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

Sponsor

National Institute on Deafness and Other Communication Disorders (NIDCD) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT04915183

Collaborator

(none)

414

Enrollment

Location

Arms

Anticipated Duration (Months)

10.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hearing Loss Head and Neck Cancer	Drug: Atorvastatin Other: Placebo	Phase 3

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 (Interventional Arm): To determine the effectiveness of atorvastatin (20 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).

Secondary Objective (Observational Arm): To examine the extent to which subjects taking other statin drugs (and other doses of atorvastatin) exhibit reduced incidence CTCAEv5.0 grade >=2 hearing loss in patients treated with cisplatin-based CRT for head and neck squamous cell carcinoma (HNSCC).

Tertiary Objectives (Interventional Arm): To determine if concomitant atorvastatin (20 mg) use alters disease-free survival or overall survival in subjects undergoing cisplatin therapy.

Endpoints:

Primary Endpoint (Interventional Arm): 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 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.

Secondary Endpoints (Observational Arm): The secondary 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 (within 2-4 months of cessation of cisplatin administration) audiogram in the observational arm of the study. Hearing loss will be defined according to CTCAEv5.0 Grade >=2 criteria and will be compared in subjects taking:

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 2-4 months of cessation of cisplatin administration.

Tertiary Endpoint (Interventional Arm): The tertiary endpoint is the overall survival and disease-free survival at 2 years after cisplatin therapy. Overall survival and disease-free survival will be compared between subjects taking atorvastatin (20 mg) vs. those not taking any statin.

Study Population: Up to 414 adult male and female patients newly diagnosed with head and neck squamous cell carcinoma scheduled to undergo cisplatin-based chemotherapy with concurrent radiation. Subjects will be recruited from 3-4 U.S.-based sites.

Phase: Phase 3

Description of Sites/Facilities Enrolling Participants: Multi-institutional study including

U.S.-based cancer centers providing standard-of-care therapy for in head and neck cancer:

Wilmot Cancer Institute at the University of Rochester Medical Center in New York, the Winship Cancer Institute at Emory University in Georgia, and possibly the University of Maryland Medical Center in Maryland.

Description of Study Intervention: Multi-institutional study including U.S.-based cancer centers providing standard-of-care therapy for in head and neck cancer: National Institutes of Health

(NIH) Clinical Center, Wilmot Cancer Institute at the University of Rochester Medical Center in New York, the Winship Cancer Institute at Emory University in Georgia, and possibly the University of Maryland Medical Center in Maryland.

Study Duration: 48 months of active study enrollment + 2 years to obtain follow-up survival data.

Participant Duration: 7 months with up to 2 year follow up.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

414 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Aug 30, 2022

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Other: 1 randomization to either placebo or atorvastin	Drug: Atorvastatin 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. Other: Placebo placebo will be formulated to also contain a white powder such that the atorvastatin and placebo are indistinguishable even if a capsule is opened.
No Intervention: 2 observational

Arm

Intervention/Treatment

Other: 1

randomization to either placebo or atorvastin

Drug: Atorvastatin

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.

Other: Placebo

placebo will be formulated to also contain a white powder such that the atorvastatin and placebo are indistinguishable even if a capsule is opened.

No Intervention: 2

observational

Outcome Measures

Primary Outcome Measures

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). [Baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 2-4 months of cessation of cisplatin administration).]
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).

Secondary Outcome Measures

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 [Baseline (prior to treatment) to a repeated audiogram at the end of treatment (within 4 months of cessation of cisplatin administration).]
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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

In order to be eligible to participate in either the observational or interventional arms of this study, an individual must meet all of the following criteria as 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
Adult patients, male or female, aged >=18
Diagnosed with squamous cell carcinoma of the head and neck, confirmed by pathologic review of surgical or biopsy specimen(s), who meets 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 of <35 Gy (to limit confounding effects of radiation).
Subjects must have hearing thresholds at or better than 70 dB SPL at 1, 2, and 4 kilohertz (kHz) at the time of their baseline audiogram.
Ability to provide consent and provision of signed and dated informed consent form

In order to be eligible to participate in the interventional arm of this study, an individual must meet all of the

following criteria:

Baseline laboratory tests in the following range: aspartate aminotransferase (AST or SGOT); alanine aminotransferase; creatine phosphokinase, creatinine <1.5x ULN.
Ability to take oral medication by mouth or by feeding tube 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.

The investigators will attempt to enroll subjects of diverse race, gender and age. However, our ability to do this will be limited by the demographics of patients typically diagnosed with HNSCC. There is a male predominance, and patients tend to be in their 5th to 7th decades of life ("Cancer of the Oral Cavity and Pharynx - Cancer Stat Facts," n.d.).

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in the observational or interventional arms of this study:

Patients with a Type B tympanogram.
Patients with bilateral cochlear implants will be excluded.
Patients with a history of prior treatment with platinum chemotherapy drugs will be excluded.
Patients for whom additional adjuvant platinum-based chemotherapy is planned after the completion of concomitant chemoradiation (e.g., patients with nasopharyngeal carcinoma) will be excluded.
Staff members of the NIDCD Sections and of the lead site investigators that are headed by the PI and LAI will be excluded.
Children will be excluded because HNSCC in children under age 18 is exceedingly rare.

An individual who meets any of the following criteria will be excluded from participation in the interventional arm of this study:

Current use of cimetidine, spironolactone, ketoconazole, cyclosporine, or protease inhibitors for HIV or hepatitis C
Pregnancy, lactation, or plan to become pregnant
Known allergic reactions to components of atorvastatin or the placebo
Other severe or unstable medical conditions for which clinical site PI believes increase risk to safety or being able to complete study.