ADVL0214, A PHASE I STUDY OF SINGLE AGENT OSI-774 (TARCEVA) FOLLOWED BY OSI-77S

ADVL0214，单药 OSI-774 (TARCEVA) 的 I 期研究，随后是 OSI-77S

• 批准号: 7374981
• 负责人: SUSAN M. BLANEY
• 金额: $ 1.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374981
• 关键词: ADVL0214; PHASE; STUDY; SINGLE; AGENT

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ERBB family consists of four closely related transmembrane receptors (ERBB1 or EGFR, ERBB2 or HER2, ERBB3 and ERBB4) which interact to form a complex signaling network. The ERBB pathways are important in cell proliferation, motility, adhesion, invasion, survival and angiogenesis. Dysregulation of the pathways play a role in the development and progression of malignancies. ERBB1 or B2 receptor expression or over-expression has been observed in pediatric high-grade gliomas, medulloblastomas, ependymomas, and osteosarcoma. OSI-774 is a potent oral EGFR tyrosine kinase inhibitor, with reported activity against ERBB2 as well. Antitumor activity has been seen in a wide range of human tumor xenografts. In adult Phase I and II clinical trials, OSI-774 has shown promising clinical efficacy and the daily dosing schedule is well tolerated. Toxicities in adults include transient diarrhea, acne -like rash and nausea. EGFR inhibitors may enhance standard cytotoxic cancer chemotherapy and at least additive effects have been seen between OSI-774 and a variety of chemotherapeutic agents. Temozolomide has demonstrated a broad-spectrum of activity in pre-clinical trials, including brain tumor, neuroblastoma and other pediatric solid tumor xenografts. Clinical trials using temozolomide in adult and pediatric patients with recurrent brain tumors have demonstrated significant anti-tumor activity. The current study is a Phase I trial and pharmacokinetic study of OSI-774 alone (using the oral solution) and in combination with temozolomide. Patients will initially receive OSI-774 alone, given once daily without a break. Pharmacokinetic studies will be done for 24 hours on day 12 +/- 2 days. Toxicity will be evaluated following 1 course (28 days) of single agent therapy. In the absence of dose-limiting toxicity that meets the criteria for removal from protocol therapy, patients will then start the combination chemotherapy component of the trial. Daily OSI-774 will be continued in conjunction with oral temozolomide 180 mg/m 2/day x 5 days every 28 days. In the absence of dose-limiting toxicity, the dose of temozolomide may be escalated to 200 mg/m 2 in all subsequent courses. After the MTD of single agent OSI-774 (administered as an oral solution) is determined in Part A of the study, additional patients will be enrolled and treated with the OSI-774 tablet formulation at the determined MTD (Part B of the study). Enrollment to Part B of the study will continue until 6 patients ? 12 years of age and 6 patients < 12 years of age have participated in the PK component of the study.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。ERBB家族由四种密切相关的跨膜受体（ERBB 1或EGFR、ERBB 2或HER 2、ERBB 3和ERBB 4）组成，它们相互作用形成复杂的信号传导网络。 ERBB通路在细胞增殖、运动、粘附、侵袭、存活和血管生成中是重要的。这些通路的失调在恶性肿瘤的发生和发展中起作用。ERBB 1或B2受体表达或过表达已在儿童高级别胶质瘤、髓母细胞瘤、室管膜瘤和骨肉瘤中观察到。OSI-774是一种有效的口服EGFR酪氨酸激酶抑制剂，据报道对ERBB 2也有活性。 抗肿瘤活性已在广泛的人类肿瘤异种移植物中观察到。 在成人I期和II期临床试验中，OSI-774显示出有希望的临床疗效，并且每日给药方案耐受性良好。对成人的毒性包括短暂性腹泻、痤疮样皮疹和恶心。EGFR抑制剂可以增强标准细胞毒性癌症化疗，并且在OSI-774和各种化疗剂之间至少观察到了累加效应。 替莫唑胺在临床前试验中表现出广谱活性，包括脑肿瘤、神经母细胞瘤和其他儿科实体瘤异种移植物。在复发性脑肿瘤的成人和儿童患者中使用替莫唑胺的临床试验已经证明了显著的抗肿瘤活性。 目前的研究是OSI-774单独（使用口服溶液）和与替莫唑胺联合的I期试验和药代动力学研究。患者最初将单独接受OSI-774，每天一次，不间断。药代动力学研究将在第12 +/- 2天进行24小时。将在1个疗程（28天）的单药治疗后评价毒性。如果不存在符合从方案治疗中移除标准的剂量限制性毒性，则患者将开始试验的联合化疗部分。每日OSI-774将继续与口服替莫唑胺180 mg/m2/天x 5天，每28天一次。 在没有剂量限制性毒性的情况下，替莫唑胺的剂量可在所有后续疗程中递增至200 mg/m2。在研究的A部分中确定单一药剂OSI-774（作为口服溶液施用）的MTD后，将招募另外的患者并以确定的MTD用OSI-774片剂制剂治疗（研究的B部分）。研究B部分的入组将持续至6例患者？12岁和6例< 12岁的患者参加了研究的PK部分。