Sodium Thiosulfate in Preventing Ototoxicity for Squamous Cell Cancer Patients Undergoing Chemoradiation With Cisplatin

Study Overview
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Brief Summary
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This phase II trial investigates how well sodium thiosulfate works in preventing ototoxicity (hearing loss/damage) in patients with squamous cell cancer of the head and neck that has spread to nearby tissue or lymph nodes (locally advanced) who are undergoing a chemoradiation. Sodium thiosulfate is a type of medication used to treat cyanide poisoning and to help lessen the side effects from cisplatin. Chemotherapy drugs, 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 chemotherapy with radiation therapy may kill more tumor cells. The purpose of this trial is to find out whether it is feasible to give sodium thiosulfate 4 hours after each cisplatin infusion along with standard of care radiation therapy in patients with head and neck cancer. Giving sodium thiosulfate after cisplatin may help decrease the risk of hearing loss.

Detailed Description
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PRIMARY OBJECTIVE: I. To establish feasibility of intravenous sodium thiosulfate (STS) after each dose of concurrent cisplatin in patients with locally advanced head and neck squamous cell carcinoma undergoing definitive radiotherapy. SECONDARY OBJECTIVES: I. To determine the rate of grade >= 2 hearing impairment based on Common Terminology Criteria for Adverse Events (CTCAE) version 5 with use of STS after concurrent chemoradiation with cisplatin 3 months post-treatment. II. To determine the rate of tinnitus measured by Patient Reported Outcomes (PRO)-CTCAE with use of STS 3 months post-treatment. III. To describe patient reported outcomes with STS measured with PRO-CTCAE for selected oral, gastrointestinal (GI), neurologic and perceptual symptoms. IV. To describe patient reported outcomes measured with Hearing Handicap Inventory for Adults - Screening (HHIA-S) compared to results from standard NRG Oncology head and neck trials (such as Radiation Therapy Oncology Group (RTOG) 1016). OUTLINE: Patients undergo standard of care radiation therapy in combination with cisplatin therapy for up to 6-7 weeks. Cisplatin treatment repeats weekly for up to 7 cycles, or every 21 days for up to 3 cycles. After each cisplatin infusion, patients also receive an infusion of sodium thiosulfate. The dosing schedule for cisplatin will be at the discretion of the treating physician. After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Official Title
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A Phase II Study of Sodium Thiosulfate (STS) for Prevention of Ototoxicity in Patients With Locally Advanced Squamous Cell Carcinoma of Head and Neck (SCCHN) Undergoing Concurrent Chemoradiation With Cisplatin

Conditions
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Clinical Stage III Human Papillomavirus (HPV)-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Locally Advanced Head and Neck Squamous Cell Carcinoma, Locally Advanced Hypopharyngeal Squamous Cell Carcinoma, Locally Advanced Laryngeal Squamous Cell Carcinoma, Locally Advanced Oral Cavity Squamous Cell Carcinoma, Locally Advanced Oropharyngeal Squamous Cell Carcinoma, Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Stage III Hypopharyngeal Carcinoma AJCC v8, Stage III Laryngeal Cancer AJCC v8, Stage III Lip and Oral Cavity Cancer AJCC v8, Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IV Hypopharyngeal Carcinoma AJCC v8, Stage IV Laryngeal Cancer AJCC v8, Stage IV Lip and Oral Cavity Cancer AJCC v8, Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVA Hypopharyngeal Carcinoma AJCC v8, Stage IVA Laryngeal Cancer AJCC v8, Stage IVA Lip and Oral Cavity Cancer AJCC v8, Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVB Hypopharyngeal Carcinoma AJCC v8, Stage IVB Laryngeal Cancer AJCC v8, Stage IVB Lip and Oral Cavity Cancer AJCC v8, Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVC Hypopharyngeal Carcinoma AJCC v8, Stage IVC Laryngeal Cancer AJCC v8, Stage IVC Lip and Oral Cavity Cancer AJCC v8, Stage IVC Oropharyngeal (p16-Negative) Carcinoma AJCC v8

Intervention / Treatment
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* Drug: Cisplatin
* Other: Hearing Handicap Inventory for Adults - Screening
* Radiation: Radiation Therapy
* Drug: Sodium Thiosulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have histologically or cytologically confirmed locoregionally advanced squamous cell carcinomas of mucosal surfaces of head and neck who are being treated with concurrent chemoradiation with cisplatin Participants must be eligible for cisplatin-based concurrent chemotherapy in conjunction with at least 6 weeks of daily fractionated radiation therapy Age >=18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%) Demonstrates adequate organ function as defined below: Absolute neutrophil count >= 1,000/microliter (mcL) Platelets >= 100,000/mcL Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) =< 3 X institutional upper limit of normal Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) =< 3 X institutional upper limit of normal Creatinine =< 1.5 x within institutional upper limit of normal OR creatinine clearance glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2, calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 Ability to understand a written informed consent document, and the willingness to sign it Individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial The effects of sodium thiosulfate (STS) on the developing human fetus are unknown. For this reason and because cisplatin used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception such as hormonal and/or barrier method of birth control for the duration of study participation and for 3 months after last administration of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after last administration of study treatment Exclusion Criteria: Participants that are not eligible for cisplatin-based chemoradiation for reasons such as chronic kidney disease, severe hearing loss, and severe peripheral neuropathy Uncontrolled inter-current illness or psychiatric illness/social situation that would limit compliance with study requirements Has known hypersensitivity to cisplatin, sodium thiosulfate or any of its excipients Has profound hearing impairment at baseline and cannot hear a sound below 90 decibels (dB) Participants with uncompensated congestive heart failure New York Heart Association (NYHA) class 3 or above Participants who cannot get secure venous access using either a Mediport or a peripherally inserted central catheter (PICC) line for safe administration of intravenous sodium thiosulfate Pregnant women are excluded from this study because cisplatin is a cytotoxic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cisplatin or sodium thiosulfate, breastfeeding should be discontinued if the mother is treated with either agent

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cisplatin, Radiotherapy, STS<br>Patients undergo standard of care radiation therapy daily in combination with cisplatin on day 1. Between 4-5 hours after each cisplatin infusion, patients also receive sodium thiosulfate over 1-2 hours on day 1. Treatment will continue on either a 1 week or 3 week cycle per physician discretion for up to 6-7 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Hearing Handicap Inventory for Adults - Screening<br>* Patient self-assessment questionnaire to measure probability of hearing impairment<br>Radiation: Radiation Therapy<br>* Radiation therapy will be delivered according to the standard of care<br>* Other names: RT;Drug: Sodium Thiosulfate<br>* Given IV<br>* Other names: Thiosulfuric Acid Disodium Salt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who successfully completed planned treatment | Evaluated as the successful completion of at least 5 weekly cisplatin or 2 high dose cisplatin without any extended treatment related delays more than 7 days. Overall successful completion is defined as completion by at least 75% of patients. | Up to 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with reported high grade ototoxicity | The proportion of participants with a reported change of grade >= 2 hearing impairments based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (for patients on a monitoring program with audiogram) will be reported with 95% confidence intervals. | Up to 18 weeks | 
| Proportion of participants reporting tinnitus by severity | The frequency of tinnitus will be measured by participant responses on the PRO-CTCAE® question In the last 7 days, what was the SEVERITY of RINGING IN YOUR EARS at its WORST?. Responses are categorized and will be reported as 'None', 'Mild', 'Moderate', 'Severe', and 'Very Severe'. | Up to 18 weeks | 
| Proportion of participants reporting STS-specific symptomology | The proportion of participants reporting STS specific adverse events will be measured by affirmative responses on the PRO-CTCAE® on any of the selected oral, gastrointestinal, neurologic and visual/perceptual symptoms | Up to 18 weeks | 
| Mean Scores on then Hearing Handicap Inventory for Adults - Screening (HHIA-S) | The Hearing Handicap Inventory for Adults (HHIA), is a 25-item self-assessment scale composed of two subscales (emotional and social/situational) and a total score. The Participants respond to each items with a Yes (4), Sometimes (2), or No (0). Scores are then summed and divided by the total points possible for overall (100), the social subscale (48) and then Emotional subscale (52). The scores are then reported as a percentage ranging from 0-100, with scores of 0%-16% = No handicap, 18%-42%= Mild-Moderate handicap, and 44% and higher indicating a significant handicap. | Up to 18 weeks |