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

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ClinicalTrials.gov Identifier: NCT01086826
Recruitment Status : Completed
First Posted : March 15, 2010
Last Update Posted : January 26, 2015
Sponsor:
Collaborator:
Mario Negri Institute for Pharmacological Research
Information provided by (Responsible Party):
Associazione Volontari Pazienti Oncologici

Tracking Information
First Submitted Date  ICMJE March 12, 2010
First Posted Date  ICMJE March 15, 2010
Last Update Posted Date January 26, 2015
Study Start Date  ICMJE March 2008
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2013)
overall survival [ Time Frame: 3 years ]
overall survival defined as the time from the date of randomization to the date of death from any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2010)
overall survival [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2011)
progression free survival [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2010)
complete response rate, progression-free survival, duration of response, hematological and non-hematological toxicity, duration of radiotherapy plus concomitant chemo or cetuximab. [ Time Frame: 3 anni ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Official Title  ICMJE 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.
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Head and Neck Squamous Cell Carcinoma
Intervention  ICMJE
  • 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 Name: Radiotherapy, Cisplatin, 5-fluoruracil
  • 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 Name: Radiotherapy, Cetuximab
  • 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 Name: Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy
  • 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 Name: Docetaxel. Cisplatin, 5-fluoruracil, Radiotherapy, Cetuximab
Study Arms  ICMJE
  • 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.

    Intervention: Drug: RT+CDDP/5-FU
  • 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.

    Intervention: Drug: RT+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

    Intervention: Drug: INDUCTION CTx(TPF)+(RT+CDDP/5-FU)
  • 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.

    Intervention: Drug: INDUCTION CTx(TPF)+(RT+CETUXIMAB)
Publications * Ghi MG, Paccagnella A, Ferrari D, Foa P, Alterio D, Codecà C, Nolè 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 23, 2011)
320
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2010)
250
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01086826
Other Study ID Numbers  ICMJE H&N07
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Associazione Volontari Pazienti Oncologici
Study Sponsor  ICMJE Associazione Volontari Pazienti Oncologici
Collaborators  ICMJE Mario Negri Institute for Pharmacological Research
Investigators  ICMJE
Principal Investigator: Maria Grazia Ghi, MD Ospedale SS Giovanni e Paolo - Venezia, Italy
PRS Account Associazione Volontari Pazienti Oncologici
Verification Date June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP