Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR

A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors

PURPOSE: Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.) panobinostat administered on different dosing schedules in patients with advanced solid tumors or lymphoma. Secondary objective was to characterize safety and tolerability, pharmacokinetic profiles, and activities of the i.v. formulation. METHODS: i.v. panobinostat was administered at escalating doses on a daily (days 1-3 and 8-10 of a 21-day cycle; days 1-3 and 15-17 of a 28-day cycle) or weekly (days 1, 8, and 15 of a 28-day cycle; days 1 and 8 of a 21-day cycle) schedule, and safety and tolerability were monitored. Serial blood samples were collected following dosing for pharmacokinetic and pharmacodynamic analyses. RESULTS: The MTD for the daily administration schedule was 7.2 g/m(2), whereas the MTD for the weekly schedule was 20.0 mg/m(2). In addition to fatigue and cardiac arrhythmias, including prolonged QTcF, DLTs associated with the study drug were principally due to myelosuppressive effects. Maximum concentrations and bioavailability of i.v. panobinostat increased dose-proportionally across all doses evaluated. CONCLUSIONS: Based on the results of this study and others, the i.v. formulation of panobinostat was well tolerated in many patients, but concerns remain regarding its potential suitability outside the study setting due to potential electrocardiogram abnormalities. Therefore, further development will focus on the panobinostat oral formulation

Intellectual Property Rights: Governing Cultural and Educational Futures

This article uses Foucauldian theories of governmentality to examine ways in which intellectual property rights regimes are embedded within broad spectrums of global and globalising discourses and yet are enacted through changing subjectivities at the local level. Using the 2004 Australia–United States Free Trade Agreement as a case in point, it shows how culture, education, free trade, foreign policy, and national security intersect and have the potential to limit access to cultural knowledge and textual resources for young people and educators

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

Edward M Wolin,1 Barbara Jarzab,2 Barbro Eriksson,3 Thomas Walter,4 Christos Toumpanakis,5 Michael A Morse,6 Paola Tomassetti,7 Matthias M Weber,8 David R Fogelman,9 John Ramage,10 Donald Poon,11 Brian Gadbaw,12 Jiang Li,12 Janice L Pasieka,13 Abakar Mahamat,14 Fredrik Swahn,15 John Newell-Price,16 Wasat Mansoor,17 Kjell Öberg3 1Markey Cancer Center, University of Kentucky, Lexington, KY, USA; 2Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; 3Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden; 4Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France; 5Gastroenterology and Neuroendocrine Tumours, Royal Free Hospital, London, UK; 6Department of Medical Oncology, Duke University Medical Center, Durham, NC, USA; 7Department of Medical and Surgical Sciences, University Hospital St Orsola, Bologna, Italy; 8Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany; 9Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA; 10Gastroenterology Unit, North Hampshire Hospital, Basingstoke, UK; 11Department of Medical Oncology, Raffles Hospital and Duke–NUS Graduate Medical School, Singapore; 12Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 13Surgery and Oncology Faculty of Medicine, Foothills Hospital, Calgary, AB, Canada; 14Department of Gastrointestinal Oncology, CHU de Nice Hôpital de l’Archet 1, Nice, France; 15Department of Clinical Science, Intervention and Technology, Karolinska Universitatssjukhuset, Huddinge, Stockholm, Sweden; 16Department of Human Metabolism, School of Medicine and Biomedical Science, The University of Sheffield, and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 17Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK Abstract: In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR. Keywords: neuroendocrine tumors, carcinoid syndrome, somatostatin analogues, pasireotide, symptom control, progression-free surviva

Genotypes of NK cell KIR Receptors, Their Ligands, and Fc? Receptors in the Response of Neuroblastoma Patients to Hu14.18-IL2 Immunotherapy

PMID: 20935224Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-Fc?R alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific Fc?R alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the Fc?R2A 131-H/H genotype showing a higher response rate than other Fc?R2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response

Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study

PMID: 20921469PURPOSE: The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks. RESULTS: Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results. CONCLUSION: Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma

Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov