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Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial.

Burtness B, Bourhis JP, Vermorken JB, Harrington KJ, Cohen EE - Trials (2014)

Bottom Line: Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur.The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.

View Article: PubMed Central - PubMed

Affiliation: Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. barbara.burtness@yale.edu.

ABSTRACT

Background: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC.

Methods/design: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.

Discussion: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.

Trial registration: ClinicalTrials.gov NCT01345669.

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Related in: MedlinePlus

Trial design.
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Fig1: Trial design.

Mentions: The LUX-Head & Neck 2 trial is a randomized, multicentre, double-blind, placebo-controlled, phase III trial. Patients will undergo magnetic resonance imaging, positron emission tomography or computed tomography approximately 8 to 12 weeks after completion of chemoradiotherapy and, if there is no evidence of disease, patients will be randomized no later than 24 weeks post-chemoradiotherapy to either afatinib or placebo in the ratio 2:1. Randomization will be conducted centrally with a validated random number-generating system at Boehringer Ingelheim, verified by a trial-independent statistician, and implemented via an interactive internet and voice-response system. Access to the randomization code will be supervised by the clinical trial support group; those directly involved in the conduct and analysis of the trial will not have access to the randomization schedule prior to database lock. Stratification will be based on patients’ nodal status (N0 to N2a versus N2b to N3, based on the TNM Staging Classification for Head and Neck Cancers) [8] and ECOG performance status (0 versus 1) at randomization. Eligible patients will receive, as adjuvant therapy, either continuous oral once-daily afatinib at a starting dose of 40 mg or placebo, which will be administered for 18 months or until disease recurrence or unacceptable adverse events occur. The dose of afatinib will be escalated to 50 mg in patients with no or minimal drug-related adverse events or will be reduced to 40 mg (if first escalated to 50 mg), 30 mg or 20 mg in patients experiencing drug-related adverse events (Figure 1).Figure 1


Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial.

Burtness B, Bourhis JP, Vermorken JB, Harrington KJ, Cohen EE - Trials (2014)

Trial design.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289298&req=5

Fig1: Trial design.
Mentions: The LUX-Head & Neck 2 trial is a randomized, multicentre, double-blind, placebo-controlled, phase III trial. Patients will undergo magnetic resonance imaging, positron emission tomography or computed tomography approximately 8 to 12 weeks after completion of chemoradiotherapy and, if there is no evidence of disease, patients will be randomized no later than 24 weeks post-chemoradiotherapy to either afatinib or placebo in the ratio 2:1. Randomization will be conducted centrally with a validated random number-generating system at Boehringer Ingelheim, verified by a trial-independent statistician, and implemented via an interactive internet and voice-response system. Access to the randomization code will be supervised by the clinical trial support group; those directly involved in the conduct and analysis of the trial will not have access to the randomization schedule prior to database lock. Stratification will be based on patients’ nodal status (N0 to N2a versus N2b to N3, based on the TNM Staging Classification for Head and Neck Cancers) [8] and ECOG performance status (0 versus 1) at randomization. Eligible patients will receive, as adjuvant therapy, either continuous oral once-daily afatinib at a starting dose of 40 mg or placebo, which will be administered for 18 months or until disease recurrence or unacceptable adverse events occur. The dose of afatinib will be escalated to 50 mg in patients with no or minimal drug-related adverse events or will be reduced to 40 mg (if first escalated to 50 mg), 30 mg or 20 mg in patients experiencing drug-related adverse events (Figure 1).Figure 1

Bottom Line: Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur.The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.

View Article: PubMed Central - PubMed

Affiliation: Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. barbara.burtness@yale.edu.

ABSTRACT

Background: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC.

Methods/design: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety.

Discussion: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo.

Trial registration: ClinicalTrials.gov NCT01345669.

Show MeSH
Related in: MedlinePlus