Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Radiation Therapy and Combination Chemotherapy in Treating Patients With Stage III or Stage IV Head and Neck Cancer

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Stanford University
ClinicalTrials.gov Identifier:
NCT00002774
First received: April 6, 2000
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

PURPOSE: Randomized phase 2 trial to compare the effectiveness of chemo-radiation therapy (RT + cisplatin + 5-FU) with or without tirapazamine for the treatment of patients with stage III or IV squamous cell carcinomas of the head and neck cancer (SCCHN).

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Radiation therapy uses high-energy x-rays to damage tumor cells.

Tirapazamine may increase the effectiveness of chemotherapy and radiation therapy by making tumor cells more sensitive to therapy.


Condition Intervention Phase
Squamous Neck Carcinoma of the Head and Neck Cancer (SCCHN)
Drug: Tirapazamine
Drug: Cisplatin
Drug: 5-fluorouracil
Radiation: Radiotherapy (RT)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Official Title: Randomized Phase 2 Trial of Tirapazamine and the Role of Tumor Hypoxia in Advanced Squamous Head and Neck Cancer

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Complete response rate (CRR) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Compare the CRR following CRT with or without tirapazamine in patients with squamous cell carcinoma of the head and neck.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    Survival was assessed at 5 years post-treatment.

  • Cause-specific survival (CSS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    CSS is also known as disease-specific survival (DSS), and in this study represents cancer survival from diagnosis until death due to cancer, in the absence of other causes of death. All other causes of death are censored.

  • Rate of freedom from recurrence (FFR) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    FFR is the period until first treatment failure, and typically includes failure to achieve CR, but does not include deaths.


Enrollment: 63
Study Start Date: June 1996
Study Completion Date: June 2005
Primary Completion Date: June 2000 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tirapazamine + cisplatin + 5-FU
2 cycles of induction chemotherapy (tirapazamine, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (tirapazamine, cisplatin, and 5-FU)
Drug: Tirapazamine

Tirapazamine is a benzotriazine with selective cytotoxicity for hypoxic cells. Under hypoxic conditions, it undergoes a 1-electron reduction to form a cytotoxic free radical that poisons topoisomerase II and causes DNA breaks, chromosomal aberrations, and cell death.

Tirapazamine was administered on Days 1 and 22 prior to the administration of neoadjuvant cisplatin and on Days 43, 45, 47, 71, 73, and 75 within 1 or 2 hours prior to each simultaneous cisplatin dose.

Tirapazamine dose was as follows:

Level 1 - 300 mg/m2 during the induction phase and 160 mg/m2 during the simultaneous phase (n = 4)

Level 2 - 330 mg/m2 during the induction phase and 260 mg/m2 during the simultaneous phase (n = 4)

Level 3 - 300 mg/m2 during the induction phase and 220 mg/m2 during the simultaneous phase (n = 25)

Other Names:
  • Tirazone
  • TPZ
  • SR 4233
  • 3-amino-1,4-benzotriazine-1-N-oxide
  • WIN 59074
Drug: Cisplatin
The simultaneous chemoradiotherapy (CRT) regimen included cisplatin 20 mg/m2 administered 3 times per week.
Other Names:
  • Cisplatinum
  • Cis-diamminedichloroplatinum(II)
  • CDDP
Drug: 5-fluorouracil

100 mg/m2 per day on Days 1 and 22, and continuous infusion (CI) 5-FU at a dose of 1000 mg/m2 per day for 120 hours per cycle starting on Days 1 and 22.

The simultaneous chemoradiotherapy (CRT) regimen included continuous infusion (CI) 5-FU 600 mg/m2 per day for 96 hours per cycle in Weeks 1 and 5 of RT.

Other Name: 5-FU
Radiation: Radiotherapy (RT)

During the CRT regimen, RT was given within 3 hrs of the tirapazamine infusion. The dose for the parallel opposed fields was 2 Gy/fraction/day given 5 dys/week up to a total dose of 66-70 Gy at the target lesion. The dose to the supraclavicular region was 50 Gy at a depth of 3 cm, delivered in 25 fractions. Supervoltage photons (≥4 megavolts) were used to treat both locations.

After 50 Gy were delivered to the primary site and regional lymph nodes, all sites were reassessed for clinical response by physical exam, direct fiber optic evaluation, and radiographic imaging (CT or MRI).

Subjects with a CR at both the primary site and the neck completed RT treatment to a total dose ≥66 Gy to the primary site and the involved lymph node(s). Subjects with a CR at the primary site but a partial response (PR) at the neck completed RT treatment to the primary site followed by neck dissection. Subjects with a PR at the primary site stopped radiation at 50 Gy and underwent salvage surgery.

Active Comparator: Cisplatin + 5-FU
2 cycles of induction chemotherapy (cisplatin + 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (cisplatin + 5-FU)
Drug: Cisplatin
The simultaneous chemoradiotherapy (CRT) regimen included cisplatin 20 mg/m2 administered 3 times per week.
Other Names:
  • Cisplatinum
  • Cis-diamminedichloroplatinum(II)
  • CDDP
Drug: 5-fluorouracil

100 mg/m2 per day on Days 1 and 22, and continuous infusion (CI) 5-FU at a dose of 1000 mg/m2 per day for 120 hours per cycle starting on Days 1 and 22.

The simultaneous chemoradiotherapy (CRT) regimen included continuous infusion (CI) 5-FU 600 mg/m2 per day for 96 hours per cycle in Weeks 1 and 5 of RT.

Other Name: 5-FU
Radiation: Radiotherapy (RT)

During the CRT regimen, RT was given within 3 hrs of the tirapazamine infusion. The dose for the parallel opposed fields was 2 Gy/fraction/day given 5 dys/week up to a total dose of 66-70 Gy at the target lesion. The dose to the supraclavicular region was 50 Gy at a depth of 3 cm, delivered in 25 fractions. Supervoltage photons (≥4 megavolts) were used to treat both locations.

After 50 Gy were delivered to the primary site and regional lymph nodes, all sites were reassessed for clinical response by physical exam, direct fiber optic evaluation, and radiographic imaging (CT or MRI).

Subjects with a CR at both the primary site and the neck completed RT treatment to a total dose ≥66 Gy to the primary site and the involved lymph node(s). Subjects with a CR at the primary site but a partial response (PR) at the neck completed RT treatment to the primary site followed by neck dissection. Subjects with a PR at the primary site stopped radiation at 50 Gy and underwent salvage surgery.


Detailed Description:

Subjects were stratified according to pO2 values (high vs low), and randomized to 1 of 2 treatment arms, differing by the addition of tirapazamine to the therapeutic regimen. Treatment consists of two 21-day cycles of induction chemotherapy, followed by radiotherapy (RT).

Induction chemotherapy was cisplatin 100 mg/m2 per day administered over 4 hours on Study Days 1 and 22 (ie, 1st day of both induction cycles) with continuous infusion (CI) 5-FU at a dose of 1000 mg/m2 per day for 120 hours per cycle starting on Study Days 1 and 22 (ie, days 1 to 5 of both induction cycles).

Patients who achieve at least partial response proceeded to chemoradiotherapy (CRT) consisting of localized RT + cisplatin IV + 5-FU +/- tirapazamine. Location of RT was based on whether the site had a CR or PR. Radiotherapy began on day 43 (week 1), and continued for 5.5 weeks. Subjects with no response or progressive disease proceeded to salvage surgery.

A total of 63 patients were accrued for this study over approximately 5 years. 1 subject withdrew consent prior to treatment for personal reasons.

  Eligibility

Ages Eligible for Study:   17 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

Biopsy proven squamous cell carcinoma of the following head and neck sites:

Hypopharynx Oral cavity Larynx Oropharynx Nasal cavity Unknown primary Paranasal sinus

Histologically proven poorly-differentiated carcinoma of the following head and neck sites:

Hypopharynx Oral cavity Larynx Oropharynx Nasal cavity Paranasal sinus Stage III/IV (T0-4 N1-3 M0-2) disease

PATIENT CHARACTERISTICS:

WBC at least 3,000/mm3 Bilirubin no greater than 2.0 mg/dL AST no greater than 100 U/L Creatinine no greater than 2.0 mg/dL Creatinine clearance at least 60 mL/min (patients in Group N2-N3) No second malignancy within 5 years except curatively treated nonmelanomatous skin carcinoma No prior RT or chemotherapy, except prior radiotherapy to primary tumor allowed Not pregnant or nursing. Negative pregnancy test required Effective contraception required of fertile women Subjects with unknown primary cancers who had metastatic cervical lymph nodes are eligible Signed informed consent previously approved by the Institutional Review Board.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00002774

Locations
United States, California
Veterans Affairs Medical Center - Palo Alto
Palo Alto, California, United States, 94304
Stanford University Medical Center
Stanford, California, United States, 94305-5408
Sponsors and Collaborators
Stanford University
Investigators
Study Chair: Harlan A. Pinto, MD Stanford University
  More Information

Additional Information:
Publications:
Responsible Party: Stanford University
ClinicalTrials.gov Identifier: NCT00002774     History of Changes
Other Study ID Numbers: IRB-12503, CA67166, NCI-T94-0119O, CDR0000064752, SQL 72951
Study First Received: April 6, 2000
Last Updated: June 19, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Stanford University:
stage III
stage IV
recurrent

Additional relevant MeSH terms:
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Carcinoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Neoplasms, Squamous Cell
Cisplatin
Fluorouracil
Tirapazamine
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014