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

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.

• Cisplatin (Drug), also known as Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, Lederplatin, Metaplatin, Neoplatin, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platiran, Platistin, Platosin: Given IV
• Hearing Handicap Inventory for Adults - Screening (Other): Patient self-assessment questionnaire to measure probability of hearing impairment
• Radiation Therapy (Radiation), also known as Cancer Radiotherapy, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, Not otherwise specified (NOS), Radiotherapeutics, Radiotherapy, RT: Radiation therapy will be delivered according to the standard of care
• Sodium Thiosulfate (Drug), also known as Cyanide Antidote Package, Disodium Thiosulfate, S-Hydril, Sodium Hyposulfate, Sodium Thiosulfate Pentahydrate, Sodium Thiosulphate, Sodothiol, Thiosulfate, Sodium, Pentahydrate, Thiosulfuric Acid Disodium Salt: Given IV

Primary outcomes

• Number of Participants Who Successfully Completed Planned Treatment [Up to 7 weeks]: 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.

Secondary outcomes

• Proportion of Participants With Reported High Grade Ototoxicity [Up to 18 weeks]: 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.
• Number of Participants Reporting Tinnitus by Severity [Up to 18 weeks]: The frequency of tinnitus will be measured by participants' worst level response at any time point on the PRO-CTCAE® question "In the last 7 days, what was the severity of ringing in your ears at its worst?". Item responses were categorized as 'None', 'Mild', 'Moderate', 'Severe', and 'Very Severe'.
• Percentage of Participants Reporting Sodium Thiosulfate (STS)-Specific Symptomology [Up to 18 weeks]: The percentage 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.
• Frequency of Hearing Handicap [Up to 18 weeks]: The Hearing Handicap Inventory for Adults -Screener (HHIA-S), is a 10-item, self-assessment screening assessment developed to quickly determine the suggested level of hearing handicap. The participants respond to each of the items with a Yes (score of 4), Sometimes (score of 2), or No (score of 0). Total Scores are then summed for overall score (range 0-40) and then assigned a category for a suggested hearing handicap; 0-8 suggesting no handicap, 10-24 suggesting a mild-moderate handicap, and 26-40 suggesting significant hearing handicap. The frequency of participants for worse reported score will be reported

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. 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
2. Participants must be eligible for cisplatin-based concurrent chemotherapy in conjunction with at least 6 weeks of daily fractionated radiation therapy
3. Age >=18 years
4. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
5. Demonstrates adequate organ function as defined below:

   1. Absolute neutrophil count >= 1,000/microliter (mcL)
   2. Platelets >= 100,000/mcL
   3. Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits
   4. Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) =< 3 X institutional upper limit of normal
   5. Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) =< 3 X institutional upper limit of normal
   6. 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
6. Ability to understand a written informed consent document, and the willingness to sign it
7. 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
8. 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:

1. Participants that are not eligible for cisplatin-based chemoradiation for reasons such as chronic kidney disease, severe hearing loss, and severe peripheral neuropathy
2. Uncontrolled inter-current illness or psychiatric illness/social situation that would limit compliance with study requirements
3. Has known hypersensitivity to cisplatin, sodium thiosulfate or any of its excipients
4. Has profound hearing impairment at baseline and cannot hear a sound below 90 decibels (dB)
5. Participants with uncompensated congestive heart failure New York Heart Association (NYHA) class 3 or above
6. 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
7. 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

Participant flow

Outcome results

• Number of Participants Who Successfully Completed Planned Treatment (Primary), Count of participants, Participants: Cisplatin, Radiotherapy, STS 15
• Proportion of Participants With Reported High Grade Ototoxicity (Secondary), Number, proportion of participants: Cisplatin, Radiotherapy, STS 0.18
• Number of Participants Reporting Tinnitus by Severity (Secondary), Number, participants: Cisplatin, Radiotherapy, STS 4
• Percentage of Participants Reporting Sodium Thiosulfate (STS)-Specific Symptomology (Secondary), Number, percentage of participants: Cisplatin, Radiotherapy, STS 100
• Frequency of Hearing Handicap (Secondary), Count of participants, Participants: Cisplatin, Radiotherapy, STS 11

Adverse events

Time frame: Up to 18 weeks

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2022-09-09)

• Hyunseok Kang, MD, Principal investigator, University of California, San Francisco