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Multi-centric Randomized Phase II Study of Pre-operative Afatinib (BIBW2992) Aiming at Identifying Predictive and Pharmacodynamic Biomarkers of Biological Activity and Efficacy in Untreated Non-metastatic Head and Neck Squamous Cell Carcinoma Patients

Phase 2
18 Years
Open (Enrolling)
Carcinoma, Squamous Cell of Head and Neck

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Trial Information

Multi-centric Randomized Phase II Study of Pre-operative Afatinib (BIBW2992) Aiming at Identifying Predictive and Pharmacodynamic Biomarkers of Biological Activity and Efficacy in Untreated Non-metastatic Head and Neck Squamous Cell Carcinoma Patients

More than 500,000 new patients with squamous cell carcinomas of the head and neck (SCCHN)
are diagnosed each year around the world. Patients who relapse after primary therapy for
locoregional disease and those who present with distant metastases have limited prognosis.

Drug therapy for cancer control and the palliation of patients with recurrent or metastatic
SCCHN is currently suboptimal. In contemporary trials the most active cytotoxic drug
combinations have response rates in the range of 30%, and are associated with frequent and
severe toxicities and treatment-related mortality.

Molecular targeting has been demonstrated in oncology as a relevant strategy in cancer
therapeutics. In March 2006, the FDA announced the approval of a chimeric monoclonal
antibody against the epidermal growth factor receptor (EGFR), cetuximab, for use in
combination with radiation therapy in patients with locally advanced SCCHN. Furthermore, the
addition of cetuximab to cisplatin and 5FU as first-line therapy in patients with recurrent
or metastatic SCCHN has significantly improved overall survival when compared to cisplatin
and 5FU alone. Phase II data of cetuximab given as monotherapy in recurrent or metastatic
SCCHN patients who have progressed on platinum-based therapy have demonstrated an overall
response rate of 13% and a median survival of about 6 months. Small molecules tyrosine
kinase inhibitors of EGFR, such as gefitinib and erlotinib, seem to be slightly less
effective than cetuximab. Based on these results, FDA has also approved cetuximab
monotherapy use for this indication in recurrent or metastatic SCCHN.

However, despite high expression of EGFR in SCCHN, EGFR inhibitor monotherapy has only had
modest activity. Potential mechanisms of resistance to EGFR-targeted therapies involve EGFR
and K-Ras mutations, epithelial-mesenchymal transition, and activation of alternative and
downstream pathways. Strategies to optimize EGFR-targeted therapy in head and neck cancer
involve the selection for patients most likely to benefit and the use of therapies to target
the network of pathways involved in tumor growth, invasion, angiogenesis, and metastasis.

Afatinib is an irreversible dual inhibitor of EGFR and HER2 tyrosine kinase. Preclinical
data suggest that Afatinib might have a larger spectrum antitumor activity than EGFR
tyrosine kinase inhibitors. In vivo and in vitro studies indeed showed that Afatinib
displays antitumor activity in erlotinib/gefitinib-resistant lung models. Afatinib compared
favourably to cetuximab in platinum-resistant metastatic SCCHN. In addition, Afatinib has
shown promising antitumor activity in HER2-overexpressing metastatic breast cancer after
trastuzumab failure and in metastatic adenocarcinomas of the lung harbouring EGFR activating

To date, predictive and pharmacodynamic biomarkers studies have mostly been performed in
pre-treated metastatic patients. Erlotinib has been the most studied EGFR-targeted agent in
terms of biomarkers identification in SCCHN. In the metastatic setting, sequential biopsies
allowed correlating potential predictive and pharmacodynamic biomarkers with the outcome of
patients treated with erlotinib. The decrease of p-EGFR in tumor tissue was associated with
increased time-to-progression (TTP) and overall survival (OS) in one study. In another
study, elevated pre-treatment levels of p27 and p-STAT3 in tumor tissue predicted for
prolonged TTP and OS, while a decrease in p-EGFR, p-NFkB and p27 correlated with increased
TTP, OS or both. However, the lack of control arm precluded to draw any definitive
conclusion. One study evaluated erlotinib in the neoadjuvant setting in untreated patients
with operable SCCHN. Baseline p21 expression in tumor tissue correlated with clinical
response to treatment. But again, the absence of control arm in this later study precluded
drawing definitive conclusions regarding the potential predictive and pharmacodynamic value
of the biomarkers under evaluation.

The main characteristics of our study are:

1. the pre-operative setting in untreated patients with the advantage of having untreated
patients for whom it is easy to get pre- and post-treatment tumor specimen, during
initial panendoscopy and surgery, respectively

2. the randomization versus no treatment which is the only way to be able to draw robust
conclusions regarding the potential predictive and pharmacodynamic value of the
biomarkers under evaluation. Single-arm phase II trials can only identify prognostic
markers of activity, but not predictive biomarkers of activity.

