Treatment-emergent Adverse Events Research Articles

Interim analysis of the multinational, post-authorization safety study (NISSO) to assess the long-term safety of sonidegib in patients with locally advanced basal cell carcinoma

Abstract Background Following the pivotal phase II trial BOLT, the Hedgehog (Hh) inhibitor sonidegib was approved in the EU to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiotherapy. We report safety data from the interim analysis of the real-world NISSO study. Methods NISSO is an ongoing non-interventional, multinational, post-authorization safety study (NCT04066504). Patients with laBCC are treated with sonidegib 200 mg orally once daily and followed for 3 years. Dose modifications were allowed according to the local prescribing information. Results Between May 6, 2019, and March 15, 2022, 321 patients with laBCC were enrolled at 46 European sites (data cut-off: June 22, 2023). Treatment was discontinued in 241 (75.1%) patients, with the main reasons being the patient/guardian decision (n = 69, 28.6%), treatment success (n = 40, 16.6%) and the physician decision (n = 35, 14.5%). The median duration of sonidegib exposure was 8.8 months (4.4–13.7 months). Overall, 284 (88.5%) patients had ≥ one treatment-emergent adverse event (TEAE). Most TEAEs were ≤ grade 2 and the most common were muscle spasms (n = 141; 43.9%), dysgeusia (n = 119; 37.1%), and alopecia (n = 97; 30.2%). After 3 months of treatment, the cumulative rates of muscle spasms, dysgeusia, and alopecia were 21.8%, 16.2%, and 3.7%, respectively. TEAEs led to treatment discontinuation in 59 (18.4%) patients, while 149 (46.4%) patients had at least one TEAE leading to dose reduction or interruption. Serious drug-related TEAEs were reported in 13 (4.1%) patients. Conclusions These results confirm the safety profile previously observed. Most patients experienced the onset of common TEAEs after 3 months of treatment, and the cumulative incidence of most common TEAEs was 10–20% lower compared to the BOLT study, except for dysgeusia and fatigue that had a similar incidence. The percentage of patients experiencing TEAEs requiring interruption or dose reduction was similar to the BOLT study, while the proportion of patients with TEAE leading to discontinuation of sonidegib was lower. This study demonstrates that the tolerability of sonidegib is manageable in routine clinical practice. Trial registration. NCT04066504.

Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial

ABSTRACT Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1–<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1–<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients. CLINICAL TRIALS This study is registered at ClinicalTrials.gov as NCT03816176 .

Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer

ImportancePatients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs.ObjectiveTo evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC.Design, Setting, and ParticipantsThis multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024.InterventionsPatients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment.Main Outcomes and MeasuresThe primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy.ResultsAmong 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62− haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively).Conclusions and RelevanceIn this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC.Trial RegistrationClinicalTrials.gov Identifier: NCT04012606

Long-term effectiveness of aripiprazole once monthly on functioning and quality of life in schizophrenia: results of year 2 of the ReLiAM study

Abstract Background Aripiprazole once-monthly (AOM) has proven effective in the treatment of schizophrenia, although little is known about its impact on global functioning and quality of life beyond 1 year. Here, we investigate the continued impact of AOM on the participants of the ReLiAM study during the second year of follow-up. Methods The participants who were evaluated at ≥ 1 time point during the second year of the ReLiAM study (months 15, 18, 21, and 24; year 1 completers) were assessed via the GAF scale. Secondary outcomes were reported on the SOFAS, CGI-S, and QLS. Results 109 (86%) completed at least 1 post-12-month visit and 33 (30.3%) patients completed the final assessment at month 24. The improvements observed in the year 1 completers in GAF total score were maintained through to year 2 completers. The improvements in CGI-S and SOFAS that were observed at the end of year 1 were also maintained through the end of the second year. Similar trends of sustained improvement in GAF total score, CGI-S score, and SOFAS were observed in the post-hoc analyses of the year 2 completers. Seventy-four percent (74.3%) of year 1 completers experienced mild treatment-emergent adverse events during the second year, the most frequently reported being weight gain, akathisia, and insomnia. Seventeen percent (17.4%) experienced serious adverse events. Similar findings regarding effectiveness and tolerability were reported in the year 1 completers and in year 2 completers. Conclusions These findings suggest that the favorable effectiveness, including tolerability observed during the first year following AOM initiation, are maintained and may even continue to improve during the second year of treatment. Trial registration ClinicalTrials.gov NCT02131415, first posted on May 6, 2014. Overall trial status: Terminated.

