Overview
- 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 3 study visits for the purpose of evaluating hearing. One before starting cisplatin treatment, one within 3 months of completing cancer treatment, and one within 2 years of completing cancer 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. They will complete 3 questionnaires at the time of each hearing test.
Participants will have 2 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.
Description
Study Description: Individuals undergoing cisplatin-based chemoradiation therapy (CRT) 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 CRT to treat head and neck cancer.
- Objectives
Primary Objective: To determine the effectiveness of atorvastatin (40 mg) in subjects with cisplatin-based CRT 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 CRT.
- 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 CRT 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 CRT). 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 CRT. 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 CRT in the placebo and atorvastatin arms.
- Incidence of hearing loss at 12 +/-4 weeks after completion of cisplatin-based CRT. Hearing loss will be defined according to ASHA Abbreviated Title: Atorvastatin Study in HNSCC Version Date: 1/25/2024 7 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.
Eligibility
- 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, 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:
- Subjects currently taking a statin drug
- Subjects with bilaterial flat, Type B tympanogram
- Subjects with bilateral cochlear implants
- Pre-existing liver or kidney disease.
- Subjects with a history of prior treatment with platinum chemotherapy drugs
- Subjects 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, gemfibrozil, clarithromysin 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