LUX-Head&Neck 1: A Phase III Trial of Afatinib (BIBW2992) Versus Methotrexate for the Treatment of Recurrent and/or Metastatic (R/M) Head and Neck Squamous Cell Cancer After Platinum Based Chemotherapy

Study Overview
=================
Brief Summary
-----------------
This randomised, open-label, phase III study will be performed in patients with R/M head and neck squamous cell carcinoma (HNSCC) who have progressed after platinum-based therapy. The objectives of the trial are to compare the efficacy and safety of afatinib versus methotrexate

Official Title
-----------------
A Randomised, Open-label, Phase III Study to Evaluate the Efficacy and Safety of Oral Afatinib (BIBW 2992) Versus Intravenous Methotrexate in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Who Have Progressed After Platinum-based Therapy

Conditions
-----------------
Head and Neck Neoplasms, Carcinoma, Squamous Cell

Intervention / Treatment
-----------------
* Drug: Afatinib
* Drug: Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Histologically or cytologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy Documented progressive disease based on investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST) following receipt of at least two cycles of cisplatin or carboplatin administered for R/M disease Measurable disease according to RECIST Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion criteria: Progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC Any other than one previous platinum based systemic regimen given for R/M disease Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules Pregnancy or breast feeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afatinib (BIBW 2992)<br>Once daily | Drug: Afatinib<br>* Once daily<br>|
| Active Comparator: Methotrexate<br>Weekly | Drug: Methotrexate<br>* Weekly<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Based on Central Independent Review | PFS was defined as the time from the date of randomisation to disease progression or death, whichever occurred first. The primary analysis of PFS considered PFS events as assessed by central independent review, including all data collected until the study completion date (06 December 2016). The date of disease progression was recorded based on RECIST version 1.1. Unequivocal progression of disease was determined if at least one of the following criteria applied: At least 20% increase in the Sum of Diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm Appearance of one or more new lesions Unequivocal progression of existing non-target lesions | From randomization until disease progression, death or study completion date (06Dec2016); Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was a key secondary endpoint of this trial. OS was defined as the time from randomisation to death (irrespective of the cause of death). Patients for whom there was no evidence of death at the study completion date (06 December 2016) were to be censored on the date that they were last known to be alive. | From randomization until death or study completion date (06Dec2016); Up to 60 months | 
| Objective Response (OR) | OR is defined as the best overall response of complete response (CR) and partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-Progressive Disease (PD) in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'. | Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months | 
| Disease Control (DC) | DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions. | Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months | 
| Tumour Shrinkage | Tumour shrinkage, defined as the maximum decrease from baseline in the sum of diameters of the target lesions, as measured by central imaging. The longest diameter of target lesions was recorded, except for lymph nodes, which were measured by their short axis. Negative values indicate a reduction in the sum of target lesion diameters and positive values an increase. Percentage of Participants with Tumour shrinkage as per the categories (>=20% increase, >=0 - <20% increase, >0 - <30% decrease, >=30 - <50% decrease, >=50% decrease) are presented. | Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months | 
| Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time | The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time | The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time | The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Status Change in Pain Scale | Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Status Change in Swallowing Scale | Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Status Change in Global Health Status Scale | Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Time to Deterioration in Pain | The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Time to Deterioration in Swallowing | The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. | 
| Time to Deterioration in Global Health Status | The time to deterioration was defined as the time from randomisation to a score decreased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death. | From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. |