Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors.

Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. TRIAL REGISTRATION: JapicCTI-132,375, JapicCTI-142,698.

Long-term safety and efficacy of lanreotide autogel in Japanese patients with neuroendocrine tumors: Final results of a phase II open-label extension study.

AIM: The aim of this study was to describe the long-term safety and efficacy of lanreotide in Japanese patients with neuroendocrine tumors. METHODS: The final analyses of a 48-week open-label phase II study (n = 32) and its extension study (n = 17) were conducted. Patients received 4-weekly subcutaneous injections of lanreotide autogel 120 mg. Safety was evaluated by adverse events. Efficacy endpoints included tumor response by RECIST and change in tumor size. Post hoc analyses including tumor growth rate were performed. RESULTS: The median (range) of lanreotide exposure in the safety analysis set (n = 17) and efficacy analysis set (n = 28) were 151.4 (52-181) and 52.7 (12-181) weeks, respectively. Sixteen patients developed adverse drug reaction; of these, upper abdominal pain and urticaria were not reported before 48 weeks. No patient discontinued lanreotide or died from an adverse event. Two serious events of bile duct stones in one patient were drug-related. Partial response was observed in 2 patients (7.1%; at 60 and 108 weeks), stable disease in 20 (71.4%) and progressive disease in 6 (21.4%). The mean of the greatest change from baseline in the sum of diameters of target lesions was -5.5%. The mean (standard deviation) tumor growth rate before treatment and from baseline to last observation was 25.3% (35.7%)/month and 6.4% (9.6%)/month, respectively. CONCLUSION: Lanreotide treatment had an acceptable safety profile and was effective over long-term treatment in Japanese patients with neuroendocrine tumors. No unexpected serious adverse events developed during prolonged use of lanreotide.

Synthesis of an alpha-fucosidase inhibitor, 5a-carba-beta-L-fucopyranosylamine, and fucose-type alpha- and beta-DL-valienamine unsaturated derivatives.

Discovery of a very potent alpha-fucosidase inhibitor 5a-carba-alpha-L-fucopyranosylamine led to preparation of its beta-anomer and the respective unsaturated derivatives, fucose-type alpha- and beta-valienamines, in order to elucidate the structure-activity relationship of carba-aminosugar inhibitors of this kind. Compound was demonstrated to be a potent inhibitor (K(i)=2.0 x 10(-7) M, bovine kidney), possessing ca. one-tenth of the activity of the parent. Interestingly, and were found to be rather weak inhibitors, contrary to the expectations based on the activity relationships between the alpha-glucosidase inhibitors, alpha-glucose-type validamine and valienamine.

Synthesis and glycosidase inhibitory activity of some N-substituted 6-deoxy-5a-carba-beta-DL- and L-galactopyranosylamines.

Chemical modification of 5a-carba-beta-DL-fucopyranosylamine (3) generated six N-substituted derivatives 9a-f, among which N-octyl 9b, decyl 9c, and phenylbutyl ones 9f were found to be very strong beta-galactosidase as well as beta-glucosidase inhibitors. The inhibitory activity appeared attributable to D-enantiomers from biological assays of prepared L-enantiomers. Therefore, 6-deoxy-5a-carba-beta-D-galactopyranosylamine (D-3) might be a promising lead compound for further design of new carba sugar-type beta-galactosidase inhibitors.

Synthesis and glycosidase inhibitory activity of some N-substituted 5a-carba-beta-fuco- and beta-galactopyranosylamines, and selected derivatives.

In the course of chemical modification of alpha-fucosidase inhibitors of 5a-carba-fucopyranosylamine type, an N-dodecyl derivative of the enantiomer 6-deoxy-5a-carba-beta-D-galactopyranosylamine demonstrated very strong inhibition of beta-galactosidase and beta-glucosidase. This finding led us to synthesize corresponding 6-hydroxy compounds, in order to elucidate structure-activity relationships for inhibitors of this type. Among four N-alkyl-5a-carba-beta-D-galactopyranosylamines prepared, the N-octyl derivative could be demonstrated to possess moderate activity toward alpha- and beta-galactosidases, and beta-glucosidase.