Cisplatin and Radiation Therapy With or Without Erlotinib Hydrochloride in Treating Patients With Stage III or Stage IV Head and Neck Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying cisplatin and radiation therapy together with or without erlotinib hydrochloride to compare how well they work in treating patients with stage III or stage IV head and neck cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also make tumor cells more sensitive to radiation therapy. Giving cisplatin and radiation therapy together with erlotinib hydrochloride may kill more tumor cells. It is not yet known whether cisplatin and radiation therapy are more effective with or without erlotinib hydrochloride in treating head and neck cancer

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the complete response rate in patients with locally advanced head and neck cancer, treated with cisplatin, radiotherapy and erlotinib (erlotinib hydrochloride) versus cisplatin and radiotherapy alone. SECONDARY OBJECTIVES: I. Evaluate whether the addition of erlotinib increases the acute and long term toxicities of cisplatin and radiotherapy, in patients with locally advanced head and neck cancer. II. Compare the disease-free and overall survivals of patients with locally advanced head and neck cancer treated with cisplatin and radiotherapy, with and without erlotinib. III. Evaluate whether the symptomatic improvement observed in the first week of erlotinib alone predicts for complete response and long term disease control. IV. Correlate epidermal growth factor receptor (EGFR), p16 and excision repair cross-complementing 1 (ERCC-1) expression with response outcome to therapy with cisplatin and radiation with and without erlotinib. V. Identify other molecular correlates that may be relevant in the pathogenesis of squamous cell carcinoma of head and neck (SCCHN) or response to therapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cisplatin intravenously (IV) on days 1, 22, and 43 and undergo 3-dimensional conformal or intensity modulated radiotherapy once daily, 5 days per week, on days 1-47. Patients also receive erlotinib hydrochloride orally (PO) once daily (QD) on days -7 to 47. ARM II: Patients receive cisplatin and undergo radiotherapy as in Arm I. Within 10-14 weeks after completion of study treatment, patients with N2 or N3 disease at the time of screening undergo a neck dissection. After completion of study treatment, patients are followed up periodically for 5 years.

Official Title
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Multicenter Randomized Phase II Study of Erlotinib, Cisplatin and Radiotherapy Versus Cisplatin and Radiotherapy in Patients With Stage III and IV Squamous Cell Carcinoma of the Head and Neck

Conditions
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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 Nasopharynx, 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 Nasopharynx, Stage IV Squamous Cell Carcinoma of the Oropharynx

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: cisplatin
* Radiation: 3-dimensional conformal radiation therapy
* Radiation: intensity-modulated radiation therapy
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytological or pathological documented squamous cell carcinoma of oral cavity, oropharynx, larynx, and hypopharynx; patients with nasopharyngeal carcinoma can be included if the patients have grades I or II tumors according to the World Health Organization (WHO) classification Stage III or IV according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Sixth Edition (2002) Unresectable or resection with significant morbidity Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Measurable Disease, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Bilirubin =< 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN Calculated creatinine clearance >= 55ml/min (using the Cockcroft-Gault formula) Platelet count >= 100 x 10^9 /L Absolute neutrophil count (ANC) >= 1.25 x 10^9 /L Signed informed consent Male and female patients with reproductive potential must use an acceptable contraceptive method Authorization from a dentist to begin radiation therapy Exclusion Criteria: Second primary malignancy that is clinically detectable or clinically significant at the time of consideration for study enrollment Inability or unwillingness to comply with radiotherapy Evidence of clinically significant congestive heart failure; patients must be able to tolerate hydration required during cisplatin chemotherapy Diarrhea > grade 1 at the time of enrollment Prior radiotherapy, chemotherapy, or investigational treatment for squamous cell carcinoma of head and neck Prior treatment with an investigational or marketed inhibitor of the EGFR pathway Use of cytochrome P450 3A4 (CYP3A4) inducers Presence of systemic metastases (M1) Pregnant or breast-feeding women Known human immunodeficiency virus (HIV) infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (chemo, radiotherapy, enzyme inhibitor/radiosensitizer)<br>Patients receive cisplatin IV on days 1, 22, and 43 and undergo 3-dimensional conformal or intensity modulated radiotherapy once daily, 5 days per week, on days 1-47. Patients also receive erlotinib hydrochloride PO once daily on days -7 to 47. | Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: OSI-774;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Radiation: 3-dimensional conformal radiation therapy<br>* 35 fractions<br>* Other names: conformal radiation therapy;Radiation: intensity-modulated radiation therapy<br>* 35 fractions<br>* Other names: IMRT;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|
| Active Comparator: Arm II (chemotherapy, radiotherapy)<br>Patients receive cisplatin and radiotherapy as in Arm I. | Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Radiation: 3-dimensional conformal radiation therapy<br>* 35 fractions<br>* Other names: conformal radiation therapy;Radiation: intensity-modulated radiation therapy<br>* 35 fractions<br>* Other names: IMRT;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Percentage of Participants With a Complete Response in Each Treatment Arm | Complete response requires both a pathological complete response (independent of observer) and a complete response radiologically (RECIST 1.0). | 12 weeks after the completion of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Assessed Through Summaries of Adverse Events and Laboratory Test Results by Treatment Arm |  | 30 days after the completion of therapy | 
| Progression Free Survival of Patients With Locally Advanced Head and Neck Cancer Treated With Cisplatin and Radiotherapy, With and Without Erlotinib Hydrochloride | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Every 3 months for up to 5 years |