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

NCT ID: NCT01086826

Last Updated: 2015-01-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 320 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2014-12-31

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.

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).

Conditions

Head and Neck Squamous Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

RT+CDDP/5-FU

Intervention Type: DRUG

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:

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.

Group Type: EXPERIMENTAL

RT+CETUXIMAB

Intervention Type: DRUG

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, 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

Group Type: ACTIVE_COMPARATOR

INDUCTION CTx(TPF)+(RT+CDDP/5-FU)

Intervention Type: DRUG

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)

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.

Group Type: EXPERIMENTAL

INDUCTION CTx(TPF)+(RT+CETUXIMAB)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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)

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Radiotherapy, Cisplatin, 5-fluoruracil; Radiotherapy, Cetuximab; Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy; Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy, Cetuximab

Eligibility Criteria

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.

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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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mario Negri Institute for Pharmacological Research

OTHER

Sponsor Role: collaborator

Associazione Volontari Pazienti Oncologici

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Maria Grazia Ghi, MD

Role: PRINCIPAL_INVESTIGATOR

Ospedale SS Giovanni e Paolo - Venezia, Italy

Locations

Istituto tumori "Giovanni Paolo II" IRCCS

Bari, Bari, Italy

Ospedale S.Martino

Belluno, Belluno, Italy

Ospedale "S. Maria Del Prato"

Feltre, Belluno, Italy

Ospedale Di Treviglio - Caravaggio

Treviglio, Bergamo, Italy

Ospedale Bellaria Di Bologna

Bologna, Bologna, Italy

Policlinico S.Orsola-Malpighi

Bologna, Bologna, Italy

Ospedale "S.Maurizio"

Bolzano, Bolzano, Italy

Istituto Clinico S.Anna

Brescia, Brescia, Italy

"Ospedale Businco"

Cagliari, Cagliari, Italy

Policlinico Universitario

Cagliari, Cagliari, Italy

A.O Pugliese-Ciaccio

Catanzaro, Catanzaro, Italy

Ospedale Clinicizzato Di Chieti

Chieti, Chieti, Italy

A.O. Ospedale Sant'Anna

S.Fermo, Como, Italy

Ospedale "AUGUSTO MURRI"

Fermo, Fermo, Italy

A.O.Universitaria

Ferrara, Ferrara, Italy

IRCCS Casa Sollievo della Sofferenza

S. Giovanni Rotondo, Foggia, Italy

Azienda Ospedaliera "Alessandro Manzoni"

Lecco, Lecco, Italy

Ospedale di Macerata

Macerata, Macerata, Italy

Ospedale "B.Eustachio" - S.Severino

San Severino Marche, Macerata, Italy

P.O. SAN VINCENZO di Messina

Messina, Messina, Italy

A.O. Universitaria Di Messina

Messina, Messina, Italy

Irccs - Ospedale "S. Raffaele"

Milan, Milano, Italy

"Istituto Europeo di Oncologia"

Milan, Milano, Italy

"Ospedale San Paolo"

Milan, Milano, Italy

A.O. Niguarda-Cà Granda

Milan, Milano, Italy

"A.O. - Policlinico Di Modena"

Modena, Modena, Italy

H.S. Gerardo dei Tintori

Monza, Moza-Brianza, Italy

Ospedale Di Camposampiero

Camposampiero, Padova, Italy

Ospedale Civile di Cittadella

Cittadella, Padova, Italy

"Istituto Oncologico Veneto"

Padua, Padova, Italy

Policlinico Universitario di Palermo

Palermo, Palermo, Italy

Casa di Cura "La Maddalena"

Palermo, Palermo, Italy

A.O.Universitaria "Ospedale Maggiore"

Parma, Parma, Italy

Osp. S. Maria della Misericordia

Perugia, Perugia, Italy

Ospedale Santa Croce Di Fano

Fano, Pesaro-urbino, Italy

A.O. "Ospedale S. Salvatore"

Pesaro, Pesaro-urbino, Italy

Ospedale "G. Da Saliceto"

Piacenza, Piacenza, Italy

Osp. S. Maria Delle Croci

Ravenna, Ravenna, Italy

A.O. "S.Camillo de' Lellis"

Rieti, Rieti, Italy

Istituto Nazionale Tumori Regina Elena

Roma, Roma, Italy

Ospedale S.Pietro "Fatebenefratelli"

Roma, Roma, Italy

Ospedale Civile Di Sondrio

Sondrio, Sondrio, Italy

Osp. S.G. Moscati

Taranto, Taranto, Italy

Ospedale "S. Chiara"

Trento, Trento, Italy

Ospedale Civile di Castelfranco

Castelfranco Veneto, Treviso, Italy

Ospedale Ca' Foncello

Treviso, Treviso, Italy

"Ospedali Riuniti"

Trieste, Trieste, Italy

Ospedale Civile di Latisana

Latisana, Udine, Italy

P.O. "S.Antonio Abate"

Tolmezzo, Udine, Italy

A.O. Santa Maria della Misericordia

Udine, Udine, Italy

Azienda Ospedaliera Di Circolo

Busto Arsizio, Varese, Italy

Azienda Ospedaliera "S.Antonio Abate"

Gallarate, Varese, Italy

Ospedale Di Circolo E Fondazione Macchi

Varese, Varese, Italy

"Ospedale dell' Angelo"

Mestre, Venezia, Italy

"Ospedale Civile di Mirano"

Mirano, Venezia, Italy

Ospedale Civile SS Giovanni e Paolo

Venezia, Venezia, Italy

"AULSS 21 Mater Salutis"

Legnago, Verona, Italy

Ospedale Civile Maggiore Borgo Trento

Verona, Verona, Italy

Ospedale "Boldrini"

Thiene, Vicenza, Italy

Ospedale civile di Vicenza

Vicenza, Vicenza, Italy

Countries

Italy

References

Ghi MG, Paccagnella A, Ferrari D, Foa P, Alterio D, Codeca C, Nole F, Verri E, Orecchia R, Morelli F, Parisi S, Mastromauro C, Mione CA, Rossetto C, Polsinelli M, Koussis H, Loreggian L, Bonetti A, Campostrini F, Azzarello G, D'Ambrosio C, Bertoni F, Casanova C, Emiliani E, Guaraldi M, Bunkheila F, Bidoli P, Niespolo RM, Gava A, Massa E, Frattegiani A, Valduga F, Pieri G, Cipani T, Da Corte D, Chiappa F, Rulli E; GSTTC (Gruppo di Studio Tumori della Testa e del Collo) Italian Study Group. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol. 2017 Sep 1;28(9):2206-2212. doi: 10.1093/annonc/mdx299.

Reference Type: DERIVED

PMID: 28911070 (View on PubMed)

Other Identifiers

H&N07

Identifier Type: -

Identifier Source: org_study_id