At least four responses (11%) were necessary to consider the regimen sufficiently active to pursue in further studies. A first stage interim analysis was planned after enrollment of MAC glucuronide α-hydroxy lactone-linked SN-38 12 patients, with early stopping to occur if no responses Mouse monoclonal to CD152(PE) were observed (resulting in a 0.54 probability of early stopping if the response rate was 5%). was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN, and the downstream target HES1. Results 37 patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues exhibited MAC glucuronide α-hydroxy lactone-linked SN-38 positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in MAC glucuronide α-hydroxy lactone-linked SN-38 the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only 6 patients had stable disease as their best response. Median PFS was 1.8 months and median OS was 6.0 months. Conclusion In this study of RO4929097 in patients with refractory metastatic colorectal malignancy, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and routine has minimal single agent activity in this malignancy. Introduction Colorectal malignancy is the MAC glucuronide α-hydroxy lactone-linked SN-38 second leading cause of cancer-related mortality in the United States with nearly 50,000 deaths each year.1 Combination chemotherapy with 5-fluorouracil, oxaliplatin, irinotecan2, bevacizumab3, and the EGFR inhibitors cetuximab4 and panitumumab5 have led to improvements in longevity,6 with median survival rates now approaching 24 months in patients with stage IV disease.7 However, response rates beyond the first line of treatment remain disappointingly low and new systemic agents are needed for patients who are resistant or intolerant of currently available therapies. New therapeutic targets include signaling pathways that regulate proliferation and differentiation of stem cells. During development and tissue remodeling, pluripotent stem cells serve as the source of differentiating cells, giving rise to non-proliferating specialized cell types. The fate of these cells appears to depend on primordial regulatory pathways that are active during development. Deregulation of these pathways is usually linked to the quick and uncontrolled proliferation of tumors. The Notch pathway is one of the major developmental signaling pathways.8,9 Notch, represented by four homologs in mammals (Notch1-Notch4), is a cell surface protein receptor involved in transmitting growth and proliferation signals to the cell.10 Activation of Notch occurs through ligand binding. Two Notch ligand families, Jagged and Delta, have been explained in mammals with five ligands recognized to date (Jagged 1 and 2, and Delta 1, 3, and 4). After ligand binding, two successive proteolytic cleavage actions occur. The first cleavage step is usually mediated by ADAM/TACE (a disintegrin and metalloprotease/tumor-necrosis factor transforming enzyme) and occurs at the S2 cleavage site. The second cleavage step occurs at the S3 cleavage site and is mediated by the -secretase complex, consisting of a catalytic MAC glucuronide α-hydroxy lactone-linked SN-38 subunit (presenilin 1 or 2 2), and accessory subunits (nicastrin, Pen-2, and Aph-1). The producing active form of Notch called IntraCellular Notch (ICN), translocates to the nucleus where it binds a transcriptional repressor known as C-promoter-binding factor (CBF-1), or CSL (CBF-1/Suppresor of Hairless/Lag1), thus activating the Notch target genes, Myc, p21, and Hes (hairy/enhancer of split).11-13. Blocking Notch signaling via -secretase inhibition produces a slower growing, less transformed phenotype in human malignancy cells <.05.20, =.1, power = 90%. This calculation yielded a total sample size of 37 patients. At least four responses (11%) were necessary to consider the regimen sufficiently active to pursue in further studies. A first stage interim analysis was planned after enrollment of 12 patients, with early stopping to occur if no responses were observed (resulting in a 0.54 probability of early stopping if the response rate was 5%). However, per-protocol, accrual was allowed to continue beyond the first stage until all initial 12 patients underwent their first two follow-up scans. Statistical Analysis The Kaplan-Meier method was used to estimate all time-to-event functions. PFS was defined as time from start of treatment until disease progression or death as a result of any cause. OS was defined as time from start of treatment until death as a result of any cause, with patients censored at the date of last follow-up if still alive. Exact 95% CIs were calculated for each proportion of interest. Statistical analysis was performed using Stata SE 9.0 software and SAS 9.2 software. Parametric survival modeling was implemented as well. Exponential distribution assumption was verified using a reduced piecewise exponential test procedure. Point estimate and the exact 95% CI of the median survival based on the exponential distribution were computed.30 For tissue analysis, Spearman's rank correlation coefficient and Kendall's tau coefficient were computed to assess the.
