This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Notch signaling plays a key role in the normal development of many tissues and cell types through diverse effects on cell fate decision, stem cell renewal, differentiation, survival, and proliferation.1 Notch signaling has been implicated in tumorigenesis.2 After activation by ligand binding, the Notch proteins are proteolytically cleaved in two steps by TNFa-converting enzyme and ?-secretase complex, releasing the active form called intracellular Notch (ICN), which modulates the expression of key proliferationand differentiation-specific genes.Notch signaling is aberrantly activated in a variety of human cancers, including solid tumors and hematological malignancies, in particular T-cell leukemia (T-ALL). Relevant to pediatric cancer, altered Notch signaling is observed in osteosarcoma, gliomas, medulloblastomas,ependymoma, and hematological malignancies. One emerging strategy to inhibit Notch signaling is the use of -secretase inhibitors (GSIs), which prevent Notch receptor activation cleavage.RO4929097 is an orally administered small molecule that is a potent and selective GSI. In preclinical studies, RO4929097 showed antitumor activity on an intermittent or daily schedule. This Phase I study will first evaluate the safety and pharmacokinetics of RO4929097 administered orally to children with relapsed/refractory solid tumors including CNS tumors, or lymphoma (part 1) on 2 schedules: once daily on a 3 day on/4 day off weekly schedule (schedule A) and once daily for 5 consecutive days weekly schedule (schedule B). The starting dose of RO4929097 for schedule A will be the equivalent in mg/m2 of the target Phase 2 dose in mg for schedule A in adults, and for schedule B, the equivalent to the weekly dose of schedule A divided over 5 days. One cycle will be 28 days in duration. In absence of progressive disease or unacceptable treatment-related toxicity, patients may continue therapy up to a total of 24 cycles. One of the major challenges in clinical development of GSIs is the potential untoward side effects on the gastrointestinal tract. Based on preclinical data suggesting that corticosteroids may ameliorate gastrointestinal toxicity (i.e., diarrhea) and increase anti-tumor activity, we will next evaluate at least one of the schedules with concomitant dexamethasone in children with solid tumors including CNS tumors, or lymphoma (part 2). After the MTD of RO4929097 plus dexamethasone has been identified, the study will begin enrollment of patients with relapsed-refractory T-ALL (part 3) to obtain initial efficacy data on RO4929097 in combination with dexamethasone in this patient population. In addition, the study includes correlative studies to study the effect of RO4929097 on components of the Notch signaling pathway in PBMCs and/or T-ALL blasts, to examine archival tumor samples for expression or amplification of target molecules, and to preliminarily assess changes after treatment using FDG PET imaging.
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