Phase Ib study of the oral PI3Kδ inhibitor linperlisib in patients with advanced solid tumors

Abstract Background Patients with advanced solid tumors have a suboptimal prognosis. This study investigated the safety and feasibility of linperlisib, a selective phosphatidylinositol 3-kinase delta isoform (PI3Kδ) inhibitor, for treating patients with advanced solid tumors. Methods In this phase Ib, single-arm, open-label, multi-center clinical trial, patients with histologically confirmed advanced solid tumors from eight centers in China were enrolled to receive oral linperlisib (80 mg/day). The primary endpoint was safety. Results Between August 2019 and June 2022, 94 patients were enrolled in the trial and received the study treatment. The most common (≥ 20%) treatment emergent adverse events (TEAEs) of all grades irrespective of causality were increased aspartate aminotransferase (AST) (26.6%), proteinuria (26.6%), decreased appetite (25.5%), increased alanine aminotransferase (ALT) (22.3%), weight loss (21.3%), and anemia (21.3%). The most common grade ≥ 3 TEAEs were diarrhea (4.3%), increased AST (3.2%), increased ALT (3.2%), neutropenia (3.2%), anemia (3.2%), increased blood alkaline phosphatase (3.2%). The objective response rate (ORR) was 1.1% (95% confidence interval [CI] 0.0–5.8), and the disease control rate (DCR) was 37.2% (95% CI 27.5–47.8). As of the data cutoff, the median follow-up time was 4.2 months (95% CI 2.8–6.9). The median progression-free survival (PFS) was 1.85 months (95% CI 1.79–1.88). The median overall survival (OS) was not reached. Conclusion Linperlisib showed an acceptable safety profile and preliminary clinical benefit in patients with a range of advanced solid tumors. Further studies of linperlisib safety and efficacy are warranted.

Abstract 4134320: Integrated safety and tolerability of mavacamten treatment over 5 years in patients with obstructive hypertrophic cardiomyopathy

Background: Mavacamten, a cardiac myosin inhibitor, is approved across 5 continents for the treatment of obstructive hypertrophic cardiomyopathy (HCM). Long-term data of mavacamten are available from multiple studies, providing the opportunity to further understand mavacamten long term safety, including adverse events (AEs) of clinical interest. Aim: To present integrated safety data of patients who received mavacamten treatment for obstructive HCM across 5 studies. Methods: The pooled population included all patients who received ≥1 dose of mavacamten in PIONEER-HCM, PIONEER-Open Label Extension (data cut-off: May 31, 2022), EXPLORER-HCM, MAVA-Long-Term Extension (EXPLORER cohort; data cut-off: August 31, 2023) and VALOR-HCM including long-term extension (data cut-off: November 11, 2022). Results: The population consisted of 368 patients (mean [SD] age: 59.4 [12.2] years; male: 57.1%; White: 90.8%), including 350 patients who continued onto an extension study after completing a parent study. The majority of patients (57.6%) had a cumulative time on study of ≥3 years. Forty (10.9%) patients permanently discontinued treatment (13 due to AEs). In total, 20.7% of patients had a treatment emergent AE (TEAE) of Grade ≥3 and 14.7% had a TEAE leading to drug interruption. Overall, 4.3% of patients had drug-related serious TEAEs and 1.6% had a TEAE leading to death. The cumulative exposure adjusted incidence rates (EAIR) of all TEAEs, including AEs of clinical interest (atrial fibrillation [AF], ejection fraction [EF] decreased and heart failure [HF]), decreased as exposure increased over time, from 347.1/100 patient-years (P-Y) at Week 60 (~year 1) to 271.8/100 P-Y at Week 252 (~year 5). The EAIR of AF decreased over time from 13.3/100 P-Y at Week 60 (~year 1) to 6.2/100 P-Y at Week 252 (~year 5) ( Figure ). The EAIR for EF decreased and HF also decreased over time ( Figure ). Conclusions: This integrated analysis of all patients with obstructive HCM treated with mavacamten across the 5 clinical studies over 5 years demonstrated that mavacamten treatment is generally well tolerated and that the EAIRs of selected TEAEs of clinical interest (AF, EF decreased and HF) decreased as exposure increased over time.

