Incidence Of Treatment-related Adverse Events Research Articles

A142 IMPACT OF HLADQA1*05G>A GENETIC-SCREENING FOR OPTIMAL ANTI-TNF THERAPY IN INFLAMMATORY BOWEL DISEASE: A PRELIMINARY REPORT

Abstract Background Genetic variation in the human leukocyte antigen ( HLA) gene is strongly associated with the formation of anti-drug antibodies to tumor necrosis factor-alpha antagonists (anti-TNF) in inflammatory bowel disease (IBD). It is also associated anti-TNF loss of response and treatment discontinuation. Aims We aimed to evaluate the utility of preemptive HLADQA1*05G>A screening to reduce the incidence of treatment-related adverse events in an IBD population by lessening the need for combination therapy in those who do not carry the risk allele. We also assessed for the occurrence of anti-TNF anti-drug antibody (ADA) formation, anti-TNF loss of response, treatment discontinuation compared to an unscreened population. Methods A non-randomized open label study is ongoing in IBD patients being considered for anti-TNF therapy. Participants received either pre-treatment HLADQA1*05G>A screening (prospective-screening group, n=25/110 recruited), with the addition of one of azathioprine or methotrexate to anti-TNF therapy (combination therapy) if identified as a high risk variant carrier (G/A or A/A) or received combination therapy without undergoing prospective HLADQA1*05A>G screening (control group, n=25/110 recruited). All participants will be followed for up to 1 year and observed for the occurrence of any adverse drug events, formation of anti-TNF drug antibodies (ADA), anti-TNF loss of response and anti-TNF discontinuation. Results To date, the prevalence of HLADQA1*05 G/A and A/A was 20% in the prospective-screening group and thus 20% (n=5/25) received combination therapy and 80% (n=20) received anti-TNF monotherapy. All participants in the control group (n=25/25) received combination therapy. Considering all groups, 78% (n=39/50) received infliximab, while 22% (n=11/50) received adalimumab. To date, the median follow-up period is 5 (IQR=4) months. Fewer adverse drug events have been reported in the prospective-screening group versus the control group (16.7% vs 33.3%, odds ratio 0.40, 95%CI=0.12–1.56, p=0.18). Anti-TNF ADA formation and treatment discontinuation were similar between groups (prospective-screening, 0% versus control, 4.2%). A higher proportion of controls experienced anti-TNF loss of response (16.7% vs 8.3%, p=0.38). Conclusions Preemptive HLADQA1*05G>A screening appears to reduce the need for combination therapy when using anti-TNF agents in an IBD population. Fewer drug-related adverse events are reported to date in the screened cohort without a concomitant increase in deleterious outcomes such as ADA formation or anti-TNF discontinuation. Completion of this study will help define whether or not HLADQA1*05G>A-screening is a clinically-actionable and relevant tool for guiding the application of combination therapy in IBD. Funding Agencies Lawson Health Research Institute

Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2)

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P = 0.032; HR = 0.70; 95% CI, 0.50–0.97). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC.

Combination of Anti-PD-1 Antibody, Anlotinib and Pegaspargase "Sandwich" With Radiotherapy in Localized Natural Killer/T Cell Lymphoma.

Asparaginase/pegaspargase containing regimens combined with radiotherapy are highly effective and considered the cornerstone of localized Natural killer/T-cell lymphoma (NKTL) treatment. However, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related adverse events (TRAEs). Herein we retrospectively evaluated the efficacy and safety of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase “sandwich” with radiotherapy in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2500 U/m2 were administered on day 1, while anlotinib (12 mg once a day) was orally administered on days 1-14. The treatment was repeated every 3 weeks. All the eight patients included received 3 cycles of the regimen followed by radiotherapy and an additional 3 cycles. The overall response rate was 100%, and the complete response rate was 87.5%. With a median follow-up time of 35.5 months (range, 34.03-40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100% and 100%, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade 4 TRAE was reported. No grade 3/4 hematological toxicity was detected, and half of the patients didn’t report any hematological toxicity. This study indicates that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma

BackgroundFirst-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma.MethodsIn this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients).ResultsA total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P=0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P=0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P=0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P=0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone.ConclusionsBoth first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.)

