2519 Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .
Although poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and bevacizumab were approved as first-line maintenance for advanced ovarian cancer (OC), evidence comparing this combination with PARPi monotherapy, especially in BRCA-mutated/homologous recombination-deficient (HRD) patients, is lacking. This study compared combined fuzuloparib (a PARPi) plus apatinib (a vascular endothelial growth factor receptor-2 inhibitor) with either fuzuloparib or placebo as first-line maintenance in patients with advanced OC. Patients who had newly diagnosed, advanced OC and responded to first-line, platinum-based chemotherapy were randomized 2:2:1 to receive combined fuzuloparib (100 mg twice daily) plus apatinib (375 mg daily), fuzuloparib (150 mg twice daily) plus placebo, or double-placebo treatment. The primary end point was blinded independent review committee (BIRC)-assessed progression-free survival (PFS). Six hundred seventy-four patients were randomized to receive fuzuloparib plus apatinib (n = 269), fuzuloparib (n = 269), or placebo (n = 136). At the final analysis (November 1, 2024; 385 BIRC-assessed PFS events; median follow-up, 40 months), the median BIRC-assessed PFS was 26.9 months with the combination versus placebo (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44-0.75; one-sided p < .0001) and 29.9 months with fuzuloparib monotherapy versus placebo (HR, 0.58; 95% CI, 0.44-0.75; one-sided p < .0001) compared with 11.1 months with placebo. A PFS benefit was observed regardless of germline BRCA1/2 mutation status. In homologous recombination-deficient patients (including those with BRCA1/2 mutations), combined fuzuloparib and apatinib produced a PFS similar to that of fuzuloparib (34.1 vs. 35.8 months, respectively); in homologous recombination-proficient patients, PFS had a trend favoring the combination (16.6 vs. 11.0 months; HR, 0.73; 95% CI, 0.45-1.19). Both treatments were well tolerated. Overall survival was immature. Both fuzuloparib and combination therapy improved PFS compared with placebo as maintenance therapy for patients who had newly diagnosed, advanced OC. Adding apatinib to fuzuloparib did not prolong PFS among homologous recombination-deficient patients. There was a PFS benefit trend among homologous recombination-proficient patients who received combination therapy compared with those who received monotherapy.
To explore the efficacy and safety of remimazolam besylate in short-term sedation in the ICU in comparison with propofol. A multicenter, randomized, single-blind, non-inferiority trial was conducted in mechanically ventilated patients, who needed light sedation, defined as Richmond Agitation–Sedation Scale (RASS) scores between −2 and + 1. The primary outcome was successful sedation, which was defined as no rescue sedative administered during the study drug infusion period while maintaining RASS scores between –2 and + 1 for at least 70
BACKGROUND:Effective topical therapies for mild-to-moderate atopic dermatitis (AD) should provide rapid itch relief, sustained anti-inflammatory efficacy and minimal local toxicity. Existing options, including corticosteroids and calcineurin inhibitors, are limited by long-term adverse effects, highlighting the need for safer, steroid-sparing alternatives. OBJECTIVES:To evaluate the efficacy and safety of ivarmacitinib ointment, a highly selective topical Janus kinase 1 inhibitor, applied twice daily in adults with mild-to-moderate AD. METHODS:This phase III evaluation was part of a multicentre randomized double-blind vehicle-controlled seamless adaptive phase II/III trial conducted at 27 sites in China. Adults aged 18-75 years with Hanifin-Rajka-defined mild-to-moderate AD were randomized (1 : 1 : 1) to ivarmacitinib ointment 0.5%, ivarmacitinib ointment 1% or vehicle for 8 weeks. Patients who initially received the vehicle were re-randomized to active treatment for a blinded extension through week 52. Co-primary endpoints were Investigator's Global Assessment (IGA) response (score 0/1 with ≥ 2-grade improvement) and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 8. RESULTS:At week 8, significantly more patients achieved an IGA response with ivarmacitinib than with vehicle [ivarmacitinib 0.5%: 21.3% vs. 10.6% (P = 0.02); ivarmacitinib 1%: 26.2% vs. 10.6% (P = 0.001)]. Likewise, EASI 75 responses were higher [ivarmacitinib 0.5%: 42.6% vs. 17.9%; ivarmacitinib 1%: 45.1% vs. 17.9% (both P < 0.001)]. Relief from pruritus was seen within 48 h and maintained through week 52, with sustained improvements in SCORing Atopic Dermatitis (SCORAD), affected body surface area and Dermatology Life Quality Index. During the vehicle-controlled period, treatment-emergent adverse events occurred in 42.6% (n = 52/122), 56.6% (n = 69/122) and 52.0% (n = 64/123) of patients in the ivarmacitinib 0.5%, ivarmacitinib 1% and vehicle groups, respectively; most were mild and infection-related events were infrequent. No treatment-related adverse event occurred in ≥ 2% of patients in the ivarmacitinib 1% or vehicle groups, while in the ivarmacitinib 0.5% group, only folliculitis (n = 5/122; 4.1%) and increased blood uric acid (n = 4/122; 3.3%) were reported in ≥ 2% of patients. No skin atrophy, telangiectasia or application-site irritation was observed. Long-term safety through week 52 remained consistent, with no new safety signals noted. CONCLUSIONS:Twice-daily ivarmacitinib ointment (0.5% or 1%) produced rapid, durable and well-tolerated improvements in the signs, symptoms and itch experienced by adults with mild-to-moderate AD, supporting its potential as a safe, steroid-sparing topical therapy.
Objective: To evaluate the efficacy and safety of Xeligekimab (GR1501), a fully human monoclonal antibody against interleukin-17A, in Chinese patients with active axial spondyloarthritis (axSpA) who did not respond or were intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs). Methods: This phase II, randomized, double-blind, placebo-controlled, multicenter study enrolled 160 patients with active axSpA. Participants were randomized equally to receive placebo or Xeligekimab at 100 mg, 200 mg, or 300 mg subcutaneously every two weeks for 16 weeks, followed by an 8-week follow-up. The primary endpoint was the Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. Secondary endpoints included ASAS40, ASDAS-CRP, BASDAI, BASFI, and patient-reported outcomes. Safety and immunogenicity were evaluated throughout the study. Results: At week 16, ASAS20 response rates were 52.5% with placebo and 77.5%, 75.0%, and 72.5% with Xeligekimab 100 mg, 200 mg, and 300 mg, respectively. The 100 mg and 200 mg groups showed significant improvement versus placebo (P < 0.05). Benefits in ASAS40, ASDAS-CRP, and BASDAI were maintained through week 24. Xeligekimab was generally well tolerated, and the overall incidence of adverse events was comparable to placebo. No treatment-emergent anti-drug antibodies were detected. Conclusion: Xeligekimab at 100 mg and 200 mg achieved meaningful clinical improvement with good tolerability in patients with active axSpA, supporting further clinical evaluation of this therapy.
