Phase III Study of Vinflunine Plus Methotrexate Versus Methotrexate Alone in Patients With Head and Neck Cancer

• Sponsor: Pierre Fabre Medicament (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02347332
• Collaborator: (none)
• Enrollment: 459
• Location: 1
• Arms: 2
• Actual Duration (Months): 55
• Patients Per Site Per Month: 8.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent or Metastatic Head and Neck Carcinoma	Drug: Vinflunine; Drug: Methotrexate	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 459 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 25, 2014
• Actual Primary Completion Date: Oct 20, 2017
• Actual Study Completion Date: Nov 23, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vinflunine plus methotrexate vinflunine IV 280 mg/m² Day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks	Drug: Vinflunine; Other Names: JAVLOR VFL
Active Comparator: Methotrexate methotrexate IV 40 mg/m² Day 1, 8 and 15 every 3 weeks	Drug: Methotrexate; Other Names: MTX

Outcome Measures

Primary Outcome Measures

1. Overall Survival in the ITT Population (Months) [Participants will be followed till death (if they are not lost for follow-up), an expected average of 7.5 months]

   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.

Secondary Outcome Measures

1. Progression Free Survival [an expected average of 4 months]

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

2. Objective Response Rate (ORR) [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.

3. Disease Control Rate [30 months]

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

4. Duration of Response [30 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma

• Documented progressive disease after chemotherapy for locoregionally advanced or recurrent/metastatic SCCHN which included a platinum derivative

• Measurable or non measurable disease

• adequate haematological, hepatic and renal functions

• WHO performance status < 1

Exclusion Criteria:

• Nasopharyngeal carcinoma

• History of brain or leptomeningeal involvement

• Albumin level < 35 g/L

• Patients with weight loss ≥ 5% within the last 3 months

• Grade > 2 peripheral neuropathy at study entry

• "Third space" fluids (pleural effusion, ascites, massive edema)

• Prior treatment with vinca-alkaloids and methotrexate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institut de Recherche Pierre Fabre	Toulouse		France

Sponsors and Collaborators

• Pierre Fabre Medicament

Investigators

• Study Director: Zahida Issiakhem, MD, Institut de Recherche Pierre Fabre

Study Documents (Full-Text)

• Study Protocol - Feb 5, 2016
• Statistical Analysis Plan - Nov 23, 2017

More Information

Publications

None provided.

• Responsible Party: Pierre Fabre Medicament
• ClinicalTrials.gov Identifier: NCT02347332
• Other Study ID Numbers: L00070 IN 309 F0
• First Posted: Jan 27, 2015
• Last Update Posted: Mar 5, 2019
• Last Verified: Feb 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pierre Fabre Medicament: Vinflunin; Vinflunin + Methotrexate; Metastatic Squamous Cell Carcinoma of the Head and Neck
• Additional relevant MeSH terms: Carcinoma; Squamous Cell Carcinoma of Head and Neck; Methotrexate

Study Results

Participant Flow

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

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Period Title: Overall Study
STARTED	230	229
COMPLETED	0	0
NOT COMPLETED	230	229

Baseline Characteristics

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate	Total
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate	Total of all reporting groups
Overall Participants	230	229	459
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	182 79.1%	175 76.4%	357 77.8%
>=65 years	48 20.9%	54 23.6%	102 22.2%
Sex: Female, Male (Count of Participants)
Female	37 16.1%	35 15.3%	72 15.7%
Male	193 83.9%	194 84.7%	387 84.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Austria	4 1.7%	3 1.3%	7 1.5%
Belarus	11 4.8%	10 4.4%	21 4.6%
Belgium	4 1.7%	4 1.7%	8 1.7%
Brazil	21 9.1%	15 6.6%	36 7.8%
Estonia	3 1.3%	2 0.9%	5 1.1%
France	31 13.5%	37 16.2%	68 14.8%
Germany	10 4.3%	6 2.6%	16 3.5%
Italy	19 8.3%	19 8.3%	38 8.3%
Mexico	3 1.3%	2 0.9%	5 1.1%
Poland	12 5.2%	11 4.8%	23 5%
Russia	58 25.2%	62 27.1%	120 26.1%
Slovakia	2 0.9%	3 1.3%	5 1.1%
Spain	13 5.7%	13 5.7%	26 5.7%
Taiwan	14 6.1%	14 6.1%	28 6.1%
Ukraine	25 10.9%	28 12.2%	53 11.5%

Outcome Measures

1. Primary Outcome

Title	Overall Survival in the ITT Population (Months)
Description	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.
Time Frame	Participants will be followed till death (if they are not lost for follow-up), an expected average of 7.5 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Measure Participants	230	229
Median (95% Confidence Interval) [Months]	7.1	6.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vinflunine Plus Methotrexate, Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8329
	Comments	Threshold significance value p<0.05
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Progression Free Survival
Description	Time measured from the date of randomisation until date of progression or death from any cause (whichever came first)
Time Frame	an expected average of 4 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Measure Participants	230	229
Median (95% Confidence Interval) [Months]	2.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vinflunine Plus Methotrexate, Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3576
	Comments	Threshold significance value p<0.05
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	The objective response is defined as the best response designation recorded across all time points from the date of randomisation until disease progression.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Measure Participants	230	229
Median (95% Confidence Interval) [Percent of participants]	17.8 7.7%	14.8 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vinflunine Plus Methotrexate, Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.467
	Comments	Threshold significance value p<0.05
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Disease Control Rate
Description	Percentage of best overall responses CR, PR and SD in the analysed population
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Measure Participants	230	229
Median (95% Confidence Interval) [% patients]	50.9	46.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vinflunine Plus Methotrexate, Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.243
	Comments	Threshold significance value p<0.05
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Vinflunine Plus Methotrexate	Methotrexate
Arm/Group Description	Vinflunine IV 280 mg/m² day 1 plus methotrexate IV 30 mg/m² Day 1 and Day 8 every 3 weeks Vinflunine	Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
Measure Participants	230	229
Median (95% Confidence Interval) [Months]	4.2	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vinflunine Plus Methotrexate, Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6289
	Comments	Threshold significance value p<0.05
	Method	Log Rank
	Comments

Adverse Events

Time Frame	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.
Arm/Group Title	Vinflunine Plus Methotrexate		Methotrexate
Arm/Group Description	Vinflunine IV 280mg/m2 Day1 plus Methotrexate IV 30mg/m2 on Day 1 and Dy 8 every 3 cycles Vinflunine		Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks Methotrexate
All Cause Mortality
	Vinflunine Plus Methotrexate		Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	185/225 (82.2%)		194/227 (85.5%)
Serious Adverse Events
	Vinflunine Plus Methotrexate		Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/225 (47.1%)		81/227 (35.7%)
Blood and lymphatic system disorders
Neutropenia	22/225 (9.8%)		5/227 (2.2%)
Anaemia	7/225 (3.1%)		8/227 (3.5%)
Febrile neutropenia	10/225 (4.4%)		1/227 (0.4%)
Leukopenia	8/225 (3.6%)		3/227 (1.3%)
Thrombocytopenia	5/225 (2.2%)		6/227 (2.6%)
General disorders
Death	5/225 (2.2%)		6/227 (2.6%)
General Physical Health Deterioration	6/225 (2.7%)		1/227 (0.4%)
Infections and infestations
Pneumonia	5/225 (2.2%)		5/227 (2.2%)
Sepsis	8/225 (3.6%)		2/227 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	12/225 (5.3%)		16/227 (7%)
Tumour Haemorrage	8/225 (3.6%)		10/227 (4.4%)
Tumour Necrosis	5/225 (2.2%)		5/227 (2.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/225 (2.2%)		5/227 (2.2%)
Asphyxia	5/225 (2.2%)		4/227 (1.8%)
Aspiration	5/225 (2.2%)		4/227 (1.8%)
Other (Not Including Serious) Adverse Events
	Vinflunine Plus Methotrexate		Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	211/225 (93.8%)		213/227 (93.8%)
Blood and lymphatic system disorders
Neutropenia	89/225 (39.6%)	219	71/227 (31.3%)	190
Anaemia	82/225 (36.4%)	245	56/227 (24.7%)	147
Leukopenia	32/225 (14.2%)	93	38/227 (16.7%)	102
Febrile neutropenia	19/225 (8.4%)	20	1/227 (0.4%)	1
Thrombocytopenia	19/225 (8.4%)	31	24/227 (10.6%)	65
Gastrointestinal disorders
Constipation	56/225 (24.9%)	163	25/227 (11%)	42
Stomatitis	53/225 (23.6%)	117	64/227 (28.2%)	158
Nausea	36/225 (16%)	66	23/227 (10.1%)	40
Vomiting	26/225 (11.6%)	37	13/227 (5.7%)	20
Diarrhoea	23/225 (10.2%)	34	13/227 (5.7%)	23
Dysphagia	18/225 (8%)	33	13/227 (5.7%)	45
Abdominal pain	16/225 (7.1%)	18	2/227 (0.9%)	2
General disorders
Asthenia	62/225 (27.6%)	181	54/227 (23.8%)	137
Pyrexia	26/225 (11.6%)	35	27/227 (11.9%)	53
Fatigue	24/225 (10.7%)	52	27/227 (11.9%)	53
Pain	19/225 (8.4%)	48	17/227 (7.5%)	55
Investigations
Weight decreased	69/225 (30.7%)	248	63/227 (27.8%)	150
Creatinine renal clearance decreased	17/225 (7.6%)	49	10/227 (4.4%)	28
Weight increased	12/225 (5.3%)	47	15/227 (6.6%)	227
Alanine aminotransferase increased	11/225 (4.9%)	26	28/227 (12.3%)	74
Metabolism and nutrition disorders
Decreased appetite	27/225 (12%)	59	23/227 (10.1%)	45
Musculoskeletal and connective tissue disorders
Neck pain	14/225 (6.2%)	40	12/227 (5.3%)	30
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	20/225 (8.9%)	58	12/227 (5.3%)	29
Malignant neoplasm progression	12/225 (5.3%)	12	16/227 (7%)	16
Dyspnoea	18/225 (8%)	26	18/227 (7.9%)	34
Nervous system disorders
Headache	24/225 (10.7%)	42	10/227 (4.4%)	27
Respiratory, thoracic and mediastinal disorders
Cough	14/225 (6.2%)	32	22/227 (9.7%)	52

Limitations/Caveats

Sponsor ended recrutement and decided to limit analysis of efficacy.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.