Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study.

BACKGROUND: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151-202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. METHODS: Patients who completed the randomized PRM-151-202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). RESULTS: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, - 6.2% (- 7.7; - 4.6) and - 5.7% (- 8.0; - 3.3) for percent predicted FVC and - 36.3 m (- 65.8; - 6.9) and - 28.9 m (- 54.3; - 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. CONCLUSIONS: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.

BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression. METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604. FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses). INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. FUNDING: F Hoffmann-La Roche.

Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials.

Objectives: To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ). Methods: Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure. Results: In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean ( s . d .) change, -2.17 (2.16) × 10 9 /l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 10 9 /l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose. Conclusion: Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.

Effects of tocilizumab on neutrophil function and kinetics.

BACKGROUND: Decreases in circulating neutrophils (polymorphonuclear leucocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and/or bone marrow trafficking without affecting neutrophil function or apoptosis. MATERIALS AND METHODS: Eighteen healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labelled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count. RESULTS: Mean day 4 neutrophil counts, as % baseline, were 101·9%, 68·3% and 44·2% in the placebo, TCZ-PMN-'high' and TCZ-PMN-'low' groups, respectively (P < 0·001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver/spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs. 127% TCZ-PMN-low, P < 0·001; day 10, 180% placebo vs. 132% TCZ-PMN-low, P < 0·01), with a trend towards higher liver/spleen neutrophil retention. CONCLUSIONS: We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity.

Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study.

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.

The Impact of Pancreatic Enzyme Replacement Therapy on Patients With Advanced Pancreatic Adenocarcinoma: A Systematic Review and Narrative Synthesis.

ABSTRACT: Advanced pancreatic cancer has a poor prognosis globally. Patients often develop pancreatic exocrine insufficiency leading to malabsorption. This systematic literature review explores the impact of pancreatic enzyme replacement therapy (PERT) on patients with advanced pancreatic cancer. Data sources include MEDLINE, CINAHL, Embase, Cochrane (CENTRAL), PsychINFO, and Joanna Briggs Institute databases from inception to January 14, 2022, with reference list checking on Google Scholar. Narrative synthesis was used as the eligible studies were likely to be heterogeneous and hard to compare. This synthesis approach uses 4 steps: theory development, preliminary synthesis, exploration of relationships, and assessment of the robustness of the synthesis. Four themes arose from analyzing the study outcomes including PERT education, efficacy of PERT, the patient experience, and lack of awareness regarding enzyme replacement. The included studies did not use validated tools or standardized measurements, which made it difficult to compare or draw conclusions. Pancreatic enzyme replacement therapy shows the potential to improve symptoms, nutrition, weight loss, and survival, but high-quality studies with standardized outcomes have not been completed. Patient and health professional education is required because there seems to be a general lack of awareness about the use of PERT in pancreatic cancer.Systematic Review Registration: PROSPERO 2020 CRD42020195986.

Comparison of the MOdified NARanjo Causality Scale (MONARCSi) for Individual Case Safety Reports vs. a Reference Standard.

INTRODUCTION: In 2018, we published the MONARCSi algorithmic decision support tool showing high inter-rater agreement, moderate sensitivity, and high specificity compared with drug-event pairs (DEPs) previously reviewed using current, industry-established approaches. Following publication, MONARCSi was implemented as a prototype system to facilitate medical review of individual case safety reports (ICSRs). This paper presents subsequent evaluation of MONARCSi-supported causality assessments against an independent, best achievable reference standard. OBJECTIVE: This paper describes the development of an independent reference standard (i.e., reference comparator) using a sample of DEPs evaluated by Roche subject matter experts (SMEs) and subsequent performance analysis for both the reference standard and MONARCSi. METHODS: Roche collected a random sample of 131 DEPs evaluated by an external vendor using the MONARCSi prototype during 2020, and collectively referred to as the VMON (Vendor using the MONARCSi system for medical review) dataset. An internal group of causality SMEs (aka CAUSMET) were recruited and trained to assess the same DEPs independently using the MONARCSi structure with Global Introspection to determine their individual assessments of causality. The CAUSMET final causality was determined using a majority voting rule. RESULTS: Binary comparison of the aggregate results showed substantial agreement (Gwet kappa = 0.81) between the VMON and reference standard CAUSMET assessments. Bayesian latent class modeling showed that both the reference standard and VMON assessments exhibited similar high posterior mean sensitivity and specificity (CAUSMET: 89 and 93%, respectively; VMON: 87 and 94%, respectively). Finally, comparison of the sensitivity and specificity suggested no obvious difference across groups. CONCLUSION: Analysis of causality results from the assessments by independent internal SMEs using MONARCSi shows there is no obvious difference in performance between the aggregate CAUSMET and VMON assessments based on the comparison of specificity and sensitivity. These results further support use of MONARCSi as a decision support tool for evaluating drug-event causality in a consistent and documentable manner.

Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer.

BACKGROUND: The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. METHODS: Patients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data. RESULTS: A total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 µg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients. CONCLUSIONS: These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients. TRIAL REGISTRATION: NCT02541604.

Short-term interactions of aniline and benzidine with three soils in both natural and artificial matrices.

The fate of aromatic amines in natural systems is important to understand due to the persistence and toxicity of these chemicals. Laboratory experiments were performed to elucidate aniline and benzidine behavior in silty-clay, sandy loam, and sandy soils, and six background matrices (rainwater, 12.5 mM CaCl(2), 25 mM CaCl(2), and each passed through soil columns). The goals of this study were to test the validity of using CaCl(2) as a laboratory simulation for rainwater and to observe how short-term sorption (24 h) of aniline and benzidine changed when these solutions were passed through soil columns. Results indicated that neither CaCl(2) solution exactly predicted the sorption of these chemicals in corresponding rainwater solutions, likely due to varying soil properties that influenced the sorption mechanisms. Statistical analyses revealed that the passage of rainwater or CaCl(2) solutions through soil columns did not significantly affect the sorption of aniline or benzidine. Cation exchange and solubility plots were created to identify the sorption mechanisms taking place in the short-term batch experiments. These plots indicated that cation exchange played a role in the sorption of both aniline and benzidine under all conditions, while solubility plots showed higher correlations for benzidine, a consequence of its lower aqueous solubility.

Benzidine transformation processes in natural sediments.

Aromatic amines, such as benzidine and 3,3'-dichlorobenzidine, are chemicals used in the pigment and dye processes. Release of these compounds into the environment is important because of their carcinogenic and toxic nature. In the present study, the sediment and water samples were collected from Lake Macatawa (Holland, MI, USA) and subsequently spiked with benzidine. The grain size distribution of the sediment samples investigated here ranged in composition from sandy to silty-clay sediment types. The sediment-water systems spiked with benzidine were incubated under anaerobic conditions at 4, 15, and 23 degrees C for 211 d. Degradation of benzidine was observed over the time-course analysis of the sediment-water mixtures. Three possible metabolites (aniline, 2-ethyl-1-hexanol, and 1-amino-2-hexene) were observed during this investigation as a result of gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. No metabolites were observed in autoclaved bottles, suggesting that the transformation of benzidine in the sediment-water mixtures was the result of microbial activity. From sediment-water distribution experiments, benzidine demonstrated higher sorption affinity for the different sediment phases than its degradation product, aniline. Therefore, microbially mediated transformation of benzidine to aniline is expected to yield a greater total concentration of the more mobile compound, aniline, in the water phase and a greater possibility for transport of aniline in the water phase.

Concentrations and distribution of 3,3'-dichlorobenzidine and its congeners in environmental samples from Lake Macatawa.

Release of 3,3'-dichlorobenzidine (DCB), an intermediate in dye manufacturing processes, is of environmental concern due to its carcinogenic nature. An 11-year field study has been conducted to elucidate the fate and behavior of DCB and its congeners in the Lake Macatawa (Holland, MI, USA) sediment-water system. The sediments were variable in composition, ranging from sandy sediments with 1-8.7% total organic carbon (OC) to silty-clay sediments with 7.5-20.6% total OC. The pH ranged from 6.3 to 7.4. The findings from this field study confirmed that DCB and its congener, benzidine, are transported over long distances. The concentration of DCB in the water phase was found to be from non-detectable to approximately 1300 times greater than the water quality criteria established for DCB (0.021 microg/l). Its congener, benzidine, which is substantially more toxic for humans than its parent compound has been found up to approximately 12300 times higher levels than the EPA guidelines suggest (0.000086 microg/l). Both DCB and benzidine were found in the sediment phase. DCB was observed at almost 70 mg/kg in a sample collected in 1993. The concentrations in both phases have declined in recent years. To assess the threat of the released pollutants, it is necessary to understand how pollutants tend to behave in various media. Therefore, it is crucial to identify and quantify all sources of the chemical and its congeners in order to meaningfully predict the fate (and transport) of a hydrophobic organic compound (HOC) in the environment.

Sorption of benzidine and 3,3'-dichlorobenzidine to lake sediments. 1. Conceptualization and development of a multiparameter model.

Aromatic amines, such as benzidine and 3,3'-dichlorobenzidine (DCB), are part of the dyes and pigments manufacturing process. The prolonged use of these carcinogenic chemicals in the past generation has introduced a significant amount of contamination to the environment. Their persistency in several mediums has sparked a number of studies in an attempt to develop predictive tools of their fate and transport in the environment. In this study, benzidine and DCB batch isotherms were developed and evaluated. The sediment samples were variable in composition, ranging from sandy to silty-clay sediment samples. The batch isotherms were then analyzed using high-performance liquid chromatography. Subsequently, a multiparameter model (MPM) that accounted for partitioning, covalent bonding, and cation exchange was developed and tested in an effort to understand the various mechanisms. Results proved the proposed model to be effective in predicting sorption of aromatic amines to lake sediments. The findings suggest that the MPM can provide a better understanding of the sorption process of aromatic amines than more conventional models.