Anti-MTD polyclonal antibody

Background Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. Methods This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. Results Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m(2) q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). Conclusions The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

Many sedimentary structures are the manifestation of fluid escape in sedimentary basins. This paper examines outcrop and seismic examples in upper Miocene deep-water sandstones and siltstones of north Taranaki, New Zealand. In outcrop examples of fluid escape features comprise discordant bodies within otherwise uniformly bedded surrounding stratigraphy, features characterized by steep sided, over-hanging, vertical or near-vertical margins, infilled with an assortment of poorly sorted or chaotically arranged sandstone and siltstone. Typically, these features are several metres wide and up to 20 m high in outcrop and always occur stratigraphically below a mass transport deposit (MTD). Examples of similar features from nearby 2D and 3D seismic reflection data consist of localized vertical to sub-vertical zones of disrupted reflectivity and are as much as 300 m in height and 10's-100's of metres in width. The structures occur in close association with the basal slide planes of seismic-scale MTDs. The close association of fluid escape structures with MTDs suggests that these features formed by the sudden loading of the sedimentary succession by the emplacement of several metre-thick overlying MTDs. We suggest recurring phases whereby the emplacement of MTDs triggered fluid escape within underlying strata and, in turn, the fluid escape contributed to further instability with potential for mobilization and transport of subsequent MTDs in a dynamic deep-water setting.