Trial Outcomes & Findings for Phase III Study of Vinflunine Plus Methotrexate Versus Methotrexate Alone in Patients With Head and Neck Cancer (NCT NCT02347332)

Last Updated: 2019-03-05

Results Overview

Time from randomization to the date of death or last follow-up. The survival duration of patients still alive, was censored at the date of last contact or last follow-up.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

459 participants

Primary outcome timeframe

Participants will be followed till death (if they are not lost for follow-up), an expected average of 7.5 months

Results posted on

2019-03-05

Participant Flow

5 patients in VFL+MET arrm and 2 patients in MET arm did not receive any treatement. These patients excluded from safety population.

Participant milestones

Participant milestones
Measure	Vinflunine Plus Methotrexate Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Overall Study STARTED	230	229
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	230	229

Reasons for withdrawal

Reasons for withdrawal
Measure	Vinflunine Plus Methotrexate Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Overall Study Not treated	5	2
Overall Study Progressive disease	141	159
Overall Study Adverse Event	50	41
Overall Study Death (Unknown, Various reasons)	6	6
Overall Study Protocol Violation	1	1
Overall Study Lost to Follow-up	2	1
Overall Study Physician Decision	4	3
Overall Study Withdrawal by Subject	20	14
Overall Study Protocol requirement	1	1
Overall Study Switch Post-Trial program	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate	Total n=459 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=230 Participants	0 Participants n=229 Participants	0 Participants n=459 Participants
Age, Categorical Between 18 and 65 years	182 Participants n=230 Participants	175 Participants n=229 Participants	357 Participants n=459 Participants
Age, Categorical >=65 years	48 Participants n=230 Participants	54 Participants n=229 Participants	102 Participants n=459 Participants
Sex: Female, Male Female	37 Participants n=230 Participants	35 Participants n=229 Participants	72 Participants n=459 Participants
Sex: Female, Male Male	193 Participants n=230 Participants	194 Participants n=229 Participants	387 Participants n=459 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Austria	4 Participants n=230 Participants	3 Participants n=229 Participants	7 Participants n=459 Participants
Region of Enrollment Belarus	11 Participants n=230 Participants	10 Participants n=229 Participants	21 Participants n=459 Participants
Region of Enrollment Belgium	4 Participants n=230 Participants	4 Participants n=229 Participants	8 Participants n=459 Participants
Region of Enrollment Brazil	21 Participants n=230 Participants	15 Participants n=229 Participants	36 Participants n=459 Participants
Region of Enrollment Estonia	3 Participants n=230 Participants	2 Participants n=229 Participants	5 Participants n=459 Participants
Region of Enrollment France	31 Participants n=230 Participants	37 Participants n=229 Participants	68 Participants n=459 Participants
Region of Enrollment Germany	10 Participants n=230 Participants	6 Participants n=229 Participants	16 Participants n=459 Participants
Region of Enrollment Italy	19 Participants n=230 Participants	19 Participants n=229 Participants	38 Participants n=459 Participants
Region of Enrollment Mexico	3 Participants n=230 Participants	2 Participants n=229 Participants	5 Participants n=459 Participants
Region of Enrollment Poland	12 Participants n=230 Participants	11 Participants n=229 Participants	23 Participants n=459 Participants
Region of Enrollment Russia	58 Participants n=230 Participants	62 Participants n=229 Participants	120 Participants n=459 Participants
Region of Enrollment Slovakia	2 Participants n=230 Participants	3 Participants n=229 Participants	5 Participants n=459 Participants
Region of Enrollment Spain	13 Participants n=230 Participants	13 Participants n=229 Participants	26 Participants n=459 Participants
Region of Enrollment Taiwan	14 Participants n=230 Participants	14 Participants n=229 Participants	28 Participants n=459 Participants
Region of Enrollment Ukraine	25 Participants n=230 Participants	28 Participants n=229 Participants	53 Participants n=459 Participants

PRIMARY outcome

Timeframe: Participants will be followed till death (if they are not lost for follow-up), an expected average of 7.5 months

Population: ITT population

Time from randomization to the date of death or last follow-up. The survival duration of patients still alive, was censored at the date of last contact or last follow-up.

Outcome measures

Outcome measures
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Overall Survival in the ITT Population (Months)	7.1 Months Interval 5.7 to 8.4	6.8 Months Interval 6.1 to 8.0

SECONDARY outcome

Timeframe: an expected average of 4 months

Population: ITT

Time measured from the date of randomisation until date of progression or death from any cause (whichever came first)

Outcome measures

Outcome measures
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Progression Free Survival	2.8 Months Interval 2.6 to 3.3	2.8 Months Interval 2.1 to 3.1

SECONDARY outcome

Timeframe: 6 weeks

The objective response is defined as the best response designation recorded across all time points from the date of randomisation until disease progression.

Outcome measures

Outcome measures
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Objective Response Rate (ORR)	17.8 Percent of participants Interval 13.1 to 23.4	14.8 Percent of participants Interval 10.5 to 20.1

SECONDARY outcome

Timeframe: 30 months

Percentage of best overall responses CR, PR and SD in the analysed population

Outcome measures

Outcome measures
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Disease Control Rate	50.9 % patients Interval 44.2 to 57.5	46.3 % patients Interval 39.7 to 53.0

SECONDARY outcome

Timeframe: 30 months

Population: ITT

Duration of objective response will be measured for responders (CR+PR) from the time for CR or PR until the 1st date of documentation of recurrent or progressive disease or the date of death any cause.

Outcome measures

Outcome measures
Measure	Vinflunine Plus Methotrexate n=230 Participants Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate n=229 Participants Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Duration of Response	4.2 Months Interval 2.5 to 5.6	4.2 Months Interval 2.7 to 5.1

Adverse Events

Vinflunine Plus Methotrexate

Serious events: 106 serious events

Other events: 211 other events

Deaths: 185 deaths

Methotrexate

Serious events: 81 serious events

Other events: 213 other events

Deaths: 194 deaths

Serious adverse events

Other adverse events

Additional Information

Zahida Issiakhem, Clinical Development Physician

Institut de Recherche Pierre Fabre, Toulouse France

Phone: +33 5 34 50 61 71

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Vinflunine Plus Methotrexate n=225 participants at risk Vinflunine IV 280mg/m2 Day1 plus Methotrexate IV 30mg/m2 on Day 1 and Dy 8 every 3 cycles Vinflunine	Methotrexate n=227 participants at risk Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	5.3% 12/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	7.0% 16/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Haemorrage	3.6% 8/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	4.4% 10/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Necrosis	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.2% 5/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.2% 5/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Respiratory, thoracic and mediastinal disorders Asphyxia	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	1.8% 4/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Respiratory, thoracic and mediastinal disorders Aspiration	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	1.8% 4/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Neutropenia	9.8% 22/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.2% 5/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Anaemia	3.1% 7/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	3.5% 8/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Febrile neutropenia	4.4% 10/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	0.44% 1/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Leukopenia	3.6% 8/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	1.3% 3/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Thrombocytopenia	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.6% 6/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders Death	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.6% 6/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders General Physical Health Deterioration	2.7% 6/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	0.44% 1/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Infections and infestations Pneumonia	2.2% 5/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	2.2% 5/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Infections and infestations Sepsis	3.6% 8/225 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	0.88% 2/227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.

Measure	Vinflunine Plus Methotrexate n=225 participants at risk Vinflunine IV 280mg/m2 Day1 plus Methotrexate IV 30mg/m2 on Day 1 and Dy 8 every 3 cycles Vinflunine	Methotrexate n=227 participants at risk Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Investigations Weight decreased	30.7% 69/225 • Number of events 248 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	27.8% 63/227 • Number of events 150 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Investigations Creatinine renal clearance decreased	7.6% 17/225 • Number of events 49 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	4.4% 10/227 • Number of events 28 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Investigations Weight increased	5.3% 12/225 • Number of events 47 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	6.6% 15/227 • Number of events 227 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Investigations Alanine aminotransferase increased	4.9% 11/225 • Number of events 26 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	12.3% 28/227 • Number of events 74 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	8.9% 20/225 • Number of events 58 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	5.3% 12/227 • Number of events 29 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	5.3% 12/225 • Number of events 12 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	7.0% 16/227 • Number of events 16 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Dyspnoea	8.0% 18/225 • Number of events 26 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	7.9% 18/227 • Number of events 34 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Respiratory, thoracic and mediastinal disorders Cough	6.2% 14/225 • Number of events 32 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	9.7% 22/227 • Number of events 52 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Neutropenia	39.6% 89/225 • Number of events 219 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	31.3% 71/227 • Number of events 190 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Anaemia	36.4% 82/225 • Number of events 245 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	24.7% 56/227 • Number of events 147 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Leukopenia	14.2% 32/225 • Number of events 93 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	16.7% 38/227 • Number of events 102 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Febrile neutropenia	8.4% 19/225 • Number of events 20 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	0.44% 1/227 • Number of events 1 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Blood and lymphatic system disorders Thrombocytopenia	8.4% 19/225 • Number of events 31 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	10.6% 24/227 • Number of events 65 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Nervous system disorders Headache	10.7% 24/225 • Number of events 42 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	4.4% 10/227 • Number of events 27 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders Asthenia	27.6% 62/225 • Number of events 181 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	23.8% 54/227 • Number of events 137 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders Pyrexia	11.6% 26/225 • Number of events 35 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	11.9% 27/227 • Number of events 53 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders Fatigue	10.7% 24/225 • Number of events 52 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	11.9% 27/227 • Number of events 53 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
General disorders Pain	8.4% 19/225 • Number of events 48 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	7.5% 17/227 • Number of events 55 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Constipation	24.9% 56/225 • Number of events 163 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	11.0% 25/227 • Number of events 42 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Stomatitis	23.6% 53/225 • Number of events 117 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	28.2% 64/227 • Number of events 158 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Nausea	16.0% 36/225 • Number of events 66 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	10.1% 23/227 • Number of events 40 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Vomiting	11.6% 26/225 • Number of events 37 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	5.7% 13/227 • Number of events 20 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Diarrhoea	10.2% 23/225 • Number of events 34 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	5.7% 13/227 • Number of events 23 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Dysphagia	8.0% 18/225 • Number of events 33 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	5.7% 13/227 • Number of events 45 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Gastrointestinal disorders Abdominal pain	7.1% 16/225 • Number of events 18 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	0.88% 2/227 • Number of events 2 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Musculoskeletal and connective tissue disorders Neck pain	6.2% 14/225 • Number of events 40 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	5.3% 12/227 • Number of events 30 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.
Metabolism and nutrition disorders Decreased appetite	12.0% 27/225 • Number of events 59 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.	10.1% 23/227 • Number of events 45 • 4 years 6 months 29 days. 5 subjects in the Vinflunine + Methotrexate arm and 2 patients in the Methotrexate arm did not receive any treatment. These patients were thus excluded from the safety population.The safety population consisted of all patients randomized and treated.