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