Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose–escalation phase 1 trial

Purpose New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Methods Part 1 featured a 3 + 3 weight-based dose–escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator’s decision, or death. Results The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. Conclusions Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

Patient characteristics predicting attendance for elective in-patient treatment of substance use disorder

Objective: Consumption of alcohol and other drugs constitutes a significant health burden. Treatment access is poor, and a number of barriers are recognised. The objective of this retrospective cohort study is to examine patient characteristics of those attending/not attending for elective in-patient withdrawal management (IWM). Methods: Records of all elective admissions for IWM between 1 March and 30 June 2019 were reviewed. Data were extracted on attendance, age, substance(s) used, pre-arranged rehabilitation admissions following discharge, wait time, legal issues and child welfare agency involvement. Results: Of 274 planned admissions, 193 (70%) attended. Attendance was predicted by residential treatment planned after withdrawal management and older age. People using amphetamines were less likely to attend. Conclusion: There are low attendance rates for elective IWM. Patient characteristics predicting lower attendance include younger age, amphetamine use and not planning rehabilitation. Further research is required to improve attendance.

Stability of early anterior open bite treatment: a 2-year follow-up randomized clinical trial

This 2-year-follow up study compared and evaluated the stability of early anterior open bite (AOB) treatment based on different appliances. Children from 7 to 10 years with Angle Class I, AOB larger than 1.0 mm and fully erupted maxillary and mandibular permanent central incisors were eligible. The initial sample was 99 patients distributed, by simple randomization, into four groups: BS (bonded spurs), CC (chincup), FPC (fixed palatal crib) and RPC (removable palatal crib). Cephalometric analysis was performed at baseline (T1), final (T2) and 2-year post-treatment (T3) by taking the overbite measurements as the main outcome. Blinding was possible to cephalometric analysis. At T3, with dropouts, there were 63 individuals, being BS (n=15; overbite 0.19 mm; 11.54 years; 10 female (F)/5 male (M)); CC (n=11; overbite -0.19 mm; 11.41 years; 8 F/3 M); FPC (n=21; overbite 1.23 mm; 11.44 years; 15 F/6 M) and; RPC (n=16; overbite 0.73 mm; 11.67 years; 6 F/10 M). Changes in dentoskeletal variables and breaking deleterious oral habits during the follow up were statically analyzed with p<.05. Mandibular skeletal linear measurements and vertical dental components have gradually increased with age, manly at pubertal growth spurt and at the establishment of permanent dentition after treatment. Incisor teeth extrusion had impact on AOB correction and stability in 4 groups, which recorded a 1.15 mm-improvement of overbite after treatment (T3-T2). The experimental appliances were effective with stable results, being FPC the device recorded the highest AOB correction and the lowest patient withdrawal rate.

Comparison of Inhaled Colistin with Inhaled Amikacin-Fosfomycin in the Treatment of Ventilator-Associated Pneumonia Caused by Extensively Drug-Resistant (XDR) Acinetobacter: A Clinical Trial

Background: This study aimed to compare the effects of inhaled colistin and inhaled amikacin-fosfomycin combination in the treatment of ventilator-associated pneumonia (VAP) caused by extensively drug-resistant (XDR) Acinetobacter. This clinical trial is the first study to evaluate the effect of inhaled fosfomycin on VAP in Iran. Methods: In this clinical trial, 60 patients with Acinetobacter VAP were divided into two groups of 30 patients. The empirical regimen changed to meropenem plus intravenous colistin in both groups. Inhaled colistin in the first group and inhaled amikacin-fosfomycin in the second group were added to the intravenous therapy. Next, the mortality rate, if any, duration of treatment success, and patient withdrawal from VAP were evaluated in the two groups. Results: Although the mean clinical pulmonary infection score (CPIS) before treatment was not significantly different between the two groups, the mean score of the amikacin-fosfomycin group was significantly lower at 72 hours and seven days after the onset of treatment and at the end of treatment. Based on the intra-group assessments, the CPIS in both groups was significantly reduced (P < 0.001). Also, in the inter-group assessments, the mean CPIS changes were significantly different between the two groups, and in the amikacin-fosfomycin group, a greater reduction in the CPIS was observed (P = 0.007). Conclusions: The findings of the present study showed that the use of amikacin-fosfomycin nebulization could lead to increased recovery and reduced treatment duration in patients with VAP, caused by drug-resistant Acinetobacter baumannii.

Acute period of polytrauma in children in the light of discriminant analysis

Introduction. The treatment of polytrauma in children requires identifying the signs that characterize the severity of the acute period and quantifying the priorities of the parameters. Collectively, these reflect the direction of drift of the leading pathophysiological manifestations at each stage of the patient withdrawal program from a state of severe shock. Purpose. This study uses discriminant analysis to clarify the tactics of children with polytrauma in the first days of overcoming its consequences. It is based on the pathogenetically sound idea that each of the observed parameters role, together in the form of a vector, reflects injury severity and the childs prognosis. Materials and methods. This analysis included 45 children (34 boys and 11 girls) with polytrauma aged from 2.5 to 17 years and hospitalized in Kemerovos intensive care unit. Two groups were analyzed: the survivors and those who were deceased. Both were dominated by severe traumatic brain injury (PMT). The injury severity score (ISS) scale was used for clinical assessment of injury severity. Results. Combined with objectively obtained data on the structure of polytrauma in the direction of drift, a successful outcome is defined as a whole. It borders on the day to day priorities, potassium, PH, white blood count, and hematocrit. Also, the vector orientation pattern was observed to increase organ failure. This progressive decline occurred despite timely surgical intervention to stop internal bleeding, very active efforts to compensate for hypovolemia, acidosis, and the use of adequate means of detoxification. The deterioration in the child's condition manifests itself by increased potassium losses against the background of almost no reaction from leukocytes. Conclusions. The application of discriminant analysis enables the better revelation of the peculiarities of a polytraumas multidimensional dynamics in children in the first few days of resuscitation. It also permits the numerical expression of the priorities of individual parameters that describe their state, and by the severity and individual patient response in real-time to optimize treatment.

Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study

Background. Combination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported. Methods. Patients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study. Results. In total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: −16.2 [−18.5, −14.0] and −0.9 [−1.0, −0.8], respectively). Conclusion. OLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.

P.064 FIREFISH Part 1: 1-year results on motor function in infants with Type 1 spinal muscular atrophy (SMA) receiving risdiplam (RG7916)

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.

COMPARATIVE EVALUATION OF THE LONG-TERM EFFICACY AND SAFETY OF THE INFLIXIMAB BIOSIMILAR BCD-055 AND REFERENCE INFLIXIMAB IN PATIENTS WITH ANKYLOSING SPONDYLITIS: RESULTS OF THE INTERNATIONAL MULTICENTER RANDOMIZED DOUBLE-BLIND PHASE III CLINICAL STUDY ASART-2

The paper gives data on the clinical efficiency and safety profile of long-term use of the infliximab (INF) biosimilar BCD-055 versus the reference drug Remicade® (REM) in a population of patients with active ankylosing spondylitis (AS).Subjects and methods. An international multicenter randomized double-blind Phase III clinical trial was conducted in 199 patients who were randomized into two groups in a 2:1 ratio and who received BCD-055 or REM at a dose of 5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks. Efficiency assessment was made at 14, 30 and 54 weeks in patients who received at least one dose of INF [intent-to-treat (ITT)], as well as at 54 weeks in those who completed the study according to the Protocol (PP) (per protocol). The efficiency endpoints were the proportion of patients who had achieved ASAS20/ASAS40 responses; changes in BASDAI, BASMI, BASFI, MASES, and SF-36 scores. Immunogenicity was assessed by the proportion of patients in each group with identified binding and neutralizing antibodies (BAbs and NAbs) against INF. The safety analysis included the overall rate of adverse events (AEs), including those that met the respective criteria for serous AEs (SAEs), and grade 3–4 toxicity, as well as the number of cases of early termination of the study because of AEs and SAEs.Results and discussion. The ITT population included 199 patients and the PP one consisted of 161 people. The groups were not statistically different in the rate of and reasons for patient withdrawal from the study. A comparable number of patients achieved ASAS20/ASAS40 responses at 14, 30, 54 weeks (р ≥ 0.05). At 54 week, the proportion of patients who received BCD-055 and REM therapy and achieved an ASAS20 response was 67.42 and 52.24% in the ITT population (p = 0.053) and 80.91 and 68.63% in the PP population (p = 0.128). The BCD-055 and drug comparison groups achieved an ASAS40 response in 53.03 and 38.81% in the ITT population (p = 0.081) and in 63.64 and 50.98% in the PP one (p = 0.177). The proportion of persons with identified BAbs and NAbs was comparable: 21.26 and 3.15% in the BCD-055 group (p = 0.920) and 20.63 and 6.35% in the group REM (p = 0.443), respectively. It was found that the presence of NAbs did not affect the therapeutic response. Both groups did not differ in the detection rate and profile of AEs and SAEs or in the rate of patient withdrawal due to AEs. Most identified AEs were mild to moderate.Conclusion. The efficacy of the INF biosimilar BCD-055 used long in patients with AS did not significantly differ from that of the original drug REM; the safety profile of both drugs was comparable.