A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer

BACKGROUND: Preclinical studies have suggested that erlotinib at high doses may inhibit additional sites downstream of the epidermal growth factor receptor (EGFR), resulting in greater antitumor efficacy. The objective of this study was to determine the tolerability and efficacy of high-dose erlotinib administered on a weekly schedule to patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted a Phase I/II trial of weekly erlotinib in patients with progressive NSCLC who had received previous chemotherapy. In the Phase I portion, patients were enrolled in 3-patient cohorts at erlotinib dose levels of 1200 mg, 1600 mg, and 2000 mg once weekly. The Phase II portion was designed to determine the major objective response rate of the dose identified in the Phase I portion of the trial. RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity was observed. Grade 1 and 2 rash and diarrhea were the principle toxicities, and each occurred in 92% of patients. Among 21 patients who were treated at the Phase II dose of 2000 mg weekly, a single objective response was identified, yielding a response rate of 5% (95% confidence interval, 0.2-22%). For this cohort, the median survival was 9.5 months. The sole radiographic response occurred in a patient whose pretreatment tumor specimen harbored an EGFR exon 19 deletion. CONCLUSIONS: Erlotinib at a dose of 2000 mg administered weekly was tolerated well by these patients with advanced NSCLC. The 5% objective response rate did not reach the stated objective at the interim efficacy analysis, prompting the closure of the study.     

Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma

BACKGROUND: The benefit of cytoreductive surgery for patients with recurrent epithelial ovarian cancer has not been defined clearly. The objective of this study was to identify prognostic factors for survival in patients who underwent secondary cytoreduction for recurrent, platinum-sensitive epithelial ovarian cancer and to establish generally applicable guidelines and selection criteria. METHODS: The authors reviewed all patients who underwent secondary cytoreduction for recurrent epithelial ovarian cancer from 1987 to 2001. Potential prognostic factors were evaluated in univariate and multivariate analyses. RESULTS: In total, 157 patients underwent secondary cytoreduction, and 153 of those patients were evaluable. After secondary cytoreduction, the median follow-up was 36.9 months (range, 0.2-125.6 months), and the median survival was 41.7 months (95% confidence interval, 36.0-47.2 months). For patients who had a disease-free interval prior to recurrence of between 6 months and 12 months, the median survival was 30 months compared with 39 months for patients who had a disease-free interval between 13 months and 30 months and 51 months for patients who had a disease-free interval >30 months (P = .005). For patients who had a single site of recurrence, the median survival was 60 months compared with 42 months for patients who had multiple sites of recurrence and 28 months for patients who had carcinomatosis (P <.001). The median survival for patients who had residual disease that measured < or =0.5 cm was 56 months compared with 27 months for patients who had residual disease that measured >0.5 cm (P <.001). On multivariate analysis, disease-free interval (P = .004), the number of recurrence sites (P = .01), and residual disease (P <.001) were significant prognostic factors. CONCLUSIONS: In the authors' analysis of secondary cytoreduction for recurrent epithelial ovarian cancer, a significant survival benefit was demonstrated for residual disease that measured < or = 0.5 cm. The disease-free interval and the number of recurrence sites should be used as selection criteria for offering secondary cytoreduction.     

Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.     

Comparison of automated docking programs as virtual screening tools

The performance of several commercially available docking programs is compared in the context of virtual screening. Five different protein targets are used, each with several known ligands. The simulated screening deck comprised 1000 molecules from a cleansed version of the MDL drug data report and 49 known ligands. For many of the known ligands, crystal structures of the relevant protein-ligand complexes were available. We attempted to run experiments with each docking method that were as similar as possible. For a given docking method, hit rates were improved versus what would be expected for random selection for most protein targets. However, the ability to prioritize known ligands on the basis of docking poses that resemble known crystal structures is both method- and target-dependent.     

VEGF expression in residual tumor cells in orbital retinoblastoma (IRSS stage III) treated with NACT: a prospective study

We prospectively evaluated vascular endothelial growth factor (VEGF) expression by immunohistochemistry in 22 consecutive IRSS stage III retinoblastoma patients who underwent enucleation after neoadjuvant chemotherapy (NACT). Positive VEGF expression was observed in 6/22 (27.3%) patients. VEGF expression was associated with local progression on MRI prior to enucleation (P = 0.004), pathological scleral (P = 0.023), and extra-scleral tumor extension (P = 0.009). EFS for VEGF positive and negative patients was 0% and 56.25%, respectively (P = 0.0002). OS for VEGF positive patients was 33.33% and 54.69% for VEGF negative patients (P = 0.207). Thus, VEGF in residual tumor cells post-NACT may represent poor response to NACT, potential for local invasion, and inferior outcome.     

Confirmation of the Zechi-Ceide syndrome

Atretic cephaloceles associated with multiple congenital anomalies are known to follow either autosomal dominant or autosomal recessive patterns of inheritance. Zechi-Ceide syndrome (OMIM 612916) is an autosomal recessive disorder, characterized by an occipital atretic cephalocele, characteristic facial features, and large feet. Here we describe a patient with findings fitting Zechi-Ceide syndrome, in whom some of the manifestations were also present in his mother, indicating either autosomal dominant inheritance with variable expression, X-linked inheritance, or a manifesting carrier of an autosomal recessive inheritance.