Main Secondary Endpoints Research Articles

Effects of remote patient management on self-care behaviour in heart failure patients: results from the TIM-HF2 trial

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Federal Ministry of Education and Research Background Remote patient management (RPM) in heart failure (HF) patients is a rapidly developing field of digital cardiology with beneficial clinical effects. RPM might affect HF specific self-care behaviour, which represents an important patient-reported outcome. Purpose To investigate the effects of RPM used in the Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial on HF-specific self-care as a prespecified secondary endpoint analysis. Methods and Results HF patients who were recently hospitalized and do not suffer from major depression were randomized to either RPM plus Usual Care (UC) or UC only, with a 12-month follow-up. Self-reported self-care behaviour at baseline and study-end were assessed by mean differences of the 9-item European Heart Failure Self-care Behaviour Scale (EHFScBS-9). 1,538 HF patients (mean age 70.3±10.5 years, 70% men, 52% NYHA class II and 47% NYHA class III, 65% LVEF ≤45%) were included, obtaining 1,321 patients with valid baseline and follow-up questionnaires. Self-care behaviour sum scores increased in the RPM group (n=667) from 78.7±17 to 84.5±14 and in the UC group (n=654) from 79.0±17 to 80.0±16 from baseline to 12 months (mean difference 4.58 95% CI 3.02, 6.14; p<0.001). The subgroup of patients living alone and having an inadequate (<70) baseline self-care behaviour score showed the highest improvement (8.66[3.52; 13.81]). There were significant changes between both groups in item "I weight myself every day" (MD -1.13; 95% CI -1.24, -1.02; p<0.001), and item "I take my medication as prescribed" (MD -0.06; 95% CI -0.10, -0.01; p=0.014). No relation was found between the self-care behaviour score and the efficacy of RPM on the primary and main secondary endpoints of the TIM-HF2 study. Conclusions RPM improves HF-specific self-care behaviour by achieving a better adherence to recommended HF regimen. Clinical endpoints were not affected by the level of self-care behaviour.

Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial

ObjectivesLupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target...

A randomized presurgical trial of alternative dosing of exemestane in postmenopausal women with early-stage ER-positive breast cancer.

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results.

8025 Background: Intravenous (IV) isatuximab (Isa) + Pd is approved for the treatment of RRMM patients (pts). SC delivery would optimize convenience of administration. Prior results showed that SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; the recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207). Methods: This multicenter Phase 1b study evaluated safety, PK and efficacy of SC vs IV Isa + Pd in RRMM pts after ≥2 prior treatment lines. Pts were randomized 2:1 to SC1000 mg or IV 10 mg/kg and to SC1400 mg or IV. An expansion cohort was later implemented with SC Isa administered at the RP2D via OBDS, a wearable bolus injector applied to the abdomen by a healthcare professional. Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS). Results: 56 pts were randomized and treated: 12 Isa IV, 12 Isa SC1000, 10 Isa SC1400 and 22 OBDS pts. At study entry, ISS stage II–III was 67% in IV, 33% in SC1000, 60% in SC1400 and 50% in OBDS pts. On Jan 20, 2022, 33% IV, 25% SC1000, 50% SC1400 and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU) was longer in IV (20.6 mo) and SC1000 (23.8 mo) than SC1400 (18.1 mo) and OBDS (6.5 mo) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Incidence of G4 neutropenia was lower in SC1000 (42%) vs the other cohorts (55–60%). The lower % of ≥G3 treatment-related AEs in OBDS (77%) vs the other cohorts (≥80%) may be due to shorter FU. Best overall responses are shown in table; longer FU is needed for OBDS pts. Median PFS was 22 mo in IV, 12.5 mo in SC1000 and not reached in SC1400 and OBDS pts. PK and CD38 receptor occupancy results in OBDS pts are consistent with those observed in SC1400 with pump. Conclusions: SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to the Phase 3 ICARIA results. Isa SC administration by OBDS is well tolerated, requires a short duration of injection and provides a convenient hands-free option. Clinical trial information: NCT04045795. [Table: see text]

AMEERA-4: A preoperative window-of-opportunity (WOO) study to assess the pharmacodynamic (PD) activity of amcenestrant or letrozole in postmenopausal patients with ER+/HER2− primary breast cancer.

528 Background: Amcenestrant is an optimized oral selective ER degrader (SERD) that antagonizes and degrades the ER and has demonstrated favorable preliminary safety and antitumor activity as monotherapy and in combination with palbociclib in postmenopausal patients with ER+/HER2− advanced breast cancer, irrespective of baseline (BL) ESR1 mutation status. Here we present the final results of AMEERA-4 (NCT04191382), a Phase 2 preoperative WOO study that evaluated the PD activity of two dose levels of amcenestrant or letrozole using paired biopsies assessed for biomarkers. Methods: Postmenopausal women with operable stage I–III (tumor size ≥ 10 mm by ultrasound) ER+/HER2− breast cancer and Ki67 levels ≥ 15% by local assessment were randomized 1:1:1 to amcenestrant 400 mg once daily (QD), amcenestrant 200 mg QD or letrozole 2.5 mg QD for 14 days before surgery. Antiproliferative activity, as measured centrally by change from BL in Ki67 using paired biopsies before and after a 14-day treatment with 2 different doses of amcenestrant vs letrozole, was the planned primary endpoint. Main secondary endpoints included ER target engagement, assessed through the change in ER expression measured by change from BL in H-Score, and safety. Results: Trial enrollment was voluntarily stopped early, as informative data supporting adjuvant development became available; therefore, no formal statistical comparisons were conducted. Among 105 randomized patients (amcenestrant 400 mg: n = 34, amcenestrant 200 mg: n = 36, letrozole: n = 35), 95 were treated and had available pre- and post-treatment Ki67 per central review (modified ITT population). No major imbalances in BL patient and tumor characteristics were observed. The geometric least squares means (LSM) estimate (95% CI) of Ki67 reduction was 75.9% (67.9, 81.9) for amcenestrant 400 mg, 68.2% (58.4, 75.7) for amcenestrant 200 mg and 77.7% (70.0, 83.4) for letrozole. The LSM estimate (95% CI) of absolute change from BL in ER H-score was −176.7 (−201.4, −152.0) for amcenestrant 400 mg, −202.9 (−226.1, −179.7) for amcenestrant 200 mg and −32.5 (−57.2, −7.7) for letrozole, with median relative changes of −65.3%, −68.3% and −9.5%, respectively. The incidence of treatment-related adverse events (TRAEs) was 21.2% for amcenestrant 400 mg, 22.2% for amcenestrant 200 mg and 25.7% for letrozole. No Grade ≥ 3 TRAEs occurred in any treatment arm. Conclusions: Both doses of amcenestrant demonstrated robust Ki67 reductions, strongly engaged the ER target, and continued to show a favorable safety profile in an early breast cancer population, consistent with previous published reports. Based on PD activity and safety, and emerging results from other ongoing amcenestrant trials, the 200 mg QD dose of amcenestrant was selected for our ongoing study in the adjuvant setting; AMEERA-6 (NCT05128773). Clinical trial information: NCT04191382.

P-118 Cetuximab rechallenge in RAS, BRAF, EGFR-ECD wild type metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies in first line: The CITRIC study

Despite recent advances in the treatment of mCRC, the survival benefit obtained with third-line treatment is modest. Anti-EGFR therapy does not provide survival benefit in mCRC patients whose tumours are mutated with respect to RAS genes, and it should be only considered in RAS and BRAF wild-type patients. Unfortunately, patients with RAS wild-type mCRC eventually progress due to molecular mechanisms of acquired resistance, with RAS/BRAF mutations and EGFR extracellular domain (EGFR-ECD) mutations as the main drivers of EGFR acquired resistance. CRC dynamically adapts to external pressure exerted by anti-EGFR blockade. Acquired RAS/BRAF and EGFR ECD mutations have been shown to decrease after anti-EGFR treatment withdrawal, while tumour cells regain sensitivity to anti-EGFR treatment. This observation provides a strong rationale for the strategy of re-challenge with anti-EGFR therapy in patients previously treated with an anti-EGFR-based treatment. Several nonrandomized phase II clinical trials have demonstrated the efficacy of this strategy is in a molecularly selected population. This is a multicenter, randomized, open-labeled, parallel-group, phase II study to evaluate the efficacy and safety of cetuximab plus irinotecan rechallenge in the third-line setting, in comparison to investigator's choice of treatment (excluding anti-EGFR therapy), in patients with RAS, BRAF and EGFR-ECD wild-type mCRC who did benefit from cetuximab or panitumumab in the first line. RAS, BRAF V600E, and EGFR-ECD mutations will be analyzed in ctDNA using Next Generation Sequencing (NGS) panels (Colorectal Cancer kit, Oncomine, Thermofisher). The primary endpoint of the study is the overall response rate, determined according to RECIST 1.1 criteria. Main secondary endpoints include disease control rate, progression-free survival and overall survival. The sample size, calculated based on a two-sided Fisher’s exact test (alfa error 0.05, beta error 0.20), is 66 patients. It is estimated that a total of 122 patients would be required to undergo molecular screening by means of liquid biopsy. During the study it is intended to perform an extended biomarker analysis in ctDNA and tissue in order to assess the expression of potential biomarkers related to treatment resistance as an exploratory objective. Study is sponsored by Associació Per la Recerca Oncològica (APRO). EudraCT Number: 2020-000443-31. Associació Per la Recerca Oncològica (APRO).

Safety and efficacy of 48 mm Xience Xpedition everolimus-eluting stent for the treatment of long coronary lesions.

Long drug-eluting stents may limit the issue of overlapping multiple stents when treating long coronary lesions. The aim of the study was to assess the safety and efficacy of the 48 mm Xience Xpedition everolimus-eluting stent (48mm-EES) for the treatment of long coronary lesions, in an all-comer population. Patients receiving at least one 48mm-EES were prospectively included from March 2014 to December 2018. The primary endpoint was target lesion failure (TLF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization (TLR) at 1 year. The main secondary endpoint was the patient-oriented composite endpoint (POCE) defined as a composite of death, stroke, myocardial infarction, and reintervention. A total of 268 patients with 276 long coronary lesions, including 94 chronic total occlusions (CTO), were successfully treated using at least one 48mm-EES. The total stent length per lesion was 66 ± 22 mm. A single 48mm-EES was suitable to successfully treat the target lesion in 48% of cases (60% for non-CTO lesions). One-year follow-up rate was 96.3%. TLF occurred in 13 patients (5.3%), mainly driven by TLR (4.1%). Two cardiac death occurred (0.7%). POCE occurred in 30 patients (11.6%) mainly driven by repeat revascularization (9.7%). Definite stent thrombosis was observed in two patients (0.7%). No difference was observed in one-year outcomes between single 48mm-EES and multiple stents implantation as well as between CTO and non-CTO lesions. The 48mm-EES is safe and effective to treat long coronary lesions, including CTOs, and provides attractive cost-effectiveness by limiting multiple stenting.

AB1289 STUDY DESIGN OF A PHASE 2/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF NIPOCALIMAB, AN FcRn ANTAGONIST, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (wAIHA)

BackgroundWarm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by inhibiting IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoimmune diseases including warm autoimmune hemolytic anemia (wAIHA).Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a recently completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). In the gMG phase 2 study, nipocalimab was well tolerated at doses from 5 mg/kg every 4 weeks to 60 mg/kg every 2 weeks. Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. A statistically significant relationship between IgG autoantibody reduction and clinical benefit was observed. This study provided proof-of-concept evidence that lowering pathogenic IgG autoantibodies can ameliorate the autoimmune condition these antibodies cause.ObjectivesTo share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo1.MethodsMale or female patients ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Patients with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab.ResultsThe following endpoints will be analyzed:Primary endpoint:Percentage of participants achieving durable response of improvement in hemoglobin (Hgb).Main secondary endpoints:Change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale at the end of the double-blind period.Number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline.ConclusionA phase 2 study investigating nipocalimab in patients with gMG provided proof of concept for a phase 2/3 interventional study with nipocalimab in patients with wAIHA. This phase 2/3 study is currently enrolling in the USA and Europe.

MO475: Dapa-CKD Patient Profile: Transposability Assessment in Real-Life Through the CKD-Rein French Cohort

Abstract BACKGROUND AND AIMS The objective of this observational study was to describe the `DAPA-CKD-like’ population and to assess the burden of illness (comorbidities, cardiovascular (CV) and renal events) and prognosis in patients with CKD in France, compared with those randomized in the DAPA-CKD RCT [1]. METHOD The CKD-REIN cohort study enrolled 3033 patients with moderate or advanced CKD from 40 nationally representative nephrology clinics in France [median age of 68 (IQR: 60–76), min-max: 19–94, 65% men, CKD stage 3 (60%) or 4 (40%)]. Inclusions started in July 2013 and ended in July 2016. The analysis describes baseline characteristics of patients with DAPA-CKD inclusion criteria (75 ≥ eGFR ≥ 25 mL/min/1.73 m2 and 5000 ≥ UACR ≥ 200 mg/g) and CV and renal outcomes >3-year follow-up. RESULTS Among the 3033 adult patients included in CKD-REIN cohort, 503 met the inclusion and exclusion criteria of the DAPA-CKD RCT. The characteristics of these 503 French `DAPA-CKD-like’ patients and those of the DAPA-CKD RCT were similar in terms of age (63.9 ± 13.6 versus 61.8 ± 12.1), gender (74% men versus 67%), eGFR (36.5 ± 9.1 mL/min/1.73 m2 versus 43.1 ± 12.4 mL/min/1.73 m2) and SBP (145 ± 21 mmHg versus 137 ± 17 mmHg). The CV and renal event rates/100 patient-year (PY) were similar between the two populations, both for the main composite outcome (eGFR decline ≥50% or end-stage kidney disease (defined as eGFR <15 mL/min/1.73 m2 long-term dialysis or kidney transplantation) or CV or renal deaths), 7.9/100 PY versus 7.5/100 PY, but also for each outcome of the main endpoint and secondary endpoints. CONCLUSION In conclusion, the DAPA-CKD RCT patient profile appears to be similar to a real-life French CKD patient profile based on the French CKD-REIN cohort meeting the inclusion and exclusion criteria of the DAPA-CKD RCT.

Epidural analgesia information sessions provided by anesthetic nurses: impact on satisfaction and anxiety of parturient women a prospective sequential study

BackgroundInformation on epidural analgesia delivered to parturient women is frequently incomplete, making it difficult for expectant mothers to make an appropriate choice for their delivery. We assessed the impact of a multimodal information session on epidural analgesia delegated to anesthetic nurses on new-mothers’ satisfaction.MethodsWe performed a prospective sequential study including parturient women who gave birth with epidural analgesia. During the first period, information on epidural analgesia was delivered by anesthetists during the scheduled anesthesia consultation, according to French standard-of-care. Then, a dedicated information session about epidural analgesia provided by anesthetic nurses was implemented. The primary endpoint was the satisfaction of women with the quality of information received. Main secondary endpoints were knowledge of women about epidural analgesia, anxiety before epidural catheter placement, and satisfaction with delivery.Results259 and 298 women were included during the first and second periods respectively, among whom 178 and 188 were analyzed. Information on epidural analgesia delivered by anesthetic nurses was associated with improvement of new-mothers’ satisfaction with information received (9 (8–10) vs. 10 (9–10) – p < 0.001). Moreover, information delivered by anesthetic nurses was associated with decreased anxiety before epidural catheter placement (4 (1–8) vs. 3 (1–6) – p = 0.006) and increased satisfaction with delivery (8 (7–10) vs. 9 (8–10) – p = 0.01). Women’s knowledge on epidural analgesia was durably increased when information was delivered by anesthetic nurses compared to conventional information by anesthetists. After adjustment, the only variable associated with both new mothers’ satisfaction with information and delivery was the information session taught by anesthetic nurses.ConclusionsInformation sessions on epidural analgesia delivered by anesthetic nurses was associated with improved satisfaction of women with their delivery. Such information sessions may be used in maternity wards to improve new-mothers’ childbirth experience.

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

IntroductionIncreased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical...

Ezabenlimab (BI 754091) and mDCF (docetaxel, cisplatin, and 5-fluorouracil) followed by chemoradiotherapy in patients with stage 3 squamous cell anal carcinoma: INTERACTION phase II study.

TPS7 Background: Even though the recurrence rate remains high, chemoradiotherapy (CRT) alone is the standard treatment in locally advanced squamous cell anal carcinoma (SCAC), in the absence of effective neoadjuvant/adjuvant treatment. Modified docetaxel, cisplatin and 5FU (mDCF) is one of the standard regimens in metastatic SCAC, and induced a radiological complete response (cCR) in 45% of patients, with a biological CR (the conversion from positive to negative HPV ctDNA by liquid biopsy) in 61% of patients. Among chemotherapy-naïve patients, the cCR was as high as 55%, with 90% of ORR and 100% of disease control rate during the first 4 months. Moreover, mDCF was associated with a decrease in Myeloid-Derived Suppressive Cells (MDSC) and an increase in the antitumor anti-hTERT immunity, two major factors correlated with prognosis in advanced SCAC, rendering mDCF a good partner to combine with immunotherapy. Anti-PD1 immunotherapy is effective in chemorefractory SCAC. In sensitive tumors, neoadjuvant anti-PD1, with or without chemotherapy, induced a high rate (30-45%) of complete or near-complete pathological response. The combination of mDCF and immunotherapy is safe. Methods: INTERACTION is an open-label, pivotal, single arm, phase II study in neoadjuvant setting for stage 3 SCAC patients (NCT04719988). Fifty-five patients will receive up to 6 cycles of mDCF (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on day 1, 5-fluorouracil 2400 mg/m2 over 46 h) every 2 weeks, in association with ezabenlimab (anti-PD1 mAb) at 240 mg every 3 weeks. CT-scan, MRI, tumor and liquid biopsies will be performed before treatment, and after 4 cycles. CRT will be start after cycle 6. Then, ezabenlimab will be administered in the adjuvant setting up to 10 months from cycle 1. Eligible candidates include patients with treatment-naïve histologically proven locally advanced SCAC, an ECOG PS of 0 or 1, and age ≥18 years. The primary endpoint is the clinical complete response rate at 10 months from the first cycle of mDCF plus ezabenlimab. Main secondary endpoints are the major pathological response (complete/near-complete response) and biological CR (HPV ctDNA negative) after induction treatment. Other secondary endpoints include the ORR, OS, PFS, RFS, HRQoL and safety. An extensive ancillary study will be performed to predict response or resistance to treatment. Peiffert D et al. JCO 2012;30:1941–8; James RD et al. Lancet Oncol 2013;14:516–24; Kim S et al. Lancet Oncol 2018; 19:1094–106; Kim S et al. TAMO 2020;12:1758835920975356; Spehner L et al. IJMS 2020;21:6838; Ott PA et al. Ann Oncol 2017;28:1036–41; Morris VK et al. Lancet Oncol 2017;18:446–53; Huang AC et al. Nat Med 2019;25:454–61; Necchi A et al. JCO 2018;36:3353–60; Forde PM et al. NEJM 2018;378:1976–86; Kim S et al. BMC Cancer 2020;20:352. Clinical trial information: EudraCT 2020-006046-40 and Clinicaltrials.gov NCT04719988.

Early versus standard initiation of terlipressin for HRS-AKI in ACLF patients- a randomized controlled trial (ETERLI).

Background and Aim: Terlipressin infusion has been shown to be effective in treatment of HRS-AKI. Progression of AKI is rapid in ACLF patients. Response to terlipressin correlates with stage of AKI and ACLF. Aims: We investigated whether early initiation of therapy might improve response to terlipressin in HRS-AKI patients by day 7. Methods: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation(40g) for 12 hours were randomized to receive early terlipressin at 2mg/24 hour plus albumin (ET, n=35) or standard therapy (ST, n=35), albumin alone for 48h followed by terlipressin. The primary end-point was AKI reversal by day 7. The main secondary end-points included need for dialysis, treatment-related adverse effects and mortality at day 28 and Day 90. Results: Baseline parameters including AKI stage and ACLF AARC scores in two groups were comparable. Full AKI response at day 7 was observed in 24/35 (68.6%) patients in ET group compared to 14/35(40 %) in ST group [P-0.03]. There was significant improvement in ACLF grades from baseline to Day 7 in ET group (ACLF grade II to I in 16 patients). Five patients in each group developed progressive AKI requiring dialysis. Significantly more patients died in ST group (23/35; 65.7 %) within 28 days compared to 14/35 (40 %) in ET group [P-0.031]. The 90-day mortality in ST group was higher (69.6% vs. 57.2%; P-0.071). Baseline MELD score [HR: 0.987 (95% CI: 0.864-3.211); P-0.02], HE at presentation [HR: 4.405 (95% CI: 1.776-10.927); P-0.001] and admission BUN [HR: 1.007 (95% CI: 1.000-1.013); P-0.036] were independent predictors of 28-day mortality. Overall, 9 patients had terlipressin related adverse effects, none was life threatening. Conclusion: In patients with ACLF, early initiation of terlipressin for AKI persisting despite 12 hours of volume expansion with albumin helps in early reversal of AKI and regression of ACLF stage with significantly short-term mortality benefit.

Effects of postoperative atorvastatin use in elderly patients with chronic subdural hematoma.

Atorvastatin has been suggested to reduce hematoma volume and improve neurological outcomes in patients with chronic subdural hematoma (CSDH). However, the benefits and harms of atorvastatin use after surgery in elderly patients are not well studied. We conducted a retrospective trial to analyze older people (> 60 years) with CSDH, those who were treated with surgical intervention. Patients were assigned to study group if they received oral atorvastatin after surgery at least 1 week, and patients without atorvastatin medication postoperatively were assigned to control group. The primary outcome was the overall rate of recurrence at 1 month after surgery. The main secondary endpoints were the scores on the modified Rankin Scale (mRS), hematoma volume, mortality, and complications after surgery. A total of 49 eligible patients were included - 21 in the study group and 28 in the control group. The baseline characteristics were similar between the 2 groups. At 1 month, recurrence of subdual hematoma requiring repeat surgery was reported in 4 of 21 patients (19.0%) in the study group and in 5 of 28 patients (17.9%) in the control group (p=0.915). The hematoma volume was similar between the 2 groups (p=0.979). A favorable outcome (a score of 2 or less on the mRS) occurred in 90.5% of patients in the study group and in 96.4% of those in the control group (p=0.390). In older people with CSDH, postoperative atorvastatin use barely reduces the incidence of recurrence and hematoma volume.

A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18–80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.

A Multi-Center, Phase 1b Study to Assess the Safety, Pharmacokinetics and Efficacy of Subcutaneous Isatuximab Plus Pomalidomide and Dexamethasone, in Patients with Relapsed/Refractory Multiple Myeloma

A Multi-Center, Phase 1b Study to Assess the Safety, Pharmacokinetics and Efficacy of Subcutaneous Isatuximab Plus Pomalidomide and Dexamethasone, in Patients with Relapsed/Refractory Multiple Myeloma

Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial

NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; P = 0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; P = 0.042) were met while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT. Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the "all treated population" during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis, arthrosis and edema that may alter limb function showed no difference between arms (4.5% vs 7.7%, 2.2% vs 0.0% and 6.7% vs 2.2% respectively in A vs B). In addition, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. Finally, second primary cancer was observed in 1 patient in arm A and 6 patients in arm B and the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site.These results demonstrate that the use of NBTXR3 did not change the late onset toxicity profile of EBRT, nor modified its bystander effect. Taken together, the long-term safety data presented here, and the previously published efficacy data reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. NCT02379845.

Transcranial versus Direct Cortical Stimulation for Motor-Evoked Potentials during Resection of Supratentorial Tumors under General Anesthesia (The TRANSEKT-Trial): Study Protocol for a Randomized Controlled Trial.

Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we designed this randomized study to compare between both methods regarding the prediction of postoperative motor deficits and extent of tumor resection. Methods: This is a multicenter (six centers in Germany and one in Switzerland), double blind, parallel group, exploratory, randomized controlled clinical trial. Patients without or with mild paresis, who are scheduled for surgical resection of motor-eloquent brain tumors under general anesthesia will be randomized to surgical resection under TES or surgical resection under DCS. The primary endpoint is sensitivity and specificity in prognosis of motor function 7 days after surgery. The main secondary endpoint is the extent of tumor resection. The study is planned to include 120 patients within 2 years. Discussion: The present exploratory study should compare TES and DCS regarding sensitivity and specificity in predicting postoperative motor deficit and extent of tumor resection to calculate the required number of patients in a confirmatory trial to test the superiority of one method over the other.

P-034: MAGNAZ trial - A prospective phase II study in patients with monoclonal gammopathy of unknown significance (MGUS) and anti-Myelin Associated Glycoprotein (MAG) Neuropathy and Zanubrutinib Treatment

<h3>Introduciton</h3> Polyneuropathy (PNP) associated with IgM monoclonal gammopathy (MGUS), also called IgM-related PNP, is mediated by the anti-neural effect of the M-protein component and is classified as one of the MGUS-related diseases. In around 70% of patients with IgM-related PNP anti-myelin associated glycoprotein (MAG) antibodies are detected. There is no established treatment for IgM-related PNP except anti-CD20 monoclonal antibody treatment with 30% or less clinical responses. There is increasing interest to use Bruton's tyrosine kinase (BTK) inhibitors, approved for the treatment of Waldenstrom Macroglobulinemia, for IgM-related PNP treatment but a formal study is currently lacking. We therefore designed a phase 2 clinical trial to investigate the effect of zanubrutinib, a next generation BTK inhibitor, combined with anti-CD20 monoclonal antibody treatment, in IgM-related PNP with anti MAG antibodies. The primary study endpoint is change from baseline in the Rasch-built Overall Disability Scale (RODS) for inflammatory neuropathies (iRODS) at the end of Cycle 12. The main secondary endpoint is to assess the safety of zanubrutinib treatment in IgM-related PNP as measured by CTCAE, version 5.0. <h3>Methods</h3> Patients will be treated for a minimum of 6 cycles; patients experiencing hematological response continue until 12 cycles of treatment. All patients will be followed for the duration of 12 cycles for the primary endpoint analysis. Patients who have an anti MAG titer > 10.000 BTU, adequate hematological, renal and hepatic function tests, no hemorrhagic disorder and no New York Heart Association (NYHA) grade 3 or 4 cardiac disease can be included after signing informed consent. Explorative analysis will consist of Next Generation Sequencing of MYD88 and CXCR4 mutations after CD19 selection of the bone marrow aspirate at start. During study participation extensive neurological testing and serum IgM and anti MAG testing will be performed. In total 40 patients will be included and the MAGNAZ study expects to start in Q4 2021.

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study.

To assess the overall effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) in a clinical practice setting. EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted in Italy that analyzed secondary data of treatment-naïve patients with nAMD. The primary endpoint evaluated the mean annualized number of anti-VEGF injections at Years 1 and 2. The main secondary endpoints analyzed the mean change in visual acuity (VA) from baseline and variables associated with visual outcomes at Years 1 and 2. Of the 752 patients enrolled, 745 (99.07%) received the first dose of anti-VEGF in 2016. Overall, 429 (57.05%) and 335 (44.5%) patients completed the 1- and 2-year follow-ups, respectively. At baseline, mean (standard deviation, SD) age was 75.6 (8.8) years and the mean (SD) VA was 53.43 (22.8) letters. The mean (SD) number of injections performed over the 2 years was 8.2 (4.1) resulting in a mean (SD) change in VA of 2.45 (19.36) (P = 0.0005) letters at Year 1 and -1.34 (20.85) (P = 0.3984) letters at Year 2. Linear regression models showed that age, baseline VA, number of injections, and early fluid resolution were the variables independently associated with visual outcomes at Years 1 and 2. The EAGLE study analyzed the routine clinical practice management of patients with nAMD in Italy. The study suggested that visual outcomes in clinical practice may be improved with earlier diagnosis, higher number of injections, and accurate fluid resolution targeting during treatment induction.