Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Participants must meet the following criteria on screening examination to be eligible to participate in the study: Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, 或通过检测NF2基因的致病突变. 美国国立卫生研究院的标准包括:

• 双侧前庭神经鞘瘤
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
• 以下两种:神经纤维瘤, meningioma, glioma, schwannoma, 幼年后囊下晶状体混浊. 曼彻斯特标准包括:
• 双侧前庭神经鞘瘤 First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR - 以下两种:神经纤维瘤, meningioma, glioma, schwannoma, 少年后囊下透镜状混浊或
• 单侧前庭神经鞘瘤和神经纤维瘤中的任意两种, meningioma, glioma, schwannoma, 幼年后囊下晶状体混浊, OR
• Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR
• 任意两种:神经鞘瘤，神经胶质瘤，神经纤维瘤，白内障. 患者必须有进展性和可测量的疾病, 定义为至少一个具有以下品质的VS:
• ≥ 0.75 ml (on volumetric analysis) that can be accurately measured by contrast-enhanced cranial MRI scan with fine cuts through the internal auditory canal (1 mm slices, no skip)
• MRI evidence of progression over the past 18 months (defined as ≥20% annualized increase in volume) 治疗第1天年龄≥6岁. 寿命大于1年. Lansky/Karnofsky性能状态≥60 器官和骨髓功能定义如下:
• 绝对中性粒细胞计数≥1500 / μl
• 血小板≥100,000/ μl
• 总胆红素≤1.5倍的制度上限为正常
• Ast (sgot)/ alt (sgpt)≤2.5倍的制度上限为正常
• 患者必须有肌酐清除率或放射性同位素GFR≥60ml/min/1.73≥60毫升/分钟/ 1.73 m2 or a normal serum creatinine based on age/gender described in the table below:
• Age: 6 to < 10 years with a Maximum Serum Creatinine (mg/dL) of 1 for Male and 1 for Female
• Age: 10 to < 13 years with a Maximum Serum Creatinine (mg/dL) of 1.男性2人，男性1人.女性2名
• Age: 13 to < 16 years with a Maximum Serum Creatinine (mg/dL) of 1.男性5人，男性1人.女性4
• 年龄:≥16岁，最大血清肌酐(mg/dL)为1.男性7人，男性1人.女性4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC. 完全从先前任何化疗的急性毒性作用中恢复, 生物调节剂或放疗 任何神经功能缺损必须稳定≥1周 Patient or parent/legal guardian must be able to provide signed informed consent and assent (as applicable for minors)

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study. Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy and molecular targeted agents), 因为这些可能会干扰研究药物 Monoclonal antibody treatment and/or agents with prolonged half-lives: At least three half-lives must have elapsed from the last dose prior to enrollment Radiation therapy to a study target tumor within 1 year prior to enrollment, 或在入组前4周内接受任何放射治疗, 因为这些可能会干扰我们评估对研究药物反应的能力 Prior treatment with any investigational drug within the preceding 4 weeks, 因为它们可能会干扰研究药物 不稳定的或迅速发展的疾病, including patients who require glucocorticoids for symptomatic control of brain or spinal tumors, as this would represent a high risk for inability to comply with the study requirements 使用已知有效的CYP3A4抑制剂的药物或食物, 包括但不限于酮康唑, 伊曲康唑, miconazole, 克拉霉素, 红霉素, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, 还有葡萄柚汁, 因为这会干扰药物代谢的研究 使用已知强效CYP3A4诱导剂的药物, 包括但不限于卡马西平, 苯巴比妥, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. 约翰的麦汁，因为这会干扰研究药物代谢 使用治疗指标较窄的CYP3A4底物药物, 包括但不限于吡莫胺, 阿立哌唑, triazolam, 双氢麦角胺, ergotamine, astemizole, cisapride, 特非那定和氟化茴香碱, 因为这会干扰药物代谢的研究 持续的心律失常，CTCAE分级≥2级, uncontrolled atrial fibrillation of any grade or prolonged QTc interval (>480 msec), as patients with these conditions would be expected to have an increased risk for cardiac toxicity related to study drug Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• 有充血性心力衰竭的症状 of New York heart Association Class III or IV
• 不稳定型心绞痛, 有充血性心力衰竭的症状, 研究药物开始后6个月内心肌梗死, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
• active (acute or chronic) or uncontrolled severe infections liver disease, 如肝硬化或严重肝功能损害(Child-Pugh C级) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of crizotinib (e.g., 溃疡性疾病, 不受控制的恶心, vomiting, diarrhea, 吸收不良综合征或小肠切除术) 孕妇或哺乳期女性患者, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 90 days after the last dose of study drug, 因为克唑替尼对未出生胎儿的影响尚不清楚. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to administration of crizotinib. Male patients whose sexual partner(s) are women of child bearing potential, who are not willing to use adequate contraception during the study and for 90 days after the last dose of study drug. History of significant noncompliance to medical regimens that would jeopardize compliance with study therapy 不愿意或不能遵守研究方案的患者