RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% versus 18.8%; spleen response, 40.0% vs 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from Baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment versus 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered asNCT01243944at ClinicalTrials.gov.
Copyright © 2016, Ferrata Storti Foundation.

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The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months’ duration.
In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 μg/kg to 10 μg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417.
Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events.
In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia.
Amgen Inc.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Out-of-specification (OOS) results were reported by a contract lab in the in vitro adventitious agent assay (AVA) for two products manufactured using mouse myeloma cells in perfusion bioreactors. Cytopathic effect observed for test article-inoculated MRC-5 monolayers resembled foci seen in tissue culture cells infected with transforming viruses. All reasonable known technologies, including highly sensitive, state-of-the-art methodologies and multiple, redundant, and orthogonal methods, were deployed to screen broadly for potential viral and microbial contaminants. Due to the appearance of apparent foci, testing for murine, bovine, and human polyomavirus contamination was heavily represented in the analytical investigation. The results obtained in this extensive screening provided convincing evidence for the lack of an infectious viral or other biological agent. Although the initial investigation produced no reason to invalidate AVA yielding OOS results or to suspect an assay artifact, an extended evaluation revealed several irregularities at the contract test lab reporting the OOS results. The extended investigation also included attempts to reproduce OOS results at alternate contract testing labs and an inter-laboratory study in which methodological differences in the AVA at the three different contract labs were investigated. Only the contract lab initially reporting the OOS results reported foci during this extended evaluation. The results of the inter-laboratory study suggested that the foci artifact might be attributed to the prolonged exposure of the MRC-5 monolayer to cell debris present in the test article. Confocal immunofluorescence microscopy and transmission electron microscopy were subsequently used to provide convincing evidence that the foci observed in test article-inoculated AVA wells were composed of a core of degraded myeloma cell debris covered by one or more layers of MRC-5 cells. The observation that the foci were detected in the AVA at a contract lab where the MRC-5 monolayer is exposed to production cell line debris for a prolonged period strongly suggests that these foci form when MRC-5 grow over the cell debris present in the test article. The cumulative results of the investigation supported the conclusion that the OOS results were artifacts of the AVA test system and not a result of contamination with a virus or other biological agent. Testing was discontinued at the contract lab generating the OOS results and validated at a second contract lab. Manufacturing resumed in consultation with health authorities. The lots were retested following a standard operating procedure (SOP) already in place and ultimately dispositioned for use in normal distribution channels.

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Simon’s two-stage designs are widely used in cancer phase II clinical trials for assessing the efficacy of a new treatment. However in practice, the actual sample size for the second stage is often different from the planned sample size, and the original inference procedure is no longer valid. Previous work on this problem has certain limitations in computation. In this paper, we attempt to maximize the unconditional power while controlling for the type I error for the modified second stage sample size. A normal approximation is used for computing the power, and the numerical results show that the approximation is accurate even under small sample sizes. The corresponding confidence intervals for the response rate are constructed by inverting the hypothesis test, and they have reasonable coverage while preserving the type I error.
Copyright © 2015 John Wiley & Sons, Ltd.

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The aim of our analysis was to evaluate the prognostic effect of programmed cell death ligand-1 (PD-L1) expression in patients with non-small-cell lung cancer (NSCLC).
PD-L1 expression among 1070 surgically resected NSCLC specimens was evaluated by immunohistochemistry. Data were analyzed using Cox proportional hazard models, adjusting for age, sex, smoking status, histology, stage, and performance status.
Sixty-eight patients (6%) were PD-L1 strong positive; 410 (38%) were PD-L1 weak positive. A significantly higher prevalence of PD-L1 positivity was observed among patients with squamous cell carcinoma and among stage IIIB/IV patients. PD-L1 expression may be associated with poorer overall survival, with an adjusted hazard ratio (HR) of 1.56 (95% confidence interval [CI], 1.08-2.26; p=0.02) for PD-L1 strong positive, 1.18 (95% CI, 0.96-1.46; p=0.12) for PD-L1 weak positive, and 1.23 (95% CI, 1.00-1.51; p=0.05) for the combined strong- and weak-positive groups compared with PD-L1 negative. Negative prognostic effect of PD-L1 expression was not statistically significant after adjusting for postsurgical chemotherapy or radiotherapy. Similar results were observed for progression-free survival. Among stage I patients, the disease recurrence rate was higher in the PD-L1-positive versus negative group (48% versus 27%, p<0.001), with an adjusted HR for disease-free survival of 2.01 (95% CI, 1.08-3.73; p=0.03) for PD-L1 strong positive and 1.57 (95% CI, 1.17-2.11; p=0.003) for PD-L1 weak positive compared with PD-L1 negative.
Tumor PD-L1 expression may be associated with poor prognosis in patients with NSCLC, although its significance weakens when postsurgical therapy is considered.
Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

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