analysis (listwise selection approach) consisting in omit those cases with missing data and to 
run the analysis on what remains, a multiple imputation based approach where complete data sets 
are drawn will be used to perform the multivariate analysis. The imputation model will be defined 
in the SAP. 
11.5.3.2.4.3. Tumour response 
The analyses of tumour response will be performed on the ITT population and on the population 
evaluable for response in the two treatment arms. 
 Objective Response and Disease Control Rate  
Objective Response Rate and Disease Control Rate in each treatment arm will be estimated and 
presented along with a corresponding 95% confidence interval. The ORR and DCR will be 


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compared between the two arms with a Cochran-Mantel-Haenszel (CMH) test. The stratification 
factors will be those defined above (see §11.5.3.2.1). 
Furthermore, the ORR and DCR will be estimated and compared between the two treatment arms 
in the subgroups of patients entering the study with measurable disease (i.e. excluding patients with 
only non-target lesions at baseline). 
A logistic regression for ORR and DCR will be performed in order to take into account the 
following prognostic factors: 
− WHO performance status (0 versus 1), 
− Refractory or resistant to platinum versus other, 
− Prior radiotherapy (yes versus no), 
− Prior treatment with anti-EGFR medication (yes versus no), 
− Age (< 50 years versus ≥ 50 years), 
− Primary tumour site (oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, other), 
− Extent of disease (locoregional recurrence versus metastatic disease with or without 
locoregional recurrence, 
− Tumour grade (well or moderately differentiated, poorly differentiated). 
 Time to first response 
The time to first response will be described in the ITT population and the evaluable population for 
response. No formal statistical comparisons are planned. 
 Duration of response and disease control 
Duration of response and duration of disease control will be analysed on the ITT and evaluable for 
response populations. A stratified log-rank test will be used to compare the two treatment arms. 
The stratification factors will be those defined above (see §11.5.3.2.1). 
Both analyses of duration of response and duration of disease control will be repeated in patients 
with measurable disease at study entry (i.e. excluding patients with only non-target lesions at 
baseline). 


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11.5.3.2.4.4. Subgroups analyses 
Descriptive subgroup analyses of Overall Survival, Progression-Free Survival, DCR and ORR will 
be performed according to: 
− WHO performance status (0 versus 1), 
− Refractory or resistant to platinum versus other, 
− Prior radiotherapy (yes versus no), 
− Prior treatment with anti-EGFR medication (yes versus no), 
− Age (< 50 years versus ≥ 50 years), 
− Primary tumour site (oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, other), 
− Extent of disease (locoregional recurrence versus metastatic disease with or without 
locoregional recurrence, 
− Tumour grade (well or moderately differentiated, poorly differentiated). 
These analyses will be conducted on the ITT and Eligible populations for Overall Survival and 
Progression-Free Survival, and on the ITT and evaluable for response populations for DCR and 
ORR. No formal statistical comparisons are planned. 
11.5.4. 
Safety assessment 
11.5.4.1. Safety parameters 
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 CTC AE version 3.0 will be used. 
11.5.4.2. Safety analyses 
The safety analysis will be performed in the evaluable population for safety. For haematological 
and biochemical parameters, the worst NCI CTCAE version 3.0 grade will be presented by patient 
and by cycle. The maximum NCI CTC AE version 3.0 grade or severity will be reported by patient 
for each treatment-emergent adverse event. All analyses will be performed in two different ways: 
regardless of relationship to study treatment and related to study treatment. 


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The analyses will present the NCI CTC AE version 3.0 grades tabulated for each MedDRA 
“System Organ Class” (SOC) and “Preferred Term” (PT) per patient. 
In order to analyse the evolution of the biochemical toxicities, the worst NCI CTC AE version 3.0 
grade will be analysed according to the grade present at baseline. 
In addition, the relationship between the presence of liver metastases at baseline and the worst NCI 
CTC AE version 3.0 grade during study will be studied for AST, ALT and bilirubin. The same 
analysis will be done for the worst NCI CTC AE version 3.0 grade of alkaline phosphatase and the 
presence of liver and/or bone metastases at baseline. 
The number of all serious adverse events and related serious adverse events will be tabulated by 
treatment arm. Serious adverse events will be reported by patient. 
11.5.5. 
Quality of life  assessment 
Change in disease related symptoms will be assessed using the EORTC QLQ-C30 questionnaire 
and the QLQ-Head and Neck 35 EORTC module. 
11.5.5.1. Health-related quality of life parameters 
Health-related quality of life parameters will be the fifteen scales that can be derived from the 30 
questions of the EORTC QLQ-C30 questionnaire: 
− A global health-related quality of life scale, 
− Five functional scales: physical, role, cognitive, emotional, social, 
− Nine symptom scales: nausea and vomiting, pain, fatigue, dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea, financial difficulties. 
The QLQ-H&N 35 EORTC module will also be used to assess health-related quality of life. 
Eighteen scales are derived from the 35 questions of the QLQ-H&N 35 EORTC module : 
− Seven multi-item scales that assessed Pain, Swallowing, Senses, Speech, Social eating, 
Social contact and Sexuality. 


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− Eleven single item : Teeth, Opening mouth, Dry mouth, Sticky saliva, Coughing, Feeling 
ill, Use of pain killers, Use of nutritional supplement, Use of feeding tube, Lost of weight 
and Gain of weight. 
11.5.5.2. Health-related quality of life analyses 
The analysis of health-related quality of life will be done on the evaluable population for quality of 
life. Compliance with the questionnaires will be displayed per evaluation. Compliance is defined as 
the number of forms actually received as a proportion of those expected. The number of QoL 
questionnaires completed and evaluable per evaluation will also be given. The number of patients 
non evaluable for health-related quality of life analysis and reasons for non-evaluability will be 
tabulated. 
Each parameter will be described at baseline. Changes of the scores from baseline of the parameters 
(15 for QLQ-C30 and 13 for QLQ-H&N 35) will be provided. Figures will be displayed in order to 
show the evolution of each scale. 
A repeated measure analysis will be performed for all scales and single items with change from 
baseline as the response. 
11.5.6. 
Interim analyses 
An Independent Data Monitoring Committee (IDMC) will be set up to ensure that for patients 
participating in the study there is no increased risk for harm. This IDMC will review study data as 
detailed below. The analyses will be performed by an internal statistician independent from the 
study. A separate IDMC charter will describe the activities of this committee. 
11.5.6.1. Early Safety Review 
An early safety review of data will be done by the IDMC after 40 patients are randomised (20 in 
each arm) and treated for at least 1 cycle. 


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11.5.6.2. Efficacy and Safety Interim Analysis 
An interim analysis based on the non progression rate at 6 weeks will be performed after tumour 
response data from the first 100 randomised patients in the test arm become available. The main 
purpose of this interim analysis is to stop the study if result indicating poor efficacy of the test 
regimen is observed. It is assumed that the test arm will be of no further interest in the second-line 
treatment of SCCHN patients if the observed non-progression rate at 6 weeks (first tumour 
assessment scheduled) is less than the lower limit of the 95% CI of the expected non-progression 
rate at 6 weeks. Assuming that this expected non-progression rate at 6 weeks is equal to 61%, the 
95% CI is [51%-71%] and the study will be stopped prematurely if > 49 progressions (or deaths for 
progression) out of 100 evaluable patients for efficacy will be observed. 
To be evaluable a patient must satisfy the following conditions: 
− Patients must have received a minimum of one study treatment administration and 
have tumour assessment at baseline and during study (after week 6) unless progression 
or death from progression is documented before the first on-study tumour assessment at 
week 6. In this case, the patient will be considered as evaluable with early progression, 
− In patients with measurable disease, all baseline target lesions must have been 
assessed at least once 6 weeks after randomisation, with the same method of 
measurement as baseline, 
− In patients with only non-measurable disease, non-target lesions must have been 
assessed at least once 6 weeks after randomisation, with the same method of 
measurement as baseline. 
No formal early stopping rule on safety criteria will be applied. However, given the toxicity 
associated with IV vinflunine and methotrexate a special attention will be paid to the rates of : 
 
- febrile neutropenia  
 
- neutropenic infection 
 
- grade 3-4 ileus 
 
- and toxic deaths 


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The results of the interim analysis will be submitted to IDMC for their recommendation to pursue 
or stop accrual in the study. 
Tumour responses will be collected as soon as patients have been evaluated by the investigators. 
Adverse events reporting will be also closely monitored. Because the projected patient accrual 
could be slow in the study, the patient enrolment will continue while waiting the decision of the 
IDMC. 
Following this interim analysis, a futility analysis has been carried out. 
The results of this analysis showed that the probability to demonstrate a significant benefit of 
overall survival at the time of the final analysis is very low. 
As a consequence, the sponsor has decided to stop the recruitment of study patients on 16th 
October 2015. 
12. STUDY MONITORING AND DATA COLLECTION  
12.1. 
DATA COLLECTION 
12.1.1. 
CRF / eCRF  
All data obtained in the study described in this protocol will be recorded on CRFs. The CRF for 
each subject will be presented in a paper or electronic folder. The CRF / eCRF will be completed 
chronologically and updated regularly in order to reflect the most recent data on the patient 
included in the study. 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study 
related duties" form, showing the signatures and initials of all those who are authorised to make or 
change entries on the CRFs / eCRFs. 
In case of paper CRF, it must be neatly filled in with a black-inked pen. For each page on which 
information is entered, the subject number must be recorded. The Registration form, end of 
treatment form and the follow-up status form(s) must be dated and signed by an authorised 


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Investigator. Errors must be corrected by drawing a single line through the incorrect entry and by 
writing the new value as close as possible to the original. The correction must then be initialled and 
dated by an authorised person. 
Although subjects may be interviewed by a research nurse or the trained equivalent (e.g. medical 
student, physician’s assistant), the Investigator must verify that all data entries are accurate and 
correct, including verification that the subject fulfils the criteria for entrance into the study before 
study medication is dispensed. Physical examinations have to be performed by a registered medical 
practitioner. 
The End of Treatment Form must be completed for each patient either finishing the study or 
dropping out from it. 
In case of paper CRF, original forms (or top pages of forms) and the first 2 copies of these forms 
are retrieved by the Sponsor. The fourth copies are retained in investigator files. 
In case of eCRF, data will be transmitted securely on a server. 
The data may have to be used to support efficacy and/or safety claims, and therefore may have to be 
submitted for inspection to Health Authorities. If the Investigator moves, the subject files will be 
kept in the hospital archives. 
12.1.2. 
Source documents 
Definition:  
• Source Data: All information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
• Source Documents: Original documents, data, and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 


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microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical trial).  
The patients must have consented to allow their medical records to be viewed by sponsor-
authorised personnel and by regulatory authorities. This information is included in the informed 
consent. 
12.2. 
STUDY MONITORING  
Before selecting an investigational centre for the study, a pre-selection visit will be performed to 
verify that the site, the equipment and the staff comply with the protocol requirements and GCP 
guidelines. 
A Clinical Research Associate (CRA) will be appointed by the Institut de Recherche Pierre Fabre 
to monitor this study and periodically contact the site, including conducting on site visits. 
CRA activities will include: 
• 
Site initiation visit to collect and distribute essential pre-study documents ; to instruct the 
investigator and site personnel about the protocol, study procedures and expectations; to obtain 
investigator’s assurance to comply with study requirements and GCP guidelines and to inform the 
investigator and appropriate study staff about study materials. 
• 
Monitoring visits : according to Good Clinical Practices, the study CRAs involved in the 
present study are fully instructed concerning confidentiality and able to perform any necessary 
control on informed consent and CRFs / eCRFs, including cross-checking clinical and laboratory 
data with the patient’s file. All observations and findings should be verifiable. During monitoring 
visits, Institut de Recherche Pierre Fabre CRA will:  
- check and assess the progress of the study, 
- review collected study data, 
- conduct Source Document Verification (hospital files), 


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- identify any issue and address its resolution. 
This will be done in order to verify that the:  
- data are authentic, accurate, and complete, 
- safety and rights of subjects are being protected, 
- study is conducted in accordance with the currently approved protocol (and any amendments), 
GCP and all applicable regulatory requirements. 
The investigator agrees to allow the CRA direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the CRA to discuss findings and any relevant issues. 
• Termination visit: at study closure. CRAs will also conduct all activities as indicated in 
section 15.3. 
13. DATA MANAGEMENT 
13.1. 
DATA ENTRY 
The study data will be entered into a database in an ongoing basis. In case of paper CRF, 
independent double data entry will be performed by two different trained operators. The two entries 
will be compared in order to identify and resolve any data entry errors. 
13.2. 
DATA REVIEW 
Consistency checks will be performed on the data. The resulting edit queries will be transmitted to 
the monitoring team. Answers to these queries endorsed by the investigator will be integrated into 
the database. 
13.3. 
DATA CODING 
Adverse events will be graded according to the NCI CTCAE version 3.0 scale. 


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Adverse events will be coded according to MedDRA Dictionary. 
Concomitant medications will be coded according to WHO drug Dictionary. 
13.4. 
DATA STORAGE 
Data will be entered in databases and stored in a secure area on a server. 
13.5. 
DATA FREEZING 
After corrections and modifications have been performed, the databases will be locked. 
The data will be extracted from the databases into the SAS data files for statistical analysis. 
14. GENERAL ETHICAL CONSIDERATIONS 
14.1. 
ETHICAL CONDITIONS  
This study will be performed in accordance with the principles stated in the Declaration of Helsinki 
and subsequent amendments (Appendix 1) and in accordance with the Good Clinical Practice 
Guideline (CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that may 
be requested will be submitted for review to an Ethics Committee whose procedures and operations 
meet the National Legal Requirements. 
Depending on National Regulations, the application is submitted to the EC by the sponsor or by the 
investigator. 
A copy of the formal written approval from the EC is provided to the sponsor (directly by the EC or 
via the investigator) with a list of names and qualifications of its members. 


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The request for authorisation by the Competent Authority or notification (depending on National 
Regulations) is carried out by the sponsor. 
The screening of subjects does not start before the approval of the EC has been obtained and the 
study authorised by the Competent Authority (or notified to the Competent Authority, depending 
on the National Regulations). 
14.3. 
SUBJECT’S INFORMATION LEAFLET, CONSENT FORM AND 
SUBJECT CARD 
14.3.1. 
Subject’s information leaflet and consent form 
Any information must be given to the subjects before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guideline. It must also describe the measures taken to safeguard subject’s privacy and protection of 
personal data, according to European Directive 95/46 EC. 
Restraints and risks must be explained, as well as the right to discontinue participation in the study 
at any stage, without affecting their further relationship with the investigator and/or their future 
care. 
The written information and consent form must be submitted to the subject with an oral 
explanation. It must be agreed and signed by the subject before any study-related procedure starts. 
This information and consent procedure is under the investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
investigator, one copy is given to the subject and the last copy is kept by the Clinical Quality 
Assurance Unit of the sponsor in a sealed envelope at the end of study. 
Specific areas of the sponsor’s copy are not triplicated to avoid the reading of the subject’s surname 
first name, address and signature. 


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If any information becomes available during the trial that may be relevant to the subject’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the subject to confirm his agreement to continue participating. 
14.3.2. 
Subject card 
The patient will receive from the Investigating Centre a personal card to be kept all along the study 
duration and providing the following information: Patient’s name, Sponsor’s name, study code, 
EUDRACT number, date of treatment start, complete address of the Investigating Centre with the 
name and phone number of the Investigator and a sponsor 24H/24 phone contact number (French 
and English languages) : 33 (0) 5 63 35 25 83. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) are entered into a 
computer under the sponsor’s responsibility in accordance with the French law, “Loi informatique 
et Libertés” (January 6, 1978 and subsequent amendments) and with the European Directive 
95/46/EC. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and ICH GCP, PFM has an insurance policy intended 
to guarantee against possible damages resulting from research. 
The studies and/or experiments performed on behalf of PFM are specifically and expressly 
guaranteed. It is advisable to underline that non compliance with the research legal conditions are 
clauses of guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES  
15.1. 
PROTOCOL AMENDMENT 
Neither the investigator nor the sponsor may alter the protocol without the permission of the other 
parties. 


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All changes to the protocol will be subject to an amendment which must be dated and signed by 
both parties and must appear as an addendum to the protocol. 
Substantial amendments are submitted for approval/authorization to Ethics Committee and 
Competent Authorities. Urgent amendments are submitted for approval/authorization to Ethics 
Committee and Competent Authorities but could be implemented immediately under specific 
conditions defined with the sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATORS FILE STORAGE 
The investigator:  
- 
keeps all trial-related documents in appropriate file folders. Records of subjects, original 
informed consent forms, source documents, case report forms, drug inventory, EC and 
sponsor correspondence pertaining to the study must be kept on file; 
- 
retains all documents relating to the screening (consent and investigation results) of all 
subjects included in the trial or not; 
- 
retains a list of the subjects names, addresses (and/or number of medical file), code 
numbers, dates of entry into and completion of the trial period, to allow checking of data 
reported on CRFs / eCRFs with those from source documents; 
- 
authorises direct access to source documents for monitoring, audits and inspections. 
The trial-related documents must be retained as strictly confidential at the investigator’s site for at 
least 15 years after the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF STUDY 
15.3.1. 
End of study 
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Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. 
Early study termination 
15.3.2.1. Early study termination decided by the sponsor 
The sponsor may discontinue the study at any time for any of the following reasons: 
• Emerging adverse events of such a serious nature that continuation of the study becomes 
unacceptable; 
• Decision to stop the study based on the results of the interim analysis; 
• Recruitment rate too low to expect completion of the study in its present form within the 
period foreseen for inclusions; 
• Deviations from Good Clinical Practice and/or regulations; 
• Decision to stop drug development. 
If the study is prematurely discontinued, all study data must be returned to IRPF. In addition, the 
site must conduct final disposition of all unused study drugs in accordance with IRPF procedures 
for the study. 
15.3.2.2. Early study termination decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if it considers that the conditions of 
authorisation are not being met or has doubt about the safety or scientific validity of the study. 
15.4. 
AUDIT 
The sponsor is responsible for making sure that both his representatives (monitor, clinical research 
assistant) and the investigator fulfil their requirements as specified by the GCP guidelines. The 
audit can be made internally at IRPF and at the investigational site where the CRFs / eCRFs are 
matched against source documents. Possibility to have a direct access to all study documentation is 


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compulsory. The practical conditions for the audit will be discussed between the investigator and 
the Clinical Quality Assurance Department. 
Oral information about the audit results will be given to the investigator. 
15.5. 
INSPECTION 
The Health Care Authorities may inspect any investigation site or the sponsor during the course of 
the study or following its completion, to verify the conduct of the study and quality of the data. The 
investigator will provide direct access to source documents. 
15.6. 
CONFIDENTIALITY 
The present materials (protocol, CRF, investigator’s brochure) contain confidential information. 
Except if agreed to in writing with the monitor, the investigators must hold such information 
confidential, and must not disclose it to others (except where required by applicable law). 
15.7. 
CLINICAL STUDY REPORT 
Data analysis, statistical reporting and clinical research report preparation will be the responsibility 
of the sponsor or its designee. Upon completion of the data analysis, a final report, including a 
review of the objectives and methods, a presentation and discussion of the results will be drawn up 
according to ICH Guidelines (Structure and Content of Clinical Study Reports, ICH-E3, 
CPMP/ICH/137/95). This report will be a clinical and statistical integrated report. This report will 
be signed by the sponsor representatives and the coordinating investigators. 
15.8. 
STUDY RESULTS COMMUNICATION 
Upon completion of the study, global results of the Research will be communicated to the 
investigator. According to the Local Regulations, the patient can ask the investigator for the results 
(only if applicable in the concerned country). 


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15.9. 
PUBLICATIONS 
The information and data collected during the conduct of this clinical study are considered 
confidential and will be used by the sponsor in connection with the development of the study drug. 
These information may be disclosed as seemed necessary by the sponsor. 
To allow for use of information derived from this clinical study and to insure compliance with 
current regulations, the investigator is obliged to provide the sponsor with complete test results and 
all data developed in this study. Only the sponsor may make information obtained during this study 
available to the physicians and to regulatory agencies, except as required by regulation. 
All the results of this study including data reports, discoveries and inventions resulting from the 
study, are the property of the sponsor. 
In the event the sponsor chooses to publish the data from this study, the sponsor may provide the 
author(s) of the study with a manuscript at least 30 days prior to the expected date of submission to 
the intended publisher.  
The investigators reserve the right to publish or present the results of this study provided that a 
copy of the manuscript or abstract is made available to Institut de Recherche Pierre Fabre for 
review at least 30 days prior to the expected date of submission to the intended publisher or 
planned presentation. 
In addition, if necessary, investigators shall withhold publication an additional 60 days to allow the 
filing of a patent application or to allow the sponsor to take any measures he deems appropriate to 
establish and preserve his proprietary rights. 
It is agreed that publication of the results of the study by each site shall be made only as part of a 
publication of the results of the study obtained by all sites performing the protocol, once the study 
is completed and finalised. This publication will be the responsibility of the sponsor and the 
investigators. 


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The names on the author list will be given according to the participation in the design of the 
protocol as well as taking into consideration the accrual of eligible and evaluable patients by the 
investigators in each centre. 
 


