Afatinib After Chemoradiation and Surgery in Treating Patients With Stage III-IV Squamous Cell Carcinoma of the Head and Neck at High-Risk of Recurrence

PRIMARY OBJECTIVES:

I. Examine disease-free survival (DFS) given afatinib/placebo adjuvant therapy in patients
with viable tumors in lymph nodes after neck dissection for suspected residual disease after
concurrent chemoradiation.

SECONDARY OBJECTIVES:

I. Evaluate the recurrence rate, recurrence patterns, development of second primary
malignancies, overall survival (OS) and toxicity of afatinib/placebo.

II. Evaluate on-target inhibition by afatinib, and determine circulating deoxyribonucleic
acid (DNA) as a biomarker of afatinib resistance.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive afatinib orally (PO) once daily (QD) on days 1-28.

ARM B: Patients receive placebo PO QD on days 1-28.

In both Arms, treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 1 year and then every 12 months for 2 years.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Patients must have pathological evidence of persistent primary and/or lymph node
disease with viable tumor cells following primary concurrent chemoradiotherapy of
locoregionally advanced (stage III/IV) HNSCC of the oral cavity, oropharynx, larynx,
hypopharynx or p16-positive unknown primary of the head and neck region; persistent
primary and/or lymph node disease with viable tumor cells will be determined by the
histological determination of tumor viability defined as tumor cells with intact
cellular compartments (i.e. cytoplasm and nucleus) that do not exhibit karyolysis,
pyknosis, or karyorrhexis on haematoxylin and eosin (H&E) staining

- Patients must have undergone a neck dissection following completion of
chemoradiotherapy and must have involved at the minimum a compartment dissection of
nodal levels with residual abnormalities on post-treatment imaging studies and/or
received a complete resection of the residual primary lesion with negative margins

- Patients must have achieved a complete response at the primary disease site after
chemoradiotherapy or complete resection of the residual primary site disease with
negative margins

- All persistent lymph node disease must have received at least 66 Gy of radiotherapy
and must have been completely surgically resected prior to registration, and surgical
incisions should be adequately healed

- Patients with extracapsular lymph node extension, perineural or lymphovascular
invasion will be eligible

- Patients must be at least 6 weeks (42 days) and no more than 36 weeks (252 days) from
completion of chemoradiation at the time of registration

- Patients will be eligible regardless of ability to swallow; patients with dysphagia
may have afatinib/placebo administered via gastrostomy tube

- Absolute neutrophil count >= 1,000/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 x the upper limit of normal (ULN)

- Aspartate amino transferase (AST) =< 3 x the ULN

- Alanine amino transferase (ALT) =< 3 x the ULN

- Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula

- Prior cetuximab or any epidermal growth factor receptor (EGFR) inhibitors will not be
permitted including cetuximab administered with a chemoradiotherapy or radiotherapy
regimen

- As all patients in this study will have received prior full dose, curative-intent
external-beam radiotherapy to the involved neck, no additional external-beam
radiotherapy will be permitted prior to or during study participation

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception

- Patients must have electrocardiogram (ECG) within 8 weeks prior to randomization to
the study

- Patients must be assessed for cardiac function by echocardiogram (ECHO) or multi-gated
acquisition scan (MUGA) within 8 weeks prior to randomization

Exclusion Criteria:

- Patients with known distant metastatic disease or with any gross residual disease
following salvage primary tumor resection or neck dissection

- Known hypersensitivity to afatinib or any of the excipients of this product

- Prior adjuvant chemotherapy (aside from the initial induction chemotherapy followed by
chemoradiotherapy or chemoradiotherapy regimen)

- History of acute myocardial infarction within 3 months prior to registration, and any
history of uncontrolled angina, uncontrolled arrhythmia, or uncontrolled heart failure

- Pregnant or breast-feeding women

- Active infections, other cancers, or history of other cancers

- Participation in any other clinical trials or taking any other experimental
medications

- Left ventricular dysfunction

- Evidence of interstitial lung disease