Clinical Activity Research Articles

Real-world clinical outcomes and rationale for initiating abatacept as a first-line biologic for patients with anticitrullinated protein antibody- and rheumatoid factor-positive rheumatoid arthritis

Aim: In rheumatoid arthritis (RA), seropositivity for both anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) is associated with disease severity and therapeutic response. Biologic (b) disease-modifying antirheumatic drugs (DMARDs) such as abatacept are recommended after inadequate response or contraindication to conventional synthetic DMARDs. This retrospective cohort study aimed to describe changes in Clinical Disease Activity Index (CDAI) measures over 12 months among patients with ACPA+ and RF+ RA with an inadequate response to methotrexate treated with abatacept as a first-line bDMARD. Patients & methods: Patient data were abstracted from medical records by treating rheumatologists. Analyses included McNemar tests for paired proportions or paired t -tests to assess longitudinal changes in CDAI scores, and Kaplan–Meier methods for time-to-event outcomes. Serious AEs and rationale for initiating treatment were recorded. Results: Overall, 296 patients were included. Mean CDAI scores improved (decreased) by 34.0, 61.0 and 74.0% (all p < 0.001) from baseline to 3–6 months, 6–12 months and ≥12 months after abatacept initiation, respectively. Of 279 patients not in CDAI low disease activity (LDA) or remission at baseline, 24.7% of patients achieved it within 6 months, 56.3% within 12 months and 71.0% at any point during follow-up after abatacept initiation. Median time to CDAI LDA/remission was 10.2 months. Serious AEs were reported in 2.4% of patients. Common reasons reported by rheumatologists for initiating abatacept were effectiveness/efficacy (52.7%), safety (31.4%) and patient preference (25.3%). Conclusion: In this analysis of patients with ACPA+ and RF+ RA treated with abatacept as a first-line bDMARD in a clinical practice setting, clinical outcomes and remission rates were improved at all time points, providing real-world evidence to further support the use of abatacept in this patient population.

Elevated Calprotectin Levels Reveal Loss of Vascular Pattern and Atrophy of Villi in Ileum by Digital Chromoendoscopy and Magnification Colonoscopy in Patients with Spondyloarthritis Without Having Inflammatory Bowel Disease

Objective: This study aimed to establish a correlation between fecal calprotectin levels (FC) and intestinal inflammation in patients with spondyloarthritis without inflammatory bowel disease. Methods: A total of 180 SpA patients were included in the study of them 20.6% required Digital chromoendoscopy (DCE). FC, C-reactive protein (CRP), HLA-B*27 and clinical indices were assessed. Results: Positive fecal calprotectin (PFC) and high fecal calprotectin (HFC) levels were observed in 27.0% and 16.0% of patients, respectively. HFC correlated with a Bath Ankylosing Spondylitis Functional Index (BASFI) score > 4.0 (p = 0.036) and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score > 4.0 (p = 0.047). Loss of vascular pattern in the ileum (LVPI) was observed in approximately 70.0% of patients (p = 0.005), which was associated with PFC and abdominal bloating (p = 0.020). LVPI was also linked to microscopic inflammation (p = 0.012) and PFC with abdominal pain (p = 0.007). HFC was significantly associated with alterations in the ileal mucosa (p = 0.009) and LVPI (p = 0.001). Additionally, HFC and diarrhea were associated with LVPI in 27.3% of patients (p = 0.037) and with erosions in the ileum (p = 0.031). Chronic ileal inflammation correlated with HFC (p = 0.015), ASDAS-CRP > 2.1 (p = 0.09), LVPI (p = 0.001), and villous atrophy (p = 0.014). Factorial analysis of mixed data (FAMD) identified significant associations between micro/macroscopic changes in chronic inflammation and HFC (CC = 0.837); increased levels of CRP and microscopic acute inflammation (CC = 0.792); and clinical activity scores of ASDAS-CRP and BASDAI (CC = 0.914). Conlusions: FC levels were significantly elevated in patients with SpA, particularly those with LVPI, suggesting their potential as a valuable biomarker for managing SpA when joint manifestations coincide with ileal villous atrophy. This indicates a shared immune pathway linked to chronic gut damage.

Lacrimal gland enlargement in thyroid eye disease.

This study aimed to investigate lacrimal gland (LG) enlargement in thyroid eye disease (TED) patients on magnetic resonance imaging (MRI). A retrospective review was conducted on TED patients who had undergone fat-suppressed contrast-enhanced T1-weighted MRI of the orbits. The lacrimal gland was segmented on OsiriX in consecutive axial and coronal slices to determine its volume. Enlargement was defined as a volume greater than 1100mm3, based on previous normative data. Asymmetric enlargement was defined if one side was enlarged but the contralateral side was not. Clinical data including presentation (active/inactive) and presence or absence of dysthyroid optic neuropathy was evaluated. The study population consisted of 88 orbits from forty-four patients with a mean age of 53 ± 15years, with 29 (65%) being female. Twelve patients (27%) had LG enlargement, with eight (18%) having bilateral enlargement and four (9%) having asymmetric enlargement. There was no significant difference in age (p = 0.17) or sex (p = 0.44) between the LG enlarged and non-enlarged groups. There was also no significant difference in the clinical activity (p = 0.46) or prevalence of dysthyroid optic neuropathy (p = 0.63) between the LG enlarged orbits and non-LG enlarged orbits. Lacrimal gland enlargement may be observed in approximately thirty percent of TED patients, with asymmetric enlargement in approximately ten percent of cases.

The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial.

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab's on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.

Sonographic and Disease Activity Findings Related With Medication Change in JIA: A Historical Cohort Study.

Musculoskeletal ultrasound (MSUS) is increasingly used to evaluate pediatric inflammatory arthritis. This study aimed to explore the relationship between MSUS findings with medication modifications in patients with juvenile idiopathic arthritis (JIA) and clinical disease activity measurements (clinical Juvenile Arthritis Disease Activity Score [cJADAS-10], active joint count [AJC], patient/parent global assessment [PPGA], and physician global assessment [PGA]). Data from patients with JIA who underwent a 12-joint (bilateral second and third metacarpophalangeal, wrist, elbow, knee, and ankle) MSUS examination during a 57-month period were collected. Patients were categorized into 2 groups: a medication change group and a control group (patients without medication change). A pediatric-specific MSUS scoring system was used to assess MSUS findings. The association between clinical and MSUS findings was examined for the study groups. A total of 38 patients, 23 in the medication change group and 15 in the control group were included. The medication change group had higher AJC, PGA, and cJADAS-10. These patients also had a statistically significant presence of abnormal knee MSUS findings. For other joints, the frequency of abnormal MSUS findings was slightly higher in patients with a medication change, but the difference was not statistically significant. No strong correlation was observed between MSUS findings and clinical disease activity measurements. Abnormal MSUS findings were not observed to be higher in patients with a change in medication except for the involvement of the knee joint. Further longitudinal studies are needed to understand the role of MSUS in the medical decision-making process in JIA.

Abstract 4114714: Impact of Cardiology Interest Groups on the Professional Development of Medical Students

Background: Launched in 2023, the American College of Cardiology Medical Student Member Community (ACC MSMC) began recognizing Cardiology Interest Groups (CIGs) at medical schools worldwide. This initiative fosters a robust network among ACC medical student members and celebrates their contributions within their institutions and broader communities. We surveyed medical students from 50 recognized CIGs to evaluate the influence of this network on their members' career trajectories. Methods: An anonymous web-based survey was sent to 50 student leaders of CIGs recognized by the ACC from 20 countries and was distributed to their members. The objective was to evaluate the impact of their involvement in these groups on their clinical knowledge, research activities and publications, professional advancement, and the promotion of diversity and equity. Results: Of 215 respondents (71% ACC members), 49.3% identified as female, with significant representation from Asia (35.7%), and the USA (17.6%). The majority joined CIGs to explore cardiology as a career path (61%), build professional networks (60%), and participate in specialized workshops (59.5%). Most rated their access to CIG resources as excellent (73.8%), supporting ACC's mission to enhance diversity and inclusion. Regarding educational outcomes, 48.6% rated their knowledge acquisition in cardiology as excellent, and 41% noted excellent preparation for a cardiology career. Additionally, 26.4% of students published research papers post-CIG involvement, with 39% attending ACC or AHA conferences. Survey feedback also highlighted strong networking (38.6% excellent) and mentoring opportunities (36.2% excellent) provided by CIGs. Conclusions: CIGs significantly enrich medical students' professional development by offering extensive networking, education, research, and mentorship opportunities. They play a crucial role in nurturing a global interest in cardiology, thereby enhancing diversity within the field. This model serves as a valuable blueprint for other scientific societies considering the establishment of student interest groups.

A Phase 2 study of acimtamig (AFM13) in patients with CD30-positive, relapsed or refractory peripheral T-cell lymphomas.

Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options. This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL. Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was overall response rate (ORR) by fluorodeoxyglucose-positron emission tomography per independent review committee; secondary and exploratory endpoints included duration of response (DoR), safety, progression-free survival, and overall survival. The ORR in 108 patients was 32.4% (95% CI: 23.7, 42.1) with a complete response rate of 10.2% (95% CI: 5.2, 17.5); median DoR was 2.3 months (95% CI: 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses (53.3% [95% CI: 34.3, 71.7]). Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint. The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic natural killer cells.

Static and dynamic pupillary features in graves disease without orbitopathy.

Pupillary contraction and dilatation are organized by the autonomic nervous system, which can also be affected by Graves' disease (GD). In this study, it was aimed to investigate the static and dynamic pupillary responses of Graves' patients in the hyperthyroid and euthyroid periods and to compare these results with the values obtained from healthy controls. 48 eyes of 24 newly diagnosed Graves' patients with clinical activity score ≤ 2 and 46 eyes of 23 age- and sex-matched healthy controls were included in the study. Patients with GD were evaluated separately in the hyperthyroid phase and after euthyroidism was achieved. After a detailed ophthalmological examination, patients undergone automatic quantitative testing to obtain static (scotopic, mesopic, low photopic, and high photopeak pupil diameters) and dynamic (pupillary contraction amplitude, latency, velocity and duration, and pupil dilation latency, velocity and duration) pupil measurements. A statistically significant difference was found between the control [4.7mm (3.7-6.9)] and hyperthyroid [5.1mm (3.6-7.8)] groups for mesopic pupil diameter (p = 0.003). Dynamic pupillometry measurements showed that hyperthyroid and euthyroid groups had greater pupil dilation delay and lower pupil dilation rate compared to the control group (p < 0.05 for all). Even in the absence of orbitopathy, patients with GD have autonomic dysregulation of pupillary functions. These changes, which prevail in the hyperthyroid phase, do not reverse when the TSH receptor antibody titer drops and the patient becomes euthyroid. Future studies are needed to elucidate the mechanism of these pupillary changes in GD.

CTNI-85. FINAL RESULTS FROM N2M2/NOA-20

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.

Predictive accuracy of fecal calprotectin for histologic remission in ulcerative colitis.

Accurate assessment of disease activity is crucial for effective management and treatment of ulcerative colitis (UC). This study evaluated the correlation between clinical, endoscopic, and histologic measures of disease activity in UC. Clinical, biochemical, endoscopic, and histologic disease activity was studied in 347 patients with UC. Agreements among various histologic classification systems, namely the Geboes Score (GS), Continuous GS, Nancy Index (NI), and Robarts Histopathology Index (RHI), were analyzed. The predictive accuracy of fecal calprotectin (FC) for endoscopic and histologic remission was assessed. We demonstrate a fair to moderate correlation between clinical, endoscopic, and histologic measures of disease activity in UC. There was a robust concordance among GS, Continuous GS, NI, and RHI in distinguishing between patients in histologic remission or activity. The NI detected 75% of patients who met the remission criteria according to the RHI, whereas the RHI identified all patients in remission as defined by the NI. FC levels below 150 μg/g had >70% accuracy in predicting endoscopic remission. FC levels below 150 μg/g showed ≥80% accuracy, and FC levels below 100 μg/g demonstrated ≥ 85% accuracy in predicting histologic remission, regardless of the scoring index applied. Elevated FC levels were associated with both acute and chronic inflammatory infiltrates in biopsy samples. FC is a reliable predictor of histologic remission, with higher accuracy at lower thresholds. The GS, Continuous GS, NI, and RHI demonstrate comparable performance. FC could help stratify patients' need for colonoscopy for the assessment of endoscopic and histologic remission.

CTNI-45. PHASE 2 STUDY OF SORAFENIB, VALPROIC ACID, AND SILDENAFIL IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA

Abstract PURPOSE Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma. PATIENTS AND METHODS Eligible patients were 18 years of age and older with an Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented CT or MRI progression or recurrence and measurable or evaluable disease. The treatment schedule was a combination of sorafenib, valproic acid, and sildenafil, each agent administered orally, twice daily continuously. A cycle consisted of 4 weeks. RESULTS Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p &amp;lt; 0.0026). A correlation between the expression of PDGFRa and OS approached significance (p &amp;lt; 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. CONCLUSIONS This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS For Phase 1 and Phase 1 expansion patients were required to be ≥2 and &amp;lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.

Efficacy and safety of sacituzumab govitecan Trop-2-targeted antibody-drug conjugate in solid tumors and UGT1A1*28 polymorphism: a systematic review and meta-analysis.

Sacituzumab govitecan (SG) is a promising Trop-2-targeted antibody-drug conjugate (ADC) approved for the treatment of metastatic triple-negative breast cancer (TNBC). Early phase clinical trials have demonstrated good clinical activity and safety profile of SG in various tumor types, albeit with differing response rates and durations. The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy and toxicity of SG and the influence of UGT1A1*28 genotype in clinical trials involving solid tumors. A systematic review of the literature from publicly available databases was performed on February 15, 2024 whereby studies published till 15 February 2024 were retrieved according to PRISMA guidelines [PROSPERO #CRD42022359943]. Data extracted included tumor type, sample size, demographic information, SG dose, UGT1A1*28 status, toxicity events, duration of follow-up, response, and survival outcomes. Risks of bias analysis was refereed using the Joanna Briggs Institute quality assessment tool for the cohort and RCT studies using 11 and 13 parameters, respectively. Statistical analysis was performed using the DerSimonian and Laird inverse variance methods. Heterogeneity was assessed using the I2 statistic and Χ2 tests. P value < 0.05 was considered as statistical significance. Eleven eligible clinical trials comprised of 1578 patients harboring various tumor types including TNBC, lung, genitourinary and gastrointestinal malignancies were included in the systematic review and meta-analysis. Pooled incidences of severe adverse events were minimal at <10%, with the exception of grade 3-4 neutropenia at 37.4%. The median PFS and OS across all studies were 4.9 (95%CI: 4.0-5.8) months and 9.6 (95%CI: 7.6-11.6) months, respectively. Objective response rate across all studies evaluated was 17.1% (95%CI: 12.0-22.1). Our systematic review and meta-analysis confirmed that SG confers good clinical activity in certain solid tumor types and was tolerable with minimal adverse events. The potential utility of UGT1A1*28 genotyping in predicting clinical response and outcomes could not be determined due to the limited number of studies with available UGT1A1 genotype data.

CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS

Abstract BACKGROUND Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS. METHODS Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO. RESULTS Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented. CONCLUSION These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.

TMOD-02. PATIENT-DERIVED GLIOBLASTOMA ORGANOIDS AS REAL-TIME AVATARS FOR ASSESSING RESPONSES TO CLINICAL CAR-T CELL THERAPY

Abstract Patient-derived tumor organoids have been increasingly leveraged for disease modeling and preclinical studies, but rarely in real-time to aid with the interpretation of patient treatment responses in the clinical setting. Whether tumor organoids can be applied to mirror clinical activity in patients and even to predict responses for personalized medicine remains uncertain. We recently demonstrated promising early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma (clinical trial identifier: NCT05168423). Determination of meaningful clinical efficacy, in particular for CAR-T cell therapy, may take months to manifest. Given this challenge, real-time analysis of patient-derived glioblastoma organoids (GBOs) could help to provide early assessment of clinical efficacy and guide patient management. We analyzed six sets of GBOs generated on the same timeline as the production of patients’ CAR-T cell products. GBOs demonstrated the presence and retention of both targeted tumor-associated antigens EGFR and IL13Rα2 by immunohistochemistry. These GBOs were then treated with the same autologous CAR-T cell products received by patients in our phase 1 study in parallel with patient treatment. CAR-T cell treatment led to target antigen reduction assessed by immunohistochemistry and flow cytometry. Furthermore, we confirmed cytolysis of tumor cells in GBOs by cleaved caspase-3 immunostaining and by co-culture in the Axion Maestro Cellular Impedance platform. Importantly, the degree of cytolysis ex vivo significantly correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF) for all six patients. Furthermore, cytotoxic activity of CAR-T cells as measured by TNFα, IL-2, and IFNγ release kinetics in GBOs mirrored cytokine levels in patient CSF samples over time. Our findings highlight a unique trial design and suggest GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and for insights into immunotherapy efficacy.

Focused ultrasound for treatment of epilepsy: a systematic review and meta-analysis of preclinical and clinical studies.

Various preclinical and clinical studies have demonstrated the neuromodulatory and ablative effects of focused ultrasound (FUS). However, the safety and efficacy of FUS in clinical settings for treating epilepsy have not been well established. This study aims to provide a systematic review of all preclinical and clinical studies that have used FUS for the treatment of epilepsy. A systematic search was conducted using Scopus, Web of Science, PubMed, and Embase databases. All preclinical and clinical studies reporting outcomes of FUS in the treatment of epilepsy were included in the systematic review.Random-effect meta-analysis was performedtodetermine safety in clinical studies and seizure activity reduction in preclinical studies. A total of 24 articles were included in the study. Meta-analysis demonstrated that adverse events occurred in 13% (95% CI = 2-57%) of patients with epilepsy who underwent FUS. The frequency of adverse events was higher with the use of FUS for lesioning (36%, 95% CI = 4-88%) in comparison to neuromodulation (5%, 95% CI = 0-71%), although this difference was not significant (P = 0.31). Three-level meta-analysis in preclinical studies demonstrated a reduced spike rate in neuromodulating FUS compared to the control group (P = 0.02). According to this systematic review and meta-analysis, FUS can be considered a safe and feasible approach for treating epileptic seizures, especially in drug-resistant patients. While the efficacy of FUS has been demonstrated in several preclinical studies, further research is necessary to confirm its effectiveness in clinical practice and to determine the adverse events.

Quantitative evaluation of clinical pharmacy activities following implementation of an enhanced weekend service at a teaching hospital

