Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
Background: Cisplatin is used to treat head and neck cancer. People who take this drug are at risk for hearing loss. Atorvastatin is a drug used to treat high cholesterol. It might reduce the risk of cisplatin-induced hearing loss. Objective: To find out if atorvastatin reduces hearing loss in people treated with cisplatin and radiation. Eligibility: People ages 18 and older with squamous cell carcinoma of the head and neck who will undergo treatment with cisplatin-based chemotherapy and radiation Design: Participants will be screened with their medical records. Participants currently taking a cholesterol-lowering statin medication are invited to participate in the observational arm of the study. Those not taking such a medication are invited to participate in the interventional arm of the study. All participants will have 2 visits. One before starting cisplatin treatment and within 3 months of completing treatment. They will have tympanograms. A small flexible tip will be placed in the ear canal. A puff of air will be delivered to assess mobility of the ear drum. They will have hearing tests. They will wear headphones. They will listen to tones that vary in loudness. They will be asked to indicate when they hear a sound. Participants in the interventional arm will have 2 additional visits for blood tests. These will occur upon consent and 12 weeks after. They will be randomly assigned to take the study drug or placebo orally, once daily. They will take it during cisplatin treatment and for 3 months after treatment. Long-term follow up will include a chart review 2 years after participants complete their cisplatin therapy.

Detailed Description
-----------------
Study Description: Individuals undergoing cisplatin-based chemoradiation therapy are at risk for developing significant, permanent hearing loss. The cholesterol-lowering drug atorvastatin has the potential to reduce the incidence and severity of hearing loss, as evidenced by our preclinical data in mice and our retrospective data in humans.Here we will compare hearing changes between subjects on a concurrent daily dose of atorvastatin vs. a placebo among individuals undergoing cisplatin therapy to treat head and neck cancer. Objectives: Primary Objective: To determine the effectiveness of atorvastatin (40 mg) at reducing the incidence of a CTCAEv5.0 Grade >=2 hearing loss in patients treated with cisplatin-based CRT for head and neck squamous cell carcinoma (HNSCC). Exploratory Objective: To determine if concomitant atorvastatin (40 mg) use alters disease-free survival or overall survival in subjects undergoing cisplatin-based CRT. Endpoints: Primary Endpoint: The primary endpoint is the change in hearing sensitivity as measured by pure-tone audiometry between the pre-treatment (before cisplatin-based CRT) hearing test and the post-treatment (after completion of cisplatin- based CRT) audiogram. Hearing loss will be defined according to CTCAEv5.0 Grade >=2 criteria and will be compared in subjects taking atorvastatin (40 mg) vs. subjects not taking any statin drug. Hearing sensitivity will be compared between audiograms collected at baseline prior to treatment to a repeated audiogram at the end of treatment within 2-4 months of cessation of cisplatin administration. Exploratory Endpoint: The exploratory endpoint is the overall and disease-free survival at 2 years after cisplatinbased CRT. Overall survival and disease-free median survival will be compared between subjects taking atorvastatin (40 mg) vs. those taking placebo.

Official Title
-----------------
Phase III Interventional Study Using Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer

Conditions
-----------------
Hearing Loss, Head and Neck Cancer

Intervention / Treatment
-----------------
* Drug: Atorvastatin
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria evaluated by the study team, including an on-site oncologist: Willingness and ability to comply with and participate in all study procedures and availability for the duration of the study Ability to provide consent and provision of signed and dated informed consent form Adult patients, male or female, aged >=18 Diagnosed with squamous cell carcinoma of the head and neck, confirmed by a pathologic review of surgical or biopsy specimen(s), who meet standard clinical and laboratory criteria and will undergo treatment with concomitant cisplatin-based chemotherapy and radiation with curative intent. This includes patients who will be treated with either intensity-modulated radiation therapy (IMRT) or proton radiotherapy, with planned dose to the cochlea <35 Gy (to limit confounding effects of radiation 64-67). Patients treated with either high-dose cisplatin (typically 100 mg/m^2 x 2-3 doses every three weeks) or low-dose, weekly cisplatin (typically 40 mg/m^2 x 6-7 doses weekly) may enroll. Subjects must have hearing thresholds at or better than 70 dB HL at 1, 2, and 4 kHz in at least one ear at the time of their baseline audiogram Baseline laboratory tests with lab values <1.5x the upper limit of normal: aspartate aminotransferase (AST or SGOT); alanine aminotransferase; creatine phosphokinase, creatinine Ability to take oral medication by mouth or by feeding tube and willingness to adhere to the daily atorvastatin or placebo regimen For females of reproductive potential: use of highly effective contraception for at least 1 month prior to enrollment and agreement to use such a method during study participation and for an additional 8 weeks after the end of atorvastatin administration EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Patients already taking a statin drug Patients with a flat, Type B tympanogram Patients with bilateral cochlear implants Patients with a history of prior treatment with platinum chemotherapy drugs Patients for whom additional adjuvant platinum-based chemotherapy is planned after the completion of concomitant chemoradiation (e.g., patients with nasopharyngeal carcinoma) Staff members of the NIDCD Sections and of the lead site investigators headed by the PIs Children will be excluded because HNSCC in children under age 18 is exceedingly rare Current use of cimetidine, spironolactone, ketoconazole, cyclosporine, or protease inhibitors Pregnancy, lactation, or plan to become pregnant Known allergic reactions to components of atorvastatin or the placebo Other severe or unstable medical conditions which clinical site PI believes increase risk to safety or ability to complete study Expected concomitant use of aminoglycoside antibiotics

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1<br>randomization to either placebo or atorvastin | Drug: Atorvastatin<br>* For the interventional arm of the study, subjects will be provided with atorvastatin (20 mg) or placebo to be taken daily by mouth or by feeding tube. The tablets may be taken whole or crushed according to patient swallowing capabilities and preference.<br>Other: Placebo<br>* placebo will be formulated to also contain a white powder such that the atorvastatin and placebo are indistinguishable even if a capsule is opened.<br>|
| No Intervention: 2<br>observational | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the effectiveness of atorvastatin (20 mg) at reducing the incidence and severity of cisplatin-induced hearing loss in patients with head and neck squamous cell carcinoma (HNSCC). | The primary endpoint is the change in hearing sensitivity (as measured by pure-tone audiometry) between the pre-treatment (before cisplatin therapy) hearing test and the post-treatment (after completion of cisplatin therapy) audiogram. Hearing loss will be defined according to CTCAE criteria and will be compared in subjects taking atorvastatin vs. subjects not taking any statin drug. Hearing sensitivity will be compared between audiograms collected at baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 2-4 months of cessation of cisplatin administration). | Baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 2-4 months of cessation of cisplatin administration). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To examine the extent to which other statin drugs (and other doses of atorvastatin) reduce the incidence and severity of cisplatin-induced hearing loss in patients with head and neck squamous cell carcinoma | The secondary endpoint is the change in hearing sensitivity (as measured by pure-tone audiometry) between the pre-treatment (before cisplatin therapy) hearing test and the post-treatment (after completion of cisplatin therapy) audiogram in the observational arm of the study. Hearing loss will be defined according to CTCAE criteria and will be compared in subjects taking: 1) any statin other than atorvastatin vs. subjects not taking any statin drug, 2) subjects taking atorvastatin at doses other than 20 mg vs. subjects not taking any statin. Hearing sensitivity will be compared between audiograms collected at baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 4 months of cessation of cisplatin administration). | Baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 4 months of cessation of cisplatin administration). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Audiogram, Statin, Chemotherapy, Squamous Cell Carcinoma