Frequent Treatment-emergent Adverse Events Research Articles

P1535: SAFETY AND TOLERABILITY OF SINGLE ESCALATING DOSES OF INTRAVENOUS NIPOCALIMAB IN HEALTHY JAPANESE ADULTS: A RANDOMIZED, PHASE 1 PLACEBO-CONTROLLED STUDY

Background: Autoimmune hemolytic anemia (AIHA) is a rare, life-threatening disorder characterized by the destruction of red blood cells (RBCs) by autoantibodies. In Japan, the estimated prevalence of AIHA is 3-10 cases per 1 million person-years. Of these, approximately 90% of patients present with warm AIHA (wAIHA), which occurs when pathogenic IgG antibodies bind to RBCs at a temperature of ~37 °C. There is currently no approved treatment for wAIHA, and patients with severe symptomatic anemia are generally managed with corticosteroids, immunosuppressants, rescue therapies, and immune cell depleting biologic therapies. Nipocalimab is a fully human, effectorless IgG1 monoclonal antibody in clinical development for wAIHA. Nipocalimab targets the IgG binding site on the neonatal Fc receptor (FcRn) to reduce circulating IgG including anti-RBC autoantibodies. In a prior phase 1 study in healthy adults receiving single and multiple ascending doses administered by intravenous (IV) infusion, nipocalimab was well-tolerated with an adverse event profile comparable to placebo. However, the proportion of Asian participants in that study was small, and therefore the safety of nipocalimab required further investigation in this population. Aims: To assess the safety and tolerability of single escalating doses of nipocalimab administered as IV infusions in healthy Japanese adults. Methods: The trial was a randomized, double-blind, placebo-controlled, escalating single dose study. Eligible participants were healthy Japanese males or females aged 18-64 years with no clinically significant medical or physical conditions. Dosing cohorts were: nipocalimab 10 mg/kg, 30 mg/kg, and 60 mg/kg or matching placebo, infused IV over 30 min. Escalation to the next dose level only proceeded following review of safety and tolerability by the principal investigator. Safety was assessed by the frequency of treatment-emergent adverse events (TEAEs), as well as abnormalities in clinical laboratory assessments, physical examinations, or vital signs. Results: A total of 24 Japanese participants (92% female) were randomized, received study drug, and completed the study. A total of 3 participants (12.5%) experienced 1 or more TEAE: 2 in the 30 mg/kg nipocalimab cohort and 1 in the 60 mg/kg nipocalimab cohort (Table). Mild (grade 1) dizziness was the most common TEAE, which was reported by 2 participants, 1 each in the 30 mg/kg and 60 mg/kg nipocalimab cohorts. Mild influenza-like illness was reported by 1 participant who received 30 mg/kg nipocalimab and mild diarrhea was reported by 1 participant who received 60 mg/kg nipocalimab; these TEAEs were considered by the investigator as unrelated to study drug. One participant in the 30 mg/kg nipocalimab cohort discontinued study drug infusion after 22 minutes due to a moderate infusion-related reaction, which was considered to be related to study treatment. This AE was managed with an antihistamine, and the participant received only 22 mg of nipocalimab. There were no clinically significant changes in laboratory parameters or vital signs, no injection site reactions, serious adverse events, or deaths. Image:Summary/Conclusion: Single doses of nipocalimab, administered at doses between 10 mg/kg and 60 mg/kg by IV infusion, were generally safe and well-tolerated in healthy Japanese adults, consistent with the prior phase 1 study in a general population, which included Asian and non-Asian participants.

P1101: PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. Aims: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥2 prior therapies. Methods: Pirtobrutinib was dose escalated in a standard 3 + 3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in ≥10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% confidence interval 38-66; 13 complete response (CR) [25%], 14 partial response (PR) [27%], 9 stable disease (SD) [17%]), 11 progressive disease (PD) [21%] and 5 [10%] discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Summary/Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented.

S189: EARLY, DEEP, AND DURABLE RESPONSES, AND LOW RATES OF CRS WITH REGN5458, A BCMAXCD3 BISPECIFIC ANTIBODY, IN A PHASE 1/2 FIRST-IN-HUMAN STUDY IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: Despite recent advances in treatment options, multiple myeloma (MM) remains incurable. REGN5458 is a BCMAxCD3 bispecific antibody currently under investigation in relapsed/refractory MM (RRMM) in an ongoing Phase 1/2 trial (NCT03761108). Preliminary data suggest that REGN5458 has a manageable safety profile with early, deep and durable responses in heavily pretreated patients (pts). Aims: Here we describe updated safety, overall response and response durability in pts treated with REGN5458 in the Phase 1 portion of this ongoing trial. Methods: The Phase 1 primary objectives are to assess safety, tolerability and occurrence of dose-limiting toxicities of REGN5458 and to determine a recommended Phase 2 dose regimen (RP2DR). Key secondary objectives include: assessment of objective response rate as determined by the investigator, duration of response (DOR) and minimal residual disease status; pharmacokinetic evaluation; and characterization of immunogenicity. Pts with progressive RRMM, who are double- or triple-refractory, or intolerant to prior lines of systemic therapy including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody are treated with REGN5458 monotherapy following a modified 3 + 3 dose-escalation design (4 + 3). Treatment consists of 16 weekly infusions of REGN5458 followed by q2w dosing until disease progression. Response assessments are measured using modified International Myeloma Working Group criteria. Results: At data cut-off (September 30, 2021), 73 pts were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3–800 mg. Median age at enrollment was 64 years (range, 41–81) and 20.5% pts were ≥75 years. As per Revised International Staging System, stage was 1, 2 or 3 in 15.0%, 57.5% and 23.3% of pts respectively. Pts had a median of 5 prior lines of systemic therapy (range, 2–17) with 38.4% of pts being penta-refractory (Table). Median duration of follow-up was 3.0 months (range, 0.7–22.1). Treatment-emergent adverse events (TEAE) were reported in 73 pts (100%), Grade (Gr) 3 in 31 pts (42.5%), Gr 4 in 24 pts (32.9%). The most common Gr 3/4 TEAEs were hematologic (39.0%). The most frequent TEAEs were fatigue in 33 pts (45.2%), Gr 1/2 in 31 pts (42.5%), Gr 3 in 2 pts (2.7%); cytokine release syndrome (CRS) in 28 pts (38.4%), Gr 1 in 25 pts (34.2%), Gr 2 in 3 pts (4.1%). No pt had Gr ≥3 CRS or discontinued treatment due to CRS. There were no Gr ≥3 neurotoxicity events. Nausea was reported in 24 pts (32.9%), Gr 1 in 17 pts (23.3%), Gr 2 in 7 pts (9.6%). Responses were observed at all dose levels. Across all dose levels, 86.5% (n=32/37) of all responders achieved at least a very good partial response and 43.2% (n=16) of responders had a complete response (CR) or stringent CR. Amongst pts treated at the 200–800 mg dose levels, the response rate was 75.0% (n=18/24). The Kaplan–Meier estimated probability of responders being in response for 8 months or more was 90.2% (95% confidence interval: 72.6–96.7), and median DOR was not reached. Image:Summary/Conclusion: REGN5458 shows a manageable safety and tolerability profile, with Gr 2 CRS in only 4.1% of pts and no Gr ≥3 CRS or neurotoxicity events. No new safety signals were observed during the additional follow-up period. Early, deep and durable responses were seen in triple- to penta-refractory pts with RRMM, with a 75.0% response rate at the combined 200–800 mg dose levels. The Phase 2 portion of the study is currently recruiting.

Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial

Background & aimsNovel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe. MethodsIn a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients. ResultsA total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], −0.8 to 12.6; P < .001; difference –0.3%; 95% CI, −7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7–48.1; P < .001; difference 37.7%; 95% CI, 20.5–52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7–18.8; P < .001; difference 8.7%; 95% CI, 1.9–15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05). ConclusionBoth vonoprazan-based regimens were superior to proton pump inhibitor–based triple therapy in clarithromycin-resistant strains and in the overall study population. ClinicalTrials.gov; NCT04167670.

A Phase 2 Study of S-588410 Maintenance Monotherapy for Platinum-Treated Advanced or Metastatic Urothelial Carcinoma.

