Abstract B50: A phase I study of various administration schedules for RO4929097 (R) with multi-parameter assessment (pharmacokinetics [PK] and primary tumor xenograft [XG]) in patients (pts) with advanced solid cancers.

摘要: Background: Dysregulated Notch signalling has been implicated in a variety of cancers. R is potent and selective inhibitor -secretase, key enzyme signalling. Phase I data demonstrated to be tolerable but PK profile revealed auto-induction with repeated dosing at high doses (Tolcher et al. ASCO 2010). The primary aim this study determine the optimal regimen using alternative schedules. Its secondary establish mouse XG from tumor biopsies enable correlative biomarker research. Methods: Pts advanced solid tumors were enrolled one 6 different schedules starting R. Serial samples collected on Day 1 steady state. Mandatory pre post treatment procured if medically safe implanted subcutaneously into NOD-SCID mice for propagation up 4 serial generations. Tumor DNA second passage was analyzed Sequenom OncoCarta Panel v1.0 (SOCP). Results: To date, 24 pts have enrolled. are available 21 pts, summarized Table 1. maximum dose C-F not reached. Commonest adverse events (AE) all grades least possible attribution fatigue (n=14), nausea (13), hypophosphatemia (11), anorexia (9) diarrhoea (8). Grade 3/4 AEs consisted (n=2), lymphopenia (2), vomiting (1) QTc prolongation (1). Data engraftment 18 (18 16 samples). Primary sites included gastrointestinal (n=6), breast (4), melanoma ovarian pancreatic (1), neuroendocrine parotid lung cancers In biopsies, rate initial 12/18 (67%); while 14/16 (88%). Further passages (2nd 3rd) viable engrafted 100% rate. SOCP analyses carried out 9 models mutations detected (KRAS [n=3] BRAF mutations), which metastatic colon Conclusions: Preliminary evaluation A B (concordant prior data), lesser degree C, D & E. It unclear whether observation due lower administered or employed. This ability generate histologies core mean 78% first implantation. We also confirmed feasibility detecting point platform specimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings AACR-NCI-EORTC International Conference: Molecular Targets Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Ther 2011;10(11 Suppl):Abstract nr B50.