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

• ClinicalTrials.gov Identifier: NCT01345682
• Recruitment Status: Completed
• First Posted: May 2, 2011
• Results First Posted: April 14, 2015
• Last Update Posted: February 15, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: April 28, 2011
• First Posted Date: May 2, 2011
• Results First Submitted Date: March 13, 2015
• Results First Posted Date: April 14, 2015
• Last Update Posted Date: February 15, 2018
• Actual Study Start Date: January 5, 2012
• Actual Primary Completion Date: March 15, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2018)

Progression-free Survival (PFS) Based on Central Independent Review [ Time Frame: From randomization until disease progression, death or study completion date (06Dec2016); Up to 60 months ]

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

• Original Primary Outcome Measures (submitted: April 29, 2011): The primary efficacy endpoint of the trial is progression free survival (PFS) [ Time Frame: Approximately 9 months ]

Current Secondary Outcome Measures (submitted: January 19, 2018)

• Overall Survival (OS) [ Time Frame: From randomization until death or study completion date (06Dec2016); Up to 60 months ]
  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.
• Objective Response (OR) [ Time Frame: 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 ]
  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'.
• Disease Control (DC) [ Time Frame: 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 ]
  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 Shrinkage [ Time Frame: 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, 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.
• Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Status Change in Pain Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Status Change in Swallowing Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Status Change in Global Health Status Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Time to Deterioration in Pain [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Time to Deterioration in Swallowing [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.
• Time to Deterioration in Global Health Status [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ]
  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.

Original Secondary Outcome Measures (submitted: April 29, 2011)

• Changes in safety laboratory parameters [ Time Frame: Approximately 9 months ]
• Overall survival (OS) is the key secondary endpoint [ Time Frame: Approximately 9 months ]
• Objective response based on RECIST [ Time Frame: Approximately 9 months ]
• Health related quality of life (HRQOL) [ Time Frame: Approximately 9 months ]
• Incidence and intensity of adverse events [ Time Frame: Approximately 9 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Head and Neck Neoplasms
• Carcinoma, Squamous Cell

Intervention

• Drug: Afatinib
  Once daily
• Drug: Methotrexate
  Weekly

Study Arms

• Experimental: Afatinib (BIBW 2992)
  Once daily
  Intervention: Drug: Afatinib
• Active Comparator: Methotrexate
  Weekly
  Intervention: Drug: Methotrexate

Publications *

• Cohen EEW, Licitra LF, Burtness B, Fayette J, Gauler T, Clement PM, Grau JJ, Del Campo JM, Mailliez A, Haddad RI, Vermorken JB, Tahara M, Guigay J, Geoffrois L, Merlano MC, Dupuis N, Kramer N, Cong XJ, Gibson N, Solca F, Ehrnrooth E, Machiels JH. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol. 2017 Oct 1;28(10):2526-2532. doi: 10.1093/annonc/mdx344.
• Clement PM, Gauler T, Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Cohen EE, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Vermorken JB; LUX-H&N 1 investigators. Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial. Ann Oncol. 2016 Aug;27(8):1585-93. doi: 10.1093/annonc/mdw151. Epub 2016 Apr 15.
• Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):583-94. doi: 10.1016/S1470-2045(15)70124-5. Epub 2015 Apr 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 10, 2015): 483
• Original Estimated Enrollment (submitted: April 29, 2011): 474
• Actual Study Completion Date: December 6, 2016
• Actual Primary Completion Date: March 15, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Histologically or cytologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy
2. 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
3. Measurable disease according to RECIST
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion criteria:

1. Progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC
2. Any other than one previous platinum based systemic regimen given for R/M disease
3. Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules
4. Pregnancy or breast feeding

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Belgium, Brazil, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Mexico, Russian Federation, South Africa, Spain, Sweden, Switzerland, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01345682
• Other Study ID Numbers: 1200.43; 2011-000391-34 ( EudraCT Number: EudraCT )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: January 2018