Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.

BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Modeled microgravity affects motility and cytoskeletal structures.

The hypothesis to be tested is that reduced cell-cell interactions between T cells and monocytes are one of the reasons for the observed depression of the "in vitro" activation of human lymphocytes in microgravity. Locomotion is essential for cell-cell contacts. Lymphocytes in suspension are highly motile in microgravity, whereas no data are available so far on the motility of adherent monocytes. It can be argued that an impaired locomotion of monocytes and cytoskeletal changes, both linked to cell contacts, could be responsible for their reduced interaction with T lymphocytes. This study is aimed at revealing how locomotion as well as cytoskeletal structures of adherent monocytes are modified under modeled microgravity conditions using the Random Positioning Machine (RPM, Dutch-Space) as earth based model of spaceflight.

Signal transduction in T lymphocites under simulated microgravity conditions: involvement of PKC isoforms.

Previous data obtained from experiments either in space or in clinostats have shown that: a) human T lymphocytes activation is strongly inhibited; b) the distribution of protein kinase C (PKC) in human leukocytes is altered; c) expression of IL-2 and IL-2-R-alpha is altered. In this study we focus our attention on different isoforms of PKC to determine whether microgravity directly affects the activity and subcellular distribution of PKC. This work was carried out with Con A and anti-CD 28 activated human T cells in simulated microgravity conditions in the Random Positioning Machine (RPM). The cellular fractions (nuclear, cytosolic and membrane) extracted were subjected to Western blotting and RT-PCR analysis.

Simulated microgravity conditions affect poly(ADP-ribose) polymerase activity in cultured human lymphocytes.

NASA: Human peripheral blood lymphocytes (PBL), activated with concanavalin A (ConA), were used to determine the effects of simulated microgravity on poly(ADP-ribose) polymerase (PARP) activity. Results indicate that the ConA stimulation of human cultured PBL induces a partial but signitficant inhibition of PARP-1 acitvity (-30%). In control PBL, not exposed to ConA, after 24 hours, there was a clear decrease in PARP-1 acitivty (-40%). In PBL exposed to ConA and simulated weightlessness, activity decreased by -37%.^ieng

Effect of chronic treatment with octreotide nasal powder on serum levels of growth hormone, insulin-like growth factor I, insulin-like growth factor binding proteins 1 and 3 in acromegalic patients.

Octreotide nasal powder is a delivery system of the somatostatin analogue developed to overcome the inconvenience of repeated subcutaneous administrations. Eight patients with clinically active acromegaly were treated for three months with octreotide nasal powder which was administered at the initial dosage of 0.125 mg tid, doubling the dosage up to 2 mg tid in order to obtain a mean GH value below 5 micrograms/l during 8 daytime hours. In 4 of these patients, treatment was prolonged till the sixth month. Blood samples were taken on days 15, 29, 43, 55, 90, 120, 150, 180 for GH, IGF-I, IGFBP-3, IGFBP-1 and insulin measurements. Before treatment, mean daytime GH and morning IGF-I serum levels were both increased but not correlated with each other. Serum IGFBP-3 levels were higher than normal and positively correlated with those of GH, IGF-I and insulin. Insulin levels were elevated and positively correlated with those of GH but not with those of IGF-I and IGFBP-1. Serum IGFBP-1 levels were in the low normal range and not correlated with any of the other parameters. Treatment with octreotide nasal powder induced in all patients a marked decrease of GH which lowered below 5 micrograms/l in 7/8 patients and IGF-I levels, which fell within the normal range in 1 patient. Serum IGFBP-3 and insulin concentrations decreased by 26% and 71%, respectively, and those of IGFBP-1 underwent an only transient increase in 5/8 patients. Opposite changes of insulin and IGFBP-1 levels, with a decrease of the former followed by an increase of the latter were noted during the 8 hours following an octreotide nasal insufflation. During chronic octreotide treatment, positive correlations were found between GH and IGF-I, GH and IGFBP-3, IGF-I and IGFBP-3, insulin and IGFBP-3 and insulin and IGF-I. An improvement of the clinical picture was registered in all patients after a few days of octreotide nasal powder administration. Treatment was well tolerated, with only mild side effects and no significant changes in the nasal mucosa, and the patients' compliance was excellent.

Efficacy of octreotide in the prevention of complications of elective pancreatic surgery. Italian Study Group.

A placebo-controlled double-blind multicentre study, with randomization into parallel groups, was performed to determine whether perioperative subcutaneous administration of octreotide 0.1 mg every 8 h reduces the rate of complications specifically related to pancreatic surgery. In all, 252 patients were evaluated (153 men, 99 women; mean(s.e.m.) age 53.1(0.8) years) who had pancreatic or periampullary tumour or other duodenal disease (157 patients) or chronic pancreatitis (95) and were undergoing elective pancreatic resection (100 Whipple's procedure, 60 distal resection, 12 others), pancreaticojejunostomy (66) or enucleation of pancreatic lesions (14). The proportion of patients with complications was significantly lower in the group treated with octreotide than in the placebo group (15.6 versus 29.2 per cent, P = 0.01). Octreotide thus appears to reduce substantially the risk of complications related to elective pancreatic surgery. Moreover, treatment acceptability was high.

Prophylaxis of complications after pancreatic surgery: results of a multicenter trial in Italy. Italian Study Group.

An Italian prospective multicentre study evaluated the efficacy of octreotide, a synthetic somatostatin analogue, in preventing the complications of elective pancreatic surgery. 303 patients with tumours of the pancreas or the ampullary region, in whom ultrasonography and computed tomography scan had shown a resectable lesion, or with chronic pancreatitis, were randomized in a double-blind fashion to treatment with octreotide 100 micrograms t.i.d. s.c. starting at least 1 h before surgery and continued till the 7th postsurgical day, or with matching placebo. Unresectable lesions were found at laparatomy in 31 patients (15% of those with tumours). In 14 others, procedures not anticipated in the study protocol had to be performed, and in 6 additional cases there were other protocol violations so that these 20 patients were excluded from the study analysis. Considering the 252 evaluable patients, the complication rate was significantly higher in the 130 placebo-treated patients than in the 122 who received octreotide (29.2 vs. 15.6%; p = 0.01). We therefore suggest that octreotide may substantially reduce the risk of complications after elective pancreatic surgery.

Identification, characterization, and biological activity of somatostatin receptors in human neuroblastoma cell lines.

To investigate the presence of biologically active somatostatin (SS) receptors in neural crest-derived tumors, radioligand binding studies, cyclic AMP accumulation, intracellular calcium, and growth assays were performed in eight human neuroblastoma (NB) cell lines. Mathematical modeling of binding experiments strongly indicates the presence of heterogeneity of sites. The first site (SSR1) is present in 40% of the NB cell lines and binds with low capacity (0.5 pmol/mg protein) and high affinity (0.1-1 nM) SS14, SS28, and analogues. The second site (SSR2) is a high capacity site (200 pmol/mg protein), widely distributed in all of the cell lines investigated, that shows relative selectivity yet low affinity (100 nM) for SS14, SS28, and [D-Trp8]SS14 without any apparent biological activity. SSR1 is coupled to a pertussis toxin-sensitive G protein, inhibits forskolin- or VIP-stimulated adenylate cyclase activity, decreases intracellular free calcium, and mediates inhibition (30%) of both DNA synthesis and cell growth. Analysis of cell cycle distribution in aphidicolin-synchronized SSR1-positive NB cells indicated that this inhibitory effect is partially mediated by a transient accumulation in G0-G1. Our data indicate high affinity binding sites for SS14, and analogues are present and biologically active in a subset of NB cells.

Single doses of ritodrine delay orocaecal transit in patients with irritable bowel syndrome.

The lactulose hydrogen breath test was used to assess the effect of a single dose of the beta 2-adrenoceptor agonist ritodrine on orocaecal transit time in 11 patients (three men) with irritable bowel syndrome. Transit time (median values, range) was significantly longer (P less than 0.01) after ritodrine than after placebo (120, 50-200 vs 75, 40-100 min). Median heart rate was similar before treatments whereas the maximal increase in heart rate was significantly greater (P less than 0.01) after ritodrine than after placebo.

Gastrointestinal transit in hyperthyroid patients before and after propranolol treatment.

Mean mouth to cecum transit time determined by the hydrogen breath test after oral lactulose in a group of 10 hyperthyroid patients (nine with regular bowel habit and one with diarrhea) was significantly lower than that observed in 10 euthyroid controls [53 min (SD 15) versus 123 min (SD 12.2), p less than 0.01]. After 5 days of propranolol treatment the patients showed a significant reduction of the heart rate but no modification of transit time [51 min (SD 7.3)].