Events Of Special Interest Research Articles

A phase 2, open-label, 2-cohort study to evaluate patient preference for nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) subcutaneous (SC) vs NIVO + RELA FDC intravenous (IV) and NIVO SC vs NIVO IV in participants with melanoma.

TPS9619 Background: The oncology burden on healthcare resources and patients increases as the number of individuals with cancer grows, necessitating treatment options offering improved convenience to patients. SC delivery of monoclonal antibodies in various cancer indications has previously been shown to be effective, well tolerated, and preferred by patients over IV infusion. In CheckMate 67T (NCT04810078), noninferiority of exposure (time-averaged serum concentration at Day 28 and trough serum concentration at steady state) and efficacy (objective response rate by BICR) were previously reported for NIVO SC 1200 mg + recombinant human hyaluronidase PH20 (rHuPH20) vs IV in patients with locally advanced/metastatic clear cell renal cell carcinoma. RELATIVITY-127 (NCT05625399) is ongoing to establish exposure noninferiority of NIVO + RELA + rHuPH20 FDC SC to IV in patients with previously untreated metastatic/unresectable melanoma. This phase 2, open-label study CA224-1044 (NCT06101134) assesses patient preference for NIVO SC or NIVO + RELA FDC SC vs IV formulations after transitioning from IV to SC in patients with melanoma and aims to further characterize the safety profile of immuno-oncology therapy during IV-to-SC switch. Methods: Cohort 1 includes adult patients with previously untreated stage III (unresectable) or stage IV (metastatic) melanoma who will receive NIVO + RELA FDC IV every 4 weeks (Q4W) for 2 cycles (28-day cycle) followed by NIVO + RELA + rHuPH20 FDC SC Q4W until disease progression, unacceptable toxicity, or a maximum total treatment duration of 2 years, whichever comes first. Cohort 2 includes adult patients with completely resected stage IIB/C, stage III or stage IV melanoma who will receive NIVO IV Q4W for 2 cycles (28-day cycle) followed by NIVO SC + rHuPH20 Q4W until disease recurrence, unacceptable toxicity, or a maximum total treatment duration of 1 year, whichever comes first. The primary endpoint is the proportion of participants preferring the SC route of administration based on question 7 of the Patient Experience and Preference Questionnaire after the Cycle 4 Day 1 dose. This question evaluates patient preference for IV or SC or no preference in treatment administration and was previously used in CheckMate 8KX. Secondary endpoints include safety outcomes such as adverse events (AEs), serious AEs, treatment-related AEs, AEs leading to discontinuation, immune-mediated AEs, other events of special interest, injection/infusion-related AEs, deaths, and laboratory abnormalities. Safety is assessed for IV period, SC period (8 weeks each) and overall study period. Exploratory endpoints include additional measures of patient experience and preference for IV vs SC. The study is recruiting to enroll 50 patients per cohort. Clinical trial information: NCT06101134 .

Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin. ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m2 or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed. Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m2 [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0-1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and -27·0% (90% CI -38·4 to -13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group. Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy. AstraZeneca.

Accounting for Competing Events When Evaluating Long-Term Outcomes in Survivors of Critical Illness.

The clinical trajectory of survivors of critical illness after hospital discharge can be complex and highly unpredictable. Assessing long-term outcomes after critical illness can be challenging because of possible competing events, such as all-cause death during follow-up (which precludes the occurrence of an event of particular interest). In this perspective, we explore challenges and methodological implications of competing events during the assessment of long-term outcomes in survivors of critical illness. In the absence of competing events, researchers evaluating long-term outcomes commonly use the Kaplan-Meier method and the Cox proportional hazards model to analyze time-to-event (survival) data. However, traditional analytical and modeling techniques can yield biased estimates in the presence of competing events. We present different estimands of interest and the use of different analytical approaches, including changes to the outcome of interest, Fine and Gray regression models, cause-specific Cox proportional hazards models, and generalized methods (such as inverse probability weighting). Finally, we provide code and a simulated dataset to exemplify the application of the different analytical strategies in addition to overall reporting recommendations.

Hypoxia-Inducible Factor-Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body's response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.

Do we miss rare adverse events induced by COVID-19 vaccination?

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused many complications, the invention of coronavirus disease 2019 (COVID-19) vaccines has also brought about several adverse events, from common side effects to unexpected and rare ones. Common vaccine-related adverse reactions manifest locally or systematically following any vaccine, including COVID-19 vaccines. Specific side effects, known as adverse events of particular interest (AESI), are unusual and need more evaluation. Here, we discuss some of the most critical rare adverse events of COVID-19 vaccines.

Effects of sodium-glucose cotransporter-2 inhibitors and aldosterone antagonists, in addition to renin-angiotensin system antagonists, on major adverse kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis.

To compare the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid receptor antagonists (MRAs), selective aldosterone antagonists and nonselective aldosterone antagonists, on top of renin-angiotensin-aldosterone system (RAAS) blockade, in reducing kidney-specific composite events, cardiovascular outcomes, and other events of special interest in participants with type 2 diabetes (T2D) and chronic kidney disease (CKD). PubMed, EMBASE and CENTRAL were searched for studies published up to January 20, 2022. Randomized clinical trials enrolling participants with T2D and CKD were included, in which SGLT2 inhibitors, nonsteroidal MRAs, selective aldosterone antagonists and nonselective aldosterone antagonists were compared with either each other, or with placebo or no treatment. A network meta-analysis using a Bayesian approach was performed. The primary outcome was a kidney-specific composite event. Secondary outcomes included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and all-cause mortality. We also examined blood pressure and safety outcomes of interest, including acute kidney injury, hyperkalaemia, hyponatraemia, and volume reduction events. All research was conducted according to a protocol registered in the PROSPERO database (CRD42022307113). This meta-analysis of 17 trials randomizing 22 981 participants found SGLT2 inhibitors (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52 to 0.73) and nonsteroidal MRAs (OR 0.76, 95% CI 0.66 to 0.88) were associated with significantly lower kidney-specific composite events than the control groups. Nonsteroidal MRAs (OR 0.78, 95% CI 0.66 to 0.92) and SGLT2 inhibitors (OR 0.57, 95% CI 0.45 to 0.72) were associated with greater reductions in hospitalization for heart failure than the control groups. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs (OR 0.73, 95% CI 0.55-0.97). SGLT2 inhibitors were associated with a reduction in cardiovascular death (OR 0.80, 95% CI 0.65 to 0.98) and all-cause mortality (OR 0.79, 95% CI 0.66 to 0.93) compared with the control groups. When compared to the control groups, both nonsteroidal MRAs (weighted mean difference [WMD] -10.96, 95% CI -20.49 to -1.46) and SGLT2 inhibitors (WMD -3.50, 95% CI -6.01 to -1.013) were linked with lower systolic blood pressure, nonsteroidal MRAs (OR 2.27, 95% CI 2.02 to 2.56) and nonselective aldosterone antagonists (OR 3.22, 95% CI 1.43 to 7.66) were associated with an increased risk of hyperkalaemia, nonsteroidal MRAs were linked with an increased risk of hyponatraemia (OR 16.56, 95% CI 2.78 to 455.19), and SGLT2 inhibitors were associated with an increased risk of volume reduction events (OR 1.28, 95% CI 1.06 to 1.56). SGLT2 inhibitors were ranked the best for our primary and secondary outcomes. Confidence in the evidence was often high or moderate. In this network meta-analysis, the use of SGLT2 inhibitors or nonsteroidal MRAs, combined with RAAS blockade, was associated with a reduction in kidney-specific composite events and hospitalization for heart failure events in patients with T2D and CKD compared to placebo or no treatment. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs. Use of SGLT2 inhibitors was associated with lower mortality than placebo or no treatment.

A bioequivalence study of a novel liquid and ready-to-use temozolomide oral suspension and temozolomide capsules in patients with primary tumors central nervous system malignancies.

e22008 Background: Oral temozolomide capsule is approved for the treatment of glioma and malignant glioblastoma in adults and in Europe in children over 3-years. As recommended by international pediatric medical associations, temozolomide is also used for the treatment of high-risk relapsed or refractory neuroblastoma, a solid tumor affecting young children. Nevertheless, capsules are not adapted to the pediatric population leading caregivers to handle temozolomide capsules, which bears major risks (i.e. dose inaccuracy, temozolomide instability and exposure to cytotoxic drug). To overcome this situation, a temozolomide oral suspension (Kimozo) was developed. The aim of this phase I study was to demonstrate bioequivalence between the temozolomide oral suspension and the temozolomide capsules (Temodal) and to assess the general and local safety in adult patients. Methods: A randomized, open-label, two-way crossover, single-dose bioequivalence study was performed in 8 centers. Adult patients with primary malignancies and treated with temozolomide 200 mg/m² as monotherapy received a single oral administration of the oral suspension (test) or capsule (reference) on days 1 and 2 of a 5-day cycle, depending on the randomization, and under fasting conditions. Fourteen blood samples were collected over 10-hr in each period for pharmacokinetic purpose. General and buccal safety was assessed along the study. The assessment of bioequivalence was based upon 90% confidence intervals (CI) for the ratio of the population geometric means (test/reference) for maximum plasma concentration (Cmax) and area under the curve (AUC0-t). Results: Among the thirty-six patients enrolled in the study, thirty were assessable for pharmacokinetic primary endpoint. The point estimate and the 90% CI of the ratios of Cmax and AUC0-t were 107.62 (98.07-118.09) and 97.18 (95.05-99.35), respectively. The results obtained satisfy the bioequivalence criteria of the Bioequivalence Guidelines (90% CI between 80.00% and 125.00%). Neither serious adverse events nor adverse events of special interest (i.e. mucositis) were reported. Conclusions: The oral suspension of temozolomide (Kimozo) and capsule of temozolomide (Temodal) are bioequivalent under fasting conditions in patients with CNS primary malignancies, supporting that they are therapeutic equivalent. Clinical trial information: NCT04467346.

Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: Further analyses from the PROfound study

BackgroundBased on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest. MethodsPatients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment. Results256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients. ConclusionsThe four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit. ClinicalTrialsgov registration number: NCT02987543.

The CLARION study design and status update: a long-term, registry-based study evaluating adverse events of special interest in patients with relapsing multiple sclerosis newly started on cladribine tablets

Objective To describe the design of the CLARION post-approval safety study (EU PAS Register number, EUPAS24484) and provide a status update, including characteristics of patients included up to 1 May 2021. Methods CLARION aims to further evaluate adverse events of special interest in patients who are newly initiating treatment with cladribine tablets for relapsing multiple sclerosis (MS). The study population consists of two cohorts: patients newly initiating cladribine tablets (cladribine cohort) and patients newly initiating oral fingolimod tablets (comparator fingolimod cohort), with an aim to include 8000 patients (4000 patients per cohort). The study relies on secondary use of data from pre-existing MS registries/data sources (except in Germany, where primary data collection is performed). The study is projected to last 15 years, with an anticipated 5-year inclusion period. Study outcomes are: malignancies; severe infections; tuberculosis; progressive multifocal leukoencephalopathy; other opportunistic infections; herpes zoster; severe lymphopenia (Grade ≥ 3); and treatment discontinuation. Results As of 1 May 2021, 2393 patients were included in CLARION from seven participating MS registries/data sources (cladribine cohort, n = 1266; fingolimod cohort, n = 1127). The majority of patients are female (cladribine cohort, 72.5%; fingolimod cohort, 68.0%), with mean age at onset of MS of 31.5 years for the cladribine cohort and 30.9 years for the fingolimod cohort. The majority of patients in both cohorts had relapsing MS (cladribine cohort, 92.1%; fingolimod cohort, 93.5%). Conclusion By providing further information on adverse events of special interest during long-term follow-up, CLARION will assist neurologists and patients regarding treatment decision-making for management of relapsing MS.

A pilot study investigating the safety and feasibility of endoscopic dilation using a radial incision and cutting technique for benign strictures of the small intestine: a study protocol

BackgroundSmall benign intestinal stenosis is usually treated by endoscopic balloon dilation (EBD) or surgery. Although EBD and surgery are able to resolve the stenosis in most cases, they are associated with several problems such as insufficient dilation and surgical stress, respectively. On the contrary, a novel approach called radial incision and cutting (RIC) is reported to have several benefits when compared to EBD and surgery. We can currently adopt RIC only for the strictures in the colon or terminal ileum and not for those stenotic lesions present further in the small intestine where balloon-assisted endoscopy is utilized, because the long-type electric knife is currently not approved for use in Japan. We will herein conduct a pilot study to investigate the safety and feasibility of RIC for treating the benign stenoses of the small intestine using the long-type electric knife.MethodsThis will be a single-center, single-arm, interventional trial. The major criteria for inclusion will be age ranging from 20 to 80 years and the presence of benign stenosis in the small intestine. We will perform RIC on 10 participants. The primary outcome is the safety of this procedure, which will be assessed by measuring the frequency of adverse events of special interest. The secondary outcomes will be technical success rate, improvement in subjective symptoms, procedure time, and duration of hospitalization.DiscussionThis pilot study will provide useful information that will aid in adopting RIC for treating the benign strictures present in the small intestine.Trial registrationjRCT Identifier, jRCTs022200040. Registered on 1 March 2021.

Effective Jet-Grouting Application for Improving the State of Deformation of Landmarks

The problem of improving the state of deformation of landmarks is an important aspect when performing civil services, because they have a historical interest and bring symbolisms which relate to an event of particular interest for the community. The engineering–geological surveys, technical evaluation and operational suitability of landmarks of national significance are performed to improve the state of deformation. The conducted analytical assessment of landslide hazard slope stability in the RocScience Slide computational complex shows that in the presence of landslide prevention works, and the stability coefficient is increased by a factor of 1.21–1.37. The regularities of deformation and strength parameters of the soil–cement obtained during the jet-grouting application indicated an increase in strength gain of amplifier elements by an average of 1.6–4.0 times. This proves the effectiveness of the jet-grouting application for improving the state of deformation of landmarks of national significance.

Incidence of venous thrombotic events and events of special interest in a retrospective cohort of commercially insured US patients

ObjectiveTo estimate the US incidence of thrombotic events and related rare diagnoses.DesignClaims-based retrospective cohort study of incidence.SettingUS commercial health insurance administrative claims database.ParticipantsAdults 25–64 years of age between 2015 and...

449. Performance of the Brighton Case Definition for Multisystem Inflammatory Syndrome in Children (MIS-C) Among a Large Single Center Cohort

BackgroundMultisystem Inflammatory Syndrome in Children (MIS-C) is a rare, life-threatening, hyperinflammatory condition presumed to follow SARS-CoV-2 infection. Whether MIS-C can also follow SARS-CoV-2 vaccination is not clear, making MIS-C an adverse event of special interest following immunization. Monitoring for post-vaccine MIS-C is complicated by the clinical overlap of MIS-C with numerous other inflammatory conditions including Kawasaki Disease, toxic shock syndrome, and viral myocarditis. A case definition for MIS-C was recently created with the Brighton Collaboration (BC). We aimed to determine the performance of the BC MIS-C case definition among a large, single-center MIS-C cohort.MethodsRetrospective review was performed for the first 100 MIS-C cases at our institution (May 2020-February 2021). All cases met the Centers for Disease Control and Prevention (CDC) case definition. Data on age, presentation, laboratory results and cardiac studies were collected and used to determine cases that fulfilled the BC case definition for MIS-C (see figure).Case Definition: Definite Case ResultsOf 100 children (age < 21 years) diagnosed with MIS-C using the CDC case definition, 93 patients also fulfilled the BC definition. All 100 patients had elevated laboratory markers of inflammation and positive SARS-CoV-2 antibodies. However, 1 patient was excluded for significant respiratory symptoms (pulmonary hemorrhage), 5 were excluded due to only 1 clinical feature, and an additional patient was excluded for having none of the measures of disease activity. Among the 93 patients fulfilling the revised case definition, 88 (95%) met criteria for a definite case. Five of the 93 patients (5%) were considered probable cases, 1 reported only 1 day of fever and 4 had only 1 measure of disease activity.ConclusionThe original case definitions for MIS-C were created rapidly following the first emerging reports of this hyperinflammatory state. Knowledge of the varied clinical presentations of this disorder has grown substantially. Modification of the case definition to include features truly representative of MIS-C will allow for more precise diagnosis in the face of conditions which mimic MIS-C, and for accurate and reliable monitoring for adverse events following immunization.Disclosures Flor M. Munoz, MD, Biocryst (Scientific Research Study Investigator)Gilead (Scientific Research Study Investigator)Meissa (Other Financial or Material Support, DSMB)Moderna (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Pfizer (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Virometix (Other Financial or Material Support, DSMB)

An open-label randomized multi-Centre study to evaluate anterior controllable Antedisplacement and fusion versus posterior Laminoplasty in patients with cervical ossification of the posterior longitudinal ligament: study design and analysis plan (STAR)

BackgroundIn treating patients with cervical ossification of the posterior longitudinal ligament (COPLL), a novel surgery technique - anterior controllable antedisplacement and fusion (ACAF) suggested promising clinical benefits in recent exploratory studies.MethodsThis is a multicentre, randomized, open-label, parallel-group, active controlled trial that will compare the clinical benefits of ACAF versus conventional posterior laminoplasty (LAMP) in severe COPLL patients. A total of 164 patients will be enrolled and randomized in a 1:1 ratio to either ACAF or LAMP group. The primary efficacy measure is cervical- Japanese Orthopaedic Association (C-JOA) recovery rate at 12 months post operation, which is to be derived by Hirabayashi’s method from JOA data (range, 0 [worst] to 17 [normal condition]). Other important secondary efficacy endpoints include visual analogue scale (VAS) pain score (range, 0 [no pain] to 10 [most severe]), 10-item neck disability index (NDI, a total range of 0 to 50 points, the highest index the worst) and 6-level Nurick disability grade (range, 0 [mild] to 5 [severe]). Safety endpoints including adverse events, perioperative complications, and adverse events of special interest will also be assessed in this study. Full analysis set for baseline and efficacy data analyses according to the intention-to-treat principle will be established as the primary analysis population. Analysis of covariance (ANCOVA) will be used to analyze the C-JOA recovery rate, with random stratification factors (if appropriate) and the treatment group as fixed factors, and the baseline level of C-JOA score as covariate.DiscussionThis study is designed to demonstrate the clinical benefits of ACAF as compared to conventional LAMP in COPLL patients. It will provide clinical evidence that the novel surgery technique – ACAF might be more favorable in treating patients with severe cervical ossification of the posterior longitudinal ligament. (Words: 290).Trial registrationClinicalTrials.gov number, NCT04968028.

DOP85 Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. Here, we report corticosteroid-free efficacy and safety among patients (pts) who received oral corticosteroids at baseline of the maintenance study (OCTAVE Sustain). Methods Pts with clinical response following OCTAVE Induction 1&amp;2 who were re-randomised to receive placebo or tofacitinib 5 or 10 mg twice daily (BID) in OCTAVE Sustain, and who were receiving oral corticosteroids at baseline of OCTAVE Sustain, were included. Corticosteroid tapering was mandatory at the beginning of OCTAVE Sustain. Steroid-free (not requiring any treatment with corticosteroids for ≥4 weeks prior to the visit) rates of remission, endoscopic improvement and clinical response were assessed at Week 24 and/or Week 52. The association between baseline characteristics and steroid-free efficacy outcomes was evaluated using logistic regression. Safety outcomes were stratified by tofacitinib dose and steroid-free remission status. Results Of 593 pts entering OCTAVE Sustain, 289 had oral corticosteroid use at baseline. Of these, 101 (34.9%) received placebo and 188 received tofacitinib (101 [34.9%] 5 mg BID; 87 [30.1%] 10 mg BID) in OCTAVE Sustain. Among pts receiving oral corticosteroids on Day 1 of OCTAVE Sustain, the mean dose (mg/day [standard deviation], prednisone equivalent) received was 15.8 (6.2), 14.9 (6.2) and 14.4 (6.0) in the placebo, tofacitinib 5 mg BID and tofacitinib 10 mg BID groups, respectively. At Week 24 or Week 52 of OCTAVE Sustain, there was a significant treatment effect for tofacitinib 5 or 10 mg BID vs placebo for steroid-free efficacy endpoints (Table 1). Prior immunosuppressant failure was associated with lower odds of achieving steroid-free remission at Week 52 of OCTAVE Sustain (odds ratio [OR] 0.47 [95% confidence interval (CI) 0.23, 0.95]), while prior tumour necrosis factor inhibitor (TNFi) failure status only had a limited effect, which was not statistically significant (OR 0.53 [95% CI 0.27, 1.02]). Oral corticosteroid dose received at baseline of OCTAVE Sustain did not affect the likelihood of achieving steroid-free remission at Week 52. Adverse events of special interest were infrequent (Table 2). Discontinuations were numerically higher among pts without steroid-free remission (Table 2). Conclusion For pts with baseline oral corticosteroid use in OCTAVE Sustain, the odds of achieving steroid-free efficacy endpoints were significantly higher for tofacitinib 5 or 10 mg BID compared with placebo. Prior TNFi failure was not associated with lower odds of achieving steroid-free remission at Week 52. There were no apparent differences in safety by steroid-free remission status. Data interpretation is limited by small pt numbers.

Imfirst: A phase IIIb, safety, single arm study of carboplatin (CB) or cisplatin (CP) plus etoposide (ET) with atezolizumab (ATZ) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) in Spain—Primary safety results of the induction phase.

8567 Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]

Luspatercept: A Review in Transfusion-Dependent Anaemia due to Myelodysplastic Syndromes or β-Thalassaemia

Luspatercept (Reblozyl®), a first-in-class erythroid maturation agent, is approved in several countries worldwide for the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS), who have failed prior erythropoiesis-stimulating therapy, or β-thalassaemia. In pivotal, placebo-controlled, phase III trials, subcutaneous luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS or β-thalassaemia. Luspatercept had a generally manageable tolerability profile in clinical trials. Adverse events of special interest include thromboembolic events, hypertension and bone pain. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS or β-thalassaemia.

P191 Secukinumab demonstrates a consistent safety profile in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis over long term: updated pooled safety analyses

P191 Secukinumab demonstrates a consistent safety profile in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis over long term: updated pooled safety analyses

An open-label, multicenter, phase IIIb study of patients with urinary tract carcinoma (UTC) (STRONG): Final analysis for fixed-dose durvalumab monotherapy (module A).

429 Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . [Table: see text]

Abstract PS12-13: Balixafortide (a CXCR4 antagonist) plus eribulin in HER2 negative metastatic breast cancer: Final analysis from the Phase 1 single arm trial

Abstract Background: Balixafortide (B) is a potent, selective antagonist of the chemokine receptor CXCR4. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in metastatic breast cancer (MBC). Efficacy and safety data were published recently from the Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC1. We report the final safety and efficacy analyses from this trial, including an assessment of dose-response and adverse events of particular interest (AEPIs) (e.g. neutropenia, peripheral neuropathy). Methods: In this single-arm, dose escalation trial, patients (pts) received E + increasing doses of B using a 3+3 design in 3 parts: Part I cohorts received low B doses (0.5−1mg/kg) + increasing E doses (1.1−1.4mg/m2); Part II dose-escalation cohort for B (1−5.5mg/kg) + 1.4mg/m2 E; Expanded Cohort (EC) to confirm safety and efficacy of B 5.5mg/kg + 1.4mg/m2 E. Most cohorts received E on days 2 and 9, and B on days 1−3 and 8−10 of 21-day cycles. Results: At entry, all 56 women (age range 33−82 years) were HER2 negative, CXCR4 positive. Most pts were Caucasian and heavily pretreated in the metastatic setting (line of chemotherapy on study: 29% 2nd line, 50% 3rd line, 21% 4th line). 75% were hormone receptor positive and 23% had triple negative breast cancer. A linear dose-exposure was observed over the entire dose range tested for B. Cmax and AUC for E were within published ranges. Safety findings (including AEPIs) remained similar to those reported previously1. No dose-limiting toxicities were confirmed; therefore, the maximum tolerated dose of B was not reached. The highest B dose evaluated was 5.5mg/kg; pharmacokinetic evaluation showed that further protocolled dose increments of B would not have provided a sufficient increase in plasma levels. In addition, the objective response rate in Part II was 3-fold greater than published for eribulin alone which suggested that the anti-tumor activity of B was worthy of further exploration at 5.5mg/kg in the EC. Efficacy data for the trial are shown in the table. These data suggest a potential dose-response relationship for B across all efficacy endpoints, with efficacy being numerically greatest in the EC. While PFS and OS should be interpreted with caution in single arm trials, these data suggest potential benefit for this combination. Further analyses will be presented. Responses were observed regardless of line of chemotherapy on study or extent of CXCR4 expression and were numerically higher in hormone receptor positive patients. Conclusions: A consistent dose response effect for B + E was suggested across all efficacy endpoints for heavily pretreated pts with HER2 negative MBC. When these results are compared with published data for E monotherapy in similar populations, the EC consistently shows numerically greater benefit for all efficacy endpoints2, 3. The safety and tolerability of B + E appear comparable to published data on E or B alone, particularly for neutropenia and peripheral neuropathy1. These results suggest that B + E could potentially provide a new treatment option in heavily pretreated patients with HER2 negative MBC. A Phase 3 trial exploring efficacy and safety of B 5.5mg/kg + E is ongoing. 1. Pernas S et al. Lancet Oncol. 2018; 19: 812−242. Cortes J et al. Lancet. 2011; 377: 914−9233. Kaufman PA et al. J Clin Oncol. 2015; 33: 594−601 Part II(N=21)Expanded Cohort(N=24)Overall Efficacy Population(N=54)Objective Response Rate (95% CI)33% (15−57)38% (19−59)30% (18−44)median duration in months (IQR)2.8 (1.4−3.3)4.4 (3.1−5.3)3.2 (2.2−4.5)Clinical Benefit Rate (95% CI)43% (22−66)63% (41−81)44% (31−59)median duration in months (IQR)5.4 (4.2−6.7)8.1 (6.3−10.8)6.9 (5.4−10.3)median PFS in months (95% CI)4.2 (3−5.4)6.2 (2.9−8.1)4.6 (3.2–5.7)median OS in months (95% CI)10.4 (7.7−18.4)18 (12.2–27.2)16.8 (10.6–18.4)Landmark OS estimate12 months (95% CI)40% (19−60)75% (53−88)60% (45−72)18 months (95% CI)30% (12−50)50% (29−68)42% (29−55)24 months (95% CI)20% (6−39)33% (16−52)25% (14−37)CI: confidence interval; IQR: interquartile range; OS: overall survival; PFS: progression free survival Citation Format: Peter A. Kaufman, Sonia Pernas, Miguel Martin, Marta Gil-Martin, Patricia Gomez Pardo, Sara Lopez-Tarruella, Luis Manso, Eva Ciruelos, Jose Alejandro Perez-Fidalgo, Cristina Hernando, Foluso O Ademuyiwa, Katherine Weilbaecher, Ingrid A Mayer, Timothy J. Pluard, Maria Martinez Garcia, Francois Ringeisen, Daniela Schmitter, Javier Cortes. Balixafortide (a CXCR4 antagonist) plus eribulin in HER2 negative metastatic breast cancer: Final analysis from the Phase 1 single arm trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-13.