Gene expression and pharmacodynamic-induced changes in 1760 SLE Patients from two phase III trials of B cell activating factor blockade with tabalumab
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE88887 | GEO | 2016/10/25
SECONDARY ACCESSION(S): PRJNA350538
REPOSITORIES: GEO
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Project description:Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
2016-10-25 | GSE88886 | GEO
Project description:Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
2016-10-25 | GSE88885 | GEO
Project description:Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
2016-10-25 | GSE88884 | GEO
Project description:Gene expression and pharmacodynamic-induced changes in 1760 SLE Patients from two phase III trials of B cell activating factor blockade with tabalumab
| PRJNA350538 | ENA
Project description:ObjectiveTo characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab.MethodsPatient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString.ResultsAt baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti-double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels.ConclusionSLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
| S-EPMC6585752 | biostudies-literature
Project description:In phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs). Data were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest. During treatment, 86.9% of patients receiving anifrolumab 300 mg (n=459) experienced AEs (≥1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (≥1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95% CI) -7.2 (-12.5 to -1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively. In this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300 mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs.
| S-EPMC7893670 | biostudies-literature
Project description:ObjectivesTo evaluate the time course of clinical response following anifrolumab treatment in patients with SLE.MethodsA post hoc analysis was conducted using pooled data from phase III, randomised, 52-week, placebo-controlled, Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of intravenous anifrolumab (every 4 weeks, 48 weeks) in patients with moderate-to-severe SLE receiving standard therapy. Anifrolumab 300 mg and placebo groups were compared for British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response over time, time to sustained BICLA response, SLE Responder Index ≥4 (SRI(4)) response over time, time to sustained Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) response and change in glucocorticoid dosage over time. All p values for comparisons were nominal.ResultsOf the 726 evaluated patients (anifrolumab 300 mg, n=360; placebo, n=366), a greater proportion attained a BICLA response in the anifrolumab versus the placebo group from Week 8 (p<0.001); treatment group differentiation was maintained at all subsequent visits to Week 52. Consistently, more patients achieved a BICLA response sustained to Week 52 in the anifrolumab versus placebo group (HR=1.73, 95% CI 1.37 to 2.20). More patients attained SRI(4) response with anifrolumab than placebo from Week 12 (p=0.005). As early as Week 8, more patients achieved CLASI-A skin response sustained to Week 52 with anifrolumab versus placebo (HR=1.72, 95% CI 1.17 to 2.55). Glucocorticoid dosage reductions from baseline were greater in anifrolumab-treated versus placebo-treated patients from Week 20 (p=0.010) through Week 52.ConclusionsAnifrolumab treatment was associated with sustained improvements in overall SLE disease activity and skin responses versus placebo from Week 8, which likely led to greater glucocorticoid reductions in the anifrolumab versus placebo groups from Week 20. These findings provide insights to physicians and patients on when to expect potential clinical responses following anifrolumab treatment.
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Project description:BackgroundStrict eligibility criteria for patient enrollment in phase III trials raise questions regarding generalization to ineligible patients. We evaluated whether pivotal phase III trials of immune checkpoint blockades (ICBs) represent the overall population of non-small cell lung cancer (NSCLC) patients.MethodsWe reviewed the inclusion and exclusion criteria of three phase III trials (CheckMate057, CheckMate017, and KEYNOTE-010). Stage IIIB or IV NSCLC patients diagnosed from 2011 to 2013 at Seoul National University Hospital (cohort 1) were reviewed. We also analyzed the criteria in 53 patients with NSCLC who were treated with nivolumab or pembrolizumab as routine practice (cohort 2).ResultsAmong the 715 patients in cohort 1, 499 (69.9%) were ineligible for the three trials. Reasons for ineligibility included: no prior platinum doublet treatment (23.6%), lack of tissue availability (22.7%), Eastern Cooperative Oncology Group performance status > 1 (14.1%), steroid use (18.2%), active cerebral nervous system metastasis (8.3%), hepatitis B/hepatitis C/human immunodeficiency virus (8.0%), and no measurable lesion (7.3%). EGFR mutations were more common in the ineligible group. In cohort 2, 67.9% of patients were classified as ineligible. Treatment outcomes of ICB in cohort 2 appeared inferior to those in the three pivotal trials, with a response rate of 11.3% and median progression-free survival of 1.67 months.ConclusionOnly 30% of NSCLC patients were eligible for ICB phase III trials. The actual efficacy in the 70% of ineligible patients is unknown. These findings suggest a huge gap between practice-changing phase III trials and the overall population of NSCLC patients.
| S-EPMC6456815 | biostudies-literature
Project description:Patient enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls, however recently some clinical trials have utilized an unequal distribution between the case and control arms. Trends and proportion of phase 3 cancer clinical trials that have an unequal allocation between the years 2010 and 2019 were studied from data extracted from clinicaltrials.gov. 323 trials with two arms and 35 trials with 3 arms were identified as randomized control trials with the primary purpose of a cancer-related treatment that provided allocation data. Amongst the trials with two arms, 238 trials had equal allocation and 85 trials had unequal allocation. Therefore, cancer clinical trials with unequal allocation represent about one in four 2-arm phase 3 trials. Amongst the eligible trials with three arms, 26 trials had equal allocation and 9 trials had unequal allocation. There was no significant difference in the annual proportion of trials with unequal allocation from 2010 to 2019. The categories of cancer which had the highest number of unequally allotted two-arm clinical trials were: gastrointestinal, breast, and genitourinary malignancies. This shift may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs and lower statistical power attached to this method.
| S-EPMC8332855 | biostudies-literature
Project description:INTRODUCTION: Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time. METHODS: We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis. RESULTS: In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033). CONCLUSIONS: The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.
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