Key Efficacy Endpoints Research Articles

Real world experience of brodalumab treatment in patients with moderate-to-severe plaque psoriasis in the Greek population: Results from an interim analysis of the BrIDGE study.

Brodalumab's clinical efficacy and favorable safety profile have been demonstrated during controlled clinical trials, but real-world data remain scarce. BrIDGE, an ongoing 104 week, observational, prospective, multicenter study conducted in Greece, enrolled moderate-to-severe plaque psoriasis patients, with body surface area (BSA) > 10 or psoriasis area severity index score (PASI) > 10 and dermatology life quality index (DLQI) > 10, based on European consensus, initiating brodalumab treatment as per routine clinical practice. This interim analysis includes evaluations 12-16 weeks following treatment initiation. Key efficacy endpoints included proportion of patients achieving static Physician's Global Assessment (sPGA) score of "clear/almost clear" (0/1) and a reduction ≥75%, 90%, 100% from baseline in PASI (PASI75, PASI90, and PASI100) at weeks 12-16. Other endpoints included time to achieve PASI100, changes in self-reported DLQI and psoriasis symptom inventory (PSI) at weeks 12-16. From 200 patients (mean age 51.4 years, 70% male, mean disease duration 13.8 years) enrolled, 72.8% achieved sPGA of 0/1, whereas 70.2%, 47.5%, and 32.0% achieved corresponding PASI75, PASI90, and PASI100 responses following 12-16 weeks of brodalumab treatment, according to the "as-observed" analysis. The mean time to achieve PASI100 was 13.7 ± 1.2 weeks for the 32% who achieved PASI100. Concurrent decreases in mean DLQI and PSI were observed. Furthermore, 90% adherence to brodalumab was noted and nine adverse events were reported. Brodalumab confers substantial clinical improvements short-term as reflected by high levels of skin clearance in moderate-to-severe plaque psoriasis patients within 12-16 weeks of treatment under everyday clinical conditions, followed by improvements in symptoms and quality of life and a favorable safety profile.

P.58 MRI muscle segmentation in Duchenne muscular dystrophy (DMD): Stepwise region of interest (ROI) contractions to minimize fat fraction variability

MRI proton density fat fraction (MRI-PDFF) to quantify fatty infiltration is a key efficacy endpoint in DMD and other neuromuscular clinical trials. We have previously shown that fat fraction variability can be reduced by contracting the ROI to eliminate noise from non-muscle tissue due to small segmentation errors. Multiple muscles are of interest due to progressive involvement in DMD, and the ideal contraction may vary depending on the muscle size or location. We tested a strategy for optimizing the segmentation of muscles of varying sizes and depths, designed to minimize the variability of fat fraction measurements while maximizing the volume of the contracted ROI. The vastus lateralis (VL) and soleus muscle bellies were segmented by two technologists from T1-weighted images and the center 3 slices were computed for the MRI-PDFF ROI (VL: N=13; soleus: N=14). Uniform axial contractions between 0 mm to 2 mm (in steps of 0.2 mm) were applied to the ROI and the resulting segmentations were registered to PDFF maps to obtain the fat fraction at every step. The minimal detectable change (MDC) for each contracted ROI was computed from the appropriate intraclass correlation coefficient (2-way or 1-way, random-effects, single-rating, absolute agreement) and pooled standard deviation. The Dice coefficient was used to record how much of the original volume is represented at each contraction. The variability approached a minimum as the Dice coefficient neared 0.9 for both muscles. The fat fraction MDC was reduced by 75% in the VL when a 1.2 mm contraction was applied (MDC=1.0%; Dice 0.91) and by 29% in the soleus when a 1.0 mm contraction was applied (MDC=1.3%; Dice 0.90). Further contracting the muscles had minimal effects on MDC. Therefore, we conclude that an axial contraction of the central ROI that represents 90% of the segmented muscle area is optimal for maximizing the interrogated muscle volume and the ability to demonstrate efficacy of disease-modifying therapeutics.

1404P A phase II study of ZEN-3694 (ZEN), enzalutamide (ENZ), and pembrolizumab (P) in metastatic castration resistant prostate cancer (mCRPC): Interim safety results

ZEN is a potent and selective BET bromodomain inhibitor (BETi) with encouraging clinical activity in combination with ENZ in patients (pts) with second generation androgen receptor signaling inhibitor (ARSI)-resistant mCRPC. ZEN has synergy with immune checkpoint inhibition in pre-clinical assays. The safety and efficacy of ZEN in combination with ENZ plus P was evaluated (NCT04471974). Pts were required to have progressive mCRPC, prior resistance to ≥ 1 second generation ARSI, and no prior chemotherapy for mCRPC. A safety lead-in (N = 6) followed by dose expansion was utilized, with a starting dose of ZEN 72 mg/day, ENZ 160 mg/day, and P 200 mg IV every 3 weeks. The primary objective was to determine the recommended phase 2 dose (RP2D); key efficacy endpoints included PSA50 response. Twenty-two pts have been enrolled to date (n = 6 safety lead-in; n = 16 dose expansion). Median age and serum PSA at study entry was 71 (range 54 – 82) and 30.6 ng/mL (range 5.6 – 560.1), respectively. Ten pts (45%) had prior treatment with > 1 ARSI. Fourteen pts (64%) remain on treatment, 7 discontinued for progression, and one discontinued due to toxicity (Grade 3 LFTs). There were no dose-limiting toxicities during safety lead-in; ZEN 72 mg daily + ENZ 160 mg/day + P 200 mg IV q 3 weeks was the RP2D. Grade 3 treatment-related adverse events (AEs) for the study cohort included fatigue (n = 3), decreased appetite (n = 1), rash (n = 1), and elevated AST/ALT (n = 1). Immune-related AEs included: skin rash (Grade 1/2: n = 9; grade 3: n = 1), colitis (Grade 1/2: n = 6; grade 3: n = 0), pruritus (grade 1/2: n = 2; grade 3: n = 0), and autoimmune hepatitis (Grade 3, n = 1). The PSA50 response proportion was 27% (6/22 pts), including 2 pts who had previously progressed on ENZ. None of the responders were MSI-high by targeted next-gen sequencing. PSA responses were durable, including 2 pts who remain on treatment for 13.6+ and 12.7+ months, respectively. The combination of ZEN, ENZ, and P had an acceptable safety profile. Preliminary clinical activity was observed, including responses in ENZ-resistant microsatellite-stable mCRPC. Further investigation of the combination is ongoing including in an AR-independent cohort.

The CONTROL study: A randomized, double-blind vehicle-controlled phase 2b study of novel topical isotretinoin formulation demonstrates improvement in recessive X-linked and autosomal recessive lamellar congenital ichthyosis

The CONTROL study: A randomized, double-blind vehicle-controlled phase 2b study of novel topical isotretinoin formulation demonstrates improvement in recessive X-linked and autosomal recessive lamellar congenital ichthyosis

PD38-11 LONG-TERM EFFICACY AND SAFETY OF VIBEGRON FOR OVERACTIVE BLADDER IN PATIENTS ≥65 YEARS OLD: ANALYSIS FROM THE EMPOWUR EXTENSION TRIAL

You have accessJournal of UrologyCME1 May 2022PD38-11 LONG-TERM EFFICACY AND SAFETY OF VIBEGRON FOR OVERACTIVE BLADDER IN PATIENTS ≥65 YEARS OLD: ANALYSIS FROM THE EMPOWUR EXTENSION TRIAL Jeffrey Frankel, Susann Varano, Heather Greene, Elizabeth Thomas, and David Staskin Jeffrey FrankelJeffrey Frankel More articles by this author , Susann VaranoSusann Varano More articles by this author , Heather GreeneHeather Greene More articles by this author , Elizabeth ThomasElizabeth Thomas More articles by this author , and David StaskinDavid Staskin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002596.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Overactive bladder (OAB) prevalence increases with age. Vibegron is a β3-adrenergic agonist approved for adults with OAB. In the phase 3 EMPOWUR extension trial, once-daily vibegron 75 mg showed long-term safety and efficacy in patients with OAB, consistent with results of the 12-week study. These post hoc analyses of the extension trial assessed safety and efficacy in patients ≥65 years old. METHODS: Patients completing EMPOWUR could enter the 40-week extension (NCT03583372). Patients previously receiving vibegron or tolterodine 4 mg extended release continued treatment; patients receiving placebo were randomized 1:1 to vibegron or tolterodine. The primary outcome was safety, assessed by adverse events (AEs). Key efficacy endpoints were change from EMPOWUR baseline at week 52 in average daily micturitions, urge urinary incontinence (UUI) episodes, and urgency episodes. Outcomes were assessed in patients ≥65 years old. RESULTS: Of 505 patients receiving ≥1 dose in the extension (n=273, vibegron; n=232, tolterodine), 235 were ≥65 years old. Of patients ≥65 years old, 71.1% were female; 75.7% had OAB wet (incontinence). After 40‒52 weeks of treatment, treatment-related AE rate was similar between vibegron (33.3%) and tolterodine (25.5%) (Table 1). The most commonly occurring AEs (vibegron/tolterodine) were hypertension (10.9%/9.4%), urinary tract infection (7.8%/12.3%), and headache (7.0%/4.7%). Patients who received 52 weeks of active treatment showed improvement in least squares mean change from baseline at week 52 in micturitions (vibegron, −2.3; tolterodine, −1.7), UUI episodes (−1.8; −1.2), and urgency episodes (−3.3; −2.4) (Table 2). Safety and efficacy outcomes were generally similar in patients ≥75 years old. CONCLUSIONS: In this subgroup analysis of the EMPOWUR extension trial, vibegron was associated with sustained reductions from baseline in micturitions, UUI episodes, and urgency episodes and was safe in older adults (≥65 y) with OAB, consistent with the overall population. Source of Funding: Urovant Sciences © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e649 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeffrey Frankel More articles by this author Susann Varano More articles by this author Heather Greene More articles by this author Elizabeth Thomas More articles by this author David Staskin More articles by this author Expand All Advertisement PDF DownloadLoading ...

Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction: a post-hoc analysis of the ATHENA trial.

AimsLimited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF.Methods and resultsATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction [LVEF] >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow‐up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69–0.84) without heterogeneity based on HF status (p interaction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (p interaction = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup.ConclusionsDronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.

Efficacy and Safety of Ceritinib 450 mg/day with Food and 750 mg/day in Fasted State in Treatment-Naïve Patients with ALK+ Non-Small Cell Lung Cancer: Results from the ASCEND-8 Asian Subgroup Analysis.

Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial. Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events. At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively. Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

Sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years old with HCV infection.

Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17years with chronic HCV of any genotype. In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100mg daily was administered to adolescents for 8weeks if DAA-naïve or for 12weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients. All patients (n=21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults. The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.

Results of the United States Food and Drug Administration Clinical Trial of the CustomFlex Artificial Iris

To evaluate safety and efficacy of a custom-manufactured artificial iris device (CustomFlex Artificial Iris; HumanOptics AG) for the treatment of congenital and acquired iris defects. Multicenter, prospective, unmasked, nonrandomized, interventional clinical trial. Patients with photophobia, sensitivity secondary to partial or complete congenital or acquired iris defects, or both. Eyes were implanted from November 26, 2013, to December 1, 2017, with a custom, foldable artificial iris by 1 of 4 different surgical techniques. Patients were evaluated 1 day, 1 week, and 1, 3, 6, and 12 months after surgery. At each examination, slit-lamp findings, intraocular pressure, implant position, subjective visual symptoms, and complications were recorded. Corrected distance visual acuity (CDVA) and endothelial cell density (ECD) were measured at 3, 6, or 12 months as additional safety evaluations. The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was used to assess health-related quality of life affected by vision. The Global Aesthetic Improvement Scale was used to assess cosmetic results. Photosensitivity, glare, visual symptoms, NEI VFQ-25 score, Global Aesthetic Improvement Scale rating, prosthesis-related adverse events, intraocular lens (IOL)-related adverse events, and surgery-related adverse events 12 months after surgery. At the 12-month postoperative examination, a 59.7% reduction in marked to severe daytime light sensitivity (P < 0.0001), a 41.5% reduction in marked to severe nighttime light sensitivity (P < 0.0001), a 53.1% reduction in marked to severe daytime glare (P < 0.0001), and a 48.5% reduction in severe nighttime glare (P < 0.0001) were found. A 15.4-point improvement (P < 0.0001) in the NEI VFQ-25 total score was found, and 93.8% of patients reported an improvement in cosmesis as measured by the Global Aesthetic Improvement Scale 12 months after surgery. No loss of CDVA of > 2 lines related to the device was found. Median ECD loss was 5.3% at 6 months after surgery and 7.2% at 12 months after surgery. The artificial iris surpassed all key safety end points for adverse events related to the device, IOL, or implant surgery and metall key efficacy end points, including decreased light and glare sensitivity, improved health-related quality of life, and satisfaction with cosmesis. The device is safe and effective for the treatment of symptoms and an unacceptable cosmetic appearance created by congenital or acquired iris defects.

P341 Pharmacokinetics and exposure-response analyses of upadacitinib in patients with moderate to severe ulcerative colitis – Analyses of induction and maintenance clinical trials

Abstract Background Upadacitinib (UPA), an oral selective and reversible JAK1 inhibitor, showed favorable efficacy and safety profile in Phase, 2b and, 3 studies in subjects with moderate to severe ulcerative colitis (UC). Population pharmacokinetics and exposure-response analyses were performed to characterize the relationships between UPA plasma exposures and key efficacy and safety endpoints using data from these studies. Methods The pharmacokinetics (PK), efficacy, and safety of UPA for induction and maintenance treatment in UC were evaluated in a Phase, 2b induction, two replicate Phase, 3 induction, and a Phase, 3 maintenance clinical trials. UPA PK was characterized using data from, 978 UC patients. UPA exposure-response relationships for key efficacy and safety endpoints at the end of induction and maintenance periods were characterized using data from, 1,234 and, 449 UC patients, respectively. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across UPA doses of, 7.5 mg to, 45 mg once daily (QD) for induction and, 15 mg to, 30 mg QD for maintenance. Results UPA PK in UC patients was consistent with other patient populations and between the induction and maintenance periods. The percentage of subjects achieving clinical and endoscopic efficacy endpoints at the end of the induction increased with increasing UPA average plasma concentration (Cavg), and became mostly flat at Cavg values approximately equivalent to the, 45 mg QD (Figure, 1). For maintenance treatment, there was a trend for increasing the percentage of subjects achieving clinical remission, steroid-free remission, endoscopic improvement, and histo-endoscopic mucosal improvement within the range of UPA plasma exposures evaluated. Exposures associated with UPA, 30 mg QD were estimated to provide a, 8% to, 10% increase in the percentage of subjects achieving these endpoints compared to, 15 mg QD (Figure, 2). There was no trend for exposure-response relationships within the range of evaluated UPA exposures for any of the evaluated safety endpoints (&amp;gt;2 g/dL decrease in hemoglobin and &amp;gt;2 g/dL decrease in hemoglobin and &amp;lt; lower limit for normal, hemoglobin &amp;lt;, 8 g/dL, lymphopenia ≥ Grade, 3, neutropenia ≥ Grade, 3, Herpes Zoster infection, serious infections, and pneumonia) at the end of induction or maintenance periods. Conclusion UPA plasma exposures associated with the, 45 mg QD induction dose maximized efficacy for clinical and endoscopic endpoints at Week, 8. Plasma exposures associated with UPA, 30 mg maintenance dose provide additional incremental benefit compared to, 15 mg QD. No trends were observed for increase in the evaluated safety events with increasing UPA plasma exposures at the end of induction or maintenance periods.

Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin.

BackgroundThe efficacy of flibanserin in treating hypoactive sexual desire disorder (HSDD) is based upon statistically significant improvements in sexual desire, satisfying sexual events, and distress. However, clinically meaningful benefit has not been well characterized.AimEvaluate clinically meaningful benefit of flibanserin.MethodsData were pooled from 3 pivotal trials evaluating flibanserin 100 mg qhs in premenopausal women (flibanserin, n = 1192; placebo, n = 1215). Flibanserin trial data in postmenopausal women (flibanserin, n = 450; placebo, n = 476) were analyzed separately. Clinically meaningful benefit was evaluated by the Patient Global Impression of Improvement (PGI-I). Responders were determined through anchor-based analyses that used the PGI-I for key efficacy endpoints: satisfying sexual events (SSE), desire domain of the Female Sexual Function Index (FSFI-d), and distress associated with decreased sexual desire (FSDS-R13). Odds ratios were calculated to assess effect size and Kaplan-Meier analyses were performed to estimate onset time for treatment benefit.OutcomesPGI-I, anchor-based analyses for key efficacy endpoints (SSE, FSFI-d, FSDS-R13), odds ratios, onset time for treatment benefit.ResultsBased on the PGI-I, more patients reported clinically meaningful benefit with flibanserin treatment versus placebo (49.8% vs 33.6%, premenopausal cohort; 40.5% vs 28.7%, postmenopausal cohort). In anchor-based analyses, responder rates were significantly higher for premenopausal women on flibanserin (46.1%–55.2%) than placebo (34.1%–44.2%) for all 3 key efficacy endpoints (P < .0001). Responder rates for postmenopausal women on flibanserin were higher compared to placebo for SSE (29.8% vs 22.9%; P = .015) and FSFI-d (38.9% vs 26.3%; P = .0001). Odds ratios for key endpoints indicated that premenopausal women were 2.0–2.4 times as likely to be responders with flibanserin treatment compared to placebo. Postmenopausal women were 1.6 times as likely to be responders with flibanserin for FSFI-d. Kaplan-Meier analyses indicated significant separation between flibanserin and placebo for the key endpoints in both premenopausal and postmenopausal cohorts (log-rank tests P < .01) with earlier median response times among patients receiving flibanserin.Clinical ImplicationsPatient-reported benefit assessments such as the PGI-I capture the patient's perspective and may be a useful approach in assessing overall clinical meaningfulness for sexual dysfunction therapies.Strengths and LimitationsStrengths include a well-powered study with large enrollment, use of validated instruments, and self-assessment of treatment benefit. Limitations include pooling of trial data in premenopausal women with slightly different study designs and use of an endpoint (SSE) indirectly related to HSDD.ConclusionAssessment of clinically meaningful benefit and additional responder analyses provide further support for flibanserin's efficacy beyond numerical improvements in endpoint measures.Simon JA, Clayton AH, Kim NN, et al. Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin. Sex Med 2022;10:100476.

Safety and Efficacy of Tocilizumab 4 or 8mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BackgroundTocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown.MethodsPatients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1–2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation.ResultsOf 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks.ConclusionsIn patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia.Clinical Trials RegistrationNCT04363736.

Safety and Efficacy of Letetresgene Autoleucel (lete-cel; GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

Safety and Efficacy of Letetresgene Autoleucel (lete-cel; GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein-Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein-Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients’ pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposure-response analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

Abstract OT-03-03: SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer

Abstract Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-03.

Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors

PurposeThe starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors.MethodsIntegrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure–response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored.ResultsTwo-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure.ConclusionBased on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.

MUSCLE IMAGING – MRI: P.157 Sources of variability in vastus lateralis fat fraction measurements using MRI in clinical trials for Duchenne muscular dystrophy (DMD) therapy

Quantifying fat replacement of the vastus lateralis (VL) by MRI proton density fat fraction (PDFF) is a key efficacy endpoint in DMD clinical trials, due to its sensitivity and lack of dependency on patient motivation. For multi-center clinical trials, a central review is recommended to reduce observer variability, in which an initial technologist measurement is overread/adjusted by a central physician reviewer. Understanding the variability associated with each role is important. We propose that the technologist is a greater source of variability in the MRI-PDFF measurements than the physician. MRI scans of the lower limb (N=13) optimized for PDFF quantitation were extracted from an anonymous clinical trial data repository. The VL was segmented from T1-weighted images by two technologists, in three slices, at the widest part of the VL. A physician reviewed the segmentation, which was applied to the PDFF map to calculate the average fat fraction in the VL. Inter-technologist variability, inter-physician variability with the same technologist, and intra-physician variability with different technologists, were assessed using an intraclass correlation coefficient (ICC) based on a single rating, absolute agreement, 2-way random-effects model. Overall reproducibility of VL fat fraction measurement was excellent. The inter-technologist variability was the largest source of measurement error (ICC = 0.972) compared to the inter-physician variability with the same technologist (ICC = 0.996). The physician overread did not reduce variability, as the intra-physician variability reflected the underlying differences between technologists (ICC = 0.973). The variability between technologists was not driven by variations in slice selection, as shown by the lack of improvement when measurements were performed on the same slices (ICC = 0.972). Instead, the greatest improvement in variability can be expected from improving the skills of the technologist to precisely contour the muscle to exclude subcutaneous fat partial volume effects.

Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies.

ObjectiveMetabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib.MethodsTofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease‐modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire‐Disability Index (HAQ‐DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C‐reactive protein, HAQ‐DI, Patient’s/Physician’s Global Assessment of Arthritis, and patient‐reported outcomes. Safety outcomes included treatment‐emergent all‐causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases.ResultsOf 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib‐treated patients with MetS.ConclusionRegardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.