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

Study Description: Individuals undergoing cisplatin-based chemotherapy 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 40 mg daily dose of atorvastatin vs. a placebo among individuals undergoing cisplatin-based chemotherapy to treat head and neck cancer.

Objectives:

Primary Objective: To determine the effectiveness of atorvastatin (40 mg) in subjects treated with cisplatin-based chemotherapy for head and neck squamous cell carcinoma (HNSCC) at reducing moderate changes in hearing sensitivity relative to baseline, as defined by CTCAEv5.0 Grade>=2 criteria.

Secondary Objectives:

• To determine disease-free survival and overall survival in subjects undergoing cisplatin-based chemotherapy.
• To determine whether atorvastatin increases grade 3-5 treatment emergent adverse events versus placebo
• To determine the effectiveness of atorvastatin (40 mg) at reducing changes in hearing sensitivity relative to baseline, as defined by ASHA criteria, in subjects treated with cisplatin- based chemotherapy for head and neck squamous cell carcinoma (HNSCC).

Endpoints:

Primary Endpoint: The incidence of hearing loss at 12 +/-4 weeks after completion of cisplatin-based chemotherapy). Hearing loss will be defined according to CTCAEv5.0 Grade >=2 criteria based on changes in sensitivity relative to baseline, in at least one ear, across 1, 2, 3, 4, 6 and 8 kHz and will be compared in subjects taking atorvastatin (40 mg) vs. subjects taking placebo.

Secondary Endpoints:

• Overall and disease-free survival at 2 years after cisplatin-based chemotherapy. Overall survival and disease-free median survival will be compared between subjects taking atorvastatin (40 mg) vs. those taking placebo.
• Incidence of new CTCAEv5.0 grade > 3 AEs through 12 weeks after chemotherapy in the placebo and atorvastatin arms.
• Incidence of hearing loss at 12 +/- 4 weeks after completion of cisplatin-based chemotherapy. Hearing loss will be defined according to ASHA criteria based on changes in sensitivity relative to baseline, in at least one ear, across 1, 2, 3, 4, 6, 8, 10, and 12.5 kHz and will be compared in subjects taking atorvastatin (40 mg) vs. subjects taking placebo.

• 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 subjects, 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 or treatment with neoadjuvant chemotherapy (NAC). This includes subjects 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 radiation64-67). Patients receiving immunotherapy in addition to cisplatin chemoradiation are eligible. Subjects 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. Cisplatin in the neo-adjuvant setting may be given within a combination chemotherapy regimen (e.g TPF= Docetaxel, Cisplatin and 5FU or DC = Docetaxel Cisplatin)
• 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. CTCAE criteria (primary endpoint) and ASHA criteria (secondary endpoint) are based on changes in hearing in at

least one ear with one ototoxicity event/grade assigned per person.

• 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:

• Subjects currently taking a statin drug
• Subjects with bilateral flat, Type B tympanogram
• Subjects with bilateral cochlear implants
• Pre-existing liver or kidney disease that in the opinion of the investigator would interfere with taking Atorvastatin 40 mg daily.
• Subjects with a history of prior treatment with cisplatin chemotherapy
• 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, protease inhibitors, gemfibrozil, clarithromycin or itraconazole
• 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