Comparison of the Effectiveness and Tolerability of Nabiximols (THC:CBD) Oromucosal Spray versus Oral Dronabinol (THC) as Add-on Treatment for Severe Neuropathic Pain in Real-World Clinical Practice: Retrospective Analysis of the German Pain e-Registry.

PurposeTo compare the effectiveness and tolerability of add-on treatment with nabiximols (NBX: delta-9-tetrahydrocannabinol: cannabidiol) oromucosal spray or oral dronabinol (DRO: synthetic tetrahydrocannabinol) in patients with severe neuropathic pain poorly responsive to established treatments.MethodsAn analysis was conducted of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with neuropathic pain who had initiated treatment with NBX or DRO between 10 March 2017 and 31 December 2019. The primary effectiveness variable was percent change from baseline in a 9-factor aggregated symptom relief (ASR-9) score, a composite index of nine distinct pain- and health-related parameters assessed using validated patient-reported instruments. Safety was assessed by the incidence of physician-confirmed treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation.ResultsPropensity score-matched data were analyzed for 337 patients treated with NBX and 337 patients treated with DRO. Mean (standard deviation) THC dose over the 24-week evaluation period was 16.6 (6.5) mg for NBX and 17.2 (7.6) mg for DRO (p<0.001). Median (standard error) improvement relative to baseline in the ASR-9 composite score was 55.4% (0.5) for NBX and 40.5% (0.5) for DRO (least squares mean difference, 14.0 (0.7), 95% confidence interval 12.6–15.4; p<0.001), and incidences of TRAEs (21.1 vs 35%) and TRAE-related discontinuations (5.9 vs 14.8%) were significantly lower with NBX than DRO (p<0.001 for both), collectively indicating pre-specified non-inferiority and superiority of NBX. More NBX- than DRO-treated patients discontinued non-cannabinoid background pain medications and rescue analgesics, especially opioid analgesics (p<0.001 for both).ConclusionAdd-on treatment with cannabinoids is effective for treatment of severe neuropathic pain with inadequate response to established treatments. In daily practice, NBX had superior effectiveness and tolerability compared to DRO. The results emphasize the importance of combining CBD with THC in this patient population.

Randomized, phase 3 study of second-line tislelizumab versus chemotherapy in advanced or metastatic esophageal squamous cell carcinoma, RATIONALE 302: Asia subgroup.

279 Background: In the global Phase 3 study RATIONALE 302 (NCT03430843), tislelizumab (TIS) demonstrated statistically and clinically significant improvement in overall survival (OS) vs chemotherapy (chemo) (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001) in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the Asia subgroup. Methods: Eligible patients who had disease progression after first-line systemic therapy were randomized 1:1 to receive TIS 200 mg intravenously once every three weeks or chemo (paclitaxel, docetaxel, or irinotecan) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS in all randomized patients (Intent-to-treat population). The key secondary endpoint was OS in patients with PD-L1 Tumor Area Positivity Score* ≥ 10%; other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life, and safety. Results: Of the 512 randomized patients, 404 (79%) were enrolled from China, Taiwan, Japan, and Korea and constituted the Asia subgroup (n=201 TIS, n=203 chemo). At data cut-off (December 1, 2020), median follow-up was 6.9 months in the Asia subgroup. Median OS was 8.5 months with TIS vs 6.3 months with chemo (HR 0.73; 95% CI 0.59, 0.90). Median PFS was 1.5 months with TIS vs 1.7 months with chemo (HR 0.81; 95% CI 0.64, 1.02). TIS resulted in a higher ORR (20.4% [95% CI 15.1, 26.6] vs 9.4% [95% CI 5.7, 14.2]) and longer median DoR (7.4 vs 4.0 months; HR 0.42, 95% CI 0.21, 0.84) vs chemo. In the safety analysis set (n=201 TIS, n=191 chemo), patients treated with TIS had fewer treatment-related adverse events (TRAEs) (74.1% vs 95.3%), fewer ≥ Grade 3 TRAEs (19.4% vs 57.1%), fewer serious TRAEs (15.4% vs 20.9%), and a similar incidence of TRAEs leading to death (2.5% vs 2.6%) vs chemo. Conclusions: In the Asia subgroup, TIS improved OS and tumor response vs chemo as second-line treatment in patients with advanced or metastatic ESCC and showed a well-tolerated safety profile. These findings were consistent with published results in the overall population. *The TAP score methodology has been previously referred to as visually-estimated combined positive score (vCPS) and was previously presented at the American Society of Clinical Oncology 2021, June 4–8, 2021, ESMO World Gastrointestinal Congress 2021, June 30–July 3, 2021, and The Chinese Society of Clinical Oncology 2021, September 25–29, 2021. Clinical trial information: NCT03430843.

A phase 3 safety study of fosnetupitant as an antiemetic in patients receiving anthracycline and cyclophosphamide: CONSOLE-BC.

BACKGROUNDFosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin‐based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double‐blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide (AC/EC) chemotherapy.METHODSPatients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (<55 vs ≥55 years) and study site. The primary end point was the incidence of treatment‐related adverse events (TRAEs) with FosNTP.RESULTSOverall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%‐34.7%) and FosAPR (22.0%; 95% CI, 11.5%‐36.0%), with any‐cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment‐related ISRs observed in 0% and 10.0%, respectively. The overall (0‐120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR.CONCLUSIONSFosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.

Based on minimal clinically important difference values, a moderate dose of tanezumab may be a better option for treating hip or knee osteoarthritis: a meta-analysis of randomized controlled trials.

Background:Tanezumab is a nerve growth factor monoclonal antibody that may regulate pain in hip or knee osteoarthritis (OA). This meta-analysis was performed to evaluate the efficacy and safety of low and moderate doses of tanezumab in treating hip or knee OA.Methods:PubMed, EMBASE, the Cochrane Library, and Web of Science were comprehensively searched for clinical trials published before 1 May 2021. Patients were assessed via efficacy and safety outcomes.Results:Twelve randomized controlled trials including 6022 patients were identified. Both low and moderate doses of tanezumab significantly improved efficacy outcomes. However, only the point estimates (mean difference, MD) of moderate-dose tanezumab significantly exceeded the minimal clinically important differences (MCIDs). There were no significant differences in the incidence of treatment-related adverse events (AEs), withdrawals due to AEs, serious AEs, and total joint replacement between the tanezumab and placebo groups, whereas the incidence of AEs was higher in the tanezumab group (relative risk, RR = 1.10; 95% confidence interval, 95% CI = 1.04–1.17). The incidence of rapidly progressive OA was significantly higher in the combined low- and moderate-dose tanezumab groups than in the placebo group (RR = 5.01; 95% CI = 1.17–21.33). Furthermore, both low and moderate doses of tanezumab significantly increased the incidence of abnormal peripheral sensation (RR = 1.99, 95% CI = 1.21–3.28; RR = 2.64, 95% CI = 1.91–3.67, respectively). Compared with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, tanezumab showed significantly improved efficacy outcomes (p < 0.05). However, the point estimates (MD) of tanezumab were not greater than the MCID. Pooled analysis showed no significant differences between tanezumab and NSAIDs and opioids in safety outcomes (p > 0.05).Conclusion:Tanezumab is efficacious in patients with hip or knee OA. Tanezumab is relatively well tolerated and safe but increases the incidence of AEs and reversible abnormal peripheral sensation. Additional studies on the occurrence of rapidly progressive OA are needed. A moderate dose of tanezumab may maximize the benefits for hip or knee OA.

Three-year follow-up and patient-reported outcomes from CheckMate 078: Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer

ObjectivesIn the phase 3 CheckMate 078 study, nivolumab prolonged overall survival (OS) and showed a favorable safety profile versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer (aNSCLC). However, long-term efficacy, safety, and health-related quality of life findings with second-line nivolumab are very limited in Asian patients with previously treated aNSCLC. Here, we report updated clinical data and patient-reported outcomes (PROs) from the phase 3 CheckMate 078 trial with a 3-year minimum follow-up. Materials and methodsPatients with aNSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included objective response rate, progression-free survival, safety, and disease-related symptom deterioration assessed using the Lung Cancer Symptom Scale (LCSS) by Week 12. Additional PRO assessments were exploratory endpoints. ResultsAt ≥ 37.3 months follow-up, 3-year OS rates were 19% with nivolumab and 12% with docetaxel; 30% and 0% of responders remained in response for ≥ 3 years, respectively. Incidence of treatment-related adverse events occurring after 2 years was lower than during the first 2 years. No new treatment-related deaths were reported. By Week 12 of treatment, rates of disease-related symptom deterioration were 32% with nivolumab and 47% with docetaxel. Completion rates for PRO questionnaires were ≥ 80% in both arms. Clinically meaningful and sustained improvements in LCSS Average Symptom Burden Index scores and delayed time to first symptom deterioration were observed with nivolumab against docetaxel. ConclusionsAt 3 years, nivolumab continued to demonstrate survival benefit versus docetaxel, exhibiting improvements in disease-related symptoms and overall health status in a predominantly Chinese patient population with previously treated aNSCLC. No new safety signals were observed. These findings are similar to the global population.

CTNI-43. CXCL12 INHIBITION IN MGMT UNMETHYLATED GLIOBLASTOMA – RESULTS OF AN EARLY PROOF-OF-CONCEPT ASSESSMENT IN THE MULTICENTRIC PHASE I/II GLORIA TRIAL (NCT04121455)

Abstract BACKGROUND Preclinical studies showed that CXCL12-mediated influx of highly angiogenic monocytes/macrophages is a key driver of tumor re-vascularization and re-growth after radiotherapy (RT) of glioblastoma (GBM). We report findings from a phase I/II proof-of concept (PoC) study on CXCL12 inhibition during and after RT of GBM. METHODS Patients ≥18years with incompletely or unresected GBM without MGMT promoter hypermethylation and ECOG≤2 were eligible to participate. Patients received continuous (24/7) i.v. infusions of 200mg/week (n=3), 400mg/week (n=3) or 600mg/week (n=3) of the CXCL12 inhibitor olaptesed pegol (OLA) for 26 weeks during and after normo- or hypofractionated RT (60Gy/40.05Gy). The primary endpoint was safety as per the incidence of treatment-related adverse events. The study was accompanied by PoC-research including multiparametric MRI biomarkers (relative cerebral blood volume, rCBV; fractional tumor burden with high perfusion, FTBhigh; apparent diffusion coefficient, ADC) and of multiplexed immunofluorescence imaging (CODEX®) of reference and patient samples. Initial results of these analyses are reported for the first six patients enrolled. RESULTS Five of six (83%) patients assessed with advanced MRI showed response under OLA in rCBV/FTBhigh and ADC. Maximum reduction in perfusion (rCBV) from baseline was 55%, maximum reduction of FTBhigh was 55% and maximum increase in ADC was 77%. Furthermore, five of six (83%) patients analyzed showed reduction of enhancing tissue volumes in at least one scan under OLA therapy. In both one patient and two reference samples CXCL12 co-localized with endothelial cells of the microvascular proliferation zone. In a paired sample (before/during OLA) of one patient, endothelial cells stained positive for CXCL12 before but not during treatment and almost all GBM cells were negative in Ki67 staining in the sample obtained under OLA therapy. CONCLUSIONS Advanced MRI and multiplexed immunofluorescence suggest efficacy of combined radiotherapy and CXCL12 inhibition in unmethylated GBM. Funded by NOXXON Pharma AG; ClinicalTrials.gov number, NCT04121455.

Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

▪IntroductionImmune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission.MethodsThis open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080).ResultsTotal 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups.ConclusionsLow-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:It includes information or discussion of off-label drug use of tacrilimus.

A Phase I/II Dose-Escalation Multi-Center Study to Evaluate the Safety of Infusion of Natural Killer Cells or Memory T Cells As Adoptive Therapy in Coronavirus Pneumonia and/or Lymphopenia: (RELEASE NCT04578210)

Background:Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients.This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19.Identification of Specific memory T cells and NK cells:i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life.ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life.Pilot Phase I- Safety, feasibility, and dose escalation:Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells.Phase II- Efficacy:Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month.This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. [Display omitted] DisclosuresSoria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.

Real-World Lenvatinib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BackgroundLenvatinib is approved for patients with advanced hepatocellular carcinoma (HCC) due to its non-inferiority to sorafenib of overall survival (OR) in clinical trials. This study was to compare the effectiveness and safety of lenvatinib and sorafenib in the real world.MethodsWe retrospectively evaluated 338 patients with unresectable HCC who had undergone lenvatinib or sorafenib treatment between January 2018 and August 2020. Propensity-score matching analysis was performed with a 1:2 ratio to reduce the real-life baseline difference between the two groups.ResultsA total of 210 patients (Male/Female: 150/60, mean age: 65.8 years) were recruited including 70 patients in the Lenvatinib group and 140 patients in the Sorafenib group. Compared with sorafenib, lenvatinib had significantly longer progression-free survival (PFS) (5.2 vs 3.3 months, p=0.019) but similar OR (13.3 vs 11.8 months, p=0.714). Additionally, lenvatinib had better disease control rates (62.3 vs 48.6%, p=0.029) and equivalent incidences of treatment-related adverse events over sorafenib. In multivariate analysis, lenvatinib was associated with better PFS over sorafenib (hazard ratio: 0.49, 95% confidence interval: 0.3–0.79, p=0.004) after adjustments of albumin-bilirubin grade and alpha-fetoprotein level; however, different agents using lenvatinib or sorafenib did not contribute to OS, whether in univariate or multivariate analysis. Patients who failed lenvatinib had a lower proportion of having sequential systemic therapies compared with the Sorafenib group (36.2 vs 47.8%, p=0.02). The most frequently used sequential therapy following lenvatinib and sorafenib was chemotherapy (n=9, 42.8%) and regorafenib (n=33, 50.8%), respectively.ConclusionsIn clinical real-life practice, lenvatinib illustrated promising survival benefits and acceptable safety for patients with unresectable HCC, while reducing the risk of progression disease compared with sorafenib. Additionally, lack of approved post-lenvatinib systemic therapies is a serious issue in the real world.

Agomelatine might be more appropriate for elderly, depressed, type 2 diabetes mellitus patients than paroxetine/fluoxetine.

Agomelatine was a novel and melatonergic antidepressant. The present study was conducted to find out whether age was an important factor for agomelatine in treating depressed type 2 diabetes mellitus (T2DM) patients. In total, 193 depressed T2DM patients were included. There were 84 patients ranged from 27 years old to 49 years old (age phase I) (n = 44 receiving agomelatine, n = 40 receiving paroxetine or fluoxetine), and 109 patients ranged from 50 years old to 70 years old (age phase II) (n = 56 receiving agomelatine, n = 53 receiving paroxetine or fluoxetine). The Hamilton Depression Rating Scale (HDRS) score, Hamilton Anxiety Rating Scale (HARS) score, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) level and body mass index (BMI) were assessed after 12 weeks treatment. After treatment, we found that among patients in age phase I, there were no significant differences in final average HDRS score, HARS score, FPG, HbA1c level, BMI, response rate and remission rate between the two groups. However, among patients in age phase II, compared to patients receiving paroxetine or fluoxetine, patients receiving agomelatine had the significantly lower average HDRS score, HARS score, HbA1c level and BMI, and significantly higher response rate and remission rate. The incidence of treatment-related adverse events was similar between the two groups in both age phases. These results suggested that age was an important factor for agomelatine in treating depressed T2DM patients. Compared to paroxetine/fluoxetine, agomelatine might be more appropriate for elderly depressed T2DM patients.

IncobotulinumtoxinA Demonstrates Safety and Prolonged Duration of Effect in a Dose-Ranging Study for Glabellar Lines.

To further explore clinical trial results indicating increasing doses of botulinum toxin A prolong duration of effect, a 2-stage, phase 2, randomized, double-blind study investigated the duration of effect and safety of incobotulinumtoxinA (INCO; Xeomin&reg;, Bocouture&reg;) doses higher than the US Food and Drug Administration-approved 20 units (U) for glabellar frown lines (GFL). The stage 1 primary efficacy and safety results were reported previously. Here, we report the results of the final analysis (stage 1 and 2), including primary and secondary efficacy and safety endpoints. A total of 241 subjects with moderate-to-severe GFL were randomized to receive a single treatment with 20 (N=61), 50 (N=60), 75 (N=61), or 100U (N=59) INCO. The primary efficacy endpoint was duration of &ge; 1-point improvement from baseline assessed by investigator at maximum frown on the Facial Wrinkle Scale. The median duration of effect was 175 days for the 20U group (95% CI 142, 185), 185 days for the 50U group (95% CI 182, 205), 210 days for the 75U group (95% CI 182, 217), and 215 days for the 100U group (95% CI 183, 237). The incidence of treatment-related adverse events was low across all doses and there were no treatment-related serious adverse events. These results demonstrate that all INCO doses were well tolerated, consistent with the known safety profile of 20U, and increasing dose prolongs the duration of effect for GFL. J Drugs Dermatol. 2021;20(10):1052-1060. doi:10.36849/JDD.6377THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Real-world safety and effectiveness of nivolumab in Japanese patients with unresectable advanced or recurrent gastric/gastroesophageal junction cancer that has progressed after chemotherapy: a postmarketing surveillance study

BackgroundThis postmarketing surveillance study evaluated the real-world safety and effectiveness of nivolumab as salvage (after ≥ 2 lines) therapy in Japanese patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer.MethodsThis multicenter, observational study was conducted at 158 centers in Japan. Patients with unresectable advanced or recurrent G/GEJ cancer were registered between Nov 1, 2017, and Oct 31, 2018, and observed for 6 months after treatment initiation with nivolumab. Correlation of background characteristics with treatment-related adverse events (TRAEs) and tumor response was explored.ResultsOverall, 654 patients were registered (safety analysis set, n = 650; effectiveness analysis set, n = 636; response evaluation set, n = 516). The incidences of all TRAEs and grade ≥ 3 TRAEs were 31.5 and 11.2%, respectively. TRAEs significantly correlated with the absence of peritoneal metastasis; C-reactive protein level < 1; prior G/GEJ cancer surgery; and past or concomitant pulmonary, thyroid, or renal disease (each p < 0.05). The incidence of TRAEs was significantly lower in patients with higher Glasgow prognostic scores (p < 0.05). No new safety signals were observed. Complete response, partial response, stable disease, and progressive disease were observed in 1.2, 10.1, 27.1, and 58.3% of the response evaluation set, respectively. Patients aged ≥ 65 years (13.9 vs 5.3%, p = 0.0083) and ≥ 75 years (18.8 vs 9.2%, p = 0.0036) showed a higher response rate than their younger counterparts.ConclusionsThe real-world safety and effectiveness of nivolumab as salvage (after ≥ 2 lines) therapy in Japanese patients with unresectable advanced or recurrent G/GEJ cancer were consistent with those observed in the phase 3 ATTRACTION-2 study.

Efficacy and safety of lenvatinib monotreatment and lenvatinib-based combination therapy for patients with unresectable hepatocellular carcinoma: a retrospective, real-world study in China

BackgroundLenvatinib and lenvatinib-based combination treatments are widely used in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice, but their curative effect and safety need further study in the real world.MethodsThis was a retrospective study involving patients with uHCC receiving lenvatinib monotherapy and lenvatinib-based combination treatment between Nov, 2018 and Sep, 2020 in Nanfang Hospital. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Treatment-related adverse events (TRAEs) were recorded and graded. Efficacy and safety of monotherapy and combination therapy were compared. Stratified analysis was performed according to systemic line of treatment and medication regimen for combination therapy.ResultsFor lenvatinib monotherapy (n = 39), OS and PFS were 80 weeks and 24.3 weeks, respectively. For combination treatment (n = 72), median OS and PFS were 99 weeks and 45.6 weeks, respectively. OS, PFS, and TTP for patients in the combination treatment cohort were significantly longer compared to those of patients in the monotreatment cohort (OS: P = 0.04, PFS: P = 0.003; TTP, P = 0.005). The incidence of TRAEs could be controlled both in the monotherapy cohort and the combination treatment cohort. In the monotherapy cohort, OS and PFS were significantly decreased in the second-line treatment group compared with the first-line treatment group, while no differences were observed in the combination cohort. The efficacy of triple therapy (lenvatinib plus PD-1 antibody plus TACE or HAIF) was similar to lenvatinib plus PD-1 antibody or lenvatinib plus TACE or HAIF.ConclusionsOur real-world study showed that lenvatinib monotherapy and lenvatinib-based combination therapy were well tolerated, with encouraging efficacies in patients with uHCC. Lenvatinib-based combination therapy showed a better curative effect compared with lenvatinib single-agent therapy. In patients who have failed first-line TKI treatment, lenvatinib-based combination therapy may be a better choice than lenvatinib single-agent therapy. Lenvatinib-based triple therapy may not have an advantage over dual therapy.

Comparing strategy of immune checkpoint inhibitors plus chemotherapy with chemotherapy alone for small cell lung cancer: a meta-analysis based on six RCTs incorporating 2800 participants.

The project is designed to compare the clinical efficacy and adverse events resulting from immune checkpoint inhibitors (ICIs) plus chemotherapy and chemotherapy alone in patients with small cell lung cancer (SCLC). PubMed Database and ClinicalTrials.gov were both searched to identify randomized controlled clinical trials for assessing ICIs in all-stage SCLC. After screening in strict accordance with the inclusion and exclusion criteria, eligible studies were evaluated in regard to the population, intervention, comparator, outcome as well as study design (PICOS) pattern. Furthermore, primary endpoints of these randomized controlled trials (RCTs) included overall survival (OS), progression-free survival (PFS) and complete/objective response rate (CRR/ORR). Statistical analyses were realized via Review Manager Version 5.3 Software. Compared with the chemotherapy alone group, the ICIs plus chemotherapy group significantly improved with respect to such indicators as OS (hazard ratio (HR) = 0.82, 95% CI 0.74-0.90, P < 0.0001), PFS (HR = 0.80, 95% CI 0.74-0.87, P < 0.00001) and ORR (64.7% versus 59.1%). According to the safety analysis, the incidence of treatment-related adverse events (trAEs) at all grades was higher in ICIs plus chemotherapy group (OR = 1.59, 95% CI 1.20-2.10, P = 0.001), bearing no statistical significance at grade 3 or above (OR = 1.21, 95% CI 0.99-1.49, P = 0.07). The combination of ICIs and chemotherapy witnessed better anti-neoplastic efficacy for SCLC. Moreover, the incidence of trAEs at all grades was elevated in ICIs plus chemotherapy group, with little discrepancy in both groups at grade 3 or above.

Outcomes of human umbilical cord blood-derived mesenchymal stem cells in enhancing tendon-graft healing in anterior cruciate ligament reconstruction: an exploratory study

BackgroundThe study investigated whether allogeneic human umbilical cord blood-derived MSCs (hUCB-MSCs) could be safely used without treatment-related adverse events, reducing tunnel enlargement, and improve clinical results in human anterior cruciate ligament (ACL) reconstruction.MethodsThirty patients were enrolled consecutively. They were divided into three groups by randomization. In the negative control group, ACL reconstruction surgery without additional treatment was performed. In the experimental group, a hUCB-MSC and hyaluronic acid mixture was applied to the tendon-bone interface of the femoral tunnels during ACL reconstruction surgery. In the positive control group, only hyaluronic acid was applied. Finally, 27 patients were analyzed after the exclusion of three patients. The incidence of treatment-related adverse events, clinical outcomes, including second-look arthroscopic findings, and the amount of tunnel enlargement, were evaluated.ResultsThere were no treatment-related adverse events in the treatment groups. Tunnel enlargement in the experimental group (579.74 ± 389.85 mm3) was not significantly different from those in the negative (641.97 ± 455.84 mm3) and positive control (421.96 ± 274.83 mm3) groups (p = 0.6468). There were no significant differences between the groups in clinical outcomes such as KT-2000 measurement (p = 0.793), pivot shift test (p = 0.9245), International Knee Documentation Committee subjective score (p = 0.9195), Tegner activity level (p = 0.9927), and second-look arthroscopic findings (synovial coverage of the graft, p = 0.7984; condition of the graft, p = 0.8402).ConclusionsAllogeneic hUCB-MSCs were used safely for ACL reconstruction without treatment-related adverse event in a 2-year follow-up. However, our study did not suggest any evidence to show clinical advantage such as the prevention of tunnel enlargement postoperatively and a decrease in knee laxity or improvement of clinical outcomes.Trial registrationCRIS, Registration Number: KCT0000917. Registered on 12 November 2013; https://cris.nih.go.kr/cris/index.jsp

MDS-404: Population Pharmacokinetics Modeling and Evaluation of Clinical Efficacy and Safety of Sabatolimab: Dose Selection and Dose-Response Analysis

Context: Sabatolimab is an investigational immuno-myeloid therapy targeting TIM-3. The STIMULUS clinical trial program has been designed to evaluate sabatolimab in multiple phase 1–3 trials in patients with MDS and AML. Here, we report PK and clinical data supporting sabatolimab doses being evaluated in the STIMULUS program. Methods: PK was evaluated in patients with advanced solid tumors (NCT02608268), or high/very-high risk MDS, or AML who were ineligible for intensive chemotherapy (NCT03066648). Main Outcome Measures: Total sabatolimab serum concentration was used in population PK modeling to simulate average (Cavg), maximal (Cmax), and trough (Ctrough) concentrations at steady-state. Total serum soluble TIM-3 was measured, and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 27 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted. Results: Sabatolimab PK was similar for patients with solid tumors (n=252) and higher-risk MDS and AML (n=155); no drug–drug interactions were observed for any combinations. Among sabatolimab+HMA regimens, sabatolimab 400 mg Q2W had the highest Ctrough at steady-state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady-state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM (>95% in ≥95% of patients with higher-risk MDS/AML), suggesting similarly high levels of TIM-3 engagement. There was no relationship between steady-state Cmax or Cavg quartiles and the incidence of treatment-related AEs. Exposure-efficacy analysis showed no clear relationship between steady-state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). Sabatolimab+HMA was safe and well-tolerated, with a low discontinuation rate due to AEs (3.4% [4/116]). Rates of most common grade ≥3 treatment-emergent AEs did not appear to be dose-dependent. Conclusions: Sabatolimab 400 mg Q2W was predicted to have the highest steady-state Ctrough and TIM-3 occupancy rate when combined with HMA; 800 mg was predicted to be an equivalent dosing regimen. No clear relationship was seen between sabatolimab dose or steady-state exposure and safety/efficacy. These results support the clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens.