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A Phase I Study Of ZD 1839 In Combination With Radiation And Chemotherapy In Locally Advanced Squamous Cell Carcinoma Of The Head And Neck


Phase 1
18 Years
N/A
Not Enrolling
Both
Stage III Squamous Cell Carcinoma of the Hypopharynx, Stage III Squamous Cell Carcinoma of the Larynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IV Squamous Cell Carcinoma of the Larynx, Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IV Squamous Cell Carcinoma of the Oropharynx

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Trial Information

A Phase I Study Of ZD 1839 In Combination With Radiation And Chemotherapy In Locally Advanced Squamous Cell Carcinoma Of The Head And Neck


PRIMARY OBJECTIVES:

I. To establish the safety profile of daily oral administration of ZD1839 ("Iressa",
AstraZeneca, Inc.) that can be given with concurrent irradiation alone or combined
concurrently with weekly cisplatin in previously untreated patients with locally advanced
HNSCC, AJCC clinical stage III-IVB, deemed not suitable for surgery. Hence, the
maximum-tolerated dose of ZD1839 will be determined.

II. To delineate and quantitate any dose-dependent local and or systemic toxicities of
ZD1839 given concurrently with irradiation or combined concurrently with weekly cisplatin to
patients with locally advanced, HNSCC, AJCC stage III-IVB, deemed not suitable for surgery.

III. To determine the feasibility and toxicity profile of protracted continuous daily dosing
of ZD1839 beginning 8 weeks after the completion of the head and neck radiation therapy for
a period not to exceed 2 years.

SECONDARY OBJECTIVES:

I. Secondary endpoints will include determination of the response rates, relapse-free
survival rates and overall survival rates for this group of patients.

II. To perform correlative studies assessing the biological effects of ZD1839 within the
primary tumor.

OUTLINE: This is a multicenter, dose-escalation study of gefitinib.

All patients receive oral gefitinib once daily beginning at least 7 days before and
continuing throughout radiotherapy or chemoradiotherapy in the absence of disease
progression or unacceptable toxicity. Patients are entered into 1 of 5 levels.

Level I: Patients undergo concurrent boost radiotherapy 5 days per week comprising once
daily radiotherapy for 3.5 weeks followed by twice daily radiotherapy for 2.5 weeks.

Level II: Patients receive escalated dose of gefitinib and undergo radiotherapy as in level
I.

Level III: Patients receive original dose of gefitinib, undergo standard fractionation
radiotherapy comprising once daily radiotherapy 5 days per week for 7 weeks, and receive
cisplatin IV over 30-60 minutes at the beginning of each week of radiotherapy.

Level IV: Patients receive escalated dose of gefitinib as in level II and undergo
radiotherapy and chemotherapy as in level III.

Level V: Patients receive the maximum tolerated dose (MTD) of gefitinib, radiotherapy 5 days
a week for 6 weeks, and chemotherapy as in level III.

Patients with clinical or radiologic evidence of residual disease are required to undergo
neck dissection approximately 8 weeks after completion of radiotherapy or chemoradiotherapy.

Patients resume oral gefitinib daily beginning 8 weeks after the completion of radiotherapy
or chemoradiotherapy (12 weeks for patients who undergo neck dissection) and continuing for
2 years in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients are enrolled sequentially beginning at level I until the MTD of
gefitinib is determined. The MTD is the dose preceding that at which at least 2 of 6
patients experience dose-limiting toxicity.

Twelve additional patients receive the MTD of gefitinib in combination with radiotherapy
with or without cisplatin.

Patients are followed every 6 months for at least 5 years.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.


Inclusion Criteria:



- Histologically confirmed locally advanced squamous cell carcinoma of the head and
neck involving the oral cavity, oropharynx, hypopharynx, or supraglotticor glottic
larynx

- Unresectable disease

- Medically inoperable resectable disease allowed

- Stage III or IV

- No distant metastases

- Only patients with intermediate stage disease (T1-2, N1-N2a or T3, N0-1) are eligible
for radiotherapy alone with gefitinib

- Performance status - ECOG 0-2

- Performance status - Karnofsky 60-100%

- More than 6 months

- WBC at least 3,000/mm^3

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 9 g/dL

- Bilirubin normal

- AST and ALT no greater than 2.5 times upper limit of normal

- Creatinine normal

- Creatinine clearance at least 60 mL/min

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No cardiac arrhythmia

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Medically suitable to withstand a course of definitive radiotherapy

- No ongoing or active infection

- No other malignancy within the past 3 years except basal cell skin cancer or
carcinoma in situ of the cervix

- No prior allergic reactions to compounds of similar chemical or biological
composition to gefitinib or other study agents

- No uncontrolled concurrent medical or psychiatric illness or social situation that
would preclude study participation

- No prior monoclonal antibodies with potential epidermal growth factor receptor (EGFR)
binding therapy

- No prior chemotherapy

- No prior radiotherapy

- No prior surgery except biopsy

- No prior anti-EGFR therapy including prior tyrosine kinase inhibitors

- No concurrent combination anti-retroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No other concurrent commercial or investigational agents or therapies intended to
treat the malignancy

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of grade 4 or greater mucositis as scored by the National Cancer Institute (NCI) Common Toxicity Criteria v2.0

Outcome Description:

Descriptive statistics (mean, median, range, standard deviation [s.d.], percentage, as appropriate) will be obtained.

Outcome Time Frame:

Up to 2 years

Safety Issue:

No

Principal Investigator

David Raben

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado, Denver

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02462

NCT ID:

NCT00033449

Start Date:

February 2002

Completion Date:

Related Keywords:

  • Stage III Squamous Cell Carcinoma of the Hypopharynx
  • Stage III Squamous Cell Carcinoma of the Larynx
  • Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage III Squamous Cell Carcinoma of the Oropharynx
  • Stage IV Squamous Cell Carcinoma of the Hypopharynx
  • Stage IV Squamous Cell Carcinoma of the Larynx
  • Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IV Squamous Cell Carcinoma of the Oropharynx
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms
  • Laryngeal Diseases
  • Hypopharyngeal Neoplasms
  • Laryngeal Neoplasms
  • Oropharyngeal Neoplasms

Name

Location

University of ColoradoDenver, Colorado  80217