Treatment-emergent Adverse Events Research Articles

Zuranolone Concentrations in the Breast Milk of Healthy, Lactating Individuals: Results From a Phase 1 Open-Label Study.

Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the United States. This study assessed zuranolone transfer into breast milk. Healthy, nonpregnant, lactating adult female participants received once-daily 30 mg zuranolone from day (D)1 through D5 in this phase 1 open-label study. The relative infant dose (RID; weight-adjusted proportion of the maternal dose in breast milk over 24 hours) for 30 mg zuranolone was assessed at D5. An RID for 50 mg zuranolone was estimated using a simulation approach across a range of infant ages and weights. Of 15 enrolled participants (mean age, 30.1 years), 14 completed the study. The mean RID for 30 mg zuranolone at D5 was 0.357%; the mean steady-state milk volume over D3 to D5 decreased from baseline by 8.3%. Overall unbound zuranolone in plasma was low (≤0.49%). Plasma concentrations peaked at D5 before decreasing in a biexponential manner. There was strong concordance between the temporal evolution of zuranolone concentrations in plasma and breast milk. The estimated mean RID for 50 mg zuranolone based on a milk intake of 200 mL/kg per day was 0.984%. All treatment-emergent adverse events reported by participants were mild, the most common being dizziness (n = 3). Zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low; the estimated RID for 50 mg zuranolone was <1%, well below the <10% threshold generally considered compatible with breastfeeding.

Perampanel as monotherapy or first adjunctive therapy in pediatric and adult patients with epilepsy: the first United States-based phase IV open-label ELEVATE study.

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13weeks), Maintenance (39weeks), and Follow-up (4weeks) Periods. During Titration, perampanel was initiated at 2mg/day and up-titrated to 4mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8weeks and 32 (59.3%) patients completed the study. Retention rate at 12months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy.

Long-term safety and efficacy of Glycopyrronium tosylate in patients with primary axillary hyperhidrosis: a systematic review and meta-analysis

Background: Hyperhidrosis, a condition characterized by excessive sweating, affects ≈ 4.8% of the US population. (1) Glycopyrronium tosylate (GT) is a topical anticholinergic drug approved for primary axillary hyperhidrosis (PAH) treatment. (2) However, no meta-analysis exists on GT’s long-term safety and efficacy. Aim: To evaluate the long-term safety and efficacy of GT as a treatment for PAH. Methods: We systematically searched PubMed, Scopus, and ClinicalTrials.gov. Study selection, quality assessment, and data extraction followed the eligibility criteria. The primary endpoints were changes in the Dermatology Life Quality Index (DLQI), Hyperhidrosis Disease Severity Scale (HDSS), and Axillary Sweating Daily Diary (ASDD) or Axillary Sweating Daily Diary – Change (ASDD-C). Safety endpoints included mydriasis, dry mouth, urinary hesitation, and treatment-emergent adverse events (TEAEs). Statistical analysis was conducted using RevMan 5.1. Results: Our meta-analysis demonstrated that topical GT is clinically effective in treating PAH. GT significantly improves the quality of life of patients, as measured by the DLQI (MD = -2.81, 95% CI = [-4.04, -1.59],P = 0.001), HDSS (OR = 3.72, 95% CI = [2.92, 4.74], P = 0.001), and ASDD/ASDD-C (OR = 4.91, 95%CI = [3.75, 6.44], P = 0.001). Adverse effects such as mydriasis, dry mouth, and urinary hesitation were observed; however, no difference was found between GT and control groups in serious TEAEs, deaths, and severe TEAEs. Conclusion: Topical GT is effective with minimal side effects, providing a valuable option for patients unresponsive to or experiencing significant side effects from other treatments.

Efficacy, safety and tolerability of rozanolixizumab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a trial and open-label extension study

BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management.MethodsCIDP01 (NCT03861481) was a...

English

Background: Bilastine is a second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis (ARC) and urticaria in adults, adolescents, and children. The pharmacokinetics and safety of oral bilastine 10 mg/d in children aged 2 to 5 years were evaluated. Methods: This was a multicenter, open-label clinical trial in children aged 2 to 5 years with seasonal or perennial ARC or urticaria treated once daily with bilastine 10 mg orodispersible tablets. The safety evaluation included treatment-emergent adverse events (TEAEs), vital signs, and physical examination. Pharmacokinetic data were pooled with data from a prior pediatric study, and pharmacokinetic modeling was performed to assess consistency. Results: A total of 37 children with ARC (81.1%), urticaria (8.1%), or both (10.8%) were included in the study, with a mean (SD) age of 3.7 (1.2) years. The highest plasma concentrations of bilastine were observed 1 hour after administration (634.91 ng/mL). Eight patients (21.6%) experienced 1 TEAE each, none of which was severe. Body weight and age were not covariates of variation in either systemic clearance or the volume of distribution in children aged 2 to 5 years and did not affect the pharmacokinetic parameters of bilastine. Conclusions: The pharmacokinetics of bilastine was linear and consistent with data from a previous trial, suggesting that a 10-mg dose may be used in children (2 to &lt;12 years). No dose adjustments are deemed necessary. Oral once-daily bilastine 10 mg presented a good safety profile in children aged 2 to 5.

Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study.

Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test. Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Safety And Efficacy Of Combination Lurbinectedin Plus Doxorubicin From A Phase 1b Trial In Patients With Advanced/Metastatic Soft Tissue Sarcoma

Abstract Purpose: While cytotoxic chemotherapy is standard first-line treatment for patients with metastatic soft tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well-tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma (LMS) and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3+3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1: 25 mg/m2 day 1; DL2 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose (MTD) and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events (TEAE) were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were 2 dose-limiting toxicities (DLTs) at DL2 (day 8 [G2 ALT/AST increase, G3 neutropenia]), and 1 DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median PFS is 16.5 months (95%CI 6.0-ND). The ORR was 60% (6/10 confirmed partial responses [PR]). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well-tolerated and demonstrated intriguing clinical activity.

A randomized, double-blind trial assessing the efficacy and safety of two doses of dulaglutide in Japanese participants with type 2 diabetes (AWARD-JPN).

To assess the efficacy and safety of dulaglutide 1.5 mg versus dulaglutide 0.75 mg in Japanese participants with type 2 diabetes (T2D). A Phase 3, multicentre, randomized, double-blind, parallel-group study was conducted in Japanese participants aged ≥20 years, with T2D for ≥6 months and inadequate glycaemic control, while on a single oral antihyperglycaemic medication (NCT04809220). The primary objective was to evaluate superiority of dulaglutide 1.5 mg versus dulaglutide 0.75 mg measured by mean change in glycated haemoglobin (HbA1c) from baseline to 26 weeks. Other efficacy and safety endpoints were evaluated at 26 and 52 weeks. All statistical analyses were conducted using the intention-to-treat population. Overall, 591 participants were randomized to once-weekly dulaglutide 1.5 mg or 0.75 mg. At Week 26, dulaglutide 1.5 mg was superior to dulaglutide 0.75 mg in HbA1c reduction from baseline (least squares mean [LSM] difference -0.29% [95% confidence interval {CI} -0.43, -0.14]). At Week 52, the dulaglutide 1.5-mg arm had a significantly greater proportion of participants who achieved HbA1c <7.0% (46.3% vs. 38.5%; p = 0.03) and showed significantly greater reduction in fasting serum glucose (LSM difference -9.4 mg/dL [95% CI -14.4, -4.3]; p < 0.001) versus the dulaglutide 0.75-mg arm. No statistically significant change in body weight was observed in either treatment arm. Overall, 442 participants (75.4%) experienced treatment emergent adverse events (TEAEs). Constipation (11.3%), diarrhoea (9.6%) and pyrexia (9.0%) were the most commonly reported TEAEs. Dulaglutide 1.5 mg once weekly demonstrated superior glycaemic control versus dulaglutide 0.75 mg once weekly, with comparable safety and tolerability, in Japanese people with T2D.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. Mirum Pharmaceuticals.

Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19.

Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir. A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days. AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.

Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements) and B (activating non-kinase domain mutations). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5%, 9.4% and 3.8%, respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

The safety of trastuzumab deruxtecan (DS-8201) with a focus on interstitial lung disease and/or pneumonitis: A systematic review and single-arm meta-analysis.

Previous studies involving risk-benefit analysis of trastuzumab deruxtecan (DS-8201) have indicated the benefit of this treatment, although it may increase the risk of interstitial lung disease (ILD) and/or pneumonitis in certain patients. This study aimed to assess the safety of DS-8201. A search was done for relevant articles in four electronic databases: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. All reports published up until November 2, 2022, were included, and study types were restricted to clinical trials; the last search was then updated to January 10, 2023. We also assessed the quality of the literature with the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Index for Non-Randomized Studies tool, and then performed a meta-analysis with R version 4.2.1. A total of 1428 patients reported in 13 articles were included in this study. The analysis revealed that the most common all-grade treatment-emergent adverse events (TEAEs) were nausea and fatigue. The most common TEAE of grade 3 or above (grade ≥3) was neutropenia. The incidences of ILD and/or pneumonitis for all-grade and grade ≥3 TEAEs were 12.5% and 2.2%, respectively. This comprehensive summary of the incidence of TEAEs associated with DS-8201 in clinical trials provides an important guide for clinicians. The most common TEAEs were gastrointestinal reactions and fatigue; meanwhile, the most common grade ≥3 TEAE was hematological toxicity. ILD and/or pneumonitis were specific adverse drug reactions associated with DS-8201, of which physicians should be particularly aware for their higher morbidity and rates of grade ≥3 TEAEs.

