This is a Phase II treatment, randomized 3:1 ratio, open label clinical trial to study the effect of short duration administration of N-acetyl cysteine on oral microbiome and on mucositis caused by concurrent chemotherapy and radiotherapy.
Primary Objective(s) I. To determine whether short duration pre-treatment with N-acetyl cysteine reduces the rate of severe mucositis that develops during the standard concurrent chemoradiotherapy in patients with locally advanced Head and Neck Squamous Cell Cancer. Secondary Objective(s) I. Identify the effect of N-acetyl cysteine on the oral microbiome. II. Identify the effect of short duration pre-treatment with N-acetyl cysteine on the duration and delay onset of severe radiation-induced mucositis developed during the standard concurrent chemoradiotherapy in patients with locally advanced Head and Neck Squamous Cell Cancer. III. Bank saliva and blood for future studies of biomarkers that will be correlated with changes in the oral microbiome and the duration of mucositis. IV. Determine if there is any effect of short duration pre-treatment with N-acetyl cysteine on tumor response to standard CRT as measured within the first year of treatment. V. Determine the relationship between human papillomavirus status and smoking status and the baseline microbiome as well as well as the possible differential effect of N-acetyl cysteine on the structure of the oral microbiome in human papillomavirus positive patients vs smokers. VI. Gather data on the incidence, severity, duration and onset of severe radiation-induced mucositis as well as data on saliva and blood biomarkers and evaluation of the oral microbiome in patients receiving standard of care primary or adjuvant chemoradiotherapy to gather preliminary data for use in designing future Phase 3 studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Treatment will be administered on an outpatient basis, either twice daily or 48 hours prior to starting chemotherapy radiation. Eligible participants will start NAC at least 9 days before definitive or adjuvant radiation therapy.
Participants will receive definitive or adjuvant concurrent chemotherapy and radiotherapy s per standard of care.
Reduction in Severe Mucositis with Pre-treatment N-acetyl cysteine
Severe mucositis will be defined as Grade III or IV mucositis as per WHO OM classification.
Time frame: 3 months post treatment
Effects of N-acetyl cysteine on oral microbiome
Oral microbiome profiling will be determined using 16S rRNA gene sequencing to characterize the bacterial diversity and composition in the saliva collected from participants before and after treatment.
Time frame: At baseline and one year post treatment
Effects of standard of care chemoradiotherapy on oral microbiome
Oral microbiome profiling will be determined using 16S rRNA gene sequencing to characterize the bacterial diversity and composition in the saliva collected from participants before and after treatment.
Time frame: At baseline and one year post treatment
Number of Incidences of Severe Mucositis on N-acetyl cysteine
Time of development of mucositis grade III or above (marked as treatment day) and time of resolution below grade III (marked as post-treatment day) will be recorded and will serve to measure duration and delay onset of severe mucositis. For the time to event data, Kaplan Meier curves will be constructed to determine the median time to occurrence of severe mucositis.
Time frame: One year post treatment
Number of Incidences of Severe Mucositis with Standard of Care Chemoradiotherapy
Time of development of mucositis grade III or above (marked as treatment day) and time of resolution below grade III (marked as post-treatment day) will be recorded and will serve to measure duration and delay onset of severe mucositis
Time frame: One year post treatment
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Number of Participants with Change in Saliva Biomarkers - N-acetyl cysteine
Banked saliva to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of saliva.
Time frame: At baseline and one year post treatment
Number of Participants with Change in Saliva Biomarkers - Standard of Care Chemoradiotherapy
Banked saliva to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of saliva.
Time frame: At baseline and one year post treatment
Number of Participants with Change in Blood Biomarkers - N-acetyl cysteine
Blood samples to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of blood.
Time frame: At baseline and one year post treatment
Number of Participants with Change in Blood Biomarkers - Standard of Care Chemoradiotherapy
Blood samples to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of blood.
Time frame: At baseline and one year post treatment
Tumor Response
Results of standard imaging studies and tumor response or progression will be collected from participant's electronic medical record and compared between participants pre-treated with N-acetyl cysteine and those no treated with N-acetyl cysteine.
Time frame: One year post treatment
Probability in Structure Changes of Microbiomes in Relation to Human Papillomavirus and Smoking Statuses and N-acetyl cysteine
Human papillomavirus status and smoking status at baseline will be examined and microbiome data collected over time will be compared between each group (i.e. smokers vs non-smokers) and (HPV+ vs HPV-) and then with both groups combined (smoker/HPV+, smoker/HPV-, non-smoker/HPV+ and non-smoker/HPV-) for continuous measures that describe the microbiome measures, a repeated measures mixed model will be used to make these comparisons where participants will be considered as random effects and HPV status, smoking status and time (and their interactions) will be considered as fixed effects.
Time frame: One year post treatment