H&N07: Treatment of Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Sponsor

Associazione Volontari Pazienti Oncologici (Other)

Overall Status

Completed

CT.gov ID

NCT01086826

Collaborator

Mario Negri Institute for Pharmacological Research (Other)

320

Enrollment

Locations

Arms

Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Squamous Cell Carcinoma	Drug: RT+CDDP/5-FU Drug: RT+CETUXIMAB Drug: INDUCTION CTx(TPF)+(RT+CDDP/5-FU) Drug: INDUCTION CTx(TPF)+(RT+CETUXIMAB)	Phase 3

Detailed 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).

Study Design

Study Type:

Interventional

Actual Enrollment :

320 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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.

Study Start Date :

Mar 1, 2008

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: RT+CDDP/5-FU RT: Tumor: 70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) Lymph nodes: at least 50 Gy (2 Gy x1/day, 5 days per week for 6 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 will be administered as continuos iv infusion Both drugs will be administered during weeks 1 and 6 of irradiation, starting from day 1 of radiotherapy.	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. Other Names: Radiotherapy, Cisplatin, 5-fluoruracil
Experimental: RT+CETUXIMAB RT: Tumor: 70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) Lymph nodes: at least 50 Gy (2 Gy x1/day, 5 days per week for 6 weeks) CETUXIMAB: Cetuximab 400 mg/m2 as first dose, 7 days before the beginning of radiotherapy as 120 minutes IV infusion. Subsequent doses of 250 mg/ m2 will be administered as 60 minutes IV infusion, weekly, for 7 times.	Drug: 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. Other Names: Radiotherapy, Cetuximab
Active Comparator: INDUCTION CTx(TPF)+(RT+CDDP/5-FU) INDUCTION CTx(TPF): DOCETAXEL: 75 mg/m², 1 hour IV infusion, Day and every 3 weeks CISPLATIN: 80mg/m², intravenous infusion over 30-minute to 3 hours,Day 1 immediately after docetaxel administration and then every 3 weeks 5-FU 800 mg/m²/day, 24 hour continous infusion over 4 days, Day 1 after the end of cisplatin infusion, and every 3 weeks. RT: Tumor: 70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) Lymph nodes: at least 50 Gy (2 Gy x1/day, 5 days per week for 6 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 will be administered as continuos iv infusion	Drug: 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) Other Names: Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy
Experimental: INDUCTION CTx(TPF)+(RT+CETUXIMAB) DOCETAXEL: 75 mg/m², 1 hour IV infusion, Day and every 3 weeks CISPLATIN: 80mg/m², intravenous infusion over 30-minute to 3 hours,Day 1 immediately after docetaxel administration and then every 3 weeks 5-FU 800 mg/m²/day, 24 hour continous infusion over 4 days, Day 1 after the end of cisplatin infusion, and every 3 weeks. RADIOTHRAPY: Tumor: 70 Gy (2 Gy x1/day, 5 days per week for 7 weeks) Lymph nodes: at least 50 Gy (2 Gy x1/day, 5 days per week for 6 weeks) CETUXIMAB: Cetuximab 400 mg/m2 as first dose, 7 days before the beginning of radiotherapy as 120 minutes IV infusion. Subsequent doses of 250 mg/ m2 will be administered as 60 minutes IV infusion, weekly, for 7 times.	Drug: 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. Other Names: Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy, Cetuximab

Outcome Measures

Primary Outcome Measures

overall survival [3 years]
overall survival defined as the time from the date of randomization to the date of death from any cause.

Secondary Outcome Measures

progression free survival [3 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically proven squamous cell carcinoma of the head and neck.
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.
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.
At least one uni or bidimensionally measurable lesion.
Tumor considered inoperable after evaluation by a multidisciplinary team (i.e. a surgeon, a medical oncologist and a radiation oncologist). Criteria for inoperability are:
technical unresectability: tumor fixation/invasion to base of the skull or cervical vertebrae, involvement of the nasopharynx, and fixed lymph nodes.
Physician decision based on low surgical curability. This category will include the following:

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.

No previous chemotherapy or radiotherapy for any reason and no previous surgery for SCCHN (other than biopsy) are allowed at time of study entry.
Age > 18 years.
Karnofsky performance status > 70. (ECOG 0-1) (Appendix II)
No active alcohol addiction.
Life expectancy > 6 months.
Signed informed consent prior to beginning protocol specific procedures.
Adequate bone marrow, hepatic and renal functions as evidenced by the following:

Hematology (Bone marrow): i) Neutrophils > 2.0 109/L ii) Platelets > 100 x 109/L

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.

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 :

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:

Pregnant or lactating women or women of childbearing potential not using adequate contraception.
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.
Symptomatic peripheral neuropathy > grade 2 by NCIC-CTG criteria
Symptomatic altered hearing > grade 2 by NCIC-CTG criteria.
Other serious illnesses or medical conditions including:
Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry.
History of significant neurologic or psychiatric disorders including dementia or seizures.
Active uncontrolled infection.
Active peptic ulcer.
Hypercalcemia.
Chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry
History of hypersensitivity reaction to polysorbate 80 (Appendix IV)
Patients requiring intravenous alimentation.
Patients who experienced a weight loss of more than 20% of their body weight in the 3 months preceding study entry.
Concomitant treatment with any other anticancer therapy.
Participation in a therapeutic clinical trial within 30 days of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale "S. Maria Del Prato"	Feltre	Belluno	Italy	32032
2	Ospedale Di Treviglio - Caravaggio	Treviglio	Bergamo	Italy	24047
3	A.O. Ospedale Sant'Anna	S.Fermo	Como	Italy	22100
4	IRCCS Casa Sollievo della Sofferenza	S. Giovanni Rotondo	Foggia	Italy	71013
5	Ospedale "B.Eustachio" - S.Severino	San Severino Marche	Macerata	Italy	62027
6	H.S. Gerardo dei Tintori	Monza	Moza-Brianza	Italy	20052
7	Ospedale Di Camposampiero	Camposampiero	Padova	Italy	35012
8	Ospedale Civile di Cittadella	Cittadella	Padova	Italy	35010
9	Ospedale Santa Croce Di Fano	Fano	Pesaro-urbino	Italy	61032
10	A.O. "Ospedale S. Salvatore"	Pesaro	Pesaro-urbino	Italy	61100
11	Ospedale Civile di Castelfranco	Castelfranco Veneto	Treviso	Italy	31033
12	Ospedale Civile di Latisana	Latisana	Udine	Italy	33057
13	P.O. "S.Antonio Abate"	Tolmezzo	Udine	Italy	33028
14	Azienda Ospedaliera Di Circolo	Busto Arsizio	Varese	Italy	21052
15	Azienda Ospedaliera "S.Antonio Abate"	Gallarate	Varese	Italy	21013
16	"Ospedale dell' Angelo"	Mestre	Venezia	Italy	30173
17	"Ospedale Civile di Mirano"	Mirano	Venezia	Italy	30035
18	"AULSS 21 Mater Salutis"	Legnago	Verona	Italy	37045
19	Ospedale "Boldrini"	Thiene	Vicenza	Italy	36015
20	Istituto tumori "Giovanni Paolo II" IRCCS	Bari		Italy	70124
21	Ospedale S.Martino	Belluno		Italy	32100
22	Ospedale Bellaria Di Bologna	Bologna		Italy	40100
23	Policlinico S.Orsola-Malpighi	Bologna		Italy	40138
24	Ospedale "S.Maurizio"	Bolzano		Italy	39100
25	Istituto Clinico S.Anna	Brescia		Italy	25127
26	"Ospedale Businco"	Cagliari		Italy	09121
27	Policlinico Universitario	Cagliari		Italy	09121
28	A.O Pugliese-Ciaccio	Catanzaro		Italy	88100
29	Ospedale Clinicizzato Di Chieti	Chieti		Italy	66100
30	Ospedale "AUGUSTO MURRI"	Fermo		Italy	63023
31	A.O.Universitaria	Ferrara		Italy	44100
32	Azienda Ospedaliera "Alessandro Manzoni"	Lecco		Italy	23900
33	Ospedale di Macerata	Macerata		Italy	62100
34	P.O. SAN VINCENZO di Messina	Messina		Italy	98039
35	A.O. Universitaria Di Messina	Messina		Italy	98151
36	Irccs - Ospedale "S. Raffaele"	Milano		Italy	20132
37	"Istituto Europeo di Oncologia"	Milano		Italy	20141
38	"Ospedale San Paolo"	Milano		Italy	20143
39	A.O. Niguarda-Cà Granda	Milano		Italy	20162
40	"A.O. - Policlinico Di Modena"	Modena		Italy	41100
41	"Istituto Oncologico Veneto"	Padova		Italy	35100
42	Policlinico Universitario di Palermo	Palermo		Italy	90100
43	Casa di Cura "La Maddalena"	Palermo		Italy	90121
44	A.O.Universitaria "Ospedale Maggiore"	Parma		Italy	43121
45	Osp. S. Maria della Misericordia	Perugia		Italy	06132
46	Ospedale "G. Da Saliceto"	Piacenza		Italy	29121
47	Osp. S. Maria Delle Croci	Ravenna		Italy	48100
48	A.O. "S.Camillo de' Lellis"	Rieti		Italy	02100
49	Istituto Nazionale Tumori Regina Elena	Roma		Italy	00144
50	Ospedale S.Pietro "Fatebenefratelli"	Roma		Italy	00189
51	Ospedale Civile Di Sondrio	Sondrio		Italy	23100
52	Osp. S.G. Moscati	Taranto		Italy	74100
53	Ospedale "S. Chiara"	Trento		Italy	38100
54	Ospedale Ca' Foncello	Treviso		Italy	31100
55	"Ospedali Riuniti"	Trieste		Italy	34100
56	A.O. Santa Maria della Misericordia	Udine		Italy	33100
57	Ospedale Di Circolo E Fondazione Macchi	Varese		Italy	21100
58	Ospedale Civile SS Giovanni e Paolo	Venezia		Italy	30174
59	Ospedale Civile Maggiore Borgo Trento	Verona		Italy	37126
60	Ospedale civile di Vicenza	Vicenza		Italy	36100