Clinical trial NCT01086826: Treatment of Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Head and Neck Squamous Cell Carcinoma
Lead sponsor: Associazione Volontari Pazienti Oncologici
Sponsor class: OTHER
Collaborators: name: Mario Negri Institute for Pharmacological Research
First posted: 2010-03-15
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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).

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.

    -

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

Primary outcomes:
measure: overall survival
timeFrame: 3 years
Secondary outcomes:
measure: progression free survival
timeFrame: 3 years
Other outcomes:
Locations:
city: Feltre
country: Italy
facility: Ospedale "S. Maria Del Prato"
state: Belluno
city: Treviglio
country: Italy
facility: Ospedale Di Treviglio - Caravaggio
state: Bergamo
city: S.Fermo
country: Italy
facility: A.O. Ospedale Sant'Anna
state: Como
city: S. Giovanni Rotondo
country: Italy
facility: IRCCS Casa Sollievo della Sofferenza
state: Foggia
city: San Severino Marche
country: Italy
facility: Ospedale "B.Eustachio" - S.Severino
state: Macerata
city: Monza
country: Italy
facility: H.S. Gerardo dei Tintori
state: Moza-Brianza
city: Camposampiero
country: Italy
facility: Ospedale Di Camposampiero
state: Padova
city: Cittadella
country: Italy
facility: Ospedale Civile di Cittadella
state: Padova
city: Fano
country: Italy
facility: Ospedale Santa Croce Di Fano
state: Pesaro-urbino
city: Pesaro
country: Italy
facility: A.O. "Ospedale S. Salvatore"
state: Pesaro-urbino
city: Castelfranco Veneto
country: Italy
facility: Ospedale Civile di Castelfranco
state: Treviso
city: Latisana
country: Italy
facility: Ospedale Civile di Latisana
state: Udine
city: Tolmezzo
country: Italy
facility: P.O. "S.Antonio Abate"
state: Udine
city: Busto Arsizio
country: Italy
facility: Azienda Ospedaliera Di Circolo
state: Varese
city: Gallarate
country: Italy
facility: Azienda Ospedaliera "S.Antonio Abate"
state: Varese
city: Mestre
country: Italy
facility: "Ospedale dell' Angelo"
state: Venezia
city: Mirano
country: Italy
facility: "Ospedale Civile di Mirano"
state: Venezia
city: Legnago
country: Italy
facility: "AULSS 21 Mater Salutis"
state: Verona
city: Thiene
country: Italy
facility: Ospedale "Boldrini"
state: Vicenza
city: Bari
country: Italy
facility: Istituto tumori "Giovanni Paolo II" IRCCS
city: Belluno
country: Italy
facility: Ospedale S.Martino
city: Bologna
country: Italy
facility: Ospedale Bellaria Di Bologna
city: Bologna
country: Italy
facility: Policlinico S.Orsola-Malpighi
city: Bolzano
country: Italy
facility: Ospedale "S.Maurizio"
city: Brescia
country: Italy
facility: Istituto Clinico S.Anna
city: Cagliari
country: Italy
facility: "Ospedale Businco"
city: Cagliari
country: Italy
facility: Policlinico Universitario
city: Catanzaro
country: Italy
facility: A.O Pugliese-Ciaccio
city: Chieti
country: Italy
facility: Ospedale Clinicizzato Di Chieti
city: Fermo
country: Italy
facility: Ospedale "AUGUSTO MURRI"
city: Ferrara
country: Italy
facility: A.O.Universitaria
city: Lecco
country: Italy
facility: Azienda Ospedaliera "Alessandro Manzoni"
city: Macerata
country: Italy
facility: Ospedale di Macerata
city: Messina
country: Italy
facility: P.O. SAN VINCENZO di Messina
city: Messina
country: Italy
facility: A.O. Universitaria Di Messina
city: Milano
country: Italy
facility: Irccs - Ospedale "S. Raffaele"
city: Milano
country: Italy
facility: "Istituto Europeo di Oncologia"
city: Milano
country: Italy
facility: "Ospedale San Paolo"
city: Milano
country: Italy
facility: A.O. Niguarda-Cà Granda
city: Modena
country: Italy
facility: "A.O. - Policlinico Di Modena"
city: Padova
country: Italy
facility: "Istituto Oncologico Veneto"
city: Palermo
country: Italy
facility: Policlinico Universitario di Palermo
city: Palermo
country: Italy
facility: Casa di Cura "La Maddalena"
city: Parma
country: Italy
facility: A.O.Universitaria "Ospedale Maggiore"
city: Perugia
country: Italy
facility: Osp. S. Maria della Misericordia
city: Piacenza
country: Italy
facility: Ospedale "G. Da Saliceto"
city: Ravenna
country: Italy
facility: Osp. S. Maria Delle Croci
city: Rieti
country: Italy
facility: A.O. "S.Camillo de' Lellis"
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: Ospedale S.Pietro "Fatebenefratelli"
city: Sondrio
country: Italy
facility: Ospedale Civile Di Sondrio
city: Taranto
country: Italy
facility: Osp. S.G. Moscati
city: Trento
country: Italy
facility: Ospedale "S. Chiara"
city: Treviso
country: Italy
facility: Ospedale Ca' Foncello
city: Trieste
country: Italy
facility: "Ospedali Riuniti"
city: Udine
country: Italy
facility: A.O. Santa Maria della Misericordia
city: Varese
country: Italy
facility: Ospedale Di Circolo E Fondazione Macchi
city: Venezia
country: Italy
facility: Ospedale Civile SS Giovanni e Paolo
city: Verona
country: Italy
facility: Ospedale Civile Maggiore Borgo Trento
city: Vicenza
country: Italy
facility: Ospedale civile di Vicenza
Study officials:
affiliation: Ospedale SS Giovanni e Paolo - Venezia, Italy
name: Maria Grazia Ghi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.