Induction Chemotherapy Followed By Cetuximab and Radiation in HPV-Associated Resectable Stage III/IV Oropharynx Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high energy x-rays to kill tumor cells. Giving paclitaxel, cisplatin, and cetuximab together with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy in treating patients with HPV-associated stage III or stage IV cancer of the oropharynx that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To evaluate the efficacy of induction therapy comprising paclitaxel, cisplatin, and cetuximab followed by cetuximab in combination with low-dose or standard-dose intensity-modulated radiotherapy, as measured by 2-year progression-free survival (PFS), in patients with human papillomavirus(HPV)-associated resectable stage III-IVB squamous cell carcinoma of the oropharynx. Secondary To assess overall survival. To evaluate the objective response, local control, and metastatic rate. To evaluate early and late toxicities of treatment. Tertiary To evaluate quality of life and speech and swallowing function as measured by Functional Assessment of Cancer Therapy - General (FACT-G), Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), and Vanderbilt Head and Neck Symptom Survey (VHNSS). To assess the effect of treatment-induced fatigue on general physical functioning in patients with head and neck cancer. To correlate functional decline with clinical, physical, and biologic correlatives. To evaluate radiation-resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and to correlate them with treatment efficacy. To demonstrate the usefulness of biomarkers, including ERCC1, epidermal growth factor receptor (EGFR), cytokine and chemokine markers, and plasma transforming growth factor alpha (TGFA) and transforming growth factor beta (TGFB) levels, in predicting progression-free survival (PFS) and other outcome parameters. To evaluate the correlation between the efficacy of cetuximab and polymorphisms in FcγR-receptors. To evaluate functional outcome and biological parameters, including telomere length, angiotensin-converting enzyme polymorphism, and C-reactive protein level. OUTLINE: This is a multicenter study. Induction therapy: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and paclitaxel IV over 3 hours and cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for 3 courses. Patients then undergo evaluation of response to induction therapy. Patients with a clinical complete response (CR) at the primary tumor site proceed to group 1 of concurrent radiotherapy and cetuximab. Patients with a clinical partial response (PR) or stable disease (SD) at the primary tumor site or those with grossly positive disease at the primary tumor site proceed to group 2 of concurrent radiotherapy and cetuximab. Concurrent radiotherapy and cetuximab: Treatment begins 14-21 days after the last day of induction therapy. Group 1 (CR): Patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. Group 2 (PR, SD, or grossly positive disease): Patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks. Patients complete questionnaires assessing fatigue, physical function, weight loss, quality of life, head and neck symptom burden, and speech and swallowing function at baseline and at 1, 6, 12, and 24 months after completion of study treatment. Tumor tissue and serum samples may be collected periodically for correlative laboratory studies. After completion of study treatment, patients are followed up periodically for 3 years. PROJECTED ACCRUAL: 83 patients

Official Title
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A Phase II Trial of Induction Chemotherapy Followed by Cetuximab (Erbitux) With Low Dose vs. Standard Dose IMRT in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx

Conditions
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Head and Neck Cancer, Precancerous Condition

Intervention / Treatment
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* Biological: cetuximab
* Radiation: intensity-modulated radiation therapy (IMRT)
* Drug: Paclitaxel
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed squamous cell carcinoma of the oropharynx as determined by Hematoxylin and eosin (H&E) staining Newly diagnosed disease Resectable disease OR disease that is expected to become resectable after study treatment Stage III, IVA, or IVB disease as determined by imaging studies (computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI) required) and a complete head and neck exam Paraffin-embedded tumor specimen available for central confirmation of HPV-associated disease as determined by H&E staining and in-situ hybridization (ISH) for HPV-16 and immunohistochemistry (IHC) for p16 HPV-associated disease is defined as p16 IHC-positive and/or HPV-16 ISH-positive Non-HPV-associated disease is defined as p16 IHC-negative NOTE: If there is limited tumor material, p16 IHC will be performed before HPV-16 ISH Measurable disease of the primary tumor or nodes by clinical and radiographic methods, defined as a lesion that is ≥ 2 cm in at least one dimension by clinical exam AND by radiographic exam with CT scan or MRI (or a lesion that is ≥ 1 cm in at least one dimension if the radiographic exam utilizes spiral CT scan) No primary tumor or nodal metastasis fixed to the carotid artery, skull base, or cervical spine No evidence of distant metastases Eastern Cooperative Oncology Group performance status 0-1 Granulocytes ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Total serum bilirubin ≤ 1.5 mg/dL Creatinine clearance ≥ 60 mL/min Negative pregnancy test Fertile patients must use effective contraception No history of another malignancy (except for carcinoma in situ of the cervix and/or nonmelanomatous skin cancer) unless it has been curatively treated and the patient has been disease-free for ≥ 2 years Patients with any of the following within the past 6 months are eligible provided they have been evaluated by a cardiologist and/or neurologist before study entry: New York Heart Association (NYHA) class III-IV congestive heart failure Cerebrovascular accident or transient ischemic attack Unstable angina Myocardial infarction (with or without ST elevation) Exclusion Criteria: Prior chemotherapy Prior radiotherapy above the clavicles Prior surgery with curative intent for this disease (complete head and neck exam with biopsy allowed) Prior therapy specifically and directly targeting the EGFR pathway Prior severe infusion reaction to a monoclonal antibody Uncontrolled diabetes, uncontrolled infection despite antibiotics, or uncontrolled hypertension within the past 30 days Concurrent illness likely to interfere with study therapy or to prevent surgical resection Pregnant or nursing

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>After induction therapy with Paclitaxel and Cisplatin, patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. | Biological: cetuximab<br>* Given IV<br>Radiation: intensity-modulated radiation therapy (IMRT)<br>* Patients undergo low-dose OR standard dose IMRT based on their clinical response to induction therapy<br>Drug: Paclitaxel<br>* Given IV, 90 mg/m^2 on days 1, 8 and 15<br>* Other names: Abraxane, Taxol;Drug: Cisplatin<br>* Given IV, 75 mg/m^2 on day 1<br>* Other names: Platinol;|
| Experimental: Group 2<br>After induction therapy with Paclitaxel and Cisplatin, patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks. | Biological: cetuximab<br>* Given IV<br>Radiation: intensity-modulated radiation therapy (IMRT)<br>* Patients undergo low-dose OR standard dose IMRT based on their clinical response to induction therapy<br>Drug: Paclitaxel<br>* Given IV, 90 mg/m^2 on days 1, 8 and 15<br>* Other names: Abraxane, Taxol;Drug: Cisplatin<br>* Given IV, 75 mg/m^2 on day 1<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-month Progression-free Survival | 24-month progression-free survival is defined as the proportion of patients who were alive and progression-free at 24 months post registration. The primary study population for this endpoint is patients who were confirmed post-induction clinical complete response (CR) at their primary sites and subsequently received 5400 cGy radiation therapy to their primary sites. | assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-months Overall Survival | OS was defined as the time from registration to death, or censored at last date known alive. Kaplan-Meier method was used to estimate the overall survival rate at 24 months. | assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry | 
| Primary Clinical Response Rate | Primary clinical response rate is defined as the proportion of patients with complete response or partial response at their primary sites after induction therapy. Response status for the primary site was classified by clinical examination using endoscopy. If, however, the clinical response status of the primary was unclear based on endoscopy, then the CT or MRI (required at the end of induction) was used to determine status of the primary. If clinical and radiological evaluation of the primary was unclear, a biopsy was considered at the discretion of the treating physician. | assessed within 14 days after delivery of the third cycle of induction therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human papilloma virus infection, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, tongue cancer