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16. REFERENCES 
 
Baselga J., Trigo J., Bourhis J., et al 
Phase II multicenter study of the Antiepidermal Growth Factor Receptor monoclonal antibody 
cetuximab in combination with platinum-based chemotherapy in patients with platinum refractory 
metastatic and / or recurrent squamous cell carcinoma of the head and neck 
J. Clin. Oncol., 2005, 23 : 5568-5577 
Bellmunt J., Theodore C., Demkov T. et al 
Phase III trial of vinflunine plus best supportive care compared with best supportive care alone 
after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the 
urothelial tract 
J. Clin. Oncol., 2009, 27 : 4454-4461 
Bennouna J, Delord JP, Campone M, Nguyen L. 
Vinflunine: a new microtubule inhibitor agent. 
Clin Cancer Res. 2008 Mar 15; 14(6) : 1625-32 
Bennouna J, Fumoleau P, Armand JP et al. 
Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min 
infusion every 3 weeks in patients with advanced solid tumours 
Ann. Oncol. 2003 14(4) : 630-637 
Bonner J.A., Harari P., Giralt J. et al 
Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck 
New Eng. J. Med. 2006, 6 : 567-578 
Calabro F., Sternberg C.N. 
The evolving role of chemotherapy in advanced urothelial cancer 
Current Opinion in Supportive and Palliative care, 2007, 1 : 180-186 
Clavel M., Vermorken JB, Cognetti F. et al 
Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus 
cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell 
carcinoma of the head and neck 
Annals of Oncology, 1994, 5 : 521-526 
Colevas D. 
Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the 
head and neck 
J. Clin. Oncol., 2006, 24 : 2644-2652 
Delord JP, Stupp R, Pinel MC et al. 
Phase I study of Vinflunine given as a 10 minute intravenous (IV) infusion on a weekly schedule in 
patients (Pts) with advanced solid tumours 
Proc. Am. Soc. Clin. Oncol. 2001; 20: 111a, abstract # 441 


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Droney J, Ross J, Gretton S 
Constipation in cancer patients on morphine 
Support Care Cancer, 2008, 16 : 453-459 
Duflos A, Kruczynski A, Barret JM 
Novel aspects of natural and modified vinca alkaloids 
Curr Med Chem Anticancer Agents. 2002; 2 : 55 
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 (2) : 228 - 247 
Elomaa J., Joensuu H., Blomqvist C. 
Vinorelbine, methotrexate and fluorouracil (VMF) as first-line therapy in metastatic breast 
cancer : a randomized phase II trial 
Annals Oncol, 2003, 14 : 699 - 703 
Etievant C, Barret JM, Kruczynski A et al 
Vinflunine (20', 20'-difluoro-3', 4'-dihydrovinorelbine) a novel vinca alkaloid, which participates 
in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro. 
Investigational New Drugs 1998; 16: 3-7 
Etievant C, Kruczynski A, Barret JM et al 
Markedly diminished drug resistance-inducing properties of vinflunine (20’, 20’-difluoro-3’, 4’-
dihydrovinorelbine) relative to vinorelbine, identified in murine and human tumour cells in vivo 
and in vitro. 
Cancer Chemotherapy Pharmacol. 2001 Jul; 48(1): 62-70 
Fahy J, Duflos A, Ribet JP, Berrier C, et al 
Vinca alkaloids in superacidic media: a method for creating a new family of antitumour 
derivatives. 
J. Am. Chem. Soc. 1997; 119: 8576-7577. 
Focan CNJ, Van Heugen JC, Kreutz F et al 
Vinflunine metabolism and disposition in cancer patients.  
Proc Am Soc Clin Oncol 2002;21:124a (Abst 495). 
Forastiere A., Metch B., Schuller D. et al 
Randomised comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus 
methotrexate in advanced squamous-cell carcinoma of the head and neck : a southwest oncology 
group study 
J. Clin. Oncol., 1992, 10 : 1245-1251 
Goerner M., Seiwert T., Sudhoff H. et al 
Molecular targeted therapies in head and neck cancer. An update of recent developments 
Head and neck Oncology 2010, 2 : 1-5 
Harker W.G., Meyers F., Freiha F. et al 
Cisplatine, methotrexate and vinblastine (CMV) : an effective chemotherapy regimen for 
metastatic transitional cell carcinoma of the urinary tract 
J. Clin. Oncol, 1985, 3 : 1463 - 1470 


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Herbst R., Arquelte M., Shin D. et al 
Phase II multicenter study of the Epidermal Growth Factor Receptor antibody cetuximab and 
cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck 
J. Clin. Oncol., 2005, 23 : 5578-5587 
Hill BT, Fiebig HH, Waud WR et al 
Superior in vivo experimental antitumour activity of vinflunine, relative to vinorelbine, in a panel 
of human tumour xenografts. 
Eur J Cancer 1999; 35(3): 512-520 
Hill BT. 
VFL, a second generation novel Vinca alkaloid with a distinctive pharmacological profile, now in 
clinical development and Prospects for future mitotic blockers 
Curr. Pharm. Design 2001; 7: 1199-1212 
Hunt K., Longton G., Williams M. et al 
Treatment of malignant mesothelioma with methotrexate and vinblastine with or without platinum 
chemotherapy 
Chest, 1996, 109 : 1239 - 1242 
Institut de Recherche Pierre Fabre 
Phases I pharmacokinetics, excretion and metabolism study of intravenous tritiated Vinflunine 
([3H]-VFL) in patients with solid tumours. 
Study report L00070 IN 103 M038, 2001. On file. 
Institut de Recherche Pierre Fabre 
Effect of ketoconazole on the pharmacokinetics of intravenous vinflunine in patients with 
advanced cancer. 
Final Clinical Study Report CA 183009 2009. On file. 
Iop A., Cartei G., Isaia A. 
Vinorelbine, bleomycin and methotrexate as a salvage therapy for patients with head and neck 
squamous cell cercinoma in relapse after cisplatin / fluorouracil 
Annals Oncol., 1998, 9 : 225 - 227 
Jacobs C., Lyman G., Velez-Garcia E. et al 
A phase III randomised study comparing cisplatin and fluorouracil as single agents and in 
combination for advanced squamous cell carcinoma of the head and neck 
J. Clin. Oncol., 1992, 10 : 257-263 
Jacquesy JC, Fabry I 
Cancer : superacidic generation of new antitumour agents in biomedical chemistry: applying 
chemical principals to the understanding and treatment of disease. 
Edited by Paul Torrens, John Wiley and Johnes. 2000 : 227-245. 
Javlor , Summary of Products Characteristics 
http://www.ema.europa.eu/humandocs/humans/EPAR/javlor.htm 
Current version 


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Johnson JI, Decker S, Zaharevitz D et al. 
Relationships between drug activity in NCI preclinical in vitro and in vivo models and early 
clinical trials. 
British Journal of Cancer. 2001; 84(10), 1424-1431 
Johnson P, Geldart T, Fumoleau P, et al. 
Phase I study of Vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks. 
Invest New Drugs. 2006; 24(3) : 223-31 
Kruczynski A, Barret JM, Etievant C et al. 
Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated vinca alkaloid. 
Biochem. Pharmacol. 1998a; 55(5) : 635-648 
Kruczynski A, Colpaert F, Tarayre JP et al. 
Preclinical in vivo antitumour activity of vinflunine, a novel fluorinated vinca alkaloid. 
Cancer Chemotherapy Pharmacol. 1998b; 41 : 437-447 
Kruczynski A, Hill B.T. 
Vinflunine, the latest Vinca alkaloid in clinical development. A review of its preclinical anticancer 
properties. 
Critical Review in Oncology Haematology 2001, 40 : 159-173 
Krzakowski M., Ramlau R., Jassem J. et al 
Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small cell lung 
cancer previously treated with platinum-containing chemotherapy 
J. Clin. Oncol., 2010, 28 : 2167-2173 
Lobert S, Ingram JW, Hill B, et al. 
A comparison of thermodynamic parameters for vinorelbine and vinflunine induced tubuline self-
association by sedimentation velocity 
Molecular Pharmacol. 1998; 53:908-915 
Machiels JP, Subramanian S., Ruzsa A et al 
Zalutumumab plus best supportive care versus best supportive care alone in patients with 
recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-
based chemotherapy : an open-label randomised phase 3 trial 
Lancet Oncology, 2011 ; 12(4) : 333-343 
Methotrexate, Summary of Product Characteristics 
http://afssaps-prd.afssaps.fr/php/ecodex/frames.php?specid=69847122&typedoc=R&ref=R0161265.htm 
Current version 
Paule B, Saliba F, Gil-Delgado M-A et al. 
Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients 
with liver dysfunction (LD) – Pharmacokinetic results 
Proc. Am. Soc. Clin. Oncol. 2007; 25: 102s, abstract #  2523 
Pierre Fabre Medicament 
Vinflunine investigator brochure No.16.1 
Version 16.1, November 2013 


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Pivot X., Wadler S., Kelly C., et al 
Results of two randomised trials comparing nolatrexed versus methotrexate in patients with 
recurrent head and neck cancer 
Annals Oncol., 2001, 12 : 1595-1599 
Pocock SJ, Simon R 
Sequential treatment assignment with balancing for prognosis factors in the controlled clinical 
trial. 
Biometrics. 1975; 31 (1): 103-115 
Porta C., Brugnatelli S., Pratuno E. et al 
Single-agent vinorelbine as segond-line treatment for advanced or recurrent squamous-cell 
carcinoma of the head and neck 
Proc. Am. Soc. Clin. Oncol, 2001, 197b - Abstract 2537 
Posner M, Hershock D, Blajman C et al 
Cisplatin and 5-fluorouracil alone or with docetaxel in head and neck cancer 
N. Eng J. Med, 2007, 357 : 1705-1715 
Puozzo C, Vermorken JB, Bauer J et al 
Phase I pharmacokinetic study of vinflunine given on a weekly schedule 
Proc. Am. Soc. Clin. Oncol. 2001; 20: 89b, abstract #  2107 
Schornagel J.H., Verveij J., de Mulder P.H. et al 
Randomized phase III of edatrexate versus methotrexate in patients with metastatic and/or 
recurrent squamous cell carcinoma of the head and neck : a European Organization for Research 
and Treatment of Cancer head and neck cancer cooperative Group study 
J. Clin. Oncol. 1995, 13 : 1649-1655 
Seideman P., Beck O., Eksborg S., et al 
The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid 
arthritis 
Br J. Clin. Pharmacol., 1993, 35 (4) : 409 - 412 
Singer WD, Jordan MA, Wilson L, et al 
Binding of Vinblastine to stabilized microtubules 
Mol. Pharmacol. 1989, 36:366-370 
Stewart S., Cohen E., Licitra L. et al 
Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell 
carcinoma of the head and neck 
J. Clin. Oncol., 2009, 27: 1864-1871 
Study L00070IN117F0 
A Phase I dose-finding and pharmacokinetic study of IV vinflunine in combination with 
methotrexate in patients with recurrent or metastatic squamous cell carcinoma of the head and 
neck previously treated with platinum-based chemotherapy 
Preliminary Clinical Evaluation, 2014 


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Testolin A., Recher C., Cristaferi V. et al 
Vinorelbine in pre-treated advanced head and neck squamous cell carcinoma : a phase II study 
Invest New Drugs, 1994, 12 : 231-234 
Therasse P, Arbuck SG, Eisenhauer EA et al 
New guidelines to evaluate the response to treatment in solid tumours 
J. Nat. Cancer Institut 2000, 92 (3) : 205 - 216 
Tourani JM, Isambert N, Mourey L et al 
Influence of age on the pharmacokinetics of IV vinflunine results of a phase I trial in elderly 
cancer patients 
Proc. Europ. Soc. Meet. Oncol, 2010, Abstract 2887 
Vermorken JB, Catimel G., De Mulder P. et al 
Randomized phase II trial of weekly methotrexate versus two schedules of triweekly paclitaxel in 
patients with metastatic or recurrent squamous cell carcinoma of the head and neck 
Proc. Am. Soc. Clin. Oncol., 1999, 18 : Abstract 1527 
Vermorken JB, Herbst R., Leon X. et al 
Overview of the efficacy of cetuximab in recurrent and / or metastatic squamous cell carcinoma of 
the head and neck in patients who previously failed platinum-based therapies 
Cancer, 2007, 112 (12) : 2710-2719 
Vermorken JB, Mesia R., Rivera F. et al 
Platinum-based chemotherapy plus cetuximab in head and neck cancer 
N. Eng. J. Med., 2008, 359 : 1116-1127 
Vermorken JB, Remenar E, van Herpen C et al 
Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer 
N. Eng. J. Med. 2007, 357 : 1695-1704 
Vermorken JB, Stupp R, Nguyen L, et al 
Phase I study of i.v. vinflunine given on a weekly schedule in previously untreated patients with
advanced solid tumours. 
Proc. Am. Soc. Clin. Oncol. 2003; 22: 221 (Abs. 887) 
Vermorken JB, Trigo J., Hitt R., et al 
Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of 
cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma 
of the head and neck who failed to respond to platinum-based therapy 
J. Clin. Oncol., 2007, 25 : 2171-2177 
 


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Appendix 1: World medical association declaration of Helsinki 


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Appendix 2: Performance status scale 


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PERFORMANCE STATUS SCALE 
KARNOFSKY AND W.H.O CLASSIFICATION 
 
 
 
 
KARNOFSKY (%) 
WHO PS 
 
 
 
100 
 
 
90 
 
 
Normal, no complaints, no evidence of 
disease 
 
Able to carry on normal activity, minor 
signs or symptoms of disease 
 
 
0 
 
Able to carry out all normal 
activity without restriction 
 
80 
 
 
 
70 
 
 
 
Normal activity with effort, some signs or 
symptoms of disease 
 
 
Cares for self, unable to carry on normal 
activity or to do active works. 
 
 
1 
 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out light work.  
 
60 
 
 
50 
 
 
Requires occasional assistance but is able to 
care for most needs. 
 
Requires considerable assistance and 
frequent medical care. 
 
 
2 
 
Ambulatory and capable of all self-
care but unable to carry out any 
work ; up about more than 50% of 
waking hours.  
 
 
40 
 
 
30 
 
 
Disabled, requires special care and 
assistance 
 
Severely disabled, hospitalisation is 
indicated although death not imminent 
 
 
3 
 
Capable of only limited self-care ; 
confined to bed or chair more than 
50 % of waking hours.  
 
20 
 
 
10 
 
 
 
Very sick, hospitalisation necessary, active 
supportive treatment necessary 
 
Moribund, fatal processes progressing 
rapidly 
 
 
4 
 
Completely disabled ; cannot carry 
out any self-care ; totally confined 
to bed or chair. 
 
 
0 
 
 
Dead 
 
 
5 
 
Dead 
 
 


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Appendix 3: Distribution of active bone marrow in the adult 


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DISTRIBUTION OF ACTIVE BONE MARROW IN THE ADULTa 
 
Site 
Percent of Totalb 
Cranium and mandible 
13 
Humeri, Scapulae, Clavicles 
8 
Sternum and Ribs 
10 
Vertebrae 
28 
Pelvic bones 
34 
Femur 
4 
a. Adpated from Ellis RE, the distribution of active bone marrow in the adult. Phys Med Bio. 5:255, 1960-1961. 
 
b. Percentage represents total radiation of site(s). 
 
 
PERCENT OF NORMAL BONE MARROW IRRADIATED USING STANDARD 
RADIATION PORTS* 
 
 
Marrow volume at risk 
Skull (not including mandible) 
12 % 
Upper limb girdle (unilateral)  
(humeral head, scapulae, clavicle) 
4 % 
Sternum  
2 % 
Ribs (all) 
8 % 
Ribs (hemithorax) 
4 % 
Cervical vertebrae (all) 
3 % 
Thoracic vertebrae (all) 
14 % 
Lumbar vertebrae (all) 
11 % 
Sacrum  
14 % 
Pelvis (including both innominates and both 
femoral heads and necks) 
26 % 
Mantle (approximate) 
25 % 
Upper para aortic nodes (approximate) 
11 % 
Inverted Y (approximate) 
45 % 
 


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Appendix 4: Treatment labelling 


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LABELLING OF VIAL OF VINFLUNINE 50MG – 2ML 
GREEN TEAR-OFF LABEL FOR DRUG ACCOUNTABILITY FORM                                     GREEN FIXED LABEL              
PIERRE FABRE MEDICAMENT 
  
 
PIERRE FABRE MEDICAMENT 
45, Place Abel Gance - 92100 Boulogne - France 
L00070 IN 309 F0 
  
 
L00070 IN 309 F0 
L0070IN 
  
 
L0070IN 
50 mg - 2 mL (25 mg /mL) 
  
 
50 mg - 2 mL (25 mg /mL) 
  
  
 
 
INTRAVENOUS USE  
PC201XXXXX - XXXX** - # YYYYY* - EXP MM/YYYY 
  
 
PC201XXXXX - XXXX** - # YYYYY* - EXP MM/YYYY 
** : TREATMENT NUMBER - * : BATCH NUMBER 
   
** : TREATMENT NUMBER - * : BATCH NUMBER 
 
LABELLING OF BOX OF VINFLUNINE 50MG – 2ML 
On the first page of the booklet label, there will be the name, the address and the phone number of the sponsor and the 
EudraCT number. The other pages of the booklet label will bear the following information : 
 
                                   PROTOCOL L00070 IN 309 F0 
 
 
 
 
 
BOX OF 10 SINGLE USE VIALS OF L0070IN VINFLUNINE  (AS 
DITARTRATE)  
50 mg - 2 mL 
25 mg / mL 
(vinflunine base) 
 
CONCENTRATE FOR SOLUTION FOR INFUSION - INTRAVENOUS 
USE  
TO BE DILUTED PRIOR TO ADMINISTRATION 
FOLLOW THE PRESCRIBED DOSES AND THE STORAGE 
CONDITIONS AFTER RECONSTITUTION 
STORE IN A REFRIGERATOR (+2°C/+8°C) 
STORE IN THE ORIGINAL BOX IN ORDER TO PROTECT FROM 
LIGHT 
STICK THE GREEN TEAR-OFF LABEL FROM THE USED VIALS 
ON THE PATIENT "DRUG ACCOUNTABILITY FORM" 
FOR CLINICAL TRIAL USE ONLY 
PACKAGING BATCH N° ………………. 
TREATMENT N° ………………………….  
EXPIRY DATE…………………………….. 
SEE ON THE 
FIRST PAGE  


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LABELLING OF VIAL OF VINFLUNINE 250MG – 10ML 
WHITE TEAR-OFF LABEL FOR DRUG ACCOUNTABILITY FORM                                     WHITE FIXED LABEL              
PIERRE FABRE MEDICAMENT 
  
 
PIERRE FABRE MEDICAMENT 
45, Place Abel Gance - 92100 Boulogne - France 
L00070 IN 309 F0 
  
 
L00070 IN 309 F0 
L0070IN 
  
 
L0070IN 
250 mg - 10 mL (25 mg /mL) 
  
 
250 mg - 10 mL (25 mg /mL) 
  
  
 
 
INTRAVENOUS USE  
PC201XXXXX - XXXX** - # YYYYY* - EXP MM/YYYY   
 
PC201XXXXX - XXXX** - # YYYYY* - EXP MM/YYYY 
** : TREATMENT NUMBER - * : BATCH NUMBER 
   
** : TREATMENT NUMBER - * : BATCH NUMBER 
 
LABELLING OF BOX OF VINFLUNINE 250MG – 10ML 
On the first page of the booklet label, there will be the name, the address and the phone number of the sponsor and the 
EudraCT number. The other pages of the booklet label will bear the following information : 
 
 
                                   PROTOCOL L00070 IN 309 F0 
 
 
 
 
 
BOX OF 10 SINGLE USE VIALS OF L0070IN VINFLUNINE  (AS 
DITARTRATE)  
250 mg - 10 mL 
25 mg / mL 
(vinflunine base) 
 
CONCENTRATE FOR SOLUTION FOR INFUSION - INTRAVENOUS 
USE  
TO BE DILUTED PRIOR TO ADMINISTRATION 
FOLLOW THE PRESCRIBED DOSES AND THE STORAGE 
CONDITIONS AFTER RECONSTITUTION 
STORE IN A REFRIGERATOR (+2°C/+8°C) 
STORE IN THE ORIGINAL BOX IN ORDER TO PROTECT FROM 
LIGHT 
STICK THE WHITE TEAR-OFF LABEL FROM THE USED VIALS 
ON THE PATIENT "DRUG ACCOUNTABILITY FORM" 
FOR CLINICAL TRIAL USE ONLY 
PACKAGING BATCH N° ………………. 
TREATMENT N° ………………………….  
EXPIRY DATE…………………………….. 
SEE ON THE 
FIRST PAGE  


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LABELLING OF THE VIAL OF METHOTREXATE 50MG 
 
 
** : Treatment number / * : Batch number 
              : fixed label                                        : tear-off label 
 
 
 
LABELLING OF THE BOX OF METHOTREXATE 50MG 
On the first page of the booklet label, there will be the name, the address and the phone number of the sponsor, the 
EudraCT number. The other pages of the booklet label will bear the following information : 
 
 
 
 
 
At the shipment, a label with the name of the investigator is sticked on each box of vinflunine 
50mg, vinflunine 250mg and methotrexate 50mg. 
 