Importantly, surgery will not be delayed in any case by the study. However, it is required
that planning of surgery will enable patients to receive between 21 and 28 days of treatment
to participate into the study given the planned date of surgery.

Inclusion Criteria:

- Age > 18 years

- Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity,
oropharynx, larynx or hypopharynx, previously untreated, amenable to curative
treatment with surgery. Patients with a diagnosis of SCCHN of occult primary may be
enrolled only with the agreement of the lead investigator upon review of the relevant
clinical records

- T2-4N0-2 tumors (except T2N0 endolaryngeal tumors)

- Absence of metastases determined by PET CT scan

- Planned date of surgery allowing the patient to receive between 21 and 28 days of

- ECOG performance status ≤ 2

- Adequate bone marrow function (absolute neutrophil count > 1,000 cells/mm3, platelets
> 75,000 cells/mm3)

- Adequate liver function (total bilirubin ≤ 1.5 x UNL [upper normal limit], AST or ALT
≤ 3 x UNL)

- Adequate renal function (serum creatinine ≤ 1.5 x UNL)

- Adequate cardiac function (a normal left ventricular ejection fraction [LVEF] of ≥
50% as measured by MUGA scan or echocardiogram within 4 weeks prior to start of study

- Potentially reproductive patients must agree to use an effective contraceptive method
while on treatment

- Women of childbearing potential must have a negative serum beta-HCG pregnancy test
within 7 days prior of enrollment and/or urine pregnancy 48 hours prior to the
administration of the first study treatment

- Patients must be able to swallow tablets

- Patients must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures

- Patients must be affiliated to a Social Security System

- Patient information and written informed consent form signed

Exclusion Criteria:

- Primary site of head and neck carcinoma in nasopharynx, or skin

- T1N0 tumors and T2N0 endolaryngeal tumors

- Patients not candidate for primary curative surgery

- Planning of surgery not allowing the patient to receive 21 to 28 days of treatment

- Patients receiving other anti-cancer medication such as chemotherapy, immunotherapy,
biologic therapy or hormonal therapy (other than leuprolide or other GnRH agonists)
within 30 days prior to the first dose of study drug and while on study treatment.

- Patients receiving other anti-cancer non-drug therapies: radiation, or tumor
embolization within 4 weeks prior to the first dose of study drug and while on study

- Patient being treated with anti-vitamin K (AVK). Low molecular weight heparin (LMWH)
is allowed.

- Patient with uncontrolled infection

- Patients with other concurrent severe and/or uncontrolled medical disease which could
compromise participation in the study, including uncontrolled diabetes,

- Clinically relevant cardiovascular abnormalities, as judged by the investigator, such
as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA
classification > III, unstable angina, myocardial infarction within six months prior
to randomisation, or poorly controlled arrhythmia, chronic liver or renal disease,
severely impaired lung function

- Significant or recent acute gastrointestinal disorders with diarrhea as a major
symptom e.g. Crohn's disease, malabsorption or CTCAE grade >1 diarrhea of any
etiology at randomisation

- Known pre-existing Interstitial Lung Disease (ILD)

- Patients requiring comedication with potent P-gp inhibitors (including Cyclosporin,
Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt with
Quinidine, Ritonavir, Valspodar, Verapamil) or inducers (including St John's wort,

- Patients with a known HIV, active hepatitis B and/or C infection

- Pregnant women, women who are likely to be pregnant or are breast-feeding

- Patients with any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before registration in the

- Patients who received any other investigational drugs within 30 days prior to the
screening visit and/or during the study

- Patients unwilling to participate in the biological investigations

- Individually deprived of liberty or placed under the authority of a tutor

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Potential predictive biological markers of activity of Afatinib

Outcome Description:

Correlation between baseline potential biomarkers and radiological response to Afatinib FDG-PET response to Afatinib To identify the predictive biomarkers, the following translational researches will be carried out on initial tumor biopsy IHC tumour characterization High throughput protein analysis Molecular analyses : FISH , Mutations by PCR , Quantitative RT-PCR

Outcome Time Frame:

15 days (FDG-PET evaluation) and about 21 days (CT scan or MRI evaluation) after start of treatment

Safety Issue:


Principal Investigator

Christophe Le Tourneau

Investigator Role:

Principal Investigator

Investigator Affiliation:

Institut Curie, Paris


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

November 2011

Completion Date:

October 2013

Related Keywords:

  • Carcinoma, Squamous Cell of Head and Neck
  • Squamous cell carcinoma of the head and neck
  • pre operative treatment
  • Afatinib
  • BIBW2992
  • Biological markers
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms