Treatment of Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Head and Neck Squamous Cell Carcinoma Clinical Trial

— H&N07  

Official title:

Neoadjuvant Docetaxel+Cisplatin and 5-fluorouracil (TPF) Followed by Radiotherapy+Concomitant Chemo or Cetuximab Versus Radiotherapy+Concomitant Chemo or Cetuximab in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck. A Randomized Phase III Factorial Study.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01086826
• Other study ID #: H&N07
• Status: Completed
• Phase: Phase 3
• First received: March 12, 2010
• Last updated: January 23, 2015
• Start date: March 2008
• Est. completion date: December 2014

Study information

• Verified date: June 2013
• Source: Associazione Volontari Pazienti Oncologici
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial Summary

This is a randomized multicenter open label phase III factorial trial evaluating the 3 years OS in patients with locally advanced squamous cell carcinoma of head and neck treated with locoregional treatment (radiotherapy plus concomitant chemotherapy or cetuximab) with or without neoadjuvant chemotherapy.

Description:

This multicenter open label randomised phase III study is the implementation of a previous phase II randomized trial evaluating the efficacy of chemoradiotherapy with or without neoadjuvant TPF chemotherapy in locally advanced Head and Neck cancer. Assuming a randomisation ratio of 1:1, using the Mantel-Cox version of the log-rank test, 204 events are required in order to achieve a power of 0.80 of detecting an hazard ratio of 0.675 in favour of the experimental treatment with a type I error of 0.05, two-sided. With a uniform accrual of 4 years and a follow-up of 2 further years, the total number of required patients is 420 (210 per arm) to detect an absolute difference of 12% in 3 year overall survival in favour of the neoadjuvant arm (from 52.5% to 64.5%).Since the 101 patients randomized in the phase II part of the study will be included in the final analysis, 319 new patients are needed to complete the trial.The total number of 420 patients will be able to detect a difference of 10%, (from 35% to 45%) in terms of grade 3/4 in-field mucosal toxicity during the concomitant treatment (radiotherapy plus chemo or cetuximab) with a power of 80%. Within the H&N07 trials was introduced a sub-study that allows to investigate the value of circulating marker evaluation as predictor of response to anti EGFR therapy in patients with cancer of the head and neck.

The expression level analysis of circulating biological markers will be evaluated on blood collected during therapy. The analysis will concern the following biological markers:Cytokines angiogenesis and cell adhesion molecules; Proteins involved in the EGFR signaling pathway (EGF, TGF-a, s-EGFR);circulating tumor cells (CTC) and circulating endothelial cells (CEC).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 320
• Est. completion date: December 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically or cytologically proven squamous cell carcinoma of the head and neck.

2. Primary tumor sites eligible : oral cavity, oropharynx, hypopharynx Although they are admittedly of squamous cell types, the following tumors will be excluded because of them responsiveness to chemotherapy: tumors of the nasal and paranasal cavities and of the nasopharynx.

3. Stage 3 or 4 disease without evidence of distant metastases verified by chest X Ray, abdominal ultrasound, or CT (liver function test abnormalities); bone scan in case of local symptoms.

4. At least one uni or bidimensionally measurable lesion.

5. Tumor considered inoperable after evaluation by a multidisciplinary team (i.e. a surgeon, a medical oncologist and a radiation oncologist). Criteria for inoperability are:

1. technical unresectability: tumor fixation/invasion to base of the skull or cervical vertebrae, involvement of the nasopharynx, and fixed lymph nodes.

2. Physician decision based on low surgical curability. This category will include the following:

i) All T3-4 stages. ii) All N2-3 stages excluding T1 N2. iii) Patients for organ preservation. Reason for inoperability will be recorded in the CRF.

6. No previous chemotherapy or radiotherapy for any reason and no previous surgery for SCCHN (other than biopsy) are allowed at time of study entry.

7. Age > 18 years.

8. Karnofsky performance status > 70. (ECOG 0-1) (Appendix II)

9. No active alcohol addiction.

10. Life expectancy > 6 months.

11. Signed informed consent prior to beginning protocol specific procedures.

12. Adequate bone marrow, hepatic and renal functions as evidenced by the following:

a) Hematology (Bone marrow): i) Neutrophils > 2.0 109/L ii) Platelets > 100 x 109/L iii) Hemoglobin > 10 g/dL b) Hepatic function i) Total bilirubin < 1 x UNL ii) ASAT (SGOT) and ALAT (SGPT) < 2.5 x ULN iii) Alkaline phosphatase < 5 x ULN Patients with ASAT or ALAT > 1.5 x ULN associated with alkaline phosphatase > 2.5 x ULN are not eligible for the study.

c) Renal function : serum creatinine < 1 x UNL. In case of borderline value the creatinine clearance > 60 ml/min (calculated by the Cockcroft-Gault method as follows :

13. Patients must be available for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating center.

Exclusion Criteria:

1. Pregnant or lactating women or women of childbearing potential not using adequate contraception.

2. Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin, or other cancer curatively treated by surgery and with no evidence of disease for at least 5 years. Any prior treatment with radiotherapy or chemotherapy is an exclusion criterion.

3. Symptomatic peripheral neuropathy > grade 2 by NCIC-CTG criteria

4. Symptomatic altered hearing > grade 2 by NCIC-CTG criteria.

5. Other serious illnesses or medical conditions including:

1. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry.

2. History of significant neurologic or psychiatric disorders including dementia or seizures.

3. Active uncontrolled infection.

4. Active peptic ulcer.

5. Hypercalcemia.

6. Chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry

6. History of hypersensitivity reaction to polysorbate 80 (Appendix IV)

7. Patients requiring intravenous alimentation.

8. Patients who experienced a weight loss of more than 20% of their body weight in the 3 months preceding study entry.

9. Concomitant treatment with any other anticancer therapy.

10. Participation in a therapeutic clinical trial within 30 days of study entry

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• RT+CDDP/5-FU
RT=70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) CDDP: 20 mg/m2/day as 30 minutes IV infusion from day 1 to day 4 5-FU: 800 mg/m2/day for 4 days Both drugs will be administered during weeks 1 and 6 of irradiation, starting from day 1 of radiotherapy.
• RT+CETUXIMAB
RT= 70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) Cetuximab= 400 mg/m2 as first dose.Subsequent doses of 250 mg/ m2, weekly, for 7 times.
• INDUCTION CTx(TPF)+(RT+CDDP/5-FU)
INDUCTION CTx(TPF):docetaxel 75 mg/m² + CDDP 80mg/m² + 5-FU 800 mg/m²/day from day 1 to day 4 will begin after the end of cisplatin infusion on day 1.Every 3 weeks. concomitant CTx= CDDP 20 mg/m2/day + 5-FU 800 mg/m2/day RT= 70 Gy(2 Gy x1/day, 5 days per week for 7 weeks)
• INDUCTION CTx(TPF)+(RT+CETUXIMAB)
INDUCTION CTx(TPF):docetaxel 75 mg/m² + CDDP 80mg/m² + 5-FU 800 mg/m²/day from day 1 to day 4 will begin after the end of cisplatin infusion on day 1.Every 3 weeks. RT= 70 Gy(2 Gy x1/day, 5 days per week for 7 weeks) CETUXIMAB= 400 mg/m2 as first dose. Subsequent doses of 250 mg/ m2, weekly, for 7 times.

Locations

Country	Name	City	State
Italy	Istituto tumori "Giovanni Paolo II" IRCCS	Bari
Italy	Ospedale S.Martino	Belluno
Italy	Ospedale Bellaria Di Bologna	Bologna
Italy	Policlinico S.Orsola-Malpighi	Bologna
Italy	Ospedale "S.Maurizio"	Bolzano
Italy	Istituto Clinico S.Anna	Brescia
Italy	Azienda Ospedaliera Di Circolo	Busto Arsizio	Varese
Italy	"Ospedale Businco"	Cagliari
Italy	Policlinico Universitario	Cagliari
Italy	Ospedale Di Camposampiero	Camposampiero	Padova
Italy	Ospedale Civile di Castelfranco	Castelfranco Veneto	Treviso
Italy	A.O Pugliese-Ciaccio	Catanzaro
Italy	Ospedale Clinicizzato Di Chieti	Chieti
Italy	Ospedale Civile di Cittadella	Cittadella	Padova
Italy	Ospedale Santa Croce Di Fano	Fano	Pesaro-urbino
Italy	Ospedale "S. Maria Del Prato"	Feltre	Belluno
Italy	Ospedale "AUGUSTO MURRI"	Fermo
Italy	A.O.Universitaria	Ferrara
Italy	Azienda Ospedaliera "S.Antonio Abate"	Gallarate	Varese
Italy	Ospedale Civile di Latisana	Latisana	Udine
Italy	Azienda Ospedaliera "Alessandro Manzoni"	Lecco
Italy	"AULSS 21 Mater Salutis"	Legnago	Verona
Italy	Ospedale di Macerata	Macerata
Italy	A.O. Universitaria Di Messina	Messina
Italy	P.O. SAN VINCENZO di Messina	Messina
Italy	"Ospedale dell' Angelo"	Mestre	Venezia
Italy	"Istituto Europeo di Oncologia"	Milano
Italy	"Ospedale San Paolo"	Milano
Italy	A.O. Niguarda-Cà Granda	Milano
Italy	Irccs - Ospedale "S. Raffaele"	Milano
Italy	"Ospedale Civile di Mirano"	Mirano	Venezia
Italy	"A.O. - Policlinico Di Modena"	Modena
Italy	H.S. Gerardo dei Tintori	Monza	Moza-Brianza
Italy	"Istituto Oncologico Veneto"	Padova
Italy	Casa di Cura "La Maddalena"	Palermo
Italy	Policlinico Universitario di Palermo	Palermo
Italy	A.O.Universitaria "Ospedale Maggiore"	Parma
Italy	Osp. S. Maria della Misericordia	Perugia
Italy	A.O. "Ospedale S. Salvatore"	Pesaro	Pesaro-urbino
Italy	Ospedale "G. Da Saliceto"	Piacenza
Italy	Osp. S. Maria Delle Croci	Ravenna
Italy	A.O. "S.Camillo de' Lellis"	Rieti
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Italy	Ospedale S.Pietro "Fatebenefratelli"	Roma
Italy	IRCCS Casa Sollievo della Sofferenza	S. Giovanni Rotondo	Foggia
Italy	A.O. Ospedale Sant'Anna	S.Fermo	Como
Italy	Ospedale "B.Eustachio" - S.Severino	San Severino Marche	Macerata
Italy	Ospedale Civile Di Sondrio	Sondrio
Italy	Osp. S.G. Moscati	Taranto
Italy	Ospedale "Boldrini"	Thiene	Vicenza
Italy	P.O. "S.Antonio Abate"	Tolmezzo	Udine
Italy	Ospedale "S. Chiara"	Trento
Italy	Ospedale Di Treviglio - Caravaggio	Treviglio	Bergamo
Italy	Ospedale Ca' Foncello	Treviso
Italy	"Ospedali Riuniti"	Trieste
Italy	A.O. Santa Maria della Misericordia	Udine
Italy	Ospedale Di Circolo E Fondazione Macchi	Varese
Italy	Ospedale Civile SS Giovanni e Paolo	Venezia
Italy	Ospedale Civile Maggiore Borgo Trento	Verona
Italy	Ospedale civile di Vicenza	Vicenza

Sponsors (2)

Lead Sponsor	Collaborator
Associazione Volontari Pazienti Oncologici	Mario Negri Institute for Pharmacological Research

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	overall survival	overall survival defined as the time from the date of randomization to the date of death from any cause.	3 years	No
Secondary	progression free survival	Secondary Objectives are: To compare the radiological and pathological complete response rate, the duration of response,the time to progression,the hematological and non-hematological toxicity,the duration of RTX plus concomitant CHT or cetuximab,the interruption number and the radiological complete response during concomitant chemoradiation and radiation plus cetuximab. To evaluate the biological profile expression,correlation between biological biomarkers expression,response to treatment and OS. To compare Quality of life.	3 years	No