Abstract Introduction Improving equity of staffing across seven-days is a strategic priority for the National Health Service (NHS).1 Development of enhanced weekend clinical pharmacy services presents opportunity to improve admission and discharge medicines reconciliation (MR), reduce medication error and increase patient counselling.2 At the study site, an enhanced weekend clinical pharmacy service was implemented in October 2021. The service was delivered 9am-5pm to all clinical specialities across 54 wards. Defined minimum staffing was 13 pharmacists and 2 medicines management pharmacy technicians (MMPT). Service specification included: clinical screen and order of medications; admission MR, review of high-risk patients (critical care patients and those prioritised by the weekday team); and discharge activities including patient counselling. Aim To evaluate provision of the enhanced weekend clinical pharmacy service post-implementation by quantification of shift fill and clinical pharmacy professional activities. Methods A quantitative study was conducted over two separate weekends one month and six months post-implementation (13th-14th November 2021 and 9-10th April 2022). Pharmacy professionals collected data using a paper activity tool validated for use at the study site. Interventions included rectification of medication error, medicines optimisation or consult. Data were collated in Microsoft Excel immediately after each study weekend. Simple descriptive statistics were performed in Microsoft Excel. The study was registered with KCH Pharmacy Research and Audit Group (07/2021), deemed service evaluation and ethics approval waived. Results Pharmacy professionals reviewed 1,056 patients over 3,645 occupied bed-days. Services were delivered by 13 pharmacists and 1 MMPT on weekend 1, 12 pharmacists and 1 MMPT on weekend 2. Data were collected for all wards on weekend 1; on weekend 2 activity data was not collected for five surgical wards (Saturday and Sunday), four post-acute medical wards (Saturday) and the acute medical unit (Sunday). Admission MR was conducted for 77% (317/412) of newly-admitted patients. Pharmacists recommended prescription amendment for 68% (217/317) of patients receiving admissions MR; affecting 517 medicines. The recorded intervention rate per patient reviewed was 0.64 (680/1056). Pharmacy professionals responded to 211 queries from healthcare professionals (HCPs), undertook 90 incidences of pro-active HCP education and counselled 92 patients/carers. Pharmacists prepared discharge medication lists or clinically screened discharge prescriptions for 205 patients. A total of 952 non-stock medicines were ordered and 313 patients own medicines checked for suitability for reuse. Discussion / Conclusion These findings add to existing evidence for seven-day clinical pharmacy services. Defined minimum staffing was not fulfilled with 90% shift fill rate. Clear benefit was demonstrated in terms of admission MR and resultant intervention, HCP education, discharge and counselling activities. The percentage of patients with a recommended prescription amendment following admission MR matched findings from a separate service evaluation during February 2021 of an enhanced weekend service introduced at our study site during the COVID-19 pandemic (68%).3 The intervention rate for reviewed patients was also comparable (0.64 compared with 0.57 during COVID-19).3 Limitations include the relatively short period of data collection at a single-site which limits generalisability of findings. There were some gaps in data collection and acceptance rate of interventions was not collected.

Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study.

Aim: We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study.Materials & methods: Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of MET, AXL, RET, NTRK, DDR2, KDR, PDGFRA, KIT or CBL received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR).Results: In total, 113 patients were enrolled following a median of 3 (range 1-18) prior systemic regimens. Altered RET (n = 31), CBL (n = 31) and MET (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with RET-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; p = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the RET-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts.Conclusion: Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.

Residual symptoms: Unmet needs for rheumatoid arthritis patients who achieved low clinical disease activity

Residual symptoms: Unmet needs for rheumatoid arthritis patients who achieved low clinical disease activity

Safety and efficacy of filgotinib in Japanese patients with rheumatoid arthritis: Week 156 interim results in FINCH 4.

To describe safety and efficacy of filgotinib 200 or 100 mg (FIL200/FIL100) in Japanese patients with rheumatoid arthritis in a long-term extension (LTE; NCT03025308). Patients who completed any of three parent studies (NCT02889796: inadequate response [IR] to methotrexate [MTX]; NCT02873936: IR to biologic disease-modifying antirheumatic drugs; NCT02886728: MTX-naïve) without rescue therapy could enter the LTE; patients taking FIL continued their dosage, and those who received comparators were rerandomised to FIL200 or FIL100. This analysis includes week 156 interim results. Among Japanese patients, 110 received FIL200, and 97 received FIL100. Mean (SD) FIL200 and FIL100 exposure was 157.0 (51.49) and 156.0 (52.45) weeks. The exposure-adjusted incidence rates (95% CI) for FIL200/FIL100 were 2.7 (1.4, 5.2)/2.4 (1.2, 5.1) for herpes zoster, 0.9 (0.3, 2.8)/1.0 (0.3, 3.2) for malignancy (excluding nonmelanoma skin cancer), and 0.6 (0.2, 2.4)/0.3 (0.0, 2.4) for major adverse cardiovascular events. More patients receiving FIL200 with prior FIL200 exposure achieved clinical remission vs other groups (including Clinical Disease Activity Index remission in 40% vs 27% or less at week 156). FIL200 and FIL100 were generally well tolerated by Japanese patients, without new, unexpected adverse events.