Combination Chemotherapy and Radiation in Treating Patients With Stage III or IV Head and Neck Cancer (Paradigm Trial)

• ClinicalTrials.gov Identifier: NCT00095875
• Recruitment Status: Completed
• First Posted: November 9, 2004
• Results First Posted: July 2, 2013
• Last Update Posted: November 19, 2013
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Robert I. Haddad, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: November 9, 2004
• First Posted Date: November 9, 2004
• Results First Submitted Date: May 15, 2013
• Results First Posted Date: July 2, 2013
• Last Update Posted Date: November 19, 2013
• Study Start Date: August 2004
• Actual Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2013)

Overall Survival [ Time Frame: 3-years ]

To compare the 3-year survival achieved by docetaxel/cisplatin/5-FU based sequential therapy with platinum based chemo radiotherapy in patients with locally advanced SCCHN. Overall survival is defined as the time from date of randomisation to death from any cause. Patients alive at the time of current analysis were censored at the date last known to be alive.Kaplan-Meier method was used to estimate overall survival

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: May 15, 2013)

Progression-free Survival and Disease-specific Survival as Assessed by Disease Progression or Death and Log Rank Tests at the Median, and 2, 3, and 5 Years [ Time Frame: 5 years ]

Progression free survival was defined as the time from date of randomisation to disease progression or death from any cause without progression whichever occurred first; otherwise, patients were censored at the date last known to be free of progression.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combination Chemotherapy and Radiation in Treating Patients With Stage III or IV Head and Neck Cancer (Paradigm Trial)
• Official Title: A Randomized Phase III Comparing Sequential Therapy With TPF/Chemoradiation (ST) To Cisplatinum-Based Chemoradiotherapy [PARADIGM TRIAL]

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, fluorouracil, and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. It is not yet known which regimen of chemotherapy and radiation therapy is most effective in treating head and neck cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different regimens of chemotherapy and radiation therapy in treating patients who have stage III or stage IV head and neck cancer.

Detailed Description

OBJECTIVES:

Primary

• Compare 3-year survival of patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck treated with induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil followed by radiotherapy and carboplatin or docetaxel vs radiotherapy and cisplatin only.

Secondary

• Compare 2-year progression-free status in patients treated with these regimens.
• Compare 5-year survival of patients treated with these regimens.
• Compare 3- and 5-year progression-free survival of patients treated with these regimens.
• Compare the complete response rate in patients treated with these regimens.
• Compare tumor site-specific survival in patients treated with these regimens.
• Compare functional organ preservation in patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.
• Correlate tissue and germline markers with response, local/regional control, and the development of distant metastases in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.
• Arm II: Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.

Quality of life is assessed at baseline and then at 3, 12, and 24 months.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 330 patients will be accrued for this study.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Head and Neck Cancer

Intervention

• Drug: carboplatin
  Given IV
  Other Name: Paraplatin
• Drug: cisplatin
  Given IV
  Other Name: Platinol
• Drug: docetaxel
  Given IV
  Other Name: Taxotere
• Drug: fluorouracil
  Given IV
  Other Name: Efudex

Study Arms

• Experimental: Arm I
  Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.
  Interventions:

  • Drug: carboplatin
  • Drug: cisplatin
  • Drug: docetaxel
  • Drug: fluorouracil
• Experimental: Arm II
  Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks.
  Intervention: Drug: cisplatin

• Publications *: Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. doi: 10.1016/S1470-2045(13)70011-1. Epub 2013 Feb 13.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 15, 2013): 145
• Original Enrollment: Not Provided
• Actual Study Completion Date: April 2012
• Actual Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

List of Inclusion Criteria:

• Histologically or cytologically confirmed squamous cell carcinoma of the head and neck

  • Stage III or IV* disease

  • One of the following primary tumor sites:

    • Oral cavity

      • No mandible invasion
    • Oropharynx
    • Hypopharynx
    • Larynx

  • The following primary tumor sites are excluded:

    • Nasal cavity
    • Paranasal cavity
    • Nasopharynx NOTE: *No evidence of distant metastases by chest x-ray, abdominal ultrasound, or CT scan (for patients with liver function test abnormalities) or bone scan (for patients with local symptoms)
• At least 1 uni- or bi-dimensionally measurable lesion

PATIENT CHARACTERISTICS:

Age

• Over 18

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• Neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 10 g/dL

Hepatic

• Bilirubin normal
• AST or ALT within eligibility range
• Alkaline phosphatase within eligibility range

Renal

• Creatinine clearance > 60 mL/min

Cardiovascular

• No unstable cardiac disease despite treatment
• No myocardial infarction within the past 6 months

Pulmonary

• No chronic obstructive pulmonary disease, defined as requiring hospitalization for pneumonia or respiratory decompensation within the past year

  • Obstruction caused by the tumor allowed

Neurologic

• No symptomatic peripheral neuropathy > grade 2
• No symptomatic altered hearing > grade 2
• No history of significant neurologic or psychiatric disorders, including dementia or seizures

Other

• No active drug addiction, including alcohol, cocaine, or intravenous drugs within the past 6 months
• No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or other cancer curatively treated by surgery alone
• No active, clinically significant, uncontrolled infection
• No autoimmune disease requiring therapy
• No unhealed or clinically active peptic ulcer disease
• No hypercalcemia
• No other serious illness or medical condition
• No involuntary weight loss > 25% of body weight within the past 2 months
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• No prior organ transplantation

• No prior surgery for this cancer

  • Biopsy allowed

Other

• More than 30 days since prior participation in another investigational study
• No other concurrent anticancer therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, United States

Administrative Information

• NCT Number: NCT00095875
• Other Study ID Numbers: DFCI 04-006; P30CA006516 ( U.S. NIH Grant/Contract ); CDR0000393548 ( Registry Identifier: NCI PDQ )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Robert I. Haddad, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Not Provided
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Robert I. Haddad, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: October 2013