Atorvastatin to Reduce Cisplatin-Induced Hearing Loss in Head and Neck Cancer Patients

项目摘要 顺铂是一种广泛使用的有效药物，用于治疗各种癌症。顺铂有几个 显著的副作用，包括永久性听力损失（耳毒性），这降低了癌症的生活质量 幸存者和剂量限制。对于减少顺铂诱导的听力损失而不损害顺铂的治疗效果的疗法，存在主要未满足的临床需求。Our published work in动物 模型表明，他汀类药物，一类FDA批准的药物，通常用于管理 高胆固醇血症，降低顺铂引起听力损失。人类接受治疗的回顾性数据 顺铂疗法治疗头颈部鳞状细胞癌（HNSCC）表明， 与未服用任何他汀类药物的患者相比，阿托伐他汀显著降低了顺铂引起的听力损失 药本研究是一项多中心、随机、安慰剂对照的干预性试验，旨在确定 阿托伐他汀降低头颈癌患者顺铂诱导的听力损失的程度。作为 我们的主要目的是确定阿托伐他汀在多大程度上降低了 HNSCC患者中顺铂引起的听力损失。既往未经治疗的HNSCC受试者， 计划进行基于顺铂的放化疗（CRT）且尚未服用他汀类药物的患者， 在整个CRT期间，随机接受每日口服阿托伐他汀（40 mg）或安慰剂。基线测听 将在顺铂治疗开始前测量阈值，并在完成所有周期后3个月再次测量阈值 顺铂主要结局是CTCAEv5.0 2级听力损失发生率的差异， 比较服用阿托伐他汀与服用安慰剂的受试者的基于顺铂的CRT。作为次要 目的：我们将评估阿托伐他汀组和安慰剂组在患者报告结局方面的差异 关注整体生活质量、听力、平衡、耳鸣和周围神经病变。作为探索性 目的：我们将评估他汀类药物是否影响HNSCC患者的生存率。将对受试者随访 CRT后2年，以估计2年总体和无病生存率。

PROJECT SUMMARY Cisplatin is a widely-used and effective drug that is used to treat a variety of cancers. Cisplatin has several significant side effects, including permanent hearing loss (ototoxicity), which reduces quality of life for cancer survivors and can be dose limiting. There is a major unmet clinical need for therapies that reduce cisplatin-induced hearing loss without compromising the therapeutic efficacy of cisplatin. Our published work in animal models suggests that statins, a class of FDA-approved drugs that are commonly used to manage hypercholesterolemia, reduce cisplatin-induced hearing loss. Retrospective data in humans undergoing cisplatin therapy to treat head and neck squamous cell carcinoma (HNSCC) indicate that subjects taking atorvastatin had significantly reduced cisplatin-induced hearing loss compared to those not taking any statin drug. This study is a multi-site, randomized, placebo-controlled interventional trial designed to determine the extent to which atorvastatin reduces cisplatin-induced hearing loss in patients with head and neck cancer. As primary objective, we will determine the extent to which atorvastatin reduces the incidence and severity of cisplatin-induced hearing loss in patients with HNSCC. Subjects with previously untreated HNSCC who are scheduled for cisplatin-based chemoradiation therapy (CRT) and are not already taking a statin will be randomized to receive either oral atorvastatin (40 mg) or placebo daily throughout CRT. Baseline audiometric thresholds will be measured prior to onset of cisplatin therapy and again 3 months after completion of all cycles of cisplatin. The primary outcome is the difference in incidence of a CTCAEv5.0 Grade 2 hearing loss following cisplatin-based CRT comparing subjects taking atorvastatin vs. those taking a placebo. As a secondary objective, we will assess for differences between atorvastatin and placebo groups in patient-reported outcomes focusing on overall quality of life, hearing, balance, tinnitus, and peripheral neuropathy. As an exploratory objective, we will estimate whether statins affect survival in patients with HNSCC. Subjects will be followed for two years after CRT to estimate 2-year overall and disease-free survival.