Evaluation of Afatinib in Maintenance Therapy in Squamous Cell Carcinoma of the Head and Neck

Head and Neck Squamous Cell Carcinoma Clinical Trial

— BIBW2992ORL  

Official title:

A Randomized, Double-blind, Placebo-controlled Phase III Study, to Evaluate the Efficacy of Afatinib (BIBW2992) in Maintenance Therapy After Post- Operative Radio-chemotherapy in Squamous-cell Carcinoma of the Head and Neck: GORTEC 2010-02

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01427478
• Other study ID #: BIBW2992 ORL
• Secondary ID: 2010-023265-22
• Status: Completed
• Phase: Phase 3
• Start date: September 2011
• Est. completion date: May 2021

Study information

• Verified date: May 2021
• Source: Centre Leon Berard
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of Afatinib in maintenance therapy after post-operative radiochemotherapy (66 Gy and Cisplatin at the dose of 100mg/m2 every 3 weeks)in squamous cell carcinoma of the head and neck.

Description:

The reference treatment for operated squamous cell carcinoma of the head and the neck is a radiochemotherapy with Cisplatin (in the dose of intravenous 100 mg / m2 IV) every 3 weeks). The Receptor of EGFR (Epidermal Growth Factor) or REGF is a membrane receptor; it's activation leads the cellular growth and inhibits apoptotic capacities. This receptor is overexpressed in numerous solid tumors, including ENT tumors. Several clinical studies showed that an over expression of the REGF in ENT tumors was a dominant factor of poor prognostic. Afatinib (BIBW2992) is a strong and irreversible inhibitor of the EGFR ( type 1 human epidermic growth factor receptor, also known as HER1) and of the HER2 (human epidermal growth factor receptor 2). Currently, 3 phase III clinical studies in postoperative situation and using an anti-REGF are in progress: 2 in concomitant situation with the radiotherapy and 1 both in concomitance and in adjuvant therapy with radiotherapy. The preliminary results of a phase II study show that Afatinib is efficient in patients with local or metastatic relapse of a squamous cell carcinoma of the sphere ENT after a first line with Cisplatin and its tolerance is correct. These data lead us to propose in post-operative situation, in patients with a squamous cell carcinoma of the head and neck, a radiochemotherapy with Cisplatin followed by a treatment of maintenance by Afatinib or by placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: May 2021
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years
• Histologically-confirmed diagnosis of non metastatic squamous-cell carcinoma of oral cavity ; oropharynx, larynx or hypopharynx.
• Macroscopically complete resection of disease.
• High-risk histological features defined as :

Microscopically incomplete tumour resection and/or invasion of regional lymph nodes with extracapsular extension (pN+R+)

• Indication of radio-chemotherapy (at least 60 Gy of radiotherapy and at least 2 cycles of chemotherapy)
• Start of radio-chemotherapy within 8 weeks after surgery
• Performance Status (PS) ECOG <= 2
• Adequate Blood tests, renal and liver functions in the 15 days prior inclusion defined as : Hemoglobin > 9 g/dL Neutrophil count > 1500 x 109/L Platelets > 100 x 109/L Total bilirubin < 1,5x upper limit of normal (ULN) SGOT and SGPT < 2,5 x ULN Alkaline Phosphatase < 2,5 xULN Serum creatinine < 110 µmol/L or creatinine clearance > 55 ml/min (estimated by Cockcroft Formula) Absence of proteinuria
• Women of childbearing age must use adequate means of contraception(oral hormon contraceptive, intrauterine contraceptive device, double barrier method of contraception).
• Mandatory affiliation with a healthy security insurance.
• Dated and signed written informed consent.

Exclusion Criteria:

• Macroscopic residual tumour after resection(R2)
• Metastatic disease
• Prior treatment for Head and neck cancer with chemotherapy, radiotherapy or any cancer target therapy
• Prior or concomitant malignancies (except for basal cell skin cancer ; in situ cervical carcinoma or other malignancies with a complete response > 5 years)
• History of heavy hypersensibility reaction to Cisplatin
• Uncontrolled pulmonary, cardiac , hepatic or renal disease.
• History of interstitial pneumopathy
• Significant cardiovascular disease :

Congestive cardiac failure> New York Heart Association (NYHA) Class II Myocardial infraction within 6 months prior to inclusion Unstable angina Severe cardiac arrythmia Uncontrolled hypertension while receiving appropriate medication (= 160 mm Hg systolic and/or = 90 mm Hg diastolic) Disorder of left ventricular function with ejection fraction < 50% Severe cerebrovascular accident within 6 months prior to inclusion History of severe thromboembolism within 6 months prior to inclusion Cardiovascular baseline QTcB >480 ms (Calculated with Bazett Formula) Bradycardia Electrolytic disorders

• Hepatic affection like : hepatitis B or C chronic advanced decompensated hepatitis hepatitic cirrhosis or newly treated chronic hepatitis or nowadays treated with immunosuppressive drugs severe auto-immune hepatitis or disease
• HIV known history
• Recent digestive symptoms with diarrhea as :

Crohn's disease malabsorption syndrome diarrhea Grade CTC = 2

• Active drug or alcohol use or dependence
• Pregnant or breast-feeding women , or no use of effective birth control methods for women of childbearing potential, , or men who don't accept to use an effective birth control methods during the study
• Impossible follow-up

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Head and Neck Squamous Cell Carcinoma
• Squamous Cell Carcinoma of Head and Neck

Intervention

Drug:
• AFATINIB
AFATINIBat the dose of 40 mg/during the 1st month and then 50 mg/d during the 11 following months
• Placebo of AFATINIB
placebo of Afatinib at the dose of 40 mg/during the 1st month and then 50 mg/d during the 11 following months

