Selenomethionine in Reducing Mucositis in Patients With Locally Advanced Head and Neck Cancer Who Are Receiving Cisplatin and Radiation Therapy

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial is studying how well selenomethionine (SLM) works in reducing mucositis in patients with locally advanced head and neck cancer who are receiving cisplatin and radiation therapy. SLM may help prevent or reduce mucositis, or mouth sores, in patients receiving chemotherapy and radiation therapy. It is not yet known whether SLM is more effective than a placebo in reducing mucositis

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To assess whether SLM reduces the incidence of grade 3 or 4 mucositis in head and neck squamous cell carcinoma (HNSCC) patients treated with concurrent chemoradiation (CRT) over 7 weeks. SECONDARY OBJECTIVES: I. To assess the impact of SLM on tumor complete response rate, relapse-free survival, overall survival and quality of life. II. To assess whether SLM reduces the incidence and severity of treatment-related toxicities including xerostomia, renal impairment and myelosuppression. III. To assess whether SLM improves chemoradiation dose delivery. IV. To determine safety of SLM at this dose. V. In New Zealand (NZ) patients only, to assess the impact of SLM on plasma free cisplatin and plasma selenium pharmacokinetics (PK) and on pharmacodynamic (PD) markers of biological activity of selenium. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive placebo orally (PO) twice daily in week 1 and then once daily in weeks 2-11. Patients also receive cisplatin intravenously (IV) over 3 hours once in weeks 2, 5, and 8 and undergo radiotherapy 5 days a week in weeks 2-8. ARM II: Patients receive selenomethionine PO twice daily in week 1 and then once daily in weeks 2-11. Patients also receive cisplatin and undergo radiotherapy as in arm I. After completion of study treatment, patients are followed up periodically.

Official Title
-----------------
Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Phase II Trial of Selenomethionine as a Modulator of Efficacy and Toxicity of Chemoradiation in Locally-Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
-----------------
Chemotherapeutic Agent Toxicity, Mucositis, Radiation Toxicity, 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 III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, 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, Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Xerostomia

Intervention / Treatment
-----------------
* Dietary Supplement: selenomethionine
* Other: placebo
* Drug: cisplatin
* Radiation: radiation therapy
* Procedure: quality-of-life assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Biopsy-proven locally-advanced HNSCC, including those with cancers of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx or paranasal sinuses Stage III, IVa or IVb disease No prior definitive surgery for present diagnosis Appropriate candidate for concurrent cisplatin and radiation as definitive treatment; patients who receive induction chemotherapy as part of a definitive treatment program that will include concurrent CRT are eligible for this study Hemoglobin >= 10 g/dL (100 g/l) Absolute neutrophil count >= 2,000 cells/mm^3 (2 x 10^9/l) Platelets >= 100,000 cells/mm^3 (100 x 10^9/l) Serum creatinine =< 1.5 mg/dL (133 umol/l) or calculated creatinine clearance >= 50 ml/min using the Cockcroft-Gault formula Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Able to give written informed consent Be willing and able to comply with study procedures Exclusion Criteria: Non-regional metastatic disease (stage IVc) Previous malignancy within the last 5 years except for adequately treated basal or squamous cell carcinoma of the skin or cervical intra-epithelial neoplasia Prior chemotherapy or radiotherapy for HNSCC, or any prior radiotherapy that would compromise delivery of a radical dose to the HNSCC Known to be positive for hepatitis C or human immunodeficiency virus (HIV) Unable to tolerate oral medication (unless a feeding tube is in place) History of hypersensitivity to platinum drugs Symptomatic peripheral neuropathy >= National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) grade II Pregnant, lactating or unwilling to use adequate contraception Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation Planned use of amifostine for prophylaxis against radiation-induced xerostomia Patients taking selenium supplements in excess of 100 ug/day Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Evidence of any other significant medical disorder or laboratory finding that in the opinion of the Investigator compromises the subject's safety during the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm I (placebo, cisplatin, and radiotherapy)<br>Patients receive placebo PO twice daily in week 1 and then once daily in weeks 2-11. Patients also receive cisplatin IV over 3 hours once in weeks 2, 5, and 8 and undergo radiotherapy 5 days a week in weeks 2-8. | Other: placebo<br>* Given PO<br>* Other names: PLCB;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|
| Experimental: Arm II (selenomethionine, cisplatin, and radiotherapy)<br>Patients receive selenomethionine PO twice daily in week 1 and then once daily in weeks 2-11. Patients also receive cisplatin and undergo radiotherapy as in arm I. | Dietary Supplement: selenomethionine<br>* Given PO<br>Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of >= Grade 3 Mucositis | Will be compared as difference in proportions with 95% confidence intervals. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Complete Response Rate | Will be compared as difference in proportions with 95% confidence intervals. Disease will be measured according to the Response Evaluation Criteria in Solid Tumors (RECIST). | Up to 5 years post-treatment | 
| Relapse-free Survival (RFS) | Assessed by Kaplan-Meier RFS curves and the proportion with an event at 1 year for RFS will be compared simultaneously to obtain more global sensitivity to differences in time-to-event. | At 1 year | 
| Overall Survival | Estimated using the Kaplan-Meier method. Log-rank tests will be used for the comparison of survival distributions among study groups. Continuous endpoints will be summarized using means, standard deviations and percentiles. | Up to 5 years post-treatment | 
| Quality of Life |  | Up to 1 year post-treatment | 
| Incidence of Grade 3 or 4 Treatment-related Toxicities, Including Xerostomia | Will be compared as difference in proportions with 95% confidence intervals. | Up to 5 years post-treatment | 
| CRT Dose Delivery | This characteristic will be included in Cox models. | Up to 8 weeks | 
| Plasma Cisplatin and Selenium PK and PD Markers (NZ Only) | Descriptive statistics will be used to describe the mean plasma cisplatin and selenium at each time point. Repeated measures analysis of variance will be used to evaluate the changes in plasma cisplatin and selenium over time. Analysis of pharmacodynamic markers will be conducted using statistical methods appropriate for within-patient sequential analyses, such as repeated measures analysis of variance. | Up to 3 months post-treatment |