Cetuximab and Radiation Therapy in Treating Patients With Stage III-IV Head and Neck Cancer

Study Overview
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Brief Summary
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This pilot clinical trial studies cetuximab and radiation therapy in treating patients with stage III-IV head and neck cancer. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cetuximab or cisplatin together with radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. 2 year (yr) locoregional control in cetuximab responders. SECONDARY OBJECTIVES: I. Assess secondary clinical endpoints such as the percent of patients receiving neoadjuvant cetuximab who progress by computed tomography (CT) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria during the neoadjuvant cetuximab, the 2 yr locoregional control for non-responders to neoadjuvant cetuximab, and the complete response rate to positron emission tomography (PET)/computed tomography (CT) scan 3 months after the completion of radiation therapy for both responders and for non-responders to neoadjuvant cetuximab. II. Analyze the relationship of known deoxyribonucleic acid (DNA) mutations in tumor per the FoundationOne genomic profile, and correlate to clinical endpoints such as locoregional control. II. Analyze any changes in protein production at the tumor in response to 3 weeks of cetuximab. III. Analyze any changes in protein production at the skin in response to 3 weeks of cetuximab. IV. To investigate whether the tumor imaging characteristics including anatomical and molecular parameters evaluated by PET/CT, either alone or combined with other biomarkers can attribute to the better prediction for the clinical outcomes, as the response to neoadjuvant cetuximab; and the final clinical endpoint, the 2-year local regional controls. OUTLINE: Patients receive cetuximab intravenously (IV) over 60-120 minutes for 3 weeks. Patients then undergo external beam radiation therapy (EBRT) over 6-7 weeks. Patients achieving response continue weekly doses of cetuximab until radiation therapy is completed. Patients unable to achieve response or progression receive cisplatin IV over 1-2 hours on days 1, 22, and 43 of radiation therapy. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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Selecting for Cetuximab Responders in Advanced Head and Neck SCC

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 Oropharynx, Stage III Verrucous Carcinoma of the Larynx, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IVA Squamous Cell Carcinoma of the Larynx, Stage IVA Squamous Cell Carcinoma of the Oropharynx, Stage IVA Verrucous Carcinoma of the Larynx, Stage IVB Squamous Cell Carcinoma of the Larynx, Stage IVB Squamous Cell Carcinoma of the Oropharynx, Stage IVB Verrucous Carcinoma of the Larynx, Tongue Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: cisplatin
* Radiation: external beam radiation therapy
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven squamous cell carcinoma of the oropharynx, hypopharynx or larynx Stage III/IVa/b squamous cell carcinoma (SCC) by American Joint Committee on Cancer (AJCC) 7 criteria (advanced, but not metastatic) Patients must give informed consent Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Platelets >= 100,000/uL Absolute neutrophil count (ANC) >= 1,500/uL Hemoglobin > 8 g/dl (use of transfusion to achieve this is acceptable) Total bilirubin < 2 X institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional ULN Serum creatinine < 2 x institutional ULN or creatinine clearance > 50 ml/min as determined by 24 hour collection or estimated by Cockcroft-Gault formula Estimated life expectancy of at least 12 weeks Negative pregnancy test Exclusion Criteria: Patients may not have received previous therapy for their head and neck SCC, including chemotherapy, radiation therapy, or surgery beyond biopsy Second primary malignancy; exceptions are 1) patient had a second primary malignancy but has been treated and disease free for at least 3 years, 2) in situ carcinoma (e.g. in situ carcinoma of the cervix), 3) non-melanomatous carcinoma of the skin Patients with metastatic disease beyond the neck and supraclavicular region will be excluded Serious concomitant systemic disorders (including active infections) that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; this includes scleroderma History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab or cisplatinum or other agents used in the study Women who are pregnant; women of childbearing age must agree to undergo a pregnancy test prior to therapy and to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 6 months after; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patients with human immunodeficiency virus (HIV) infection are not automatically excluded, but must meet the following criteria: cluster of differentiation (CD)4 count is > 499/cu mm and their viral load is < 50 copies/ml; use of highly active anti-retroviral therapy (HAART) is allowed Patients who have had either myocardial infarction, coronary artery bypass graft, coronary artery stenting, hospital admission for heart related issues such as congestive heart failure or arrhythmia within the last 3 months, will not be allowed on protocol Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events [CTCAE], version [v]. 4): Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention to normalize levels Potassium < 3.5 mmol/L or > 6 mmol/L despite intervention to normalize levels Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cetuximab, cisplatin, EBRT)<br>Patients receive cetuximab IV over 60-120 minutes for 3 weeks. Patients then undergo EBRT over 6-7 weeks. Patients achieving response continue weekly doses of cetuximab until radiation therapy is completed. Patients unable to achieve response or progression receive cisplatin IV over 1-2 hours on days 1, 22, and 43 of radiation therapy. | Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Radiation: external beam radiation therapy<br>* Undergo EBRT<br>* Other names: EBRT;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Control in Cetuximab Responders | Target number of patients for the study was 27. At the termination of the study, 8 patients were accrued and finished treatment but 1 patient dropped out before follow up, leaving an evaluable number of 7. As the enrollment in the study did not reach the target number of patients, we were not able to produce statistically reliable results to detect the expected difference. Therefore, we have decided to provide summary statistics of primary and secondary outcomes. Among 3 cetuximab responders, two did not have progression within 2 year follow-up time and one had a locoregional recurrence and expired. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients Who Progress During Neoadjuvant Cetuximab by CT RECIST 1.1 Criteria | Among 7 patients, no one progressed during neoadjuvant cetuximab per RECIST 1.1 CT criteria (0%). | Day 14-21 after the first dose of cetuximab | 
| Locoregional Control for Non-responders to Neoadjuvant Cetuximab | Among 4 cetuximab non-responders, none had locoregional failure at 2 years. Two patients had known HPV status; one patient was HPV+ and another patient HPV-. HPV status for the other two was unknown. HPV positive patient had no sign of progression within 2 years of follow-up. HPV negative patient had no sign of progression for 210 days until the last follow-up. One HPV unknown patient did not show progression within 2 years of follow-up, and the other HPV unknown patient had no progression for 115 days until the last follow-up. | 2 years |