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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。ERBB家族由四个密切相关的跨膜受体（ERBB1或EGFR， ERBB2或HER2， ERBB3和ERBB4）组成，它们相互作用形成一个复杂的信号网络。ERBB通路在细胞增殖、运动、粘附、侵袭、存活和血管生成中起重要作用。这些通路的失调在恶性肿瘤的发生和发展中起作用。ERBB1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，具有抗ERBB2的活性。抗肿瘤活性已在广泛的人类肿瘤异种移植物中被发现。在成人I期和II期临床试验中，OSI-774显示出良好的临床疗效，每日给药计划耐受性良好。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的细胞毒性癌症化疗，并且至少在OSI-774和各种化疗药物之间发现了叠加效应。替莫唑胺在临床前试验中显示出广谱的活性，包括脑肿瘤、神经母细胞瘤和其他儿童实体瘤异种移植。替莫唑胺用于成人和儿童复发性脑肿瘤患者的临床试验显示出显著的抗肿瘤活性。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osii -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。单药治疗1个疗程（28天）后评估毒性。在没有剂量限制性毒性符合方案治疗移除标准的情况下，患者将开始试验的联合化疗部分。每日osi774将继续与口服替莫唑胺180 mg/m 2/天x 5天，每28天。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增加到200mg / m2。在研究的A部分确定单药osii -774（作为口服溶液给药）的MTD后，将招募更多的患者，并在确定的MTD下使用osii -774片剂配方进行治疗（研究的B部分）。B部分研究的入组将持续到6名患者。12岁和6名< 12岁的患者参加了本研究的PK部分。

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.