Abstract 4131951: The Safety Profile Of Inclisiran In Patients With Dyslipidemia And Intermediate To High Atherosclerotic Cardiovascular Disease Risk: A Systematic Review And Meta-Analysis

Introduction: Inclisiran is a novel drug that employs ribonucleic acid (RNA) interference to lower levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, thereby improving the clearance of low-density lipoprotein (LDL) cholesterol from the bloodstream. It is given through subcutaneous injections at specified intervals and significantly reduces LDL cholesterol levels in patients with dyslipidemia and with intermediate to high risk of atherosclerotic cardiovascular disease (ASCVD). Goal: We aim to evaluate the safety of the use of inclisiran in patients with dyslipidemia and intermediate to high ASCVD risk. Methods: Three electronic databases of MEDLINE, Web of Science, and Embase were searched from inception to May 5th 2024 to identify relevant randomized controlled trials (RCTs) comparing safety profiles of inclisiran versus the control group . The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events (MACE), injection-site reaction and all treatment-emergent adverse events (TEAE). The effect estimates of outcomes were assessed using risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method given the inter-study variance was inevitable. The subgroup analysis was performed based on different dosing regimens. Results: We included 7 RCTs enrolling 4790 patients (63.8 ± 9.7 years, 66.8 % males) who received inclisiran. Compared to the control group, the use of inclisiran did not yield a significant effect on all-cause mortality (RR, 0.92; 95% CI, 0.54 to 1.54; I 2 = 0%), MACE (RR, 0.98; 95% CI, 0.82 to 1.17; I 2 = 0%), and TEAE (RR, 1.76; 95% CI, 0.74 to 4.15; I 2 = 74%). However, inclisiran use significantly increased injection-site reaction (RR, 7.08; 95% CI, 3.42 to 14.64; I 2 = 27%). Results are illustrated in the accompanying figure. Conclusions: Inclisiran use significantly increased injection-site reaction, with no increase in mortality and TEAE. Further trials are required to comprehensively assess the safety of inclisiran in the management of dyslipidemia in patients with ASCVD risk.

Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis refractory to biologic therapy: 2-year clinical and radiographic results from the open-label extension of the SELECT-AXIS 2 study

Abstract Background The efficacy and safety of upadacitinib in patients with ankylosing spondylitis (AS) and inadequate response/intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR) were evaluated through 1 year in the SELECT-AXIS 2 study. Here, we assess 2-year efficacy, safety, and imaging outcomes in SELECT-AXIS 2. Methods Patients who received continuous upadacitinib, and those who switched from placebo to upadacitinib at week 14, could enter the open-label extension (OLE). Efficacy endpoints included Assessment of SpondyloArthritis international Society (ASAS) and Axial Spondyloarthritis Disease Activity Score (ASDAS) responses, and changes from baseline in measures of disease activity, back pain, function, and quality of life. Radiographic progression was evaluated using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). As observed (AO) and AO with non-responder imputation (AO-NRI) analyses were used for binary endpoints; AO with mixed-effects model for repeated measures (AO-MMRM) for continuous endpoints; and AO-analysis of covariance for mSASSS. Treatment-emergent adverse events (TEAEs) in patients receiving ≥ 1 upadacitinib dose through week 104 are presented as events (E)/100 patient-years (PY). Subgroup analyses were performed by prior tumor necrosis factor/interleukin-17 inhibitor exposure and bDMARD lack of efficacy/intolerance. Results Of 420 patients who entered the bDMARD-IR AS study, 409 entered the OLE, and 331 (continuous upadacitinib, n = 163; placebo to upadacitinib, n = 168) completed week 104. Improvements in efficacy measures were sustained through the OLE, with similar response rates between the continuous upadacitinib and placebo to upadacitinib groups at week 104. At week 104, 64.9% and 61.7% of patients, respectively, had achieved ASAS 40% response (AO-NRI). Mean changes from baseline were similar between the two groups at week 104 across measures (ASDAS: -2.1 and -2.0; total back pain: -4.9 and -4.6, respectively; AO-MMRM). Over 93.0% of patients showed no radiographic progression (mSASSS mean change from baseline < 2) at week 104. The overall TEAE rate was 165.2 E/100 PY, with low rates of major adverse cardiovascular and venous thromboembolic events (0.3 E/100 PY each). Conclusions Upadacitinib efficacy, including very low rates of radiographic progression, was demonstrated through 104 weeks in treatment-refractory patients with active AS. Treatment was well tolerated, with no newly identified safety signals. Trial registration NCT04169373.

Phase Ib clinical and pharmacodynamic study of the TIE2 kinase inhibitor rebastinib with paclitaxel or eribulin in HER2-negative metastatic breast cancer

Abstract Purpose: Breast cancer cells disseminate to distant sites via Tumor Microenvironment of Metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC). Patients and Methods: This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib PO BID in combination with weekly paclitaxel 80 mg/m2 (if ≤ 2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 & 8 (if ≥ 1 prior regimen). Safety, tolerability and pharmacodynamic parameters indicating TIE2 kinase inhibition and TMEM doorway function were evaluated. Results: No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events (AEs) were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). AEs attributed to rebastinib include muscular weakness and myalgias. Intraocular pressure increased at the 100 mg rebastinib dose level, whereas angiopoietin-2 levels increased at both dose levels, providing pharmacodynamic evidence for TIE2 blockade. Circulating tumor cells decreased significantly with the combined treatment. Objective response occurred in 5/23 (22%) evaluable patients. Conclusions: In patients with MBC, the recommended phase 2 dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg PO BID in combination with paclitaxel or eribulin.

CTIM-16. SAFETY AND PRELIMINARY EFFICACY OF AZD1390 + RADIATION THERAPY FOR GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. AZD1390, an ataxia telangiectasia mutated kinase inhibitor, aims to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood–brain barrier penetration, confirmed in healthy volunteers (NCT03215381) and patients with glioblastoma (Phase 0; NCT05182905). This Phase 1, open-label study (NCT03423628) evaluated safety and efficacy of AZD1390 and IMRT in patients with glioblastoma. METHODS Adult patients received escalating once-daily AZD1390 doses with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent glioblastoma) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly-diagnosed O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma). Patients received 2 additional weeks of adjuvant AZD1390 post-IMRT. Primary objective was safety; secondary objectives included efficacy and pharmacokinetics. RESULTS As of Feb 6, 2024, 115 patients (Arm A=75; Arm C=40) received AZD1390 10–900 mg/day. Pharmacokinetics were linear, with a slightly more-than dose-proportional increase and mean elimination half-life ~9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE), most commonly fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 patients. The maximum tolerated dose was 400 mg (Arm A) and 300 mg (Arm C). Dose-limiting toxicities included creatinine kinase elevation (Arm A) and radiation skin injury (Arm C). AEs led to AZD1390 discontinuation in 15/115 patients. Safety profiles were mostly consistent across Arms despite different radiation schedules. At target-engaging doses, median overall survival was 12.7 months (95% CI: 10.7–18.9; Arm A) and still maturing (Arm C). CONCLUSIONS Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment. Clinical investigation is ongoing.

Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis

BackgroundDevelopment of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.ObjectiveTo describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).MethodsThis analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed.ResultsTreatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness.ConclusionIn patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients.Clinical trial registrationClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).

CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE

Abstract INTRODUCTION CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM. METHODS HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint. RESULTS As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented. CONCLUSIONS CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.

DDDR-20. CLINICAL EFFICACY OF PYROTINIB COMBINING WITH STEREOTACTIC RADIOSURGERY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES

Abstract BACKGROUND Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system (CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. METHODS This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guang dong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. RESULTS 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). CONCLUSIONS Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.

Effectiveness of Ayush Rasayana A and B on the Quality of Life of Older Adults: Protocol for a Cluster Randomized Controlled Trial

Background With advancing age among older adults, the associated debilities increase, indicating a deteriorating health status as there is a gradual loss of muscle mass, strength, and functionality. Ayush Rasayana A and B are coded Ayurvedic medicines developed from herbal extracts. This study has been planned to prevent debilitating conditions and improve the quality of life (QOL) in older adults. Objective This study aimed to assess the effectiveness of Ayush Rasayana A and B on the QOL, quality of sleep, and functionality of older adults, along with the tolerability of the intervention. Methods This was a multicenter, open-label, cluster randomized controlled trial conducted with 720 participants aged 60 to 75 years. The participants were divided into 2 groups (intervention and control), with both receiving Ayurvedic ancillary treatment for 3 months. The intervention group additionally received 10 g of Ayush Rasayana A orally once daily at bedtime for 6 days, followed by 1.5 g of Ayush Rasayana B orally twice daily before food for the remaining 84 days. The assessment criteria included the Older People’s Quality of Life Questionnaire Brief, Katz Index of Independence in Activities of Daily Living, Pittsburgh Sleep Quality Index, Five Times Sit-to-Stand Test, and shoulder and scapular movements. Any change in hematological and biochemical parameters and occurrence of treatment-emergent adverse events were also assessed during the study period. Results The recruitment of the participants started in December 2023, and the final follow-up was completed in April 2024. Out of the total 720 enrolled participants, 686 (95.3%) completed the study up to the last follow-up. Conclusions This study may provide evidence-based data to establish preventive treatment protocols for enhancing the QOL and functionality among older adults. The study results may also be helpful for the planning of interdisciplinary health policies for improving the health conditions of different populations International Registered Report Identifier (IRRID) DERR1-10.2196/58186

RBIO-05. IPAX-2: PHASE 1 SAFETY AND DOSE FINDING STUDY OF [131I]IPA PLUS STANDARD OF CARE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) overexpresses the L-type amino transporter (LAT) 1 & 2, which supports internalization of the therapeutic small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine ([131I]IPA) and its companion diagnostic, 18F-FET. Previous studies of [123I]IPA SPECT have shown uptake by >85% of gliomas. Results from a phase 1 trial (IPAX-1) that explored [131I]IPA + radiotherapy in patients with recurrent GBM demonstrated a favorable safety and tolerability profile and promising efficacy. The objective of IPAX-2 (NCT05450744) is to evaluate the safety and tolerability of [131I]IPA in patients newly diagnosed with GBM. METHODS IPAX-2 is a phase 1, multicenter, open-label, single-arm, parallel-group, dose-finding study to evaluate the safety of ascending radioactive dose levels of [131I]IPA + best standard of care in newly diagnosed patients with GBM. Eligible participants (N=12) will be 18-65 years of age with histologically-confirmed intracranial GBM following surgical resection; no prior systemic therapy or radiation for GBM; a Karnofsky Performance Status ≥70; a plan to begin chemoradiation 3-6 weeks after surgical resection with Stupp regimen; adequate organ function; and adequate tissue samples previously archived. Four cohorts will encompass a 3 + 3 dose escalation, with [131I]IPA administered in 2 fractions corresponding to ½ of full dose activity via intravenous infusion (2x3.0 GBq, 2x4 GBq, 2x5 GBq, 2x6 GBq). Dose 1 will be administered prior to external beam radiation therapy (EBRT), and Dose 2 will be administered following completion of EBRT. 18F-FET PET will be used to identify suitable candidates with LAT1/2 overexpression, establish a baseline, and provide quantitative follow-up information. Primary outcome measures are 1) incidence rate treatment-emergent adverse events and 2) safety and tolerability by determining the dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. DISCLOSURES: Telix Pharmaceuticals is the sponsor of this study.

Longer-term safety and efficacy of baricitinib for atopic dermatitis in pediatric patients 2 to

Background Baricitinib, an oral selective Janus kinase inhibitor, improved clinical signs and symptoms of moderate-to-severe atopic dermatitis (AD) at week 16 in the phase 3 pediatric study BREEZE-AD-PEDS. Objective To assess longer-term efficacy and safety of baricitinib in pediatric patients aged 2 to <18 years. Methods In BREEZE-AD-PEDS long-term extension, responders and partial responders (validated Investigator Global Assessment-Atopic Dermatitis [vIGA-AD®] 0/1/2) at Week 16 remained on double-blind treatment to which they were randomized (placebo, baricitinib [1-mg equivalent, 2-mg equivalent, or 4-mg equivalent); non-responders (vIGA-AD 3 or 4) at Week 16 transitioned to open-label baricitinib 4-mg equivalent. Safety was summarized for all randomized patients who received ≥1 dose of study treatment. Results In total 467 patients received baricitinib for 750.7 patient-years. Proportion of responders/partial responders (at Week 16) who achieved vIGA-AD 0/1 at Week 52 was greater for baricitinib 4-mg equivalent (56.8%) versus all other treatment groups (42.2%, 47.7%, and 39.7% for 2-mg equivalent, 1-mg equivalent, and placebo, respectively). Most treatment-emergent adverse events were mild/moderate in severity. No deaths, pulmonary emboli, deep vein thromboses or arterial thrombotic events, major adverse cardiovascular events, malignancies, tuberculosis events, or gastrointestinal perforations were reported. Conclusions Baricitinib demonstrated sustained long-term efficacy. No new safety signals were identified. Trial Registration ClinicalTrials.gov Identifier: NCT03952559

Comparing two transitioning strategies to paliperidone palmitate once-every-6-months.

A double-blind, randomized, active-controlled, parallel-group, noninferiority trial (NCT03345342) demonstrated that paliperidone palmitate once-every-6-months (PP6M) was noninferior to paliperidone palmitate once-every-3-months (PP3M) in preventing relapse in clinically stable adults with schizophrenia. This post hoc analysis assessed efficacy and safety following transition to PP6M from paliperidone once-monthly (PP1M) versus PP3M. Adults with schizophrenia who were clinically stable on moderate/high doses of PP1M or PP3M were randomly assigned 1:2 to dorsogluteal PP3M or PP6M treatment for 12months. The primary efficacy measure was time to relapse during the 12-month DB phase. Secondary endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total and subscale scores, Clinical Global Impression-Severity (CGI-S) scale score, and Personal and Social Performance (PSP) scale score. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory tests. Of 702 patients in the study, 231 transitioned from PP1M to PP6M and 247 transitioned from PP3M to PP6M. Low relapse rates for PP6M were observed regardless of transition pathway (PP1M/PP6M: 7.8%; PP3M/PP6M: 7.3%). Changes from DB baseline to endpoint in PANSS total, PSP, and CGI-S scores were similar between transition groups. In the DB phase, ≥1 TEAE was observed in 61.0% and 63.2% of patients in the PP1M/PP6M and PP3M/PP6M, groups, respectively. Adults with schizophrenia who transitioned to PP6M from either PP1M or PP3M experienced similarly low relapse rates. Additionally, symptom and functionality scores supported the primary analysis and, along with TEAE incidences, were comparable between transition groups.