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treatedmostly on an outpatient basis with observation. No treatment-related deaths were observed. Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Effect of food on the pharmacokinetics and safety profiles of a new PARP inhibitor fuzuloparib capsules in healthy volunteers.

This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules. A randomized, open-label, two-cycle, two-sequence, crossover clinical trial was conducted. 20 subjects were randomly assigned to 2 groups at a 1:1 ratio. The first group subjects were orally administered 150mg fuzuloparib capsules under fasting condition in first dosing cycle. The same dose of fuzuloparib capsules were taken under postprandial state after a 7-day washout period. The second group was reversed. 3ml whole blood was collected at each blood collection point until 72h post dose. PK parameters were calculated. Furthermore, safety assessment was performed. The time to maximum concentration (Tmax) was prolonged to 3h and maximum concentration (Cmax) decreased by 18.6% on high-fat diets. 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for Cmax, area under the concentration-time curve from time zero to time t (AUC0-t), and area under the concentration-time curve extrapolated to infinity (AUC0-∞) after high-fat meal were 71.6-92.6%, 81.7-102.7% and 81.6-102.5%, respectively. All treatment-emergent adverse events (TEAEs) were grade 1; No serious adverse events (SAEs), serious unexpected suspected adverse reaction (SUSAR) or deaths were reported. Food decreased the absorption rate and slowed time to peak exposure of fuzuloparib capsules, without impact on absorption extent. Dosing with food was found to be safe for fuzuloparib capsules in this study. This study was registered with chinadrugtrials.org.cn (identifier: CTR20221498).

Pharmacokinetics and Safety of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P-gp and CYP2D6 inhibitor. A phase 1 open-label study evaluated the effect of P-gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co-administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co-administration. The overall systemic exposure, the area under the plasma concentration-time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co-administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment-emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1-2 days. Co-administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co-administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P-gp.

The DARPin antiviral ensovibep for non-hospitalized patients with COVID-19: Results from EMPATHY, a randomized, placebo-controlled Phase 2 study

Abstract Background The COVID-19 pandemic was characterized by rapid evolution of SARS-CoV-2 variants, affecting viral transmissibility, virulence, and response to vaccines/therapeutics. EMPATHY (NCT04828161), a Phase 2 study, investigated the safety/efficacy of ensovibep, a multi-specific designed ankyrin repeat protein (DARPin) with multi-variant in vitro activity, in ambulatory patients with mild-to-moderate COVID-19. Methods Non-hospitalized, symptomatic patients (N = 407) with COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600 mg) or placebo and followed until Day 91. The primary endpoint was time-weighted change from baseline in log10 SARS-CoV-2 viral load through Day 8. Secondary endpoints included proportion of patients with COVID-19-related hospitalizations, emergency room (ER) visits, and/or all-cause mortality to Day 29; time to sustained clinical recovery to Day 29; and safety to Day 91. Results Ensovibep showed superiority versus placebo in reducing log10 SARS-CoV-2 viral load; treatment differences versus placebo in time-weighted change from baseline were: −0.42 (p = 0.002), –0.33 (p = 0.014), and –0.59 (p &amp;lt; 0.001) for 75, 225, and 600 mg, respectively. Ensovibep-treated patients had fewer COVID-19-related hospitalizations, ER visits, and all-cause mortality (relative risk reduction: 78%; 95% CI: 16–95%); and a shorter median time to sustained clinical recovery than placebo. Treatment-emergent adverse events occurred in 44.3% versus 54.0% of patients in the ensovibep and placebo arms; grade 3 events were consistent with COVID-19 morbidity. Two deaths were reported with placebo and none with ensovibep. Conclusions All 3 doses of ensovibep showed antiviral efficacy and clinical benefits versus placebo and an acceptable safety profile in non-hospitalized patients with COVID-19 (Funded by Novartis).

Abstract PO2-04-13: TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY

Abstract Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex inhibition at the spindle assembly checkpoint and is required for chromosome alignment and error correction. TTK inhibition results in premature mitosis exiting with unattached chromosomes potentially leading to aneuploidy and cell death. High TTK tumor levels correlate with worse prognosis and contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK, inhibits the growth of a variety of human cancer-derived cell lines. A first-in-human phase 1 study of CFI-402257 (NCT02792465) demonstrated a tolerable safety profile when enrolled as a monotherapy in solid tumors, and in combination with fulvestrant in hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer1. The dose for expansion was 168 mg, dose limiting toxicity was dose-dependent neutropenia which was manageable and reversible. Investigator-confirmed partial responses (cPR) were observed in 5 pts (8%) with 32 (50.8%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors (N=25), there were 4 cPR’s with a median duration of response of 223 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors for dose confirmation then focus on advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: In TWT-203 study, safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients (pts) with advanced solid tumors (Part A) or in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response. Results: At data cutoff of 11 May 2023, 14 pts were enrolled. All received monotherapy treatment. Median treatment duration was 2.1 months (range, 0.2-7.3+). Median age was 67 years (57-76). Median number of prior regimens was 3.5 (2-12). Tumor types enrolled were colorectal (n=6, 43%), breast (3, 21%), and endometrial, hepatocellular, leiomyosarcoma, pancreatic, and sarcoma (1 each, 7%). 4 dose levels, from 126 to 252 mg, were studied. Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. Disease control rate (CR, PR, or SD ≥ 6 weeks from baseline) was 54.5% (6 pts/11): all achieved SD. 3 of the 6 pts remain on study. Conclusion: CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence. 1. John Hilton et al. Cancer Res 2023;83(5 Suppl): P6-10-13. Citation Format: Justin Call, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu, Robert Wesolowski. TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-13.

Abstract PS11-05: Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study

Abstract Background: Leptomeningeal carcinomatosis (LMC) occurs in approximately 5-15% of patients (pts) with advanced breast cancer (ABC) and is associated with poor survival and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity, leading to its widespread clinical use. DEBBRAH is evaluating the efficacy and safety of T-DXd in pts with HER2[+] and HER2-low ABC with a history of brain metastases (BM) and/or LMC. Here, we report results from cohort 5 that included pts with pathologically confirmed LMC. Methods: DEBBRAH (NCT04420598) is a single-arm, open-label, five-cohort, phase 2 study conducted across 18 sites in Spain and Portugal. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC and LMC with positive cerebrospinal fluid cytology. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response, clinical benefit rate (CBR) according to RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions); and safety and tolerability as per NCI-CTCAE v.5.0. OS was tested with the maximum likelihood exponential method (H0: median OS ≤2 months; H1: median OS≥6 months). We estimate that 7 pts are needed to attain an 80% power at the nominal level of one-sided α of 0.05. Results: Between Apr 14, 2021, and Apr 5, 2022, 7 pts were allocated into cohort 5. Median age was 57 (range, 42–69) years, 3 (42.9%) pts were HER2[+], 6 (85.7%) pts had synchronous extracranial metastases, 2 of whom (28.6%) also presented BM, and 3 (42.9%) pts had measurable disease. Median number of previous lines of therapy for advanced disease was 4 (range, 1-8) and no patient received prior local treatment for central nervous system involvement. At data cut-off (Apr 4, 2023), median follow-up was 12 months (range, 2.5-18.6). Median duration of treatment was 9.0 months (range, 2.1-18.6). Two (28.6%) pts remained on treatment: 1 HER2[+] and 1 HER2-low, after 18.6 and 12.0 months, respectively. Median OS rate was 13.3 months (95% CI, 5.7-NA, p&amp;lt; 0.001) meeting the primary endpoint. Among 5 pts with disease progression, none had intracranial progression. A total of 4 (57.1%) pts presented extracranial progression and 1 (14.3%) patient had clinical worsening. No objective responses were observed, but 5 out of 7 pts had prolonged stabilization (≥24 weeks) for an overall CBR of 71.4% (95% CI, 29.0-96.3) and a median PFS of 8.9 months (95% CI, 4.9-NA) according to RECIST v.1.1. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were nausea (57.1%; 14.3% G3), fatigue (42.9%; 0% G3), vomiting (42.9%; 0% G3), headache (42.9%; 0% G3), and urinary tract infection (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most frequent hematological TEAEs. No cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 4 (57.1%) of 7 pts, and 1 patient experienced a related serious TEAE (nausea G3). No treatment-related deaths were reported. Conclusions: T-DXd showed promising activity with no new safety concerns in HER2[+] and HER2-low pts with previously untreated, pathologically confirmed LMC. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. Citation Format: Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez-Castedo, Fabriccio Racca, Salvador Blanch, Manuel Ruíz - Borrego, Adela Fernández, María Fernández-Abad, Vega Iranzo, Maria Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofía Braga, Javier Cortés. Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-05.

Abstract GS01-10: HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer

Abstract Background Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor approved in combination with trastuzumab and capecitabine for previously treated HER2+ locally advanced or metastatic breast cancer (LA/MBC). Trastuzumab emtansine (T-DM1) is a HER2-directed antibody-drug conjugate approved to treat HER2+ LA/MBC previously treated with trastuzumab and a taxane. This is the first report of HER2CLIMB-02 (NCT03975647), a randomized, double-blind, placebo-controlled phase 3 study assessing the efficacy and safety of tucatinib combined with T-DM1 in patients with previously treated HER2+ LA/MBC. Methods Eligible patients had HER2+ LA/MBC previously treated with trastuzumab and a taxane in any setting with ECOG performance status ≤1 and adequate hepatic, renal, hematologic, and cardiac function. Patients with previously treated stable, progressing, or untreated brain metastases (BMs) not requiring immediate local therapy were also eligible. Patients were randomly assigned 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice a day [PO BID]) or placebo (PO BID), combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was progression-free survival (PFS) by investigator assessment per RECIST v1.1. Alpha-controlled secondary endpoints included overall survival (OS) and objective response rate (ORR) per RECIST v1.1 for the overall population, and PFS and OS for the subset of patients with BMs at baseline. Safety was analyzed as a secondary endpoint. Results From October 8, 2019, to June 16, 2022, 463 patients were randomly assigned, comprising 228 to the tucatinib arm (tucatinib + T-DM1) and 235 to the control arm (placebo + T-DM1). The median duration of follow-up (OS) was 24.4 months for the overall population. Patient demographics and baseline characteristics were balanced between the 2 arms. Almost half (44.1%) of the overall population had either active or stable BMs at baseline. As of the data cutoff (June 29, 2023), the study met its primary endpoint with a statistically significant improvement in PFS in the tucatinib arm vs control arm. The risk of progression or death decreased by 24.1% in the tucatinib arm (hazard ratio [HR]=0.759 [95% CI, 0.607-0.950]; P=0.0163). Median PFS was 9.5 months (95% CI, 7.4-10.9) vs 7.4 months (95% CI, 5.6-8.1) for the tucatinib and control arms, respectively. HRs for PFS across all prespecified subgroups were consistent with the HR of the overall population, including patients with BMs at baseline (HR=0.639 [95% CI, 0.459-0.891]). The interim OS results were immature with 134 of 253 total required events (53%) and did not meet the prespecified crossing boundary. The confirmed ORR was numerically higher in the tucatinib arm (42.0%) vs the control arm (36.1%). The most common treatment-emergent adverse events (TEAEs) included nausea (65.4% vs 49.4% for tucatinib and control arms, respectively), diarrhea (56.7% vs 26.6%), and fatigue (48.9% vs 37.3%). The most common grade ≥3 TEAEs in the tucatinib arm were alanine and aspartate aminotransferase elevations, each reported in 38 patients (16.5%) in the tucatinib arm and 6 patients (2.6%) in the control arm. TEAEs associated with any treatment discontinuation occurred in 51 patients (22.1%) in the tucatinib arm and 27 (11.6%) in the control arm. TEAEs leading to deaths occurred in 3 patients (1.3%) in the tucatinib arm and 2 patients (0.9%) in the control arm. Conclusion HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC, including those with BMs. Although discontinuations due to TEAEs were more common in the tucatinib arm, no new safety signals emerged for the combination therapy. Citation Format: Sara Hurvitz, Sherene Loi, Joyce O'Shaughnessy, Alicia Okines, Sara Tolaney, Joo Hyuk Sohn, Cristina Saura, Xiaofu Zhu, David Cameron, Thomas Bachelot, Erika Hamilton, Giuseppe Curigliano, Antonio Wolff, Nadia Harbeck, Norikazu Masuda, Linda Vahdat, Khalil Zaman, Frances Valdes-Albini, Margaret Block, Timothy Pluard, Tira Tan, Chelsea Gawryletz, Arlene Chan, Philippe Bedard, Rinat Yerushalmi, Binghe Xu, Konstantinos Tryfonidis, Michael Schmitt, Joan Xie, Virginia Borges. HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-10.

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-10.