Effective maintenance therapy for urothelial carcinoma (UC) is needed to delay progression after first-line chemotherapy. To evaluate S-588410, a cancer peptide vaccine containing five human leukocyte antigen (HLA)-A*24:02-restricted epitope peptides derived from five cancer-testis antigens (DEPDC1, MPHOSPH1, URLC10, CDCA1, and KOC1) in chemotherapy-treated, clinically stable patients with advanced or metastatic UC. This open-label, international, phase 2 trial enrolled patients with UC who had completed≥4 cycles of first-line platinum-containing chemotherapy without disease progression. Forty-five HLA-A*24:02-positive patients received subcutaneous injections of S-588410 (Montanide ISA 51 VG with 1 mg/mL of each peptide) weekly for 12 weeks then once every 2 weeks thereafter for up to 24 months. Thirty-six HLA-A*24:02-negative patients did not receive S-588410 (observation group). The primary endpoint was the rate of cytotoxic T-lymphocyte (CTL) induction against≥1 of the peptides at 12 weeks. The CTL induction rate in the S-588410 group was 93.3% (p < 0.0001, one-sided binomial test with a rate of≤50% as the null hypothesis). The antitumor response rate was 8.9% in the S-588410 group and 0% in the observation group; median progression-free survival was 18.1 versus 12.5 weeks and median overall survival was 71.0 versus 99.0 weeks, respectively. The most frequent treatment-emergent adverse event was injection-site reactions (47 events, grades 1-3) reported in 93.3% (n = 42/45) of participants. S-588410 demonstrated a high CTL induction rate, acceptable safety profile, and modest clinical response, as maintenance therapy in participants with advanced or metastatic UC who had received first-line platinum-based chemotherapy (EudraCT 2013-005274-22).

A phase II study to evaluate the safety and efficacy of IMM-101 in combination with checkpoint inhibitors in patients with advanced melanoma: Final results of the IMM-101-015 trial.

9554 Background: IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC 13365), which enhances the innate immune response and dendritic cell maturation. In animal models, it increases antigen specific responses and number of CD8+ CTL and CD4 + Th1 cells. The clinical studies with IMM-101 have shown promising efficacy signals in pancreatic cancer when combined with gemcitabine and in melanoma as adjunctive or single agent. Methods: IMM-101-015 is an open-label Phase 2a study to investigate the safety and efficacy of IMM-101 in combination with checkpoint inhibitors (CPIs) in patients (pts) with advanced melanoma who were either treatment-naive (cohort A), or whose disease had progressed during PD-1 blockade (cohort B). Pts with evaluable lesions, adequate performance status and organ function were eligible. Pts received 1.0 mg of IMM-101 every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then every 2 weeks for the next 3 doses, and thereafter every 4 weeks. Nivolumab was given every 2 or 4 weeks (dependent on Investigator choice). Pts in cohort B had the option to change to ipilimumab and IMM-101 if their disease continued to progress. Biopsies and blood samples were obtained at baseline and during treatment for assessment of tumor biomarkers and immune correlatives. The primary objectives of the study were to evaluate the overall response rate (ORR) after a maximum of 18 months of treatment by RECIST 1.1 and to assess the safety and tolerability of the combination of IMM-101 + CPIs. Results: Sixteen pts (11 Cohort A and 5 Cohort B) were treated between October 2018 and May 2021. The median age was 68.5 yrs (range 36-92) and 11 (69%) were male. The ECOG ps was 0 in 9 (56%) and 1 in 7 (44%) pts. Four (25%) had unresectable stage III melanoma and 12 (75%) stage IV. In Cohort A (3 stage III, 5 stage IV M1b and 3 M1c) 3 pts (27%) had an elevated baseline LDH, 6 (55%) a positive PD-L1 status and 3 (27%) a BRAF mutation. Pts in cohort A were on study for a median time of 8.5 months (range 1.5 - 19.1) and those in cohort B for 3.0 months (range 1.5 - 7.4). All pts were evaluated for response. The ORR was 73% (95% CI 39.03, 93.98) in cohort A whereas all pts in cohort B reported progressive disease. With respect to cohort A, 2 (18%) pts had CR, 6 (55%) PR and 1 (9%) SD. The median progression-free survival time was 10.2 months (95% CI 2.50, NE) with 41% of the pts progression-free at 18 months. The most frequent treatment emergent adverse events (TEAEs) were injection site reaction (63%), pruritus (44%), fatigue (38%), skin rash (25%), hypothyroidism (25%) and diarrhoea (19%). There were no grade 4 TEAEs. Grade 3 TEAEs occured in 10 patients (63%), mostly skin toxicity (19%) and lab abnormalities (13%). Conclusions: IMM-101 in combination with nivolumab is safe and shows encouraging antitumor activity in treatment-naive patients with advanced melanoma. Clinical trial information: NCT03711188.

Safety and efficacy of tusamitamab ravtansine (SAR408701) in long-term treated patients with nonsquamous non–small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).

9039 Background: Tusamitamab ravtansine (tusa) is a novel antibody-drug conjugate that selectively targets CEACAM5, a cell surface glycoprotein highly expressed in several tumor types. In previously reported results from an open-label Phase 1/2 study (NCT02187848), tusa showed promising antitumor activity in patients (pts) with heