Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study.

INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up. CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.

GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

PURPOSE: The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. METHODS: The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. RESULTS: DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. CONCLUSION: GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. TRIAL REGISTRATION NUMBER AND REGISTRATION DATE: NCT03785964; December 24, 2018.

Effect of Additives on the Surface Morphology, Energetics, and Contact Resistance of PEDOT:PSS.

For a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) film employed in a device stack, charge must pass through both the bulk of the film and interfaces between adjacent layers. Thus, charge transport is governed by both bulk and contact resistances. However, for ultrathin films (e.g., flexible devices, thin-film transistors, printed electronics, solar cells), interfacial properties can dominate over the bulk properties, making contact resistance a significant determinant of device performance. For most device applications, the bulk conductivity of PEDOT:PSS is typically improved by blending additives into the solid film. Doping PEDOT:PSS with secondary dopants (e.g., polar small molecules), in particular, increases the bulk conductivity by inducing a more favorable solid morphology. However, the effects of these morphological changes on the contact resistance (which play a bigger role at smaller length scales) are relatively unstudied. In this work, we use transfer length method (TLM) measurements to decouple the bulk resistance from the contact resistance of PEDOT:PSS films incorporating several common additives. These additives include secondary dopants, a silane crosslinker (typically used to stabilize the PEDOT:PSS film), and multi-walled carbon nanotubes (conductive fillers). Using conductive atomic force microscopy, Kelvin probe force microscopy, Raman spectroscopy, and photoelectron spectroscopy, we connect changes in the contact resistance to changes in the surface morphology and energetics as governed by the blended additives. We find that the contact resistance at the PEDOT:PSS/silver interface can be reduced by (1) increasing the ratio of PEDOT to PSS chains, (2) decreasing the work function, (3) decreasing the benzoid-to-quinoid ratio at the surface of the solid film, (4) increasing the film uniformity and contact area, and (5) increasing the phase-segregated morphology of the solid film.

Synthesis of PEDOT:PSS Brushes Grafted from Gold Using ATRP for Increased Electrochemical and Mechanical Stability.

We report PEDOT:PSS brushes grafted from gold using surface-initiated atom-transfer radical polymerization (SI-ATRP) which demonstrate significantly enhanced mechanical stability against sonication and electrochemical cycling compared to spin-coated analogues as well as lower impedances than bare gold at frequencies from 0.1 to 105 Hz. These results suggest SI-ATRP PEDOT:PSS to be a promising candidate for use in microelectrodes for neural activity recording. Spin-coated, electrodeposited, and drop-cast PEDOT:PSS have already been shown to reduce impedance and improve biocompatibility of microelectrodes, but the lack of strong chemical bonds of the physisorbed polymer film to the metal leads to disintegration under required operational stresses including cyclic mechanical loads, abrasion, and electrochemical cycling. Rather than modifying the metal electrode or introducing cross-linkers or other additives to improve the stability of the polymer film, this work chemically tethers the polymer to the surface, offering a simple, scalable solution for functional bioelectronic interfaces.

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

PURPOSE: Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. METHODS: In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). RESULTS: Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. CONCLUSIONS: Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.

PURPOSE: Ch14.18 improves survival in children with high-risk neuroblastoma but is associated with substantial toxicity. Ch14.18 pharmacokinetics were previously reported to be highly variable and characterized by a higher clearance in children than in adults, and a large volume of distribution. Identifying factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. METHODS: Plasma sampling was performed prior to, during, and for 25 days after four daily 10-h infusions of 25 mg/m(2) of ch14.18 administered with sargramostim. Ch14.18 concentrations were quantified with an electrochemiluminescence immunoassay, and pharmacokinetic parameters were derived using non-compartmental methods and from fitting a two-compartment model. Human anti-chimeric antibody (HACA) was measured before each course. RESULTS: Fourteen subjects (median age, 4.3 years) were enrolled; seven had sampling on two courses to assess intra-subject variability. Mean peak ch14.18 plasma concentration was 11 µg/mL, and disappearance was biexponential with half-life of 7 days. Mean trough (day 28) concentration was 0.2 µg/mL. Mean AUC0-∞ was 1,380 µg h/mL and was less variable than previously reported (CV 29 %). Intra-patient variability was also minimal, but one subject who developed HACA had a 41 % decrease in AUC 0-tlast from courses 1 to 3. Clearance (2 L/day m(2)) was fourfold higher in children than in adults and appeared to be age dependent. Steady state volume of distribution was 0.4 L/kg. Two-compartment model parameters were used to simulate alternative dosing schedules. CONCLUSIONS: Ch14.18 disposition in children is less variable than previously reported. Clearance is age dependent and more rapid in younger children.