Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase study

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0.0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0.43 [95% CI 0.32-0.58]; median progression-free survival 14.6 months [95% CI 10.4-not estimable] vs 6.2 months [4.2-7.9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma

Non-standard asymptotics in an inhomogeneous gamma process

Asymptotics, maximum likelihood estimation, modulated power law process, power law process, recurrent event,

Effect of extrusion cooking on anti-nutritional factor tannin in linseed (Linum usitatissimum) meal

Primary objective Various oilseeds and their by-products usually constitute a major source of dietary protein as aquafeeds for warmwater herbivorous/omnivorous fish species. The oilseed meals available in India are fairly rich in protein and most of them are traditionally used as valuable feed for farm animals. However, among the factors that limit incorporation of these ingredients in aquafeeds are amino-acid imbalance and presence of anti-nutritional factors. Enhancement of the nutritive value of these ingredients and reduction (or removal) of anti-nutritional factors can be attempted by processing so as to increase the bio-availability of these nutrients. It has been found that various anti-nutritional factors can be destroyed by the process of extrusion cooking. Extrusion is a process whereby raw feed material is exposed to controlled conditions of high temperature, pressure and moisture. In the present experiment, extrusion cooking is used to reduce the anti-nutritional factor tannin in linseed (Linum usitatissimum) meal. Research design A single-screw cooking extruder, designed and manufactured at the Indian Institute of Technology, Kharagpur, was used for the study. Experiments were carried out following a rotatable central composite design to determine the optimum values of the process variables for which maximum reduction of tannin (Y) occurs. The process variables selected for the study were: barrel temperature (X1) (60-100° C), extruder speed (X2) (60-100 rpm) and oilseed moisture content (X3) (30-50%). Following the design, a second-order response model was fitted. Main outcomes and results The optimized values of the process variables were found to be X1=82.5°C, X2=90 rpm and X3=41.22%, and the value of the predicted response (i.e. reduction of tannin Y) was found to be 61.25%

Etiology of vaginal/cervical discharge syndrome: Analysis of data from a referral laboratory in eastern India

Context: Sexually transmitted infections (STIs) and reproductive tract infections (RTIs) constitute important public health problem worldwide. Syndromic diagnosis of vaginal/cervical discharge (VCD) is often inaccurate leading to over- or under-treatment. Aims: This study aimed to ascertain the laboratory-confirmed diagnosis of VCD and their relative frequency in a group of patients presenting to a STI clinic in eastern India and to determine the sensitivity and specificity of clinical diagnosis. Settings and Design: This was a cross-sectional study. Materials and Methods: Data of 5301 consecutive patients with VCD were analyzed for etiological diagnosis and the findings were compared with laboratory data of 3110 asymptomatic cases. Statistical Analysis Used: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of clinical diagnosis of vaginal discharge syndrome were obtained considering the results of the laboratory diagnosis as gold standard. The strength of agreement was computed using Kappa statistic. Results: Of 5301 cases of VCD, 90.83% had STI/RTIs. The most prevalent infection was trichomoniasis (35.23%), followed by bacterial vaginosis (33.05%) and vulvovaginal candidiasis (19.67%). Sensitivity, specificity, PPV, and NPV of vaginal discharge as an indicator of STI/RTI were 85.5%, 99.0%, 99.3%, and 80%, respectively, with agreement of 90.49% and kappa value of 0.8, indicating “almost perfect” agreement. Many cases with VCD also suffered from other STIs such as herpes simplex virus-2, hepatitis B, human immunodeficiency syndrome, and syphilis and some asymptomatic cases suffered from one or more STIs. Conclusions: All patients with VCD with high-risk behavior should preferably undergo laboratory evaluation of the VCD syndrome to avoid over- or under-treatment

Corticosteroid tapering is a safe approach in patients with relapsed or refractory multiple myeloma receiving subcutaneous daratumumab: part 3 of the open-label, multicenter, phase 1b PAVO study

Daratumumab is approved as monotherapy and in combination regimens for the treatment of relapsed or refractory multiple myeloma (RRMM) or newly diagnosed multiple myeloma [Citation1,Citation2]. The PAVO study (ClinicalTrials.gov Identifier: NCT02519452) of daratumumab plus recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA) in a mix-and-deliver formulation (part 1) or a pre-mixed subcutaneous formulation (DARA SC; part 2) demonstrated consistent safety, pharmacokinetics, and efficacy as the daratumumab intravenous (IV) formulation in patients with RRMM [Citation3–5].This study was sponsored by Janssen Research & Development, LLC [ClinicalTrials.gov Identifier: NCT02519452]. Medical writing and editorial support were provided by Austin Horton, PhD, and Kristin Runkle, PhD, of Lumanity Communications Inc., and were funded by Janssen Global Services, LLC

First-in-human, open-label, phase 1/2 study of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced cancers.

To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability-high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1-high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016-002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017