Recurrent or Metastatic Head and Neck Carcinoma
Conditions
Keywords
Vinflunin, Vinflunin + Methotrexate, Metastatic Squamous Cell Carcinoma of the Head and Neck
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
Interventions
DRUGVinflunine
DRUGMethotrexate
Sponsors
Pierre Fabre Medicament
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| Disease Control Rate | 30 months | Percentage of best overall responses CR, PR and SD in the analysed population |
| 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. |
Countries
France
Participant flow
Pre-assignment details
5 patients in VFL+MET arrm and 2 patients in MET arm did not receive any treatement. These patients excluded from safety population.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 230 |
| Methotrexate Methotrexate IV 40 mg/m² days 1, 8 and 15 every 3 weeks
Methotrexate | 229 |
| Total | 459 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 50 | 41 |
| Overall Study | Death (Unknown, Various reasons) | 6 | 6 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Not treated | 5 | 2 |
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Progressive disease | 141 | 159 |
| Overall Study | Protocol requirement | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Switch Post-Trial program | 0 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 14 |
Baseline characteristics
| Characteristic | Vinflunine Plus Methotrexate | Total | Methotrexate |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 48 Participants | 102 Participants | 54 Participants |
| Age, Categorical Between 18 and 65 years | 182 Participants | 357 Participants | 175 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Austria | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Belarus | 11 Participants | 21 Participants | 10 Participants |
| Region of Enrollment Belgium | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Brazil | 21 Participants | 36 Participants | 15 Participants |
| Region of Enrollment Estonia | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment France | 31 Participants | 68 Participants | 37 Participants |
| Region of Enrollment Germany | 10 Participants | 16 Participants | 6 Participants |
| Region of Enrollment Italy | 19 Participants | 38 Participants | 19 Participants |
| Region of Enrollment Mexico | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Poland | 12 Participants | 23 Participants | 11 Participants |
| Region of Enrollment Russia | 58 Participants | 120 Participants | 62 Participants |
| Region of Enrollment Slovakia | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Spain | 13 Participants | 26 Participants | 13 Participants |
| Region of Enrollment Taiwan | 14 Participants | 28 Participants | 14 Participants |
| Region of Enrollment Ukraine | 25 Participants | 53 Participants | 28 Participants |
| Sex: Female, Male Female | 37 Participants | 72 Participants | 35 Participants |
| Sex: Female, Male Male | 193 Participants | 387 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 185 / 225 | 194 / 227 |
| other Total, other adverse events | 211 / 225 | 213 / 227 |
| serious Total, serious adverse events | 106 / 225 | 81 / 227 |
Outcome results
Primary
Overall Survival in the ITT Population (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.
Time frame: Participants will be followed till death (if they are not lost for follow-up), an expected average of 7.5 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Methotrexate | Overall Survival in the ITT Population (Months) | 7.1 Months |
| Methotrexate | Overall Survival in the ITT Population (Months) | 6.8 Months |
p-value: 0.8329Log Rank
Secondary
Disease Control Rate
Percentage of best overall responses CR, PR and SD in the analysed population
Time frame: 30 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Methotrexate | Disease Control Rate | 50.9 % patients |
| Methotrexate | Disease Control Rate | 46.3 % patients |
p-value: 0.243Log Rank
Secondary
Duration of Response
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
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Methotrexate | Duration of Response | 4.2 Months |
| Methotrexate | Duration of Response | 4.2 Months |
p-value: 0.6289Log Rank
Secondary
Objective Response Rate (ORR)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Methotrexate | Objective Response Rate (ORR) | 17.8 Percent of participants |
| Methotrexate | Objective Response Rate (ORR) | 14.8 Percent of participants |
p-value: 0.467Log Rank
Secondary
Progression Free Survival
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
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Methotrexate | Progression Free Survival | 2.8 Months |
| Methotrexate | Progression Free Survival | 2.8 Months |
p-value: 0.3576Log Rank