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McDermott D.,Beth Israel Deaconess Medical Center | Haanen J.,Netherlands Cancer Institute | Chen T.-T.,Bristol Myers Squibb | Lorigan P.,Christie Hospital NHS Trust | O'Day S.,Los Angeles Skin Cancer Institute
Annals of Oncology

Background: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived >2 years. Methods: Patients were randomized (3: 1: 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with >2 years' survival were analyzed. Results: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived >2 and >3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with >2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. Conclusions: Ipilimumab results in survival of >2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. Trial Registration ID: NCT00094653. © The Author 2013. Source

Shalet S.M.,Christie Hospital NHS Trust
Clinical Endocrinology

Quantitatively, GH secretion exists as a continuum in states ranging from good health through to hypopituitarism. Currently, GH replacement is considered only for adults designated as being severely GH deficient (GHD). In clinical practice the gold standard, on which the biochemical diagnosis of severe GHD is based, centres on the presence of two or more additional anterior pituitary hormone deficits. Cohorts of adults with partial GHD (Growth Hormone Insufficiency [GHI]) have been reported with adverse body composition changes, dyslipidaemia, insulin resistance, altered cardiac performance and increased carotid intima-media thickness. The diagnosis of GHI in an individual patient, however, is extremely difficult because such patients rarely exhibit additional anterior pituitary hormone deficits, and the levels of GH-dependent proteins, including IGF-I, are normal in the majority. Currently, GH replacement therapy should only be considered in a patient characterized as GHI by dynamic GH testing in whom there is a plausible cause for hypopituitarism and in whom the IGF-I level is pathologically low. © 2010 Blackwell Publishing Ltd. Source

Peters S.,University of Lausanne | Taron M.,University of Barcelona | Bubendorf L.,University of Basel | Blackhall F.,Christie Hospital NHS Trust | Stahel R.,University of Zurich
Lung Cancer

The recent approval of crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC) in the US and other countries has provoked intense interest in ALK rearrangements as oncogenic drivers, and promises to revolutionise the way in which NSCLC is diagnosed and treated. Here, we review clinical data to date for the use of crizotinib to treat patients with advanced, ALK-positive NSCLC and consider issues surrounding the detection of ALK-positivity including the use of fluorescence in situ hybridisation and the other potential techniques available, and their suitability for ALK screening. We also discuss the emergence of resistance to crizotinib therapy and the range of other ALK inhibitors currently in development. © 2013 Elsevier Ireland Ltd. Source

Thatcher N.,Christie Hospital NHS Trust | Heighway J.,Cancer Communications and Consultancy Ltd.

Globally, lung cancer is the leading cause of cancerrelated mortality. Current chemotherapy combinations for the first-line treatment of advanced disease (stage IIIB with malignant pleural effusion/stage IV) and chemoradiotherapy regimens for the treatment of unresectable locally advanced disease (stage IIIA and IIIB without malignant pleural effusion) appear to have reached an efficacy plateau. The addition of new compounds including targeted agents to standard first-line cytotoxic doublets, administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after such treatment, has been shown to improve efficacy beyond this plateau in patients with advanced disease. However, to date, such approaches have been less successful in the treatment of patients with unresectable locally advanced stage III disease. The purpose of this review is to summarize the data from recent randomized phase III studies involving agents administered as maintenance or consolidation therapy in the treatment of unresectable stage III/IV non-small cell lung cancer (NSCLC).Apossible alternative approach to the use of cytotoxic or molecularly targeted agents in this setting is the administration of therapeutic anticancer vaccines, which are designed to stimulate a host immunological response against the tumor. Current data in relation to the potential of vaccine therapy for NSCLC are therefore also reviewed, with a particular focus on belagenpumatucel- L and L-BLP25 vaccines, which are currently undergoing phase III evaluation as maintenance therapies in patients with unresectable stage III/IV NSCLC who have tumor control following first-line therapy. © AlphaMed Press. Source

Samol J.,St. Georges Hospital | Ranson M.,Christie Hospital NHS Trust | Scott E.,University of Leicester | MacPherson E.,Astrazeneca | And 3 more authors.
Investigational New Drugs

Background: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day×3 days or 1.0 mg/m2/day×3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. Results:: Twentyone patients were enrolled and 19 received treatment. Doselimiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m2/day× 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. Conclusion:s Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD. © Springer Science+Business Media, LLC 2011. Source

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