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

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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.