Locations

Country	Name	City	State
France	Centre Paul Papin	Angers
France	Institut Sainte-Catherine	Avignon
France	CHU Bordeaux - Hôpital Saint-André	Bordeaux
France	Polyclinique de Bordeaux Nord	Bordeaux
France	CHRU Brest - Hôpital Morvan	Brest
France	Centre François Baclesse	Caen
France	CHIC Créteil	Créteil
France	Centre Guillaume le Conquérant	Le Havre
France	Centre Hospitalier Bretagne Sud	Lorient
France	Centre Léon Bérard	Lyon
France	AP-HM La Timone Adultes	Marseille
France	Centre Antoine Lacassagne	Nice
France	CHU Poitiers	Poitiers
France	Centre Eugène Marquis	Rennes
France	Centre Henri Becquerel	Rouen
France	Institut de Cancérologie de la Loire	Saint Priest en Jarez
France	Institut de Cancérologie de l'Ouest	Saint-Herblain
France	Pôle Hospitalier Mutualiste- Centre Etienne Dolet	Saint-Nazaire
France	Strasbourg Oncologie Libérale	Strasbourg
France	Hopitaux du Léman	Thonon-les-bains
France	Clinique Pasteur Bâtiment l'Atrium	Toulouse
France	Institut Claudius Regaud	Toulouse
France	CHU TOURS (Hôpital Bretonneau)	Tours
France	Centre de Radiothérapie Marie Curie	Valence
France	Institut de Cancérologie de lorraine (ICL)	Vandoeuvre-les-Nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Centre Leon Berard	Boehringer Ingelheim

Country where clinical trial is conducted

France, 

References & Publications (16)

Baselga J. New therapeutic agents targeting the epidermal growth factor receptor. J Clin Oncol. 2000 Nov 1;18(21 Suppl):54S-9S. Review. — View Citation

Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M; European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004 May 6;350(19):1945-52. — View Citation

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Chao KS, Majhail N, Huang CJ, Simpson JR, Perez CA, Haughey B, Spector G. Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques. Radiother Oncol. 2001 Dec;61(3):275-80. — View Citation

Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK; Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004 May 6;350(19):1937-44. — View Citation

Fan Z, Mendelsohn J. Therapeutic application of anti-growth factor receptor antibodies. Curr Opin Oncol. 1998 Jan;10(1):67-73. Review. — View Citation

Grandis JR, Tweardy DJ. TGF-alpha and EGFR in head and neck cancer. J Cell Biochem Suppl. 1993;17F:188-91. Review. — View Citation

Grégoire V, Eisbruch A, Hamoir M, Levendag P. Proposal for the delineation of the nodal CTV in the node-positive and the post-operative neck. Radiother Oncol. 2006 Apr;79(1):15-20. Epub 2006 Apr 17. — View Citation

Grégoire V, Levendag P, Ang KK, Bernier J, Braaksma M, Budach V, Chao C, Coche E, Cooper JS, Cosnard G, Eisbruch A, El-Sayed S, Emami B, Grau C, Hamoir M, Lee N, Maingon P, Muller K, Reychler H. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines. Radiother Oncol. 2003 Dec;69(3):227-36. — View Citation

Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 2006.

Lapeyre M, Henrot P, Alfonsi M, Bardet E, Bensadoun RJ, Dolivet G, Favrel V, Gallocher O, Giraud P, Graff P, Guerif S, Lagarde P, Lartigau E, Marchesi V, Pommier P, Rives M, Tortochaux J, Toussaint B, Verrelle P, Bourhis J, Calais G; Groupe Oncologie Radiothérapie Tête et Cou. [Propositions for the selection and the delineation of peritumoral microscopic disease volumes in oral cavity and oropharyngeal cancers (lymph nodes excluded)]. Cancer Radiother. 2005 Jun;9(4):261-70. Epub 2005 Apr 25. Review. French. — View Citation

Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res. 1997 Dec;3(12 Pt 2):2703-7. Review. — View Citation

Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J, Fan Z. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res. 2000 Feb;6(2):701-8. — View Citation

Prescribing, Recording, and Reporting Intensity-Modulated Photon-Beam Therapy (IMRT)(ICRU Report 83) ICRU Report 83, Journal of the ICRU Vol. 10 No. 1. 2011.

Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. Review. — View Citation

Seiwert, TC, clement, P. M, Del Campo, J, de Mont-Serrat, H., Thurm, H. C., Blackman, A. S., and Cohen, E. E. BIBW 2992 versus cetuximab in patients with metastatic or recurrent head and neck cancer (SCCHN) after failure of platinum-containing therapy with a cross-over period for progressing patients: Preliminary results of a randomized, open-label phase II study. Journal of Clinical Oncology 28(15 suppl). 2010.

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Free Survival 2 years after the end of radiotherapy		2 years after the end of radiotherapy
Secondary	Safety profile	Safety profile is characterized by type; frequency and seriousness of the toxicities showed by the patients and graded using CTCAE - V04	Every 28 days during the maintenance therapy,every 2 months during 1 year after maintenance therapy; and every 3 months during the following 3 years
Secondary	Quality of life of patient, evaluated by questionnary	Quality of life will be evaluated at baseline; at the end of radiotherapy and also at 1 and 2 years after the beginning of maintenance treatment. The EORTC's questionnaire QLQ-C30 and the additional module " Head and neck " QLQ-H&N35 will be used.	Baseline; at the end of radiotherapy, at 1 and 2 years after the beginning of maintenance treatment
Secondary	Overall Survival (OS)	OS is the time from randomization to the date of death due to any cause or date of the last news.	Death