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.

A Phase 2 Study of PEGylated Recombinant Human Growth Hormone for 52 Weeks in Short Children Born Small for Gestational Age in China.

Children born small for gestational age (SGA) are at increased risk of health issues. This study evaluated the efficacy, safety and optimal dose of PEGylated-recombinant human growth hormone (PEG-rhGH) in these children. In this multicentre, randomised, open-label, Phase 2 trial conducted at nine clinical sites in China, patients were randomised 1:1 to receive subcutaneous injections of PEG-rhGH at 0.1 mg/kg/week (low dose) or 0.2 mg/kg/week (high dose) for 52 weeks. Ninety-six children were born SGA. The primary endpoint was the change in height standard deviation score (HT-SDS) at Week 52. At Week 52, the change in HT-SDS in the high- and low-dose groups was 0.923 ± 0.352 (p < 0.0001) and 0.511 ± 0.336 (p < 0.0001), respectively (least-squares means difference, 0.410; 95% confidence interval 0.270-0.551; p < 0.0001). Height velocity (9.94 ± 1.55 vs. 8.37 ± 1.50 cm/year) was also significantly higher in the high-dose than in the low-dose group (p < 0.0001). Change in insulin-like growth factor (IGF)-1 SDS was 1.867 ± 1.747 and 1.168 ± 1.193 in the high- and low-dose groups, respectively (p = 0.0189). IGF-1/IGF binding protein-3 and bone maturity were improved in both groups at Week 52. Most treatment-emergent adverse events were mild to moderate; the safety profile was similar in both groups. PEG-rhGH at either dose for 52 weeks was effective and well tolerated in children born SGA. Patients in the high-dose group achieved greater improvement in HT-SDS than in the low-dose group. ClinicalTrials. gov identifier: NCT02375620.

Roxadustat Efficacy and Safety in Patients Receiving Peritoneal Dialysis: Pooled Analysis of Four Phase 3 Studies

Background/Objectives: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved to treat anemia of chronic kidney disease (CKD). The efficacy and safety of roxadustat compared with parenteral erythropoiesis-stimulating agents (ESAs) were evaluated in patients with anemia of CKD receiving peritoneal dialysis (PD). Methods: This analysis pooled data from four phase 3, multicenter, randomized, open-label, active-comparator studies (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES). The primary endpoints evaluated were hemoglobin change from baseline (CFB) to Weeks 28–36 without rescue therapy and hemoglobin CFB to Weeks 28–52 regardless of rescue therapy use. Safety data were reported. Results: This analysis included 422 patients (215 roxadustat, 207 ESA). Hemoglobin CFB to Weeks 28–36 without rescue therapy and hemoglobin CFB to Weeks 28–52 regardless of rescue therapy achieved non-inferiority for roxadustat vs. ESAs. The mean weekly dose of roxadustat was maintained over time (Weeks 1–4, 3.86 mg/kg/week; Weeks 101–104, 3.27 mg/kg/week), whereas the mean weekly ESA dose increased by 24% (Weeks 1–4, 115.70 IU/kg/week; Weeks 101–104, 143.40 IU/kg/week). Fewer patients treated with roxadustat received intravenous iron supplementation and rescue therapy, and patients treated with an ESA required blood transfusions sooner. Roxadustat-treated patients experienced a greater decrease in low-density lipoprotein cholesterol levels relative to baseline vs. ESA-treated patients. Treatment-emergent adverse events were similar in both treatment groups. Major adverse cardiovascular event (MACE), MACE plus unstable angina or congestive heart failure, and all-cause mortality hazard ratios were &lt;1; the lower limit of the 95% CIs was &lt;0.6, and the upper limit was &gt;1.3. Conclusions: Roxadustat was non-inferior to ESAs in correcting and maintaining hemoglobin levels, with stable dosing and a comparable safety profile, in anemic patients receiving PD.