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

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.

• selenomethionine (Dietary supplement): Given PO
• placebo (Other), also known as PLCB: Given PO
• cisplatin (Drug), also known as CACP, CDDP, CPDD, DDP: Given IV
• radiation therapy (Radiation), also known as irradiation, radiotherapy, therapy, radiation: Undergo radiotherapy
• quality-of-life assessment (Procedure), also known as quality of life assessment: Ancillary studies

Primary outcomes

• Incidence of >= Grade 3 Mucositis [Up to 5 years]: Will be compared as difference in proportions with 95% confidence intervals.

Secondary outcomes

• Tumor Complete Response Rate [Up to 5 years post-treatment]: 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).
• Relapse-free Survival (RFS) [At 1 year]: 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.
• Overall Survival [Up to 5 years post-treatment]: 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.
• Quality of Life [Up to 1 year post-treatment]
• Incidence of Grade 3 or 4 Treatment-related Toxicities, Including Xerostomia [Up to 5 years post-treatment]: Will be compared as difference in proportions with 95% confidence intervals.
• CRT Dose Delivery [Up to 8 weeks]: This characteristic will be included in Cox models.
• Plasma Cisplatin and Selenium PK and PD Markers (NZ Only) [Up to 3 months post-treatment]: 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Incidence of >= Grade 3 Mucositis (Primary)
• Tumor Complete Response Rate (Secondary)
• Relapse-free Survival (RFS) (Secondary)
• Overall Survival (Secondary)
• Quality of Life (Secondary)
• Incidence of Grade 3 or 4 Treatment-related Toxicities, Including Xerostomia (Secondary), Number, number of xerostomia events: Arm I (Placebo, Cisplatin, and Radiotherapy) 1; Arm II (Selenomethionine, Cisplatin, and Radiotherapy) 0
• CRT Dose Delivery (Secondary)
• Plasma Cisplatin and Selenium PK and PD Markers (NZ Only) (Secondary)

Adverse events

Serious adverse events by term

Other adverse events by term

35 more terms not shown.

Limitations and caveats: Due to the study's early termination and inadequate number of patients, no patients were analyzed.

• Anurag Singh, Principal investigator, Roswell Park Cancer Institute