 
                                   PROTOCOL L00070 IN 309 F0 
 
 
 
 
 
 
BOX OF 10 VIALS OF METHOTREXATE MYLAN 50mg-2mL, 
SOLUTION FOR INJECTION - INTRAVENOUS USE 
FOLLOW THE PRESCRIBED DOSES 
STORE BELOW 25°C 
STORE IN THE ORIGINAL BOX IN ORDER TO PROTECT 
FROM LIGHT 
TO BE ADMINISTERED WITHIN 12 HOURS AFTER 
DILUTION 
STICK THE TEAR-OFF LABEL FROM THE USED VIAL ON 
THE PATIENT "DRUG ACCOUNTABILITY FORM" 
FOR CLINICAL TRIAL USE ONLY 
PACKAGING BATCH N° ………………. 
TREATMENT N° …………………………. 
SEE ON THE 
FIRST PAGE 
PIERRE FABRE MEDICAMENT 
45, Place Abel Gance - 92100 Boulogne - France 
L00070 IN 309 F0 
METHOTREXATE 
50mg - 2mL (25mg/mL) 
INTRAVENOUS USE 
PC201XXXXX - XXXX** - # YYYYY* 
EXP MM/YYYY 
PIERRE FABRE MEDICAMENT 
L00070 IN 309 F0 
METHOTREXATE 
50mg - 2mL (25mg/mL) 
 
PC201XXXXX - XXXX** - # YYYYY*- 
EXP MM/YYYY 


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Appendix 5: Serious adverse event report form 


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Appendix 6: Drug accountability form 


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    Original: monitor   
 
    1st copy: investigator/pharmacist  
 
Drug : VINFLUNINE 
Protocol No : L00070 IN 309 F0 
Page  1 / 1 
Subject No 
|__|__|__|__|__|__| 
Subject’s Drug Accountability Form 
A PHASE III TRIAL OF IV VINFLUNINE IN COMBINATION WITH METHOTREXATE 
VERSUS METHOTREXATE ALONE IN PATIENTS WITH RECURRENT OR METASTATIC 
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK PREVIOUSLY TREATED 
WITH PLATINUM-BASED THERAPY 
 
ARM A 
 
 
 CYCLE N° : |__|__| 
DATE OF DISPENSATION :  |__|__|   |__|__|   |__|__|__|__| 
• VINFLUNINE 
Dispenser’s 
Initials 
Dose level  
(mg/m²) 
Dose  
dispensed (mg) 
Number of vials  
50 mg / 2 mL 
Number of vials  
250 mg / 10 mL 
Date control 
CRA 
 
|__|__|__| |__|__|__| 
|__|__| 
|__|__| 
 
When possible, please use the vials in chronological order and stick here the labels. 
 
 
 
 
 
 
Comments : ________________________________________________________________  
 _________________________________________________________________________  
 
Date :   |__|__|  |__|__|  |__|__|__|__| 
INVESTIGATOR/PHARMACIST:  
Name :  
 _______________________________________ Signature :  
 
C.R.A.: 
Name :  
 _______________________________________ Signature :  


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    Original: monitor   
 
    1st copy: investigator/pharmacist  
 
Drug : VINFLUNINE 
Protocol No : L00070 IN 309 F0 
Page  1 / 1 
Subject No 
|__|__|__|__|__|__| 
Subject’s Drug Accountability Form 
A PHASE III TRIAL OF IV VINFLUNINE IN COMBINATION WITH METHOTREXATE 
VERSUS METHOTREXATE ALONE IN PATIENTS WITH RECURRENT OR METASTATIC 
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK PREVIOUSLY TREATED 
WITH PLATINUM-BASED THERAPY 
 
ARM A OR B 
 
 
CYCLE N°: |__|__|  DAY: |__|__|  DATE OF DISPENSATION : |__|__|  |__|__|  |__|__|__|__| 
• METHOTREXATE 
Dispenser’s Initials 
Dose level  
(mg/m²) 
Dose  
dispensed (mg) 
Number of vials  
50 mg / 2 mL 
Date control CRA 
 
|__|__|__| 
|__|__|__| 
|__|__| 
 
When possible, please use the vials in chronological order and stick here the labels. 
 
 
 
 
 
 
Comments : ________________________________________________________________  
 _________________________________________________________________________  
 
Date :   |__|__|  |__|__|  |__|__|__|__| 
INVESTIGATOR/PHARMACIST:  
Name :  
 _______________________________________ Signature :  
 
C.R.A.: 
Name :  
 _______________________________________ Signature :  
 


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Appendix 7: EORTC questionnaire 


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EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that 
you provide will remain strictly confidential. 
Please fill in your initials: 
|__||__||__||__| 
Your birthdate (Day, Month, Year): 
|__|__||__|__||__|__|__|__| 
Today's date (Day, Month, Year):  
31 |__|__||__|__||__|__|__|__| 
 
Not at 
A 
Quite 
Very 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week 
Not at 
A 
Quite 
Very 
 
All 
Little 
a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page 


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During the past week 
Not at 
A 
Quite 
Very 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best 
applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
© 
Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 


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EORTC  QLQ - H&N35 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you 
have experienced these symptoms or problems during the past week. Please answer by circling the number that best 
applies to you. 
 
 
 
During the past week: 
Not  
A  
Quite  
Very 
 
at all  
little  
a bit  
much 
31. Have you had pain in your mouth? 
1 
2 
3 
4 
32. Have you had pain in your jaw?  
1 
2 
3 
4 
33. Have you had soreness in your mouth?  
1 
2 
3 
4 
34. Have you had a painful throat?  
1 
2 
3 
4 
35. Have you had problems swallowing liquids?  
1 
2 
3 
4 
36. Have you had problems swallowing pureed food?  
1 
2 
3 
4 
37. Have you had problems swallowing solid food?  
1 
2 
3 
4 
38. Have you choked when swallowing?  
1 
2 
3 
4 
39. Have you had problems with your teeth?  
1 
2 
3 
4 
40. Have you had problems opening your mouth wide?  
1 
2 
3 
4 
41. Have you had a dry mouth?  
1 
2 
3 
4 
42. Have you had sticky saliva?  
1 
2 
3 
4 
43. Have you had problems with your sense of smell?  
1 
2 
3 
4 
44. Have you had problems with your sense of taste?  
1 
2 
3 
4 
45. Have you coughed?  
1 
2 
3 
4 
46. Have you been hoarse?  
1 
2 
3 
4 
47. Have you felt ill?  
1 
2 
3 
4 
48. Has your appearance bothered you?  
1 
2 
3 
4 
 
During the past week: 
Not  
A  
Quite  
Very 
 
at all  
little  
a bit  
much 
49. Have you had trouble eating?  
1 
2 
3 
4 
50. Have you had trouble eating in front of your family?  
1 
2 
3 
4 
51. Have you had trouble eating in front of other people?  
1 
2 
3 
4 
52. Have you had trouble enjoying your meals?  
1 
2 
3 
4 
53. Have you had trouble talking to other people?  
1 
2 
3 
4 
54. Have you had trouble talking on the telephone?  
1 
2 
3 
4 
55. Have you had trouble having social contact with your family?  
1 
2 
3 
4 
56. Have you had trouble having social contact with friends?  
1 
2 
3 
4 
57. Have you had trouble going out in public?  
1 
2 
3 
4 
58. Have you had trouble having physical 
 
contact with family or friends?  
1 
2 
3 
4 
59. Have you felt less interest in sex?  
1 
2 
3 
4 
60. Have you felt less sexual enjoyment?  
1 
2 
3 
4 
 
During the past week: 
 
 
No 
Yes 
61. Have you used pain-killers? 
 
 
1 
2 
62. Have you taken any nutritional supplements (excluding vitamins)? 
 
 
1 
2 
63. Have you used a feeding tube?  
 
 
1 
2 
64. Have you lost weight?  
 
 
1 
2 
65. Have you gained weight?  
 
 
1 
2 
 


Confidential 
Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
142/145 
 
Appendix 8: Inducers or inhibitors of CYP3A4 


Confidential 
Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
143/145 
 
 
Non-exhaustive list of inducers and inhibitors of CYP 3A4 
These treatments should be stopped at least 4 days before the 1st drug administration of the pharmacokinetic study 
However, their topical form is authorised. 
They are allowed, if necessary during the compassionate use of vinflunine. 
Inducers of isoform cytochrome P450 3A4 
 
Millepertuis (Hypericum ; St John’s Wort) 
Antiepileptic  
Barbiturate: Phenobarbital, Primidone 
Non barbiturate: Phenytoin, Carbamazepine, Oxcarbazepine 
Antiretroviral 
Efavirenz, Nevirapine 
Antifungal 
Griseofulvin 
Antimycobacterial 
Rifabutin, Rifampicin 
Corticosteroid 
Dexamethasone 
Antihypertensive 
Bosentan 
Antidepressant 
Fluvoxamine 
Inhibitors of isoform of cytochrome P450 3A4 
Grape fruit juice 
Antiretroviral 
Amprenavir, Delavirdine, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Atazanavir, Darunavir 
Antibacterial  
Macrolide: Troleandromycin, Erythromycin, Telithromycin, Clarithromycin 
Chloramphenicol 
Antimycobacterial 
Isoniazid 
Antifungal 
Triazole: Fluconazole, Itraconazole, Voriconazole 
Imidazole: Ketoconazole, Miconazole 
Oestrogen 
Ethinylestradiol 
Androgen 
Danazol 
Calcium-channel blocker 
Diltiazem, Nicardipine, Verapamil 
Anti-arrhythmic agent 
Amiodarone 
Leukotriene antagonist 
Zafirlukast 
Reference list  
Hansten P.H, Horn J.R. 
The top 100 drug interactions. A guide to patient management, 2007 Edition, H&H Publication 
Affsaps  
Referenciel national des interactions médicamenteuses – Interactions médicamenteuses et cytochromes, April 2005. 


Confidential 
Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
144/145 
 
Appendix 9: Diagram of categories of eligible patients according to inclusion criterion no.3 


Confidential 
Study Code: L00070 IN 309 F0 
Clinical Study Protocol – Version No.7 
Date: 5th February 2016 
145/145 
 
 
locoregionally advanced cancer 
 
induction 
chemotherapy 
with cisplatin* 
 
any treatment 
 
  
 
 
 
metastatic  
cancer 
 
radiotherapy 
(alone or with CT or 
with cetuximab) 
 
recurrence < 6 months  
 
± induction 
chemotherapy 
 
Radio-CT 
with cisplatin 
(cumulative dose 
 cisplatin ≥ 200 mg/m²) 
recurrence < 6 months 
recurrence < 12 months 
recurrence 
(local or metastatic) 
CT with cisplatin 
or carboplatin 
(± cetuximab) 
STUDY ENTRY 
 
CT with cisplatin 
or carboplatin 
(± cetuximab) 
 
locoregionally 
cancer 
 
 
 
 
* cisplatin + 5-FU or docetaxel + cisplatin + 5-FU 
CT = chemotherapy 
recurrence < 12 months 
 

SAP_001.pdf: 
Statistical Analysis Plan / L00070 IN 309 F0                                                       Version n° 4 (23/11/2017) 
 
 
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 309 F0 
Title of the study:  
 
 
A PHASE III STUDY OF IV VINFLUNINE IN COMBINATION WITH 
METHOTREXATE VERSUS METHOTREXATE ALONE IN PATIENTS WITH 
RECURRENT OR METASTATIC SQUAMOUS  
CELL CARCINOMA OF THE HEAD AND NECK PREVIOUSLY TREATED 
WITH PLATINUM-BASED CHEMOTHERAPY 
 
  
 
Author Name :  
 
Benjamin POIRIER (Biostatistician - Axiodis) 
 
 
 
 
 
Reviewers Names :   
Stéphanie JEAN-ALPHONSE (Head of Statistical Dep.) 
 
 
 
 
Zahida ISSIAKHEM (Clinical Study Physician) 
 
Date of approval :   
 23/11/2017 
 
Date of version :  
       
Version n° 4 (23/11/2017) 
Date of previous version : Version n° 3 (28/05/2014) 
 
Reasons for change: 
Modification according to the protocol amendment (PA11)  
 
 
 
 
Simplification of analyses due to study early termination 
 
 
 
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.  
 


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Title
Name
(First & Last name) 
Consistency 
between SAP 
and study 
protocol  
Date
Signature
Author 
Statistician 
Benjamin POIRIER 
(Axiodis) 
NA 
 
 
Reviewer 
Clinical Study 
Physician 
Zahida ISSIAKHEM, 
MD 
NA 
 
 
Approving 
Officer 
Head of 
Statistical 
Department 
Stéphanie JEAN-
ALPHONSE 
 Confirmed  
 


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TABLES OF CONTENTS  
1. 
STUDY OBJECTIVES .............................................................................................................................. 9 
2. 
STUDY DESIGN ....................................................................................................................................... 9 
3. 
SAMPLE SIZE ........................................................................................................................................ 10 
4. 
EFFICACY PARAMETERS ................................................................................................................... 10 
4.1. 
PRIMARY EFFICACY PARAMETERS ............................................................................................... 11 
4.1.1. 
Overall survival ................................................................................................................................. 11 
4.2. 
SECONDARY EFFICACY PARAMETERS ......................................................................................... 11 
4.2.1. 
Progression free survival .................................................................................................................. 11 
4.2.2. 
Objective response rate .................................................................................................................... 11 
4.2.3. 
Disease control rate .......................................................................................................................... 12 
4.2.4. 
Duration of response ........................................................................................................................ 13 
4.2.5. 
Duration of disease control ............................................................................................................... 13 
4.2.6. 
Time to treatment failure ................................................................................................................... 13 
4.2.7. 
Time to first response ....................................................................................................................... 14 
5. 
SAFETY PARAMETERS ....................................................................................................................... 14 
5.1. 
ADVERSE EVENTS ............................................................................................................................ 14 
5.1.1. 
Adverse Events Of Special Interest .................................................................................................. 15 
5.1.2. 
Serious Adverse Event ..................................................................................................................... 15 
5.2. 
FEBRILE NEUTROPENIA ................................................................................................................... 16 
5.3. 
HAEMATOLOGICAL PARAMETERS ................................................................................................. 16 
5.4. 
BIOCHEMICAL PARAMETERS .......................................................................................................... 16 
6. 
OTHER PARAMETERS ......................................................................................................................... 17 
6.1. 
CONCOMITANT MEDICATIONS ........................................................................................................ 17 
6.2. 
QUALITY OF LIFE PARAMETERS ..................................................................................................... 17 
6.2.1. 
Primary parameter ............................................................................................................................ 19 
6.2.2. 
Secondary parameter ....................................................................................................................... 19 
6.2.3. 
Windows ........................................................................................................................................... 19 
6.3. 
FURTHER ANTI-CANCER THERAPY ................................................................................................ 20 
7. 
DEFINITION OF POPULATIONS .......................................................................................................... 20 
7.1. 
INTENT-TO-TREAT POPULATION (ITT) ........................................................................................... 20 
7.2. 
ELIGIBLE POPULATION .................................................................................................................... 20 


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7.3. 
EVALUABLE POPULATION FOR RESPONSE ................................................................................. 20 
7.4. 
EVALUABLE POPULATION FOR SAFETY........................................................................................ 20 
7.5. 
EVALUABLE POPULATION FOR HEALTH-RELATED QUALITY OF LIFE ASSESSMENT ............ 20 
7.5.1. 
Evaluable population for QLQ-C30 .................................................................................................. 20 
7.5.2. 
Evaluable population for QLQ-H&N 35 EORTC module .................................................................. 20 
8. 
STATISTICAL METHODS ..................................................................................................................... 21 
8.1. 
STATISTICAL SOFTWARE AND METHODOLOGY .......................................................................... 21 
8.2. 
STATISTICAL METHODS FOR CATEGORICAL VARIABLES .......................................................... 21 
8.3. 
STATISTICAL METHODS FOR ORDINAL VARIABLES .................................................................... 21 
8.4. 
STATISTICAL METHODS FOR CONTINUOUS VARIABLES ............................................................ 21 
8.5. 
STATISTICAL METHODS FOR TIME DEPENDENT DATA .............................................................. 22 
8.6. 
STATISTICAL METHODS FOR HEALTH-RELATED QUALITY OF LIFE DATA ............................... 22 
9. 
TREATMENT GROUP DESCRIPTION ................................................................................................. 22 
9.1. 
DESCRIPTION AT BASELINE ............................................................................................................ 22 
9.1.1. 
Overview of the study ....................................................................................................................... 22 
9.1.2. 
Characteristics at baseline ............................................................................................................... 23 
9.2. 
DESCRIPTION DURING THE STUDY ............................................................................................... 26 
9.2.1. 
Dose intensity per cycle .................................................................................................................... 27 
9.2.2. 
Relative dose intensity per cycle ...................................................................................................... 27 
9.2.3. 
Dose intensity per patient ................................................................................................................. 28 
9.2.4. 
Relative dose intensity per patient ................................................................................................... 28 
9.2.5. 
Dose reductions ................................................................................................................................ 28 
9.2.6. 
Treatment cancellation ..................................................................................................................... 29 
9.2.7. 
Dose interruption .............................................................................................................................. 30 
9.2.8. 
Treatment delay ................................................................................................................................ 30 
9.2.9. 
Dose discontinuations ...................................................................................................................... 30 
9.2.10. 
Route of administration and setting ................................................................................................ 31 
9.2.11. 
Concomitant medications ............................................................................................................... 32 
10. 
EFFICACY ANALYSES ....................................................................................................................... 32 
10.1. 
PRIMARY EFFICACY ANALYSIS ..................................................................................................... 32 
10.2. 
SUPPORTIVE ANALYSIS OF THE PRIMARY EFFICACY PARAMETER ...................................... 32 
10.3. 
SENSITIVITY ANALYSES OF THE PRIMARY EFFICACY PARAMETER ...................................... 32 
10.4. 
SECONDARY EFFICACY ANALYSES ............................................................................................. 33 
10.4.1. 
Progression Free Survival .............................................................................................................. 33 


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10.4.2. 
Tumour response ........................................................................................................................... 33 
10.4.3. 
Subgroups analyses ....................................................................................................................... 34 
11. 
SAFETY ANALYSES ........................................................................................................................... 34 
11.1. 
OVERVIEW OF THE SAFETY .......................................................................................................... 34 
11.2. 
ADVERSE EVENTS .......................................................................................................................... 34 
11.2.1. 
All adverse events .......................................................................................................................... 34 
11.2.2. 
Selected adverse events ................................................................................................................ 35 
11.2.3. 
Serious adverse events .................................................................................................................. 35 
11.2.4. 
Deaths ............................................................................................................................................ 35 
11.3. 
LABORATORY TESTS ..................................................................................................................... 36 
11.3.1. 
Haematological toxicities ................................................................................................................ 36 
11.3.2. 
Biochemical toxicities ..................................................................................................................... 36 
12. 
OTHER ANALYSES ............................................................................................................................ 36 
12.1. 
HEALTH-RELATED QUALITY OF LIFE ANALYSES ....................................................................... 36 
12.1.1. 
Evaluable questionnaire ................................................................................................................. 36 
12.1.2. 
Descriptive analyses ....................................................................................................................... 37 
13. 
CHANGES INTERFERED SINCE LAST VERSION ............................................................................ 37 
14. 
REFERENCES ..................................................................................................................................... 38 
15. 
APPENDICES ...................................................................................................................................... 39 
15.1. 
APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS ........................................................... 40 
15.2. 
APPENDIX 2: STATISTICAL ANALYSIS CONVENTIONS .............................................................. 44 
15.2.1. 
Conventions for calculation of duration .......................................................................................... 44 
15.2.2. 
Missing data ................................................................................................................................... 44 
15.2.3. 
Date of first response and date of progression .............................................................................. 45 
15.2.4. 
Toxicity............................................................................................................................................ 45 
15.2.5. 
End of study .................................................................................................................................... 47 
15.3. 
APPENDIX 3: ADVERSE EVENTS OF SPECIAL INTEREST ......................................................... 48 
15.4. 
APPENDIX 4: ANALYSIS OF TUMOUR LOCATION AT BASELINE ............................................... 54 
 


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LIST OF TABLES 
 
Table 4-1: Definitions of ORR and DCR ........................................................................................................ 12 
Table 9-1 : Categorized dose of vinflunine .................................................................................................... 26 
Table 9-2 : Categorized dose of methotrexate .............................................................................................. 26 
Table 9-3: Planned dose intensity in mg/m²/wk of vinflunine ........................................................................ 27 
Table 9-4: Planned dose intensity in mg/m²/wk of methotrexate .................................................................. 27 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
 
AEs 
Adverse Events 
AEOSI 
Adverse Events Of Special Interest 
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 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
DCR 
Disease control rate 
DI 
Dose Intensity 
EGFR 
Epidermic Growth Factor Receptor. 
EORTC 
European Organisation for Research and Treatment of Cancer 
ER 
Estrogen Receptor 
FISH 
Fluorescent In Situ Hybridisation 
FN 
Febrile Neutropenia 
HB 
Haemoglobin 
HLGT 
High Level Group Term 
HLT 
High Level Term 
HR 
Hormone Receptor 
i.v. 
Intravenous 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
ITT 
Intent-To-Treat 
LLT 
Lowest Level Term 
MedDRA 
MEDICAL DICTIONARY FOR REGULATORY ACTIVITIES 
MTX 
Methotrexate 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progression Disease 
PDI 
Planned Dose Intensity 
PgR 
Progesterone Receptor 
PLT 
Platelets 


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PR 
Partial Response 
PS 
Performance Status 
PFS  
Progression-Free Survival 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Preferred Term 
pt (s) 
Patient (s) 
QoL 
Quality of Life 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SCCHN 
Squamous Cell Cracinoma of Head and Neck 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SIADH 
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TTF 
Time to Treatment Failure 
ULN 
Upper Limit of Normal 
VFL 
Vinflunine 
WBC 
White Blood Cells 
WHO 
World Health Organisation 
Wk(s) 
Week(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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1. STUDY OBJECTIVES 
The primary objective of the trial was to compare the overall survival of the i.v. vinflunine in 
combination with methotrexate versus methotrexate alone in incurable recurrent/metastatic squamous 
cell carcinoma of the head and neck (SCCHN) patients who have failed platinum-based 
chemotherapy. 
The results of the 2nd interim analysis (August 2015) of efficacy have led the IDMC to recommend the 
implementation of a futility analysis of overall survival which is the primary endpoint of study 309. This 
futility analysis was carried out by IDDI, a CRO expert in biostatistics, independently from the sponsor 
and the results reviewed by the IDMC. 
 
The results of the futility analysis showed that the probability to demonstrate a significant benefit of 
overall survival at the time of the final analysis is very low. 
 
As a consequence, Pierre Fabre has decided to stop the recruitment of study patients on 16th October 
2015. 
This SAP is aimed to adapt the statistical analysis according to the protocol amendment 11. 
2. STUDY DESIGN 
This multicentre, open-label, randomized, Phase III study will enrol 530 patients with SCCHN who 
have failed platinum-based chemotherapy. Patients will be randomised in a 1:1 ratio to receive i.v. 
vinflunine plus methotrexate (arm A) or methotrexate alone (arm B). 
Randomisation will be stratified according to a minimisation procedure (Pocock SJ, 1975): 
- WHO performance status (0 versus 1) 
- Refractory or resistant to platinum versus other 
- Prior radiotherapy (yes versus no) 
- Prior treatment with any anti-EGFR medication (yes versus no)  
- Center 
Patients will be randomised to receive: 
- Arm A : i.v. vinflunine 280 mg/m² on day 1 and methotrexate 30 mg/m2 on days 1 and 8 every 3 
weeks. 
- Arm B : methotrexate 40 mg/m2/week. 
Overall survival (OS) will be the primary endpoint of the study. The final analysis will require at least 
437 deaths. The study has been powered at 90% to show an improvement of survival from 5.5 months 
in the control arm to 7.5 months in the test arm. 
Throughout the study, patients will be closely monitored for safety evaluation and will be assessed for 
tumour response every 6 weeks. Patients will receive at least 2 cycles unless they experienced 
unacceptable toxicity or early disease progression. Patients who respond or have stable disease will 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
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C O N FI D E N TI A L 
 
r e c ei v e 2 a d diti o n al c y cl e s a n d will b e r e e v al u at e d f or t u m o ur r e s p o n s e. P ati e nt s wit h pr o gr e s si v e 
d is e a s e will b e r e m o v e d w hil e p ati e nt s w h o r e s p o n d or h a v e st a bl e di s e a s e m a y c o nti n u e st u d y 
tr e at m e nt u ntil di s e a s e pr o gr e s si o n.  
3. 
S A M P L E SI Z E  
T h e pri m ar y o bj e cti v e of t h e st u d y w a s t o s h o w t h at t h e vi nfl u ni n e pl u s m et h otr e x at e ( ar m A) i s 
s u p eri or t o m et h otr e x at e al o n e ( ar m B) i n t er m s of o v er all s ur vi v al. T h e fi n al a n al y si s will r e q uir e at 
l e a st 4 3 7 d e at h s; t hi s i s t h e n u m b er of e v e nt s n e e d e d f or a t w o si d e d, l o g-r a n k t e st at a n al p h a = 0. 0 5 
si g nifi c a n c e l e v el t o h a v e 9 0 % p o w er t o s h o w a st ati sti c all y si g nifi c a nt diff er e n c e w h e n t h e tr u e h a z ar d 
r ati o i s 0. 7 3 3 (i. e., w h e n t h e m e di a n O S i n t h e vi nfl u ni n e ar m i s 7. 5 m o nt h s a n d t h e m e di a n O S i n t h e 
c o ntr ol ar m i s 5. 5 m o nt h s). A n e x p e ct e d t ot al n u m b er of 5 3 0 p ati e nt s w a s pl a n n e d. It w a s e sti m at e d 
t h at t h e st u d y will t a k e a p pr o xi m at el y 1 9 m o nt h s t o a c cr u e a n d t h e O S a n al y si s i s e x p e ct e d t o b e 
p erf or m e d t e n m o nt h s f oll o wi n g t h e l a st p ati e nt a c cr u e d. T h e a nti ci p at e d l o st t o f oll o w- u p i s e sti m at e d 
t o b e 5 %. 
F oll o wi n g t h e d e ci si o n t o st o p t h e r e cr uit m e nt: 
•   
T h e st ati sti c al a n al y si s will a ct u all y b e c o n d u ct e d o n t h e 4 5 9 r a n d o mi s e d p ati e nt s. 
•   
3 2 5 e v e nt s s h o ul d b e o b s er v e d at t h e e n d of st u d y all o wi n g a p o w er of 8 0 %. 
W h at e v er t h e n u m b er of e v e nt s at t h e e n d of st u d y, t h e fi n al a n al y si s of O S ( pri m ar y a n al y si s) will b e 
p erf or m e d o n t h e I T T p o p ul ati o n. O nl y d e s cri pti v e a n al y s e s will b e p erf or m e d o n all s e c o n d ar y effi c a c y 
a n al y s e s f or I T T p o p ul ati o n. 
 
4. 
E F FI C A C Y P A R A M E T E R S 
T u m o ur a s s e s s m e nt will b e p erf or m e d a c c or di n g t o t h e r e vi s e d R E CI S T g ui d eli n e s v er si o n 1. 1 
(T h er a s s e P, 2 0 0 0, Ei s e n h a u er E, 2 0 0 9). A s s e s s m e nt of all l e si o n s w a s pl a n n e d t o b e c arri e d o ut at 
b a s eli n e t h e n e v er y 6 w e e k s ( +/- 3 w or ki n g d a y s) u ntil di s e a s e pr o gr e s si o n, r e g ar dl e s s of t h e ti mi n g of 
t h e tr e at m e nt c y cl e s a n d w h at e v er t h e tr e at m e nt a d mi ni st er e d.  
F or p ati e nt s w h o di s c o nti n u e d t h e st u d y tr e at m e nt b ef or e t h e o c c urr e n c e of di s e a s e pr o gr e s si o n, 
cli ni c al a n d r a di ol o gi c al a s s e s s m e nt s of all l e si o n s h a d t o b e p erf or m e d e v er y 6 w e e k s fr o m ti m e of 
r a n d o mi s ati o n u ntil di s e a s e pr o gr e s si o n i s d o c u m e nt e d, t h e n s ur vi v al i nf or m ati o n w a s c oll e ct e d 
a p pr o xi m at el y e v er y m o nt h f or t h e fir st 6 m o nt h s a n d t h e n e v er y 3 m o nt h s u ntil d e at h. 
F or p ati e nt w h o di s c o nti n u e d t h e st u d y tr e at m e nt d u e t o P D, s ur vi v al i nf or m ati o n w a s c oll e ct e d 
a p pr o xi m at el y e v er y m o nt h f or t h e fir st 6 m o nt h s a n d t h e n e v er y 3 m o nt h s u ntil d e at h. 


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C O N FI D E N TI A L 
 
A c c or di n g t o t h e pr ot o c ol a m e n d m e nt 1 1, n o f oll o w- u p vi sit will b e p erf or m e d. At t h e ti m e of t hi s 
a m e n d m e nt: 
-  
p ati e nt s u n d er tr e at m e nt will st o p t h e st u d y at t h e E O T 
-  
p ati e nt s u n d er f oll o w- u p will st o p i m m e di at el y 
T h e e n d of st u d y i s d efi n e d a s t h e d at e of t h e l a st st u d y tr e at m e nt pl u s 3 0 d a y s f or t h e l a st p ati e nt o n 
tr e at m e nt ( E O T of t h e l a st p ati e nt). 
 
4. 1.  
P RI M A R Y E F FI C A C Y P A R A M E T E R S 
4. 1. 1. 
O v er all s ur vi v al 
T h e pri m ar y effi c a c y p ar a m et er i s o v er all s ur vi v al d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e d at e 
o f d e at h or l a st f oll o w- u p. F or p ati e nt s w h o h a v e n ot di e d, s ur vi v al d ur ati o n will b e c e n s or e d at t h e 
d at e of l a st c o nt a ct or l a st f oll o w- u p. 
4. 2.  
S E C O N D A R Y E F FI C A C Y P A R A M E T E R S 
 
T h e s e c o n d ar y effi c a c y p ar a m et er s ar e:  
•   
T h e Pr o gr e s si o n- Fr e e s ur vi v al i n b ot h ar m s, 
•   
T h e O bj e cti v e R e s p o n s e a n d Di s e a s e C o ntr ol r at e s i n b ot h ar m s, 
•   
T h e d ur ati o n of r e s p o n s e, di s e a s e c o ntr ol a n d ti m e t o fir st r e s p o n s e i n b ot h ar m s 
4. 2. 1. 
Pr o gr e s si o n fr e e s ur vi v al 
Pr o gr e s si o n-fr e e s ur vi v al will b e c al c ul at e d fr o m t h e d at e of r a n d o mi s ati o n u ntil t h e d at e of pr o gr e s si o n 
o r d e at h ( w h at e v er t h e r e a s o n of d e at h). P ati e nt s l o st t o f oll o w- u p, or wit h o ut a k n o w n r e c or d of 
pr o gr e s si o n or d e at h at ti m e of a n al y si s will h a v e t h e pr o gr e s si o n-fr e e s ur vi v al c e n s or e d at t h e d at e of 
l a st t u m o ur a s s e s s m e nt or t h e d at e of l a st c o nt a ct of a f oll o w- u p s h o wi n g n o pr o gr e s si o n, w hi c h e v er 
o c c ur s l a st. 
4. 2. 2. 
O bj e cti v e r e s p o n s e r at e 
T h e b e st o v er all r e s p o n s e of p ati e nt s i s d efi n e d a s t h e b e st r e s p o n s e d e si g n ati o n r e c or d e d a cr o s s all 
tim e p oi nt s fr o m t h e d at e of r a n d o mi s ati o n u ntil di s e a s e pr o gr e s si o n. O v er all b e st r e s p o n s e s a s s e s s e d 
aft er t h e e n d of st u d y p eri o d (l a st a d mi ni str ati o n + 3 0 d a y s) will n ot b e r e p ort e d i n t h e r e s p o n s e r at e.  
N o c o nfir m ati o n will b e n e e d e d f or t h e b e st o v er all r e s p o n s e.  
If a p ati e nt h a d t o e n d t h e tr e at m e nt b e c a u s e of pr o gr e s si o n b ef or e t h e fir st a s s e s s m e nt, h e/ s h e will 
b e c o n si d er e d e arl y pr o gr e s si v e a n d t h e b e st o v er all r e s p o n s e of t h e p ati e nt will b e c o n si d er e d a s 
pr o gr e s si o n.   
T h e o bj e cti v e R e s p o n s e R at e ( O R R) i s d efi n e d a s a p er c e nt a g e of c o m pl et e a n d p arti al r e s p o n s e s 
( C R a n d P R) o b s er v e d i n t h e p o p ul ati o n a n al y s e d: 


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(
)
N
PR
CR
ORR ∑
+
=
#
#
 
with:  
- 
# CR = number of patients whose best response is CR, 
- 
# PR = number of patients whose best response is PR, 
- 
N = number of patients qualified for efficacy analysis. 
4.2.3. Disease control rate  
Disease control rate (DCR) is defined as a percentage of best overall responses CR, PR and SD in 
the analysed population: 
(
)
N
SD
PR
CR
DCR ∑
+
+
=
#
#
#
 
with:  
- 
# CR = number of patients whose best response is CR, 
- 
# PR = number of patients whose best response is PR, 
- 
# SD = number of patients whose best response is SD (SD does not include non 
CR/non PD), 
- 
N = number of patients qualified for efficacy analysis. 
Of note, patients with only non-measurable disease at baseline assigned a best overall response of 
Non-CR/non-PD, will not be considered as stable and will not be counted as patient having disease 
control (Table 4-1). 
Table 4-1: Definitions of ORR and DCR 
Type of population 
analysed 
Observed number of best responses
Measurable and/or 
non-measurable 
disease 
CR 
PR 
ORR =(CR + PR)/N
SD 
DCR = (CR + PR + SD)/N 
Non CR/Non PD* 
PD 
NE 
Total (N) 
Measurable disease 
only 
CR 
PR 
ORR = (CR + PR)/N 
SD 
DCR = (CR + PR + SD)/N 
PD 
NE 
Total (N) 
                                 * for patients with only non measurable disease 


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4.2.4. Duration of response  
The duration of objective response will be measured for responders (CR + PR) from the time that 
measurement criteria are first met for complete or partial response (whichever status is recorded first), 
until the first date that recurrent or progressive disease is objectively documented or the date of death 
due to any cause. The duration of response of patients who are lost to follow-up or reach the time 
point of analysis without a known record of progression or death will have the duration of response 
censored at the date of last tumour assessment or last contact date of a follow-up showing no 
progression, whichever occurred last. For patients who receive a new anti-cancer treatment in the 
absence of progression, the duration of overall response will be censored at the date of first 
administration of the new anti-cancer treatment. 
Following the protocol amendment 11, the number of censored patient will be higher than expected. 
The result should be interpreted with cautiously.  
4.2.5. Duration of disease control  
The duration of disease control will be measured for patients with objective response or stable 
disease, from the date of randomisation until the date of progression or the date of death whatever the 
cause. The duration of disease control of patients who are lost to follow-up or reach the time point of 
analysis without a known record of progression or death will have the duration of disease control 
censored at the date of last tumour assessment or last contact date of a follow-up showing no 
progression, whichever occurred last. For patients who received a new anti-cancer treatment in the 
absence of progression, the duration of disease control will be censored at the date of first 
administration of this new anti-cancer treatment. 
Following the protocol amendment 11, the number of censored patient will be higher than expected. 
The result should be interpreted with cautiously.  
4.2.6. Time to treatment failure 
Time-to-treatment failure will be calculated from the date of randomisation up to the date of failure 
(progression, relapse, death or withdrawal due to adverse event, patient’s refusal to continue, lost to 
follow-up or start of new anti-cancer therapy). Patients who reach the time point of analysis without 
failure as defined above will have the time to treatment failure censored at the date of last tumour 
assessment or last contact of a follow-up not showing progression. Patients who discontinued 
treatment for other reason and who are lost to follow-up will be censored at the date of last contact. 
Following the protocol amendment 11, the number of censored patient will be higher than expected. 
The result should be interpreted with cautiously.  


Statistical Analysis Plan / L00070 IN 309 F0                                                       Version n° 4 (23/11/2017) 
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4.2.7. Time to first response 
Time to first response will be calculated among the responders (i.e. CR and PR) from the 
randomisation date up to the date of first documented CR or PR. 
Following the protocol amendment 11, the number of censored patient will be higher than expected. 
The result should be interpreted with cautiously.  
 
5. SAFETY PARAMETERS 
5.1. 
ADVERSE EVENTS 
Each patient will be assessed for occurrence of adverse events. The CTCAE version 3.0 (publish date 
9 Aug 2006) 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 Events (TEAE) will be considered for analysis of adverse events. 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 sign or 
symptom, or 
- 
Any sign or symptom becoming serious during the study period, or 
- 
Any sign or symptom requiring a modification of the study drug administration, or 
- 
Any sign or symptom becoming possibly, probably or definitely related to the study drug 
An adverse event that meets 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 events during the pre-study period (within 2 weeks prior 
to treatment),  
- 
the seriousness of the event during the pre-study period, 


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T hi s sit u ati o n will b e u s e d a s c o m p ar at or t o d et er mi n e w h et h er a n e xi sti n g a d v er s e e v e nt d uri n g st u d y 
p e ri o d b e c o m e s tr e at m e nt- e m er g e nt. 
T h e a d v er s e e v e nt s will b e cl a s sifi e d u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A). 
T h e i m pl e m e nt ati o n of t hi s i nt er n ati o n al t er mi n ol o g y i n t h e Or a cl e Cli ni c al  d at a b a s e will b e p erf or m e d 
u s i n g t h e a v ail a bl e v er si o n of M e d D R A ( V er si o n 1 9. 0). E a c h d e s cri pti o n of t h e t o xi cit y ( v er b ati m) will 
b e a s s o ci at e d wit h t h e fi v e f oll o wi n g it e m s: 
-  
S y st e m Or g a n Cl a s s ( S O C), 
-  
Hi g h L e v el Gr o u p T er m ( H L G T), 
-  
Hi g h L e v el T er m ( H L T), 
-  
Pr ef err e d T er m ( P T), 
-  
L o w e st L e v el T er m ( L L T). 
T w o s et s of e v e nt s will b e c o n si d er e d:  
  
all a d v er s e e v e nt s r e g ar dl e s s of r el ati o n s hi p t o tr e at m e nt, 
  
t h e a d v er s e e v e nt s t h at ar e p o s si bl y, pr o b a bl y or d efi nit el y r el at e d t o tr e at m e nt,  
Of n ot e, if t h e c a u s alit y i s mi s si n g , t h e A E will b e c o n si d er e d a s r el at e d t o st u d y tr e at m e nt 
A p ati e nt will b e e v al u a bl e f or n o n- h a e m at ol o gi c al t o xi cit y if at l e a st o n e dr o p of a n y tr e at m e nt w a s 
gi v e n a n d t h e t o xi cit y h a s b e e n a s s e s s e d b y t h e i n v e sti g at or. T h e p ati e nt will b e a n al y s e d i n t h e 
tr e at m e nt ar m h e/ s h e w a s eff e cti v el y tr e at e d. 
5. 1. 1. 
A d v er s e E v e nt s Of S p e ci al I nt er e st 
A d v er s e E v e nt s Of S p e ci al I nt er e st ( A E O SI) will b e pr e s e nt e d t o f a cilit at e m o nit ori n g of t h e f oll o wi n g 
M e d D R A pr ef err e d t er m s or Hi g h e st L e v el T er m s of s p e ci al i nt er e st: 
M y el o s u pr e s si o n, F e bril e 
N e utr o p e ni a, I nf e cti o n s wit h s e v er e n e utr o p e ni a: cli ni c all y r el e v a nt I nf e cti o n s ( p ot e nti al b a ct eri al 
ori gi n), C o n sti p ati o n, Il e u s, I nt e sti n al o b str u cti o n, A b d o mi n al p ai n, N a u s e a, V o miti n g, St o m atiti s / 
M u c o siti s, 
Di arr h o e a, 
M y o c ar di al i nf ar cti o n/ I s c h e mi a, 
C ar di a c arr h yt h mi a s, 
C ar di a c c o n d u cti o n 
di s or d er s, L o c al i nj e cti o n/i nf u si o n sit e r e a cti o n s, E xtr a v a s ati o n, 
P eri p h er al s e n s or y n e ur o p at h y, 
P eri p h er al 
m ot or 
n e ur o p at h y, 
A ut o n o mi c 
n e ur o p at h y, 
A st h e ni a/f ati g u e, 
M y al gi a, I m m e di at e 
h y p er s e n siti vit y, SI A D H, P R E S, H e p ati c d y sf u n cti o n,. 
 
A E O SI will b e pr o gr a m m ati c all y d et er mi n e d fr o m a pr e d efi n e d li st pr e s e nt e d i n a p p e n di x 3. 
5. 1. 2. 
S eri o u s A d v er s e E v e nt 
A s eri o u s a d v er s e e v e nt ( S A E) i n cl u d e s, b ut i s n ot n e c e s s aril y r e stri ct e d t o, a n y e v e nt w hi c h:  
•  R e s ult s i n d e at h ( w h at e v er m a y b e t h e c a u s e), 
•  I s lif e-t hr e at e ni n g, 
•  
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y, 
•  
R e q uir e s p ati e nt h o s pit ali s ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali s ati o n, 


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C O N FI D E N TI A L 
 
•  I s a c o n g e nit al a n o m al y or birt h d ef e ct, 
•  Ot h er e v e nt s i n cl u di n g c a n c er, o v er d o s a g e, pr e g n a n c y a n d a n y a d diti o n al a d v er s e e x p eri e n c e 
or a b n or m al l a b or at or y v al u e s o c c urri n g d uri n g t h e st u d y p eri o d d efi n e d b y t h e pr ot o c ol a s 
s eri o u s or w hi c h t h e i n v e sti g at or c o n si d er s si g nifi c a nt e n o u g h or t h at s u g g e st s a si g nifi c a nt 
h a z ar d, c o ntr ai n di c ati o n s, si d e eff e ct or pr e c a uti o n will b e h a n dl e d a s a s eri o u s a d v er s e e v e nt. 
 
A n y o v er d o s a g e m e eti n g s eri o u s n e s s crit eri a s h o ul d b e r e p ort e d a s a S A E. 
A n y pr e g n a n c y o c c urri n g aft er p ati e nt e x p o s ur e t o st u d y dr u g( s), s h o ul d b e r e p ort e d o n t h e S A E 
n otifi c ati o n f or m. 
All d e at h s o c c urri n g w hil e t h e p ati e nt i s o n st u d y i n cl u di n g d e at h s d u e t o di s e a s e pr o gr e s si o n a n d 
d e at h s wit hi n 3 0 d a y s of l a st a d mi ni str ati o n of st u d y dr u g s h o ul d b e n otifi e d a s S A E. 
5. 2.  
F E B RI L E N E U T R O P E NI A 
A c c or di n g t o C T C A E v er si o n 3. 0, f e bril e n e utr o p e ni a ( F N) i s d efi n e d a s A N C < 1. 0 x 1 0 9 / L a n d f e v er 
≥ 3 8. 5° C  of u n k n o w n ori gi n wit h o ut cli ni c all y or mi cr o bi ol o gi c all y d o c u m e nt e d i nf e cti o n. 
5. 3.  
H A E M A T O L O GI C A L P A R A M E T E R S 
H a e m at ol o gi c al t o xi cit y will b e a s s e s s e d b y l a b or at or y i n v e sti g ati o n s of h a e m o gl o bi n, W B C, A N C a n d 
pl at el et s. Gr a d e s will b e c al c ul at e d a c c or di n g t o C T C A E v er si o n 3. 0. 
A c y cl e will b e e v al u a bl e f or h a e m at ol o gi c al t o xi cit y a n al y si s if t h e f oll o wi n g crit eri a ar e f ulfill e d: 
  
At l e a st o n e dr o p of a n y tr e at m e nt, 
  
At l e a st o n e bl o o d c ell c o u nt b et w e e n D a y 2 a n d D a y 1 of n e xt c y cl e or e n d of tr e at m e nt p eri o d 
f or t h e l a st a d mi ni st er e d c y cl e, 
  
At l e a st o n e of t h e f o ur h a e m at ol o gi c al p ar a m et er s a n al y s e d h a s b e e n m e a s ur e d. 
A p ati e nt i s e v al u a bl e f or h a e m at ol o gi c al t o xi cit y a n al y si s if at l e a st o n e c y cl e i s e v al u a bl e. 
5. 4.  
BI O C H E MI C A L P A R A M E T E R S 
Bi o c h e mi c al t o xi cit y will b e a s s e s s e d b y l a b or at or y i n v e sti g ati o n s of li v er f u n cti o n t e st s (i. e. t ot al 
bi lir u bi n, al k ali n e p h o s p h at a s e, A S T, A L T), r e n al f u n cti o n t e st s ( cr e ati ni n e a n d c al c ul at e d ( C o c kr oft-
G a ult f or m ul a) cr e ati ni n e cl e ar a n c e) a n d gl u c o s e, t ot al pr ot ei n s, al b u mi n, ur e a, s o di u m, p ot a s si u m, 
c al ci u m, bi c ar b o n at e, m a g n e si u m, c hl ori d e. Gr a d e s will b e c al c ul at e d a c c or di n g t o t h e C T C A E v er si o n 
3. 0. 
A c y cl e will b e e v al u a bl e f or bi o c h e mi c al t o xi cit y a n al y si s if t h e f oll o wi n g crit eri a ar e f ulfill e d: 
  
At l e a st o n e dr o p of a n y tr e at m e nt h a s b e e n a d mi ni st er e d, 


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C O N FI D E N TI A L 
 
 
At l e a st o n e bi o c h e mi str y t e st  b et w e e n D a y 2 a n d D a y 1 of n e xt c y cl e or e n d of tr e at m e nt p eri o d 
f or t h e l a st a d mi ni st er e d c y cl e, 
  
At l e a st o n e of t h e si xt e e n bi o c h e mi c al p ar a m et er s a n al y s e d h a s b e e n m e a s ur e d. 
 
A p ati e nt will b e e v al u a bl e f or bi o c h e mi c al t o xi cit y a n al y si s if at l e a st o n e c y cl e i s e v al u a bl e. 
I n a d diti o n, A S T, A L T a n d bilir u bi n will b e a n al y s e d a c c or di n g t o t h e pr e s e n c e or n ot of li v er l e si o n s at 
b a s eli n e i n or d er t o a s s e s s t h e r el ati o n s hi p b et w e e n li v er m et a st a si s a n d w or st gr a d e d uri n g st u d y. 
T h e s a m e a n al y si s will b e d o n e f or al k ali n e p h o s p h at a s e a c c or di n g t o t h e pr e s e n c e or n ot of 
li v er/ b o n e m et a st a s e s. 
6. 
O T H E R P A R A M E T E R S 
6. 1.  
C O N C O MI T A N T M E DI C A TI O N S 
I n t h e s a m e w a y a s t h e a d v er s e e v e nt s, c o n c o mit a nt m e di c ati o n s will b e c o d e d u si n g t h e s p e cifi c 
in t er n ati o n al t er mi n ol o g y W H O- Dr u g Di cti o n ar y v er si o n 2 0 1 1, Q 2. 
6. 2.  
Q U A LI T Y O F LI F E P A R A M E T E R S  
T h e E ur o p e a n Or g a ni s ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er ( E O R T C) s c or e q u e sti o n n air e 
( QL Q- C 3 0) will b e a n al y s e d a s w ell a s t h e Q L Q- H e a d a n d N e c k 3 5 E O R T C m o d ul e, t o m e a s ur e t h e 
h e alt h-r el at e d q u alit y of lif e.  
T h e 
Q L Q- C 3 0 a n d t h e 
Q L Q- H e a d a n d 
N e c k 3 5 E O R T C 
m o d ul e 
will b e c o m pl et e d pri or t o 
r a n d o mi z ati o n, e v er y 6 w e e k s a n d at t h e e n d of tr e at m e nt e v al u ati o n. 
 E 0  Q o L     
            E 1  Q o L                   E 2  Q o L                     E n  Q o L 
 
 
  
      W1   
       W
4    
     W7    
    W1 0   
     W1 3   
 W1 6   
     W6 n + 1       E n d of St u d y E v al u ati o n 
 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I       I  
 
  
       
R a n d o mi s ati o n 
H e alt h-r el at e d q u alit y of lif e p ar a m et er s will b e t h e fift e e n s c al e s t h at c a n b e d eri v e d fr o m t h e 3 0 
q u e sti o n s of t h e E O R T C Q L Q- C 3 0 q u e sti o n n air e: 
− 
A gl o b al h e alt h-r el at e d q u alit y of lif e s c al e, 
− 
Fi v e f u n cti o n al s c al e s: p h y si c al, r ol e, c o g niti v e, e m oti o n al, s o ci al, 
− 
Ni n e s y m pt o m s c al e s: n a u s e a a n d v o miti n g, p ai n, f ati g u e, d y s p n o e a, i n s o m ni a, a p p etit e 
l o s s, c o n sti p ati o n, di arr h o e a, fi n a n ci al diffi c ulti e s. 
Of n ot e, a hi g h er v al u e i n f u n cti o n al s c al e s will r efl e ct a b ett er l e v el of f u n cti o n, b ut f or “ s y m pt o m s” 
s c al e s a hi g h er v al u e will r e v e al a d et eri or ati o n of t h e c o n diti o n. 
 


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C O N FI D E N TI A L 
 
E a c h s c al e i n t h e E O R T C Q L Q- C 3 0 q u e sti o n n air e will b e s c or e d ( 0 t o 1 0 0) a c c or di n g t o t h e E O R T C 
re c o m m e n d ati o n s i n t h e E O R T C Q L Q- C 3 0 S c ori n g 
M a n u al. T h e s c ori n g 
m et h o d i s s u m m ari z e d 
b el o w. I n t hi s s u m m ar y Qi r ef er s t o t h e i t h q u e sti o n o n t h e  E O R T C Q L Q- C 3 0. 
F u n cti o n al s c al e s: 
  
P h y si c al f u n cti o ni n g:  
( 1 - (( Q 1 + Q 2 + Q 3 + Q 4 + Q 5)/ 5 - 1)/ 3) * 1 0 0 
  
R ol e f u n cti o ni n g:   
( 1 - (( Q 6 + Q 7)/ 2- 1)/ 3) * 1 0 0 
  
E m oti o n al f u n cti o ni n g:  
( 1 - (( Q 2 1 + Q 2 2 + Q 2 3 + Q 2 4)/ 4- 1)/ 3) * 1 0 0 
  
C o g niti v e f u n cti o ni n g:  
( 1 - (( Q 2 0 + Q 2 5)/ 2- 1)/ 3) * 1 0 0 
  
S o ci al f u n cti o ni n g:  
( 1 - (( Q 2 6 + Q 2 7)/ 2- 1)/ 3) * 1 0 0 
Gl o b al h e alt h st at u s: 
  
Gl o b al h e alt h st at u s/ Q O L: (( Q 2 9 + Q 3 0)/ 2- 1)/ 6 * 1 0 0 
S y m pt o m s c al e s/It e m s: 
  
F ati g u e:   
  
(( Q 1 0 + Q 1 2 + Q 1 8)/ 3- 1)/ 3 * 1 0 0 
  
N a u s e a a n d v o miti n g:  
(( Q 1 4 + Q 1 5)/ 2- 1)/ 3 * 1 0 0 
  
P ai n:  
  
  
(( Q 9 + Q 1 9)/ 2- 1)/ 3 * 1 0 0 
  
D y s p n o e a:  
  
(( Q 8- 1)/ 3 * 1 0 0 
  
I n s o m ni a:   
  
( Q 1 1- 1)/ 3 * 1 0 0 
  
A p p etit e l o s s:  
  
( Q 1 3- 1)/ 3 * 1 0 0 
  
C o n sti p ati o n:  
  
( Q 1 6- 1)/ 3 * 1 0 0 
  
Di arr h o e a:  
  
( Q 1 7- 1)/ 3 * 1 0 0 
  
Fi n a n ci al diffi c ulti e s:  
( Q 2 8- 1)/ 3 * 1 0 0 
 
T h e Q L Q- H & N 3 5 E O R T C m o d ul e will al s o b e u s e d t o a s s e s s h e alt h-r el at e d q u alit y of lif e. Ei g ht e e n 
s c al e s ar e d eri v e d fr o m t h e 3 5 q u e sti o n s of t h e Q L Q- H & N 3 5 E O R T C m o d ul e : 
− 
S e v e n m ulti-it e m s c al e s t h at a s s e s s e d P ai n, S w all o wi n g, S e n s e s, S p e e c h, S o ci al e ati n g, 
S o ci al c o nt a ct a n d S e x u alit y. 
− 
El e v e n si n gl e it e m : T e et h, O p e ni n g m o ut h, Dr y m o ut h, Sti c k y s ali v a, C o u g hi n g, F e eli n g ill, 
U s e of p ai n kill er s, U s e of n utriti o n al s u p pl e m e nt, U s e of f e e di n g t u b e, L o st of w ei g ht a n d 
G ai n of w ei g ht. 
 
E a c h s c al e i n t h e Q L Q- H & N 3 5 E O R T C q u e sti o n n air e will b e s c or e d ( 0 t o 1 0 0). T h e s c ori n g a p pr o a c h 
f or t h e Q L Q- H & N 3 5 i s i d e nti c al i n pri n ci pl e t o t h at f or t h e s y m pt o m s c al e s / si n gl e it e m s of t h e Q L Q-
C 3 0 a n d i s s u m m ari z e d b el o w. I n t hi s s u m m ar y Qi r ef er s t o t h e i t h q u e sti o n o n t h e Q L Q- H & N 3 5 
E O R T C.  
M ulti-it e m s c al e s/It e m s: 
  
P ai n:  
  
  
(( Q 1 + Q 2 + Q 3 + Q 4)/ 4- 1)/ 3 * 1 0 0 
  
S w all o wi n g:  
  
(( Q 5 + Q 6 + Q 7 + Q 8)/ 4- 1)/ 3 * 1 0 0 
  
S e n s e s pr o bl e m s:  
(( Q 1 3 + Q 1 4)/ 2- 1)/ 3 * 1 0 0 
  
S p e e c h pr o bl e m s:  
(( Q 1 6 + Q 2 3 + Q 2 4)/ 3- 1)/ 3 * 1 0 0 


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Trouble with social eating: ((Q19+Q20+Q21+Q22)/4-1)/3 * 100 
 
Trouble with social contact: ((Q18+Q25+Q26+Q27+Q28)/5-1)/3 * 100 
 
Less sexuality: 
 
((Q29+Q30)/2-1)/3 * 100 
 
Single items: 
 
Teeth: 
 
 
(Q9-1)/3 * 100 
 
Opening mouth:  
(Q10-1)/3 * 100 
 
Dry mouth: 
 
(Q11-1)/3 * 100 
 
Sticky saliva:  
 
(Q12-1)/3 * 100 
 
Coughing: 
 
(Q15-1)/3 * 100 
 
Felt ill: 
 
 
(Q17-1)/3 * 100 
 
Pain killers 
: 
(Q31-1)/3 * 100 
 
Nutritional supplements: (Q32-1)/3 * 100 
 
Feeding tube: 
 
(Q33-1)/3 * 100 
 
Weight loss: 
 
(Q34-1)/3 * 100 
 
Weight gain: 
 
(Q35-1)/3 * 100 
If a question was filled in by circling more than one answer, the internal convention at Pierre Fabre is 
to consider the answer as missing. 
A questionnaire is considered to be completed if more than two thirds of the questions are answered. 
Otherwise the questionnaire is ignored for the analysis. 
6.2.1. Primary parameter 
The primary quality of life parameter will be the global health status. 
6.2.2. Secondary parameter 
The secondary quality of life parameters will be the fourteen other scales of QLQ-C30 questionnaire 
and the eighteen scales of the QLQ-H&N 35 EORTC. Each analysis will be presented by functional 
and/or “symptoms” scales for QLQ-C30 questionnaire and by multi-items scales and/or single items for 
the QLQ-H&N 35 EORTC. 
6.2.3. Windows 
The Quality of life of a patient at the time of an administration will be based on the answers provided 
by the patient in the last questionnaire completed and evaluable. 
At baseline, only questionnaires which were completed within the window of seven days prior to the 
randomisation (and including any questionnaire filled that day) will be considered. If more than one 
questionnaire is available within this window the last non-missing questionnaire will be analysed.  
Any questionnaire that would be completed after the date of last administration plus 30 days therefore 
out of study treatment (not as per protocol) would not be analysed. 


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6.3. 
FURTHER ANTI-CANCER THERAPY 
Further anti-cancer therapies include any anti-tumour treatment given to the patient after withdrawal 
from study drug treatment. 
 
7. DEFINITION OF POPULATIONS 
7.1. 
INTENT-TO-TREAT POPULATION (ITT) 
All randomised patients will be included in the Intent-To-Treat (ITT) population. They will be analysed 
in the arm they were assigned by randomisation. 
7.2. 
ELIGIBLE POPULATION 
Following the protocol amendment 11, the eligible population will not be defined and used.  
7.3. 
EVALUABLE POPULATION FOR RESPONSE 
Following the protocol amendment 11, the evaluable population for response will not be defined and 
used.  
 
7.4. 
EVALUABLE POPULATION FOR SAFETY 
All randomised and treated patients will be included in the safety analysis. They will be analysed in the 
treatment arm they actually received. 
7.5. 
EVALUABLE POPULATION FOR HEALTH-RELATED QUALITY OF LIFE 
ASSESSMENT 
7.5.1. Evaluable population for QLQ-C30 
To be evaluable for the QLQ-C30 questionnaire, randomised patients should have completed at least 
two thirds (i.e. at least 20 questions) of the questions of the baseline QLQ-C30 questionnaire within 7 
days prior to randomisation, and at least two thirds of the questions of a QLQ-C30 questionnaire 
during the study period or at the end of study (during last cycle). 
7.5.2. Evaluable population for QLQ-H&N 35 EORTC module 
To be evaluable for the QLQ-H&N 35 EORTC module, randomised patients should have completed at 
least two thirds of the questions (i.e. at least 23 questions) of the baseline the QLQ-H&N 35 EORTC 


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C O N FI D E N TI A L 
 
m o d ul e wit hi n 7 d a y s pri or t o r a n d o mi s ati o n, a n d at l e a st t w o t hir d s of t h e q u e sti o n s of a Q L Q- H & N 3 5 
E O R T C m o d ul e d uri n g t h e st u d y p eri o d or at t h e e n d of st u d y ( d uri n g l a st c y cl e).  
8. 
S T A TI S TI C A L M E T H O D S 
8. 1.  
S T A TI S TI C A L S O F T W A R E A N D M E T H O D O L O G Y 
T h e st ati sti c al a n al y si s will b e p erf or m e d b y I n stit ut d e R e c h er c h e Pi err e F a br e. D at a will b e a n al y s e d 
u s i n g t h e S A S s y st e m s oft w ar e v er si o n 9. 4 ( or l at er if a v ail a bl e) f or Wi n d o w s. All st ati sti c al t e st s will 
b e  t w o- si d e d at a 5 % l e v el of si g nifi c a n c e u nl e s s ot h er wi s e s p e cifi e d. 
S u m m ar y t a bl e s will b e pr o vi d e d a c c or di n g t o t h e st a n d ar d f or m at of I n stit ut d e R e c h er c h e Pi err e 
F a br e d e v el o p e d f or t h e vi nfl u ni n e c h e m ot h er a p y. 
All d e s cri pti v e st ati sti c s will b e pr e s e nt e d i n s u m m ar y t a bl e s b y tr e at m e nt ar m.  
C o nti n u o u s d at a will b e s u m m ari z e d wit h t h e f oll o wi n g it e m s: fr e q u e n c y, m e di a n (if n ≥ 3), r a n g e a n d 
m e a n a n d st a n d ar d d e vi ati o n if r el e v a nt. 
C at e g ori c al d at a will b e pr e s e nt e d i n c o nti n g e n c y t a bl e s wit h fr e q u e n ci e s a n d p er c e nt a g e s of e a c h 
m o d alit y (i n cl u di n g mi s si n g d at a m o d alit y). 
8. 2.  
S T A TI S TI C A L M E T H O D S F O R C A T E G O RI C A L V A RI A B L E S 
T h e χ ² t e st will b e p erf or m e d t o c o m p ar e pr o p orti o n s or r e pl a c e d b y Fi s h er’ s e x a ct t e st if t h e e x p e ct e d 
fr e q u e n c y i n o n e c ell of t h e c o nti n g e n c y t a bl e i s l e s s t h a n 5. T h e 9 5 % c o nfi d e n c e i nt er v al f or 
pr o p orti o n s will b e c o m p ut e d f oll o wi n g t h e e x a ct m et h o d. If a str atifi e d a n al y si s i s r e q uir e d a C o c hr a n-
M a nt el- H a e n s z el ( C M H) t e st will b e u s e d. 
8. 3.  
 S T A TI S TI C A L M E T H O D S F O R O R DI N A L V A RI A B L E S 
C o m p ari s o n s b et w e e n t h e t w o tr e at m e nt ar m s will b e pr o vi d e d f or or di n al d at a u si n g t h e n o n-
p a r a m etri c Wil c o x o n r a n k s u m t e st. 
8. 4.  
S T A TI S TI C A L M E T H O D S F O R C O N TI N U O U S V A RI A B L E S 
T h e di stri b uti o n s of q u a ntit ati v e d at a will b e e x a mi n e d b y t h e K ol m o g or o v- S mir n o v t e st i n or d er t o t e st 
f or n or m alit y. I n c a s e of G a u s si a n di stri b uti o n, t h e c o m p ari s o n b et w e e n t h e 2 tr e at m e nt ar m s will b e 
m a d e wit h a St u d e nt t-t e st. If t h e di stri b uti o n i s n ot c o n si d er e d a s G a u s si a n t h e n t h e n o n- p ar a m etri c 
Wil c o x o n t e st will b e p erf or m e d. 


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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 
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 center) used at the time of randomisation. 
According to the protocol amendment 11, no multivariate analysis will be performed. 
8.6. 
STATISTICAL METHODS FOR HEALTH-RELATED QUALITY OF LIFE DATA 
Following the protocol amendment 11, no repeated measure analysis will be performed.  
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, progressive disease, lost to 
follow up, protocol deviation and other reasons.  
The patient status (dead or alive) at the cut-off date will be displayed together with each reason of 
death (progressive disease, related adverse event, other). 
The number of patients randomised, treated (evaluable for safety) and evaluable for quality of life will 
be presented by treatment group. Patients with at least one protocol deviations will be tabulated by 
treatment arm and by type of protocol deviation. 
 
For arm A, the treatment duration is defined as the time elapsed between the date of 1st administration 
and the date of the last VFL administration (if MTX not given) + 21 days or the date of the last MTX 
administration (if given) + 14 days. For arm B, the treatment duration is defined as the time elapsed 
between the date of the 1st administration and the date of the last D1 administration of the last cycle + 
21 days (if D8 and D15 not given) or the date of the last D8 administration of the last cycle + 14 days 
(if D15 not given) or the date of the last D15 administration of the last cycle + 7 days (if D15 given). 
Treatment duration will be tabulated by treatment arm. 
Time between randomisation and first administration will be tabulated by treatment arm. 


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C O N FI D E N TI A L 
 
T h e d ur ati o n of f oll o w- u p i s d efi n e d a s t h e ti m e el a p s e d b et w e e n t h e d at e of r a n d o mi s ati o n a n d t h e 
d a t e of l a st n e w s or d e at h, d e at h b ei n g a c e n s or e d o b s er v ati o n.  
9. 1. 2. 
C h ar a ct eri sti c s at b a s eli n e 
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s of p ati e nt s will b e di s pl a y e d. T h e f oll o wi n g v ari a bl e s will b e 
a n al y s e d o n t h e I T T p o p ul ati o n a c c or di n g t o t h e ar m a s si g n e d at r a n d o mi s ati o n: 
D e m o gr a p hi c d at a   
  
A g e at t h e ti m e of r a n d o mi s ati o n 
  
C at e g ori z e d gr o u p s of a g e : < 3 5, [ 3 5 – 5 0[, [ 5 0 – 6 5[, [ 6 5 – 7 5[, [ 7 5 – 8 0[ a n d > 8 0 y e ar s 
  
S e x 
  
B o d y w ei g ht, 
  
W H O P erf or m a n c e St at u s  
 
Str atifi c ati o n d at a E xtr a ct fr o m t h e I W R S d at a b a s e   
  
W H O p erf or m a n c e st at u s ( 0 v s. 1), 
  
R efr a ct or y or r e si st a nt t o pl ati n u m v er s u s ot h er 
  
Pri or r a di ot h er a p y ( y e s v er s u s n o) 
  
Pri or tr e at m e nt wit h a n y a nti- E G F R m e di c ati o n ( y e s v er s u s n o)  
 
T u m o ur c h ar a ct eri sti c s at di a g n o si s 
  
A n at o mi c sit e of c a n c er, 
  
Hi st o p at h ol o gi c al gr a d e, 
  
T N M cl a s sifi c ati o n, 
  
St a g e, 
 
T u m o ur c h ar a ct eri sti c s at st u d y e ntr y 
  
E xt e nt of t h e di s e a s e at st u d y e ntr y, 
  
P ati e nt c at e g or y, 
  
I nt er v al fr o m di a g n o si s t o st u d y e ntr y (r a n d o mi s ati o n), 
  
C at e g ori z e d gr o u p s of I nt er v al fr o m di a g n o si s t o st u d y e ntr y ( < 2 y e ar s v s. > 2 y e ar s), 
 
Pr o gr e s si o n-fr e e i nt er v al *, 
  
Cat e g ori z e d gr o u p s of pr o gr e s si o n-fr e e i nt er v al ( < 6 m o nt h s v s. > 6 m o nt h s), 
 
Tr e at m e nt fr e e i nt er v al **, 
  
Cat e g ori z e d gr o u p s of tr e at m e nt fr e e i nt er v al ( < 6 m o nt h s v s. > 6 m o nt h s), 
 
Di s e a s e fr e e i nt er v al*** 
  
C at e g ori z e d gr o u p s of di s e a s e fr e e i nt er v al** : < 2 y e ar s, ≥ 2 y e ar s, 
  
Pr e s e n c e of vi s c er al i n v ol v e m e nt (l u n g +/- li v er),  
  
Pr e s e n c e of vi s c er al i n v ol v e m e nt ( s u c h a s li v er, l u n g, pl e ur a, h e art, p eri c ar di u m, ki d n e y, t h yr oi d 
a n d  s u pr ar e n al gl a n d, d et ail e d li st i n a p p e n di x 4) 
  
C at e g ori z e d gr o u p s of n u m b er of or g a n s i n v ol v e d: 1, 2 a n d ≥ 3 or g a n s, 


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C O N FI D E N TI A L 
 
 
D et ail of or g a n s i n v ol v e d, gr o u pi n g pr o vi d e d i n a p p e n di x 4 
 
M e a s ur a bl e/ n o n- m e a s ur a bl e di s e a s e****. 
* : T h e pr o gr e s si o n fr e e i nt er v al  i s t h e ti m e i nt er v al el a p s e d b et w e e n t h e d at e of e n d of t h e l a st pri or 
c h e m ot h er a p y gi v e n f or m et a st ati c i nt e nt a n d t h e d at e of r el a p s e or pr o gr e s si o n aft er t hi s l a st li n e of 
c h e m ot h er a p y. T hi s pr o gr e s si o n fr e e i nt er v al of p ati e nt s r el a p si n g or pr o gr e s si n g d uri n g t h e l a st li n e 
tr e at m e nt will b e e sti m at e d t o l a st o n e d a y. 
** : T h e tr e at m e nt fr e e i nt er v al i s t h e ti m e el a p s e d b et w e e n t h e d at e of e n d of t h e l a st tr e at m e nt 
( pri or c h e m ot h er a p y, pri or r a di ot h er a p y, pri or tr e at m e nt wit h c et u xi m a b, w hi c h e v er o c c ur s l a st) a n d t h e 
fir st a d mi ni str ati o n of st u d y tr e at m e nt.  
*** T h e di s e a s e fr e e i nt er v al i s t h e ti m e i nt er v al el a p s e d b et w e e n t h e d at e of e n d of t h e l a st pri or 
c h e m ot h er a p y a c c or di n g t o i nt e nt s i n d u cti o n/ c o n c o mit a nt wit h r a di ot h er a p y a n d t h e d at e of r el a p s e or 
pr o gr e s si o n.  
**** M e a s ur a bl e di s e a s e  d efi n e d a s: 
•  
Y e s if t h e n u m b er of t ar g et e d l e si o n s i s > 0,  
•  
N o if n u m b er of t ar g et e d l e si o n s i s n ot > 0 a n d t h e n u m b er of n o n-t ar g et e d l e si o n s i s > 0 
•  
N o di s e a s e i n ot h er c a s e s  
 
 
Pri or t h er a p y 
A n o v er vi e w of pri or t h er a pi e s f or S C C H N will b e pr o vi d e d gi vi n g: 
  
N u m b er of p ati e nt s wit h at l e a st o n e pri or t h er a p y 
  
N u m b er of p ati e nt s tr e at e d b y m e di c ati o n 
  
N u m b er of p ati e nt s tr e at e d b y c h e m ot h er a p y 
  
N u m b er of p ati e nt s tr e at e d b y c et u xi m a b 
  
N u m b er of p ati e nt s tr e at e d b y ot h er a nti n e o pl a sti c dr u g 
  
N u m b er of p ati e nt s w h o u n d er w e nt a s ur g er y, e x cl u di n g bi o p si e s, 
  
N u m b er of p ati e nt s w h o u n d er w e nt a r a di ot h er a p y 
  
F or t h e l a st M e di c ati o n (i n cl u di n g c h e m ot h er a p y, c et u xi m a b, a nti n e o pl a sti c t h er a p y): i nt e nt, ti m e 
b et w e e n st o p d at e of m e di c ati o n a n d d at e of r el a p s e/ pr o gr e s si o n ( e x pr e s s e d i n w e e k s). 
  
F or s ur g eri e s: n u m b er of s ur g eri e s 
  
F or t h e l a st r a di ot h er a p y: i nt e nt 
  
N u m b er of p ati e nt s b y c o m bi n ati o n of t h er a pi e s: 
o  
C h e m ot h er a p y + r a di ot h er a p y + s ur g er y 
o  
C h e m ot h er a p y + r a di ot h er a p y 
o  
C h e m ot h er a p y + s ur g er y 
 
S ur g er y 
  
D et ail s of s ur g eri e s u si n g M e d D R A s y st e m or g a n cl a s s a n d pr ef err e d t er m, 
 
R a di ot h er a p y 
  
N u m b er of p ati e nt s w h o u n d er w e nt a r a di ot h er a p y (f or S C C H N) wit h i nt e nt a n d i nt e nt of l a st 
r a di ot h er a p y, 
 


Statistical Analysis Plan / L00070 IN 309 F0                                                       Version n° 4 (23/11/2017) 
25/55   
CONFIDENTIAL 
 
Chemotherapy 
 
Number of patients who underwent a chemotherapy (for SCCHN) with intent and intent of last 
chemotherapy, 
 
Number of lines, 
 
Number of patients treated with a prior platinum agent (Cisplatin, Carboplatin, …), 
 
Type of prior platinum-based chemotherapy by intent 
 
Number of refractory/resistant/other failure patients by intent for prior platinum-based 
chemotherapy 
 
Class of prior adjuvant/induction chemotherapy: (Platinum single agent, Platinum + Taxane, 
Platinum + Other, Taxane single agent, Taxane + Other) 
 
Class of prior metastatic chemotherapy: (Platinum single agent, Platinum + Taxane, Platinum + 
Other, Taxane single agent, Taxane + Other) 
 
Number of cycles of chemotherapy by intent and by class of chemotherapy, 
 
Best response of the last chemotherapy by intent and by class of chemotherapy, 
 
Other prior treatments 
 
Number of patients who underwent a treatment with cetuximab (including panitumumab) with 
intent and intent of last treatment, 
 
Number of patients who underwent a prior treatment with other antineoplastic drugs with intent, 
 
Clinical examination 
 
Electrocardiogram (normal/abnormal but not clinically significant/abnormal clinically significant), 
 
Baseline biological abnormalities, 
 
Baseline haematological abnormalities. 
 
Temperature, Blood Pressure, Pulse 
 
Concomitant medications at baseline 
 
Concomitant medications whatever the indication, according to the WHO-Drug dictionary, 
 
Concomitant medications with a tumour related indication, according to the WHO-Drug 
dictionary, 
 
Concomitant medications with a prophylactic indication, according to the WHO-Drug dictionary 
 
Concomitant medications with pre-treatment event indication, according to the WHO-Drug 
dictionary, 
 
Concomitant medications with a medical history indication, 
 
Prior medical history 
 
Prior medical history according to MedDRA System Organ Classification (SOC) and Preferred 
Term (PT),  
 
Listing of prior medical or surgical history, 
 
Pre-treatment events 
 
Pre-treatment events according to MedDRA System Organ Classification (SOC) and Preferred 
Term (PT), 
 
Listing of Pre-treatment events at baseline. 
 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
2 6 / 5 5   
C O N FI D E N TI A L 
 
9. 2.  
D E S C RI P TI O N D U RI N G T H E S T U D Y 
D e s cri pti o n d uri n g t h e st u d y will b e d o n e o n all tr e at e d p o p ul ati o n. 
A  s u m m ar y t a bl e will pr o vi d e b y tr e at m e nt ar m ( a n d b y tr e at m e nt), t h e f oll o wi n g it e m s: 
  
D ur ati o n of e x p o s ur e, 
  
N u m b er of p ati e nt wit h at l e a st o n e d o s e p er m a n e ntl y di s c o nti n u e d, 
  
N u m b er of p ati e nt wit h at l e a st o n e d o s e c a n c ell e d, 
  
N u m b er of p ati e nt s wit h at l e a st o n e d o s e r e d u c e d, 
  
N u m b er of p ati e nt s wit h at l e a st o n e d o s e d el a y e d, 
  
N u m b er of p ati e nt s wit h at l e a st o n e i nf u si o n i nt err u pt e d. 
 
T h e t ot al n u m b er of c y cl e s gi v e n d uri n g t h e st u d y, t h e m e di a n n u m b er of c y cl e s a s w ell a s t h e n u m b er 
of p ati e nt s b y c y cl e will b e gi v e n. T h e n u m b er of m et h otr e x at e a d mi ni str ati o n will b e pr e s e nt e d i n e a c h 
ar m. 
T h e a ct u al d o s e of ( m g/ m²) will b e c al c ul at e d fr o m t h e t ot al d o s e a d mi ni st er e d ( m g) di vi d e d b y t h e 
B S A.  
T h e B S A will b e r e c al c ul at e d at e a c h c y cl e. 
T h e B o d y S urf a c e Ar e a ( B S A) will b e c al c ul at e d a s f oll o w s : 
1 0 0 0 0
8 4
.
7 1
B S A
7 2 5
.0
4 2 5
.0






×
×
=
H
W
 
w h er e : 
  
W = W ei g ht (i n k g) at c y cl e b ef or e c y cl e i, or l a st w ei g ht a v ail a bl e if mi s si n g, 
  
H = H ei g ht (i n c e nti m etr e s) at t h e b e gi n ni n g of t h e st u d y. 
B S A a s p er i n v e sti g at or will b e u s e d a s a n e sti m at e w h e n h ei g ht i s n ot pr o vi d e d at b a s eli n e. 
T h e f oll o wi n g c at e g ori e s of vi nfl u ni n e d o s e s will b e u s e d: 
T a bl e 9- 1 : C at e g ori z e d d o s e of vi nfl u ni n e 
D o s e c at e g or y  
i n m g/ m² 
 
D o s e of vi nfl u ni n e  
i n m g/ m² 
> 3 2 0  
] 3 3 5 – ∞] 
3 2 0  
] 3 0 0 – 3 3 5 ] 
2 8 0  
] 2 6 5 - 3 0 0 ] 
2 5 0  
] 2 3 7. 5 - 2 6 5 ] 
2 2 5  
] 2 1 2. 5- 2 3 7. 5 ] 
< 2 2 5  
] 0 - 2 1 2. 5 ] 
 
T h e f oll o wi n g c at e g ori e s of m et h otr e x at e d o s e s will b e u s e d: 
T a bl e 9- 2 : C at e g ori z e d d o s e of m et h otr e x at e 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
2 7 / 5 5   
C O N FI D E N TI A L 
 
D o s e c at e g or y  
i n m g/ m² 
 
D o s e of m et h otr e x at e  
i n m g/ m² 
> 4 0  
] 4 5 - ∞[ 
4 0  
] 3 5 - 4 5 ] 
3 0  
] 2 5 – 3 5 ] 
2 0  
] 1 5 - 2 5 ] 
< 2 0  
] 0 - 1 5 ] 
T h e d o s e i nt e n sit y ( m g/ m²/ w k) a n d r el ati v e d o s e i nt e n sit y ( %) will b e c al c ul at e d p er p ati e nt a n d p er 
c y cl e f or e a c h tr e at m e nt dr u g. C u m ul ati v e d o s e of vi nfl u ni n e or m et h otr e x at e ( m g/ m²) will al s o b e 
pr o vi d e d p er p ati e nt. D e s cri pti v e st ati sti c s s u c h a s m e di a n a n d r a n g e will b e pr o vi d e d. 
M or e o v er, f or b ot h tr e at m e nt ar m s, r el ati v e d o s e i nt e n sit y will b e c at e g ori s e d ( < 5 0 %, [ 5 0 % - 7 0 %[, 
[ 7 0 % - 9 0 %[, [ 9 0 % - 1 1 0 %[, ≥ 1 1 0 %) p er p ati e nt a n d p er c y cl e.  
9. 2. 1. 
D o s e i nt e n sit y p er c y cl e 
A ct u al d o s e i nt e n sit y p er c y cl e will b e d efi n e d a s f oll o w s : 
(
) (
)]
i
  
c ycle
at 
 
date
 
C o urse
1
i  
c ycle
at 
 
date
 
C o urse
[
i
  
c ycle
at  
  
recei ve d
  
d ose
  
Act ual
( w k)
  i  
c ycle
 
of
d urati o n 
  
Act ual
i
  
c ycle
at  
  
recei ve d
  
d ose
  
Act ual
i
  
c ycle
at 
 
DI
−
+
=
=
 
T h e c y cl e d ur ati o n at c y cl e n will b e e q u al t o t h e ti m e el a p s e d b et w e e n t h e d a y 1 a d mi ni str ati o n d at e 
of c y cl e n a n d t h e d a y 1 a d mi ni str ati o n d at e of c y cl e n + 1. T h e d ur ati o n of t h e l a st c y cl e will b e 
e sti m at e d t o b e 3 w e e k s.  
9. 2. 2. 
R el ati v e d o s e i nt e n sit y p er c y cl e 
R el ati v e d o s e i nt e n sit y ( %) at c y cl e n° i w ill b e t h e r ati o of t h e a ct u al d o s e i nt e n sit y ( m g/ m²/ w k) at c y cl e 
i t o t h e pl a n n e d d o s e i nt e n sit y ( m g/ m²/ w k) t h at i s t o s a y : 
1 0 0
i nte nsit y 
  
d ose
  
Pla n ne d
 i  
c ycle
at  
 
i nte nsit y 
  
d ose
  
Act ual
1 0 0
P DI
i  
c ycle
at  
  
DI
i  
c ycle
at  
  
R DI
×






=
×






=
 
w h er e : 
( w k)
 i  
c ycle
  
of
d urati o n  
  
T he orical
d ose
  
Pla n ne d
i  
c ycle
at 
 
P DI
=
 
T h e t h e or eti c al c y cl e d ur ati o n i s 3 w e e k s. T h e pl a n n e d d o s e f or e a c h dr u g i s d efi n e d a s f oll o w:  
T a bl e 9- 3: Pl a n n e d d o s e i nt e n sit y i n m g/ m²/ w k of vi nfl u ni n e  
Pl a n n e d D o s e 
( m g/ m²) p er 
c y cl e 
C y cl e d ur ati o n 
( w k) 
P. D.I 
( m g/ m²/ w k) 
2 8 0 
3 
9 3. 3 3 
 
T a bl e 9- 4: Pl a n n e d d o s e i nt e n sit y i n m g/ m²/ w k of m et h otr e x at e 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
2 8 / 5 5   
C O N FI D E N TI A L 
 
Tr e at m e nt ar m  
Pl a n n e d D o s e 
( m g/ m²) p er 
c y cl e 
C y cl e d ur ati o n 
( w k) 
P. D.I 
( m g/ m²/ w k) 
Ar m A 
6 0 
3 
2 0 
Ar m B 
1 2 0 
3 
4 0 
9. 2. 3. 
D o s e i nt e n sit y p er p ati e nt 
A ct u al d o s e i nt e n sit y p er p ati e nt will b e d efi n e d a s f oll o w s: 
∑
=
∑
=
=
=
n
i
d ur ati o n
n
i
d os e
i
i
1
1
( wk)
d urati o n 
Treat me nt 
d os e
 
C u m ulati ve
DI
 
w h er e: 
  
d o s ei = a ct u al d o s e r e c ei v e d ( m g/ m²) at c y cl e i, 
 
d ur ati o n i = a ct u al d ur ati o n ( w k s) of c y cl e i, 
 
n = t ot al n u m b er of c y cl e( s) p er p ati e nt. 
9. 2. 4. 
R el ati v e d o s e i nt e n sit y p er p ati e nt 
R el ati v e d o s e i nt e n sit y ( %) will b e t h e r ati o of t h e a ct u al d o s e i nt e n sit y ( m g/ m²/ w k) t o t h e pl a n n e d d o s e 
i nt e n sit y ( m g/ m²/ w k) t h at i s t o s a y : 
 
 
P DI i s d efi n e d f or e a c h ar m i n t h e s e cti o n 9. 2. 2. 
 
9. 2. 5. 
D o s e r e d u cti o n s  
D o s e r e d u cti o n s ar e all o w e d b y t h e st u d y pr ot o c ol. T h e n u m b er of p ati e nt s a n d c y cl e s wit h a d o s e 
re d u cti o n i n e a c h ar m will b e pr e s e nt e d a s w ell a s t h e r e a s o n s. 
9. 2. 5. 1. Vi nfl u ni n e d o s e r e d u cti o n ( Ar m A) 
  
N u m b er of p ati e nt s wit h at l e a st o n e d o s e of vi nfl u ni n e r e d u c e d at d a y 1. 
 
N u m b er of c y cl e s wit h a d o s e of vi nfl u ni n e r e d u c e d at d a y 1. 
 
  
R e a s o n s f or vi nfl u ni n e d o s e r e d u cti o n: 
1 0 0
i nte nsit y 
  
d ose
  
Pla n n e d
i nte nsit y
  
d ose
  
Act u al
1 0 0
P DI
DI
R DI
×






=
×




=


Statistical Analysis Plan / L00070 IN 309 F0                                                       Version n° 4 (23/11/2017) 
29/55   
CONFIDENTIAL 
 
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 
% 
Adverse Event 
Other
 
 
Listing of the reasons for vinflunine dose reduction in arm A. 
 
9.2.5.2.Methotrexate dose reductions  
 
Number of patients with at least one dose reduction of methotrexate: 
 
Number of cycles with at least dose reduction of methotrexate: 
 
Number of administrations with a dose reduction of methotrexate: 
 
Reasons for methotrexate dose reductions (as per protocol) in arm A: 
Reason for dose reduction  
Dose reduction as per protocol 
(from X to Y) in mg/m² 
N cycles
 
30
20 
30
<20 
N(%)
N(%)
N(%)
Adverse Event 
Other
 
Reasons for methotrexate dose reductions (as per protocol) in arm B: 
Reason for dose reduction  
Dose reduction as per protocol (from X to Y) in 
mg/m² 
N cycles
 
40
30 
40
20 
40
<20 
30
20 
30
<20 
20
<20 
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
N(%)
Adverse Event 
Other
 
 
Listing of the reasons for methotrexate dose reductions,  
 
The format of the tables may be slightly modified according to observed data. 
9.2.6. Treatment cancellation 
Cancellation of day 1 vinflunine administration is not allowed by the protocol. Methotrexate dosing may 
be cancelled in both arms (D8 in Arm A and D8/D15 in Arm B) as per protocol (§ 5.2.3 and § 5.2.4 of 
the protocol). 
The number of cycles with at least one day of methotrexate cancelled and number of patients with at 
least one day of dosing cancelled will be displayed. Reasons for treatment cancellation will be 
provided. 
 
Number of patients with at least one methotrexate dose cancelled, 
 
Number of cycles with at least one methotrexate dose cancelled, 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
3 0 / 5 5   
C O N FI D E N TI A L 
 
 
R e a s o n s f or m et h otr e x at e o n D 1 / D 8 / D 1 5 d o s e c a n c ell ati o n, p er p ati e nt a n d p er c y cl e, 
 
Li sti n g of m et h otr e x at e d o s e c a n c ell e d a n d r e a s o n, 
 
If c a n c ell ati o n ar e o b s er v e d f or Vi nfl u ni n e, t h e y will b e d e s cri b e d i n t h e s a m e w a y a s f or M et h otr e x at e. 
9. 2. 7. 
D o s e i nt err u pti o n 
F or b ot h ar m s, t h e n u m b er of p ati e nt s a n d c y cl e s wit h a n i nf u si o n i nt err u pti o n will b e pr e s e nt e d a s w ell 
a s  t h e r e a s o n s. 
  
N u m b er of p ati e nt s wit h at l e a st o n e i nf u si o n i nt err u pti o n, 
  
N u m b er of c y cl e s wit h at l e a st o n e i nf u si o n i nt err u pti o n, 
  
R e a s o n s f or i nf u si o n i nt err u pti o n, 
  
Li sti n g of t h e r e a s o n s f or i nf u si o n i nt err u pti o n, 
 
9. 2. 8. Tr e at m e nt d el a y 
T h e n u m b er of p ati e nt s a n d c y cl e s d el a y e d will b e pr e s e nt e d wit h r e a s o n s f or tr e at m e nt d el a y.  
A  tr e at m e nt c y cl e will b e c o n si d er e d a s d el a y e d if a d mi ni st er e d ≥ 4 d a y s aft er t h e pl a n n e d d at e wit h a 
t hr e e w e e k s i nt er v al fr o m d a y 1 of pr e vi o u s c y cl e.  
T h e d el a y s will b e c at e g ori z e d a s f oll o w s: 
  
[ 4 – 7 d a y s[, 
  
[ 7 – 1 4 d a y s[, 
 
≥ 1 4 d a y s. 
 
T h e f oll o wi n g i nf or m ati o n will b e d e s cri b e d: 
  
N u m b er of p ati e nt s wit h at l e a st o n e c y cl e d el a y e d b y f o ur d a y s or m or e, b y ar m  
  
N u m b er of c y cl e s d el a y e d, b y ar m 
  
C at e g ori z e d gr o u p s of c y cl e d el a y, b y ar m 
  
R e a s o n s f or c y cl e d el a y of f o ur d a y s or m or e, b y ar m 
  
Li sti n g of t h e c y cl e s d el a y e d wit h r e a s o n s, 
9. 2. 9. 
D o s e di s c o nti n u ati o n s  
P ati e nt s i n ar m A w h o r e q uir e di s c o nti n u ati o n of m et h otr e x at e m a y r e m ai n o n vi nfl u ni n e al o n e f or t h e 
re m ai n d er of t h e st u d y. Li k e wi s e, p ati e nt s w h o r e q uir e di s c o nti n u ati o n of vi nfl u ni n e m a y r e m ai n o n 
m et h otr e x at e al o n e f or t h e r e m ai n d er of t h e st u d y. 
T h e f oll o wi n g i nf or m ati o n will b e pr o vi d e d f or p ati e nt s tr e at e d i n ar m A: 
 N u m b er of p ati e nt s a n d c y cl e s wit h di s c o nti n u ati o n of vi nfl u ni n e or m et h otr e x at e ( ar m A), 


Statistical Analysis Plan / L00070 IN 309 F0                                                       Version n° 4 (23/11/2017) 
31/55   
CONFIDENTIAL 
 
 Number of cycles, cumulative dose (by patient), dose intensity (by patient) and relative dose 
intensity (by patient) of vinflunine / methotrexate given in monotherapy, 
 Listing of patients with discontinuation of vinflunine or methotrexate with drug administration for 
cycles given in monotherapy (arm A), 
 
9.2.10. Route of administration and setting 
The route of vinflunine and methotrexate administration and setting will be presented by patient and by 
cycle. 
 
Route of administration and setting by patient and by treatment arm: 
 
Arm A 
Arm B 
N
%
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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Route of administration by administration (Methotrexate only) 
Courses  
Arm A 
Arm B 
Central 
venous 
line 
N (%) 
Peripheral 
vein 
N (%) 
Central 
venous 
line 
N (%) 
Peripheral 
vein 
N (%) 
Number of 
administrati
ons of MTX 
 
Courses  
Arm A 
Arm B 
Central 
venous 
line 
N (%) 
Peripheral 
vein 
N (%) 
Central 
venous 
line 
N (%) 
Peripheral 
vein 
N (%) 
1
 
2
 
 
 
3
4
 
5
 
 
 
6
…
Number of 
cycles 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
3 2 / 5 5   
C O N FI D E N TI A L 
 
9. 2. 1 1. C o n c o mit a nt m e di c ati o n s 
M e di c ati o n s a d mi ni st er e d c o n c o mit a ntl y wit h t h e st u d y tr e at m e nt will b e s u m m ari z e d a c c or di n g t o t h e  
p ro p h yl a cti c i n di c ati o n, t u m o ur r el at e d i n di c ati o n, a d v er s e e v e nt i n di c ati o n, pr e-tr e at m e nt e v e nt s 
i n di c ati o n, m e di c al hi st or y i n di c ati o n a n d w h at e v er t h e i nt e nt, b y p ati e nt a n d b y c y cl e.  
1 0. E F FI C A C Y A N A L Y S E S  
 
1 0. 1. 
P RI M A R Y E F FI C A C Y A N A L Y SI S 
 
T h e fi n al a n al y si s of o v er all s ur vi v al w a s pl a n n e d t o b e c o n d u ct e d o n c e t h e r e q uir e d n u m b er of e v e nt s 
( 4 3 7 d e at h s) h a s b e e n o b s er v e d. T h e st ati sti c al a n al y si s will a ct u all y b e c o n d u ct e d o n t h e 4 5 9 
r a n d o mi s e d p ati e nt s. 
T h e pri m ar y effi c a c y p o p ul ati o n will b e t h e i nt e nt-t o-tr e at (I T T) p o p ul ati o n. 
T h e h y p ot h e si s of s u p eri orit y i n t er m s of O S of vi nfl u ni n e i n c o m bi n ati o n wit h m et h otr e x at e v er s u s 
m et h otr e x at e al o n e will b e a c c e pt e d if t h e p- v al u e fr o m a str atifi e d l o g-r a n k t e st i s s m all er t h a n 0. 0 5. 
T h e str atifi c ati o n f a ct or s will b e: 
•   
W H O p erf or m a n c e st at u s ( 0 v s 1), 
•   
R efr a ct or y or r e si st a nt t o pl ati n u m v er s u s ot h er, 
•   
Pri or r a di ot h er a p y ( y e s v er s u s n o), 
•   
Pri or tr e at m e nt wit h a n y a nti- E G F R m e di c ati o n ( y e s v er s u s n o)  
C e ntr e will n ot b e u s e d f or t h e a n al y si s b e c a u s e of t h e hi g h n u m b er of p arti ci p ati n g c e ntr e s. 
T h e str atifi e d l o g-r a n k t e st, h a z ar d r ati o a n d 9 5 % c o nfi d e n c e i nt er v al of t h e h a z ar d r ati o will b e 
c o m p ut e d u si n g t h e S A S ® pr o c e d ur e « P H R E G ». T h e tr e at m e nt ar m will b e e nt er e d a s a c o v ari at e i n 
t h e C o x pr o p orti o n al h a z ar d m o d el a n d t h e v ari a bl e s of str atifi c ati o n at r a n d o mi s ati o n ( e x c e pt c e ntr e) 
will b e e nt er e d a s str atifi c ati o n f a ct or s i n t h e m o d el. 
1 0. 2. 
S U P P O R TI V E A N A L Y SI S O F T H E P RI M A R Y E F FI C A C Y P A R A M E T E R 
A c c or di n g t o t h e pr ot o c ol a m e n d m e nt 1 1, n o s u p p orti v e a n al y si s of t h e pri m ar y effi c a c y p ar a m et er will 
b e  p erf or m e d. 
1 0. 3. 
S E N SI TI VI T Y A N A L Y S E S O F T H E P RI M A R Y E F FI C A C Y P A R A M E T E R 
A c c or di n g t o t h e pr ot o c ol a m e n d m e nt 1 1, n o s e n siti v e a n al y si s of t h e pri m ar y effi c a c y p ar a m et er will 
b e  p erf or m e d.  


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10.4. SECONDARY EFFICACY ANALYSES 
10.4.1. Progression Free Survival 
The analysis of Progression Free Survival (PFS) will be conducted in the ITT population. 
10.4.1.1.Primary analysis of PFS 
The primary analysis of PFS will be done in the ITT. The stratified log-rank test, 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. 
10.4.2. Tumour response 
The analyses of tumour response will be performed in the ITT population.  
10.4.2.1.Objective response rate and disease control rate 
 
Objective Response Rate (ORR) and Disease Control Rate (DCR) in each treatment arm will be 
estimated and presented along with a corresponding 95% confidence interval. The ORR and DCR will 
be compared between the two arms with a Cochran-Mantel-Haenszel (CMH) test. The stratification 
factors will be those defined above. 
10.4.2.2.Duration of overall response and disease control  
Duration of response and duration of disease control will be analysed on the ITT population. A 
stratified log-rank test will be used to compare the two treatment arms. The stratification factors will be 
those defined above. 
10.4.2.3.Time to first response 
The time to first response will be described in the ITT population. No formal statistical comparisons are 
planned. 
10.4.2.4.Time to treatment failure 
The time to treatment failure will be described in the ITT population. No formal statistical comparisons 
are planned. 
 


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10.4.3. Subgroups analyses  
Following the protocol amendment 11, no subgroup analysis of Overall Survival, Progression-Free 
Survival, DCR and ORR will be performed. 
 
11. SAFETY ANALYSES 
Safety analysis will be performed on the safety evaluable population 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 patient, and by treatment arm, regardless or not to the relationship to 
treatment. 
For definition of evaluable patient for non-haematological and evaluable cycle/patient for 
haematological and biochemistrical toxicity, see § 5.1 , § 5.3 and §5.4, respectively. 
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 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  
 
Patients with at least one SAE 
 
Patients with at least one related TEAE  
 
Patients with at least one related TESAE 
 
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  


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For all these items, the overall incidence, the incidence of grade 3/4, the incidence of grade 5 and the 
incidence of grade NA will be provided. 
Overall incidences per patient 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 according to the relationship with study treatment. 
Of note, some laboratory toxicities will be presented in the non-haematological adverse event tables 
when reported as adverse events as per study completion guidelines.  However, biochemical and 
haematological event should be interpreted from the tables described in section 5.1 
 
11.2.2. Selected adverse events 
The worst CTCAE grade per patient of Adverse Events Of Special Interest (AEOSI) listed in section 
5.1. will be presented for patients treated in both arms and regarding the relationship to treatment.  
11.2.3. 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 toxicities will also be provided with the following variables: patient number, 
cycle number, seriousness, CTCAE grade, relationship to treatment, date of onset, date ceased and 
significant consequences. 
11.2.4. 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. 
Two listings will be provided depicting the patients who died:  
 
patients who died within 30 days after the last administration, 
 
patients who died more than 30 days after the last administration. 
These listings will contain the following variables: patient number, cycle number, date of death, reason 
of death, source of information. 


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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 by patient and the worst grade experienced during a cycle. 
Cycles where a grade 3/4 haematological toxicity occurred will be listed by patient number. 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. 
Cycles where grade 3/4 biochemical toxicity occurred will be listed by patient number. 
In addition, the relationship between liver involvement at baseline and the worst CTCAE grade during 
study will be studied for SGOT and SGPT. The same analysis will be done for the worst CTCAE grade 
of alkaline phosphatase and liver and/or bone metastases at baseline. 
12. OTHER ANALYSES 
12.1. HEALTH-RELATED QUALITY OF LIFE ANALYSES 
The analysis of health-related quality of life will be done for each questionnaire (EORTC QLQ-C30 and 
QLQ-Head and Neck 35 EORTC module) on each evaluable population. 
12.1.1. Evaluable questionnaire 
To be evaluable for health-related quality of life assessment, patients should have completed one 
questionnaire (at least two thirds of the questions) within seven days prior to randomisation, and at 
least one questionnaire (at least two thirds of the questions) during the study period. To be considered 
evaluable, the questionnaires should be available in the native language of the patient, otherwise, the 
patient will not be evaluable for quality of life. For definition of evaluable population for QOL, see § 5.1. 
At baseline, only questionnaires which were completed within the window of seven days prior to the 
day of randomisation (and including any questionnaire filled that day) will be considered. The end of 
study questionnaire needs to be filled in within 30 days after the last administration in order to be 
evaluable. Any later questionnaire will not be analysed.  


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
3 7 / 5 5   
C O N FI D E N TI A L 
 
If 
m or e t h a n o n e q u e sti o n n air e i s a v ail a bl e 
wit hi n a n e v al u ati o n p eri o d t h e l a st n o n- mi s si n g 
q u e sti o n n air e will b e a n al y s e d. 
1 2. 1. 2. D e s cri pti v e a n al y s e s 
T h e n u m b er of Q o L q u e sti o n n air e s c o m pl et e d a n d e v al u a bl e p er e v al u ati o n will al s o b e gi v e n.  
T h e q u alit y of lif e will b e a s s e s s e d ( u si n g t h e E O R T C q u e sti o n n air e s, wit h o ut a n y m e di c al st aff 
i nfl u e n c e) at b a s eli n e b ef or e r a n d o mi s ati o n, e v er y 6 w e e k s d uri n g t h e st u d y a n d at t h e e n d of 
tr e at m e nt e v al u ati o n ( wit hi n 3 0 d a y s of t h e l a st d o s e a d mi ni str ati o n).  
Mi s si n g d at a i s a t y pi c al pr o bl e m of Q o L a n al y si s. T h er e ar e t w o l e v el s of mi s si n g d at a : 
  
Mi s si n g it e m( s) i n a q u e sti o n n air e fill e d i n b y t h e p ati e nt, 
  
C o m pl et el y mi s si n g q u e sti o n n air e at a gi v e n e v al u ati o n. 
F or t h e fir st l e v el, if m or e t h a n o n e t hir d of t h e it e m s i s mi s si n g t h e n t h e q u e sti o n n air e i s n o n-
e v al u a bl e.  
E a c h p ar a m et er will b e d e s cri b e d at b a s eli n e. C h a n g e s of t h e s c or e s fr o m b a s eli n e of t h e p ar a m et er s 
( 1 5 f or Q L Q- C 3 0 a n d 1 3 f or Q L Q- H & N 3 5) will b e pr o vi d e d f or e a c h ( m e a n, st a n d ar d d e vi ati o n, 
m e di a n, Q 1, Q 3, mi ni m u m a n d m a xi m u m).  
 
1 3. C H A N G E S I N T E R F E R E D SI N C E L A S T V E R SI O N 
 
A c c or di n g t o t h e pr ot o c ol a m e n d m e nt P A 1 1 ( 0 5/ 0 2/ 2 0 1 6) a n d t h e a s s o ci at e d pr ot o c ol v er si o n 7 
( 0 5/ 0 2/ 2 0 1 6), t h e st ati sti c al a n al y si s w a s r e d u c e d t o: 
•   
D e s cri pti o n of st u d y, p ati e nt s a n d di s e a s e c h ar a ct eri sti c s, 
•   
Effi c a c y: a n al y si s of t h e pri m ar y effi c a c y v ari a bl e ( O S) a n d t h e s e c o n d ar y effi c a c y e n d p oi nt o n 
t h e I T T p o p ul ati o n o nl y ( n o ot h er effi c a c y p o p ul ati o n will b e d efi n e d), 
•   
S af et y: e x h a u sti v e d e s cri pti o n of s af et y p ar a m et er s. 
•   
Ot h er: d e s cri pti o n of Q u alit y of Lif e. 
 
T h er ef or e, i n or d er t o p erf or m a n a b br e vi at e d Cli ni c al St u d y R e p ort ( C S R), i n c o m p ari s o n t o t h e 
pr e vi o u s v er si o n of t h e S A P ( v er si o n 3 d at e d 2 8/ 0 5/ 2 0 1 4), t h e f oll o wi n g a n al y s e s h a v e b e e n d el et e d: 
•   
A n al y si s of pri m ar y a n d s e c o n d ar y effi c a c y crit eri a o n ot h er p o p ul ati o n t h a n I T T, 
•   
A n al y si s of effi c a c y crit eri a o n s u b gr o u p s of p ati e nt s, 
•   
M ulti v ari at e a n al y s e s of effi c a c y crit eri a, 
•   
D e s cri pti o n o v er ti m e of v al u e s a n d c h a n g e s fr o m b a s eli n e f or l a b or at or y d at e, b e c a u s e 
C T C A E gr a d e s will b e pr o vi d e d, 
•   
S o m e d et ail e d t a bl e s of di s e a s e hi st or y, pri or t h er a pi e s a n d c o n c o mit a nt m e di c ati o n s, li miti n g 
t h e a n al y s e s t o a n o v er vi e w of t h e s af et y a n d p ati e nt s a n d di s e a s e c h ar a ct eri sti c s, 
•   
Ot h er a n al y s e s i n cl u di n g cli ni c al b e n efit, f urt h er a nti- c a n c er t h er a p y, p h ar m a c o e c o n o mi c 
a n al y s e s. 
 
 
S u m m ar y t a bl e s of a d v er s e e v e nt s, pri or t h er a pi e s f or S C C H N a n d e x p o s ur e h a v e b e e n a d d e d.  
 
All d at a will b e pr o vi d e d i n i n di vi d u al d at a li sti n g s i n a p p e n di x 1 6. 2 of t h e Cli ni c al St u d y R e p ort. 


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14. REFERENCES  
 
Pocock SJ, Simon R. 
Sequential treatment assignment with balancing for prognosis factors in the controlled 
clinical trial. 
Biometrics. 1975; 31 (1): 103-115.  
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 
 
Therasse P, Arbuck SG, Eisenhauer EA et al 
New guidelines to evaluate the response to treatment in solid tumoursJ. Nat. Cancer Institut 
2000, 92 (3) : 205 - 216  


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15. APPENDICES  
 
Appendix 1: LIST OF TABLES, LISTINGS AND FIGURES 
Appendix 2: STATISTICAL ANALYSIS CONVENTIONS 
Appendix 3: ADVERSE EVENTS OF SPECIAL INTEREST 
Appendix 4: ANALYSIS OF TUMOUR LOCATION AT BASELINE 
 


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15.1. APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS 
SECTION 
Title 
RTF reference 
10.1 
Number of Patients enrolled, randomized, treated and evaluable for Quality of Life 
[All patients] 
10_1a.RTF 
10.1 
Patient disposition [ITT] 
10_1b.RTF 
10.1 
Patients with at least one Protocol deviations by type [ITT] 
10_1c.RTF 
11.2 
Demographic data [ITT] 
11_2_1.RTF 
11.2 
Stratification factors [ITT] 
11_2_2.RTF 
11.2 
Disease History[ITT] 
11_2_3.RTF 
11.2 
Summary of Prior therapies for SCCHN [ITT] 
11_2_6.RTF 
11.2 
Prior therapies: chemotherapy [ITT] 
11_2_7.RTF 
11.2 
Prior therapies: radiotherapy [ITT] 
11_2_8.RTF 
11.2 
Prior therapies: surgeries by SOC and PT [ITT] 
11_2_9.RTF 
11.2 
Prior therapies: Other therapies [ITT] 
11_2_10.RTF 
11.2 
Clinical examinations at baseline [ITT] 
11_2_11.RTF 
11.2 
Haematological CTCAE grades at study entry [ITT] 
11_2_12.RTF 
11.2 
Biochemical CTCAE grades at study entry [ITT] 
11_2_13.RTF 
11.4.1.1 
Overall Survival (OS-months) [ITT] 
11_4_1_1.RTF 
11.4.1.1 
Overall Survival (OS-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_4.RTF 
12.1 
Exposure: Cumulative dose, actual dose intensity and relative dose intensity by 
patient [ITT] 
12_1_5.RTF 
12.1 
Exposure: Actual dose intensity and relative dose intensity by cycle [ITT] 
12_1_6.RTF 
12.1 
Dose delayed and reasons [ITT] 
12_1_7a.RTF 
12.1 
Listing of the reasons of dose delayed [ITT] 
12_1_7b.RTF 
12.1 
Dose reduction of Vinflunine and reasons [ITT] 
12_1_8a.RTF 
12.1 
Reasons by dose reduction of Vinflunine [ITT] 
12_1_8b.RTF 
12.1 
Listing of the reasons of Vinflunine dose reductions [ITT] 
12_1_8c.RTF 
12.1 
Dose reduction of Methotrexate and reasons [ITT] 
12_1_8d.RTF 
12.1 
Reasons by dose reduction of Methotrexate in VFL+MTX group [ITT] 
12_1_8e.RTF 
12.1 
Reasons by dose reduction of Methotrexate in MTX group [ITT] 
12_1_8f.RTF 
12.1 
Listing of the reasons of Methotrexate dose reductions [ITT] 
12_1_8g.RTF 
12.1 
Methotrexate cancellations and reasons [ITT] 
12_1_9a.RTF 
12.1 
Listing of the reasons of Methotrexate cancellations [ITT] 
12_1_9b.RTF 
12.1 
Vinflunine cancellations and reasons [ITT] 
12_1_9c.RTF 
12.1 
Listing of the reasons of Vinflunine cancellations [ITT] 
12_1_9d.RTF 
12.1 
Treatment interruption and reasons [ITT] 
12_1_10a.RTF 
12.1 
Listing of the reasons of treatment interruptions [ITT] 
12_1_10b.RTF 
12.1 
Dose discontinuations of Vinflunine or Methotrexate [ITT] 
12_1_11a.RTF 
12.1 
Listing of patients with discontinuation of VInflunine or Methotrexate [ITT] 
12_1_11b.RTF 
12.2.1 
Summary of Adverse Events [Safety set] 
12_2_1.RTF 


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SECTION 
Title 
RTF reference 
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_1c.RTF 
12.2.2 
Drug-related adverse events  – Worst grade events per cycle by SOC and PT 
[Safety set] 
12_2_2_1d.RTF 
12.2.2 
AEOSI whatever their relationship to study drug – Worst grade events per patient by 
type [Safety set] 
12_2_2_2a.RTF 
12.2.2 
AEOSI whatever their relationship to study drug – Worst grade events per type 
[Safety set] 
12_2_2_2b.RTF 
12.2.2 
Drug-related AEOSI – Worst grade events per patient by type [Safety set] 
12_2_2_2c.RTF 
12.2.2 
Drug-related AEOSI – Worst grade events per cycle by type [Safety set] 
12_2_2_2d.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 
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 CTCAE grade of SGOT/AST by patient according to the presence of liver 
metastases at baseline [Safety set]
12_2_2_4_2d.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_2e.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_2f.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, reason of death, 
relationship to treatment [Safety set]  
12_3_1_1b.RTF 
12.3.1.1 
Listing of dead patients within 30 days more than 30 days after last administration, 
reason of death, relationship to treatment [Safety set]  
12_3_1_1c.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 
14.2 
Progression-Free Survival (PFS-months) [ITT] 
14_2_1.RTF 
14.2 
Progression-Free Survival (PFS-months) [ITT] 
14_2_1_FIG.RTF 
14.2 
Objective Response Rate (ORR) [ITT] 
14_2_2.RTF 
14.2 
Disease Control Rate (DCR) [ITT] 
14_2_3.RTF 


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SECTION 
Title 
RTF reference 
14.2 
Duration Of Response (months) [ITT] 
14_2_4.RTF 
14.2 
Duration Of Response (months) [ITT] 
14_2_4_FIG.RTF 
14.2 
Duration of Disease Control (months) [ITT] 
14_2_5.RTF 
14.2 
Duration of Disease Control (months) [ITT] 
14_2_5_FIG.RTF 
14.2 
Time to Treatment Failure (months) [ITT] 
14_2_6.RTF 
14.2 
Time to Treatment Failure (months) [ITT] 
14_2_6_FIG.RTF 
14.2 
Time to First Response (months) [ITT] 
14_2_7.RTF 
14.2 
Time to First Response (months) [ITT] 
14_2_7_FIG.RTF 
14.3 
Electrocardiogram: listing of abnormalities at baseline [Safety Set] 
14_3_1.RTF 
14.3 
Electrocardiogram: listing of abnormalities during treatment period [Safety Set] 
14_3_2.RTF 
14.4.1a 
Concomitant medications whatever the indication per patient [ITT] 
14_4_1a.RTF 
14.4.1b 
Concomitant medications whatever the indication per cycle [ITT] 
14_4_1b.RTF 
14.4.2a 
Concomitant medications with a tumour related indication per patient [ITT] 
14_4_2a.RTF 
14.4.2b 
Concomitant medications with a tumour related indication per cycle [ITT] 
14_4_2b.RTF 
14.4.3a 
Concomitant medications with a prophylactic indication per patient [ITT] 
14_4_3a.RTF 
14.4.3b 
Concomitant medications with a prophylactic indication per cycle [ITT] 
14_4_3b.RTF 
14.4.4a 
Concomitant medications with pre-treatment event indication per patient  [ITT] 
14_4_4a.RTF 
14.4.4b 
Concomitant medications with pre-treatment event indication per cycle [ITT] 
14_4_4b.RTF 
14.4.5a 
Concomitant medications with medical history indication per patient  [ITT] 
14_4_5a.RTF 
14.4.5b 
Concomitant medications with medical history indication per cycle [ITT] 
14_3_5b.RTF 
14.5 
EORTC QLQ-C30 (Global Health Status) : Values and changes from baseline Over 
Time and at last cycle [Evaluable Pop for QLQ-C30] 
14_5_1a.RTF 
14.5 
EORTC QLQ-C30 (Functional scales): Values and changes from baseline Over 
Time and at last cycle [Evaluable Pop for QLQ-C30] 
14_5_1b.RTF 
14.5 
EORTC QLQ-C30 (Symptom Scales/Items) : Values and changes from baseline 
Over Time and at last cycle [Evaluable Pop for QLQ-C30] 
14_5_1c.RTF 
14.5 
QLQ-Head and Neck EORTC 35 Module (Multi-item scales) : Values and changes 
from baseline Over Time and at last cycle [Evaluable Pop for QLQ-H&N 35] 
14_5_2a.RTF 
14.5 
QLQ-Head and Neck EORTC 35 Module (Single items) : Values and changes from 
baseline Over Time and at last cycle [Evaluable Pop for QLQ-H&N 35] 
14_5_2b.RTF 
16.2.1 
Discontinued patients 
16_2_1_1.RTF 
16.2.1 
Follow-Up data 
16_2_1_2.RTF 
16.2.2 
Protocol Deviations at study entry 
16_2_2_1.RTF 
16.2.2 
Protocol Deviations on treatment 
16_2_2_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 SCCHN 
16_2_4_3a.RTF 
16.2.4 
Prior radiotherapy for SCCHN 
16_2_4_3b.RTF 
16.2.4 
Prior chemotherapy for SCCHN 
16_2_4_3c.RTF 
16.2.4 
Prior treatment for SCCHN 
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 of Vinflunine 
16_2_5_1.RTF 


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SECTION 
Title 
RTF reference 
16.2.5 
Treatment administration of Methotrexate 
16_2_5_2.RTF 
16.2.5 
Treatment modifications 
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 
16.2.6 
Tumour assessments 
16_2_6_1.RTF 
16.2.6 
Work-Up 
16_2_6_2.RTF 
16.2.6 
Efficacy parameters (1/2) 
16_2_6_3.RTF 
16.2.6 
Efficacy parameters (2/2) 
16_2_6_4.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 
16_2_11 
EORTC QLQ-C30  
16_2_11_1_1.RTF 
16_2_11 
EORTC QLQ-C30, derived scores 
16_2_11_1_2.RTF 
16_2_11 
QLQ Head & Neck 35 EORTC module  
16_2_11_2_1.RTF 
16_2_11 
QLQ Head & Neck 35 EORTC module, multi-item scales 
16_2_11_2_2.RTF 
 


St ati sti c al A n al y si s Pl a n / L 0 0 0 7 0 I N 3 0 9 F 0                                                       V er si o n n° 4 ( 2 3/ 1 1/ 2 0 1 7) 
4 4 / 5 5   
C O N FI D E N TI A L 
 
1 5. 2. 
A P P E N DI X 2: S T A TI S TI C A L A N A L Y SI S C O N V E N TI O N S 
 
1 5. 2. 1. C o n v e nti o n s f or c al c ul ati o n of d ur ati o n 
1 5 . 2. 1. 1. C al c ul ati o n of a d ur ati o n i n m o n ht s or y e ar s 
D ur ati o n i n y e ar s or m o nt h s (i. e. tr e at m e nt d ur ati o n, d ur ati o n of f oll o w- u p, di s e a s e a n d tr e at m e nt fr e e 
i nt er v al s, ti m e fr o m di a g n o si s t o st u d y e ntr y, ti m e t o fir st r e s p o n s e, d ur ati o n of r e s p o n s e, st a bili s ati o n 
a n d di s e a s e c o ntr ol, P F S a n d o v er all s ur vi v al)  will b e c al c ul at e d a s f oll o w s : 
3 0. 4 3 7 5
1
1 
Date
 - 2 
Date
m o nt hs)
(i n  
D urati o n  
+
=




 
wi t h D at e 2   ≥ D at e 1. 
3 6 5. 2 5
1
1 
Date
 - 2 
Date
years)
(i n  
D urati o n  
+
=




 
F o r e x a m pl e, a g e of t h e p ati e nt s will b e c al c ul at e d a s f oll o w s : 
3 6 5. 2 5
1
birt h
 
of
 
Date
 -
o n 
re gistrati
 
of
 
Date
years)
(i n  
  
A ge
+
=




 
 
 
1 5. 2. 1. 2. C al c ul ati o n of a d el a y or ti m e d ur ati o n i n d a y s 
 
D e l a y s or ti m e d ur ati o n s, u s u all y i n d a y s, (i. e. n u m b er of d a y s of d el a y i n a c y cl e, d el a y b et w e e n 
r a n d o mi s ati o n a n d fir st a d mi ni str ati o n, n u m b er of d a y s b et w e e n l a st a d mi ni str ati o n or vi sit a n d d e at h, 
d el a y b et w e e n di a g n o si s a n d st u d y e ntr y, d el a y b et w e e n di a g n o si s a n d pr o gr e s si o n, ti m e fr o m 
r a n d o mi s ati o n t o fir st c o n c o mit a nt r a di ot h er a p y) will b e c al c ul at e d a s f oll o w s : 
1 
Date
 - 2 
Date
da ys)
(i n  
Dela y  
=
 
wit h D at e 2 ≥ D at e 1. 
 
1 5. 2. 2. Mi s si n g d at a 
1 5 . 2. 2. 1. G e n er al c o n v e nti o n s 
F oll o wi n g i nt er n al bi o m etr y c o n v e nti o n s ar e u s e d: 
 
 “ M” st a n d s f or a n i nf or m ati o n n ot pr e s e nt o n C R F f or m, 


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15.2.2.2.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). 
15.2.2.3.Dose modifications 
Dose modifications will be determined between two subsequent cycles. Variation will be calculated by 
comparing actual dose received. 
15.2.2.4.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. 
15.2.3. Date of first response and date of progression 
15.2.3.1.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 Tumour 
assessment form of the eCRF. 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. 
15.2.3.2.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 the Tumour Assessment Form of the eCRF (during the study or during the follow-up, i.e. 
after the end of the treatment period),, 
 
In Death Report Form of the eCRF 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.  
  
15.2.4. Toxicity 
15.2.4.1.Haematological toxicities 
The following units for HGB, WBC, PLT and ANC will be used for the analysis of haematological 
toxicity : 
 


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Parameters 
Units 
HGB 
g/dl 
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 
]20 – 12] 
]15 – 4] 
]500 – 100] 
]10 – 2] 
Grade 1 
]12 – 10] 
]4 – 3] 
]100 – 75] 
]2 – 1.5] 
Grade 2 
]10 – 8] 
]3 – 2] 
]75 – 50] 
]1.5 – 1] 
Grade 3 
]8 – 6.5] 
]2 – 1] 
]50 – 10] 
]1 – 0.5] 
Grade 4 
< 6.5 
< 1 
< 10 
< 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. 
15.2.4.2.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. 
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 


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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. 
15.2.4.3.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. 
15.2.4.4.Treatment duration  
For arm A, the treatment duration is defined as the time elapsed between the date of 1st administration 
and the date of the last VFL administration (if MTX not given) + 21 days or the date of the last MTX 
administration (if given) + 14 days. For arm B, the treatment duration is defined as the time elapsed 
between the date of the 1st administration and the date of the last D1 administration of the last cycle + 
21 days (if D8 and D15 not given) or the date of the last D8 administration of the last cycle + 14 days 
(if D15 not given) or the date of the last D15 administration of the last cycle + 7 days (if D15 given). 
Treatment duration will be tabulated by treatment arm, and listed by patient. 
15.2.5.  End of study 
15.2.5.1.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. 
 


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15.3. APPENDIX 3: ADVERSE EVENTS OF SPECIAL INTEREST 
 
 
Adverse Events of Special Interest 
MedDRA (v19.0) Preferred Terms (PT) or High 
Level Terms (HLT)  if specified or graded from 
laboratory values if specified 
1 
Myelosupression 
neutropenia, leukopenia, anaemia, thrombocytopenia to be graded 
from haematological lab values 
2,1 
Febrile Neutropenia 
  
 
PT 
febrile neutropenia 
2,2 
Infections with severe neutropenia (Clinically 
relevant Infections (potential bacterial origin)) 
Time window is defined as 2 days before through 1 day after the 
onset of an infection during which time grade 3 or 4 neutropenia or 
grade 4 leukopenia coincides.  
 
PT 
neutropenic infection 
 
PT 
neutropenic sepsis 
 
PT 
abscess limb 
 
PT 
bacteraemia 
 
PT 
bacterial infection 
 
PT 
blood culture positive 
 
PT 
bronchitis bacterial 
 
PT 
cellulitis 
 
PT 
cystitis 
 
PT 
ear infection 
 
PT 
febrile infection 
 
PT 
fungal infection 
 
PT 
gastrointestinal infection 
 
PT 
infection 
 
PT 
lobar pneumonia 
 
PT 
localised infection 
 
PT 
lower respiratory tract infection bacterial 
 
PT 
lower respiratory tract infection 
 
PT 
lung infection 
 
PT 
oral infection 
 
PT 
pneumonia 
 
PT 
pneumonia bacterial 
 
PT 
sepsis 


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PT 
septic shock 
 
PT 
sinusitis 
 
PT 
sinusitis bacterial 
 
PT 
skin infection 
 
PT 
tooth abscess 
 
PT 
tooth infection 
 
PT 
urinary tract infection 
 
PT 
urosepsis 
 
PT 
catheter related infection 
 
PT 
wound infection 
3,1 
Constipation  
  
 
PT 
constipation 
3,2 
Ileus  
  
 
PT 
ileus paralytic 
 
PT 
ileus spastic 
 
PT 
ileus 
 
PT 
subileus 
 
PT 
megacolon 
3,3 
Intestinal Obstruction 
  
 
PT 
gastrointestinal obstruction 
 
PT 
intestinal obstruction 
 
PT 
small intestinal obstruction 
 
PT 
large intestinal obstruction 
 
PT 
mechanical ileus 
 
PT 
colonic obstruction 
 
PT 
gastrointestinal stenosis 
 
PT 
intestinal stenosis 
 
PT 
colonic stenosis 
3,4 
Abdominal Pain 
  
 
PT 
Abdominal pain 
 
PT 
Abdominal pain lower 
 
PT 
abdominal pain upper 
 
PT 
abdominal rebound tenderness 


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PT 
abdominal tenderness 
 
PT 
gastrointestinal pain 
 
PT 
visceral pain 
4,1 
Nausea 
  
 
PT 
Nausea 
4,2 
Vomiting 
  
 
PT 
Vomiting 
4,3 
Stomatitis/mucositis 
  
 
PT 
aphthous stomatitis 
 
PT 
mouth ulceration 
 
PT 
mucocutaneous ulceration 
 
PT 
mucosal inflammation 
 
PT 
mucosal ulceration 
 
PT 
stomatitis 
 
PT 
stomatitis haemorrhagic 
4,4 
Diarrhoea 
  
 
PT 
Diarrhoea 
5,1 
Myocardial Infarction/ Ischaemia 
  
 
PT 
acute myocardial infarction 
 
PT 
myocardial infarction 
 
PT 
silent myocardial infarction 
 
PT 
papillary muscle infarction 
 
PT 
acute coronary syndrome 
 
PT 
angina pectoris 
 
PT 
angina unstable 
 
PT 
Prinzmetal angina 
 
PT 
myocardial ischaemia 
 
PT 
ECG signs of myocardial ischaemia 
5,2 
Cardiac Arrhythmias 
  
 
HLT 
Rate and rhythm disorders NEC 
 
HLT 
supraventricular arrhythmias  
 
HLT 
Ventricular arrhythmias and cardiac arrest 
5,3 
Cardiac Conduction Disorders 
  


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HLT 
Cardiac Conduction disorders 
6,1 
Local Injection/Infusion Site Reactions 
  
 
HLT 
injection and infusion site reactions (minus Infusion Site 
Extravasation and Injection Site Extravasation) 
6,2 
Extravasation 
  
 
PT 
Extravasation 
 
PT 
Infusion site extravasation 
 
PT 
Injection site extravasation 
7,1 
Peripheral Sensory Neuropathy 
  
 
PT 
Acute polyneuropathy 
 
PT 
Burning sensation 
 
PT 
Dysaesthesia 
 
PT 
Hyperaesthesia 
 
PT 
Hypoaesthesia 
 
PT 
Neuritis 
 
PT 
Neuropathy Peripheral 
 
PT 
Allodynia 
 
PT 
Pallanaesthesia 
 
PT 
Paraesthesia 
 
PT 
Peripheral sensory neuropathy 
 
PT 
Polyneuropathy 
 
PT 
Toxic neuropathy 
7,2 
Peripheral Motor Neuropathy 
  
 
PT 
Neuromuscular toxicity 
 
PT 
Peripheral motor neuropathy 
 
PT 
Peripheral sensorimotor neuropathy 
7,3 
Autonomic Neuropathy 
  
 
PT 
autonomic neuropathy 
 
PT 
cardiac autonomic neuropathy 
 
PT 
neurogenic bowel 
 
PT 
impaired gastric emptying 
8,1 
Asthenia/fatigue 
  
 
PT 
fatigue 


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PT 
asthenia 
8,2 
Myalgia 
  
 
PT 
Myalgia 
9 
Immediate Hypersensitivity 
events must be study drug related and occur on the day of study 
drug infusion (day 1 or within 24 hours after infusion of vinflunine) 
 
 
PT 
Allergic oedema 
 
PT 
Anaphylactic reaction 
 
PT 
Anaphylactic shock 
 
PT 
Anaphylactoid reaction 
 
PT 
Anaphylactoid shock 
 
PT 
Angioedema 
 
PT 
Bronchospasm 
 
PT 
Bronchial oedema 
 
PT 
Circulatory collapse 
 
PT 
Circumoral oedema 
 
PT 
Drug hypersensitivity 
 
PT 
Drug eruption 
 
PT 
Epiglottic oedema 
 
PT 
Eyelid oedema 
 
PT 
Face oedema 
 
PT 
Flushing 
 
PT 
Hypersensitivity 
 
PT 
Laryngeal oedema 
 
PT 
Laryngospasm 
 
PT 
 Laryngotracheal oedema 
 
PT 
Lip swelling 
 
PT 
Lip oedema 
 
PT 
Pharyngeal oedema 
 
PT 
Pruritus generalised 
 
PT 
Rash pruritic 
 
PT 
Shock 
 
PT 
Type I hypersensitivity 
 
PT 
Urticaria  


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10 
SIADH 
  
 
PT 
Inappropriate antidiuretic hormone secretion  
 
PT 
blood antidiuretic hormone increased 
11 
PRES 
 
 
HLT 
Encephalopathy  NOS 
12 
Hepatic dysfunction 
use total bilirubin of grade >2 combined with either AST grade >2, 
ALT grade >2 or alkaline phosphatase grade >2 
 


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15.4. APPENDIX 4: ANALYSIS OF TUMOUR LOCATION AT BASELINE 
Tumour Location at Baseline 
Visceral Involvement 
Groups for detail of organs involved 
ABDOMEN 
Yes 
OTHER 
ADIPOSE TISSUE 
No 
OTHER 
ADRENALS 
Yes 
OTHER 
AREA IN THE LARINGECTOMY ZONE No
OTHER 
BONE 
No
OTHER 
CERVICAL 
No
OTHER 
CERVICAL MASS 
No
OTHER 
CERVIX 
No
OTHER 
CHEST 
No
OTHER 
COSTAL 
No
OTHER 
DENSIFICATION INFILTRATIVE 
APPEARANCE OF CERVICAL FAT 
PLANES AND CERVI 
No
OTHER 
FACE 
No
OTHER 
HYPOPHARYNX 
No
HYPOPHARYNX 
KIDNEY 
Yes 
OTHER 
LARYNX 
No
LARYNX 
LEFT SUBMANDIBULAR GLAND 
No
SUBMANDIBULAR GLAND 
LEFT SUBMANDIBULARIS AREA 
No
SUBMANDIBULAR GLAND 
LESION UNDER THE CHIN 
No
OTHER 
LIVER 
Yes 
OTHER 
LUNG 
Yes 
OTHER 
LYMPH NODE(S) 
No
LYMPH NODE(S) 
MAXILARY SINUS 
No 
NASAL SINUS 
MEDIASTINUM 
No
OTHER 
MUSCL 
No
OTHER 
MUSCLE 
No
OTHER 
NECK 
No
NECK SOFT TISSUE 
NECK (SOFT TISSUE) 
No
NECK SOFT TISSUE 
NOSE 
No
NASAL SINUS 
ORAL CAVITY 
No
ORAL CAVITY 
OROPHARYNX 
No
OROPHARYNX 
PARA-PHARYNX 
No
PHARYNX 
PARANASAL SINUS 
No
NASAL SINUS 
PARATHYROIDS 
Yes 
OTHER 
PHARYNX 
No 
PHARYNX 
PLEURA 
Yes 
OTHER 
PLEURAL 
Yes 
OTHER 
PLEURAL EFFUSSION 
Yes 
OTHER 
REGION PARAMEDIAN LEFT 
No 
OTHER 
RENAL 
Yes 
OTHER 
RIGHT SUBMANDIBULAR GLAND 
No 
SUBMANDIBULAR GLAND 


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SKIN 
No
OTHER 
SOFT TISSUE 
No
NECK SOFT TISSUE 
SOFT TISSUE  SUBMANDIBULAR 
REGION 
No
SUBMANDIBULAR GLAND 
SOFT TISSUE OF THE CHIN RIGHT 
SIDE 
No
NECK SOFT TISSUE 
SOFT TISSUE SUBMANDIBULAR 
REGION 
No
SUBMANDIBULAR GLAND 
SOFT TISSUES OF THE NECK 
No
NECK SOFT TISSUE 
SPLEEN 
No
OTHER 
SUBCLAVICULAR 
No
OTHER 
SUBCUTIS 
No
OTHER 
SUBMANDIBULAR GLAND 
No
SUBMANDIBULAR GLAND 
SUPRACLAVICULAR 
No
OTHER 
THE SOFT TISSUES OF THE NECK 
No
NECK SOFT TISSUE 
THORAX WALL 
No
OTHER 
VENTRAL SEGMENT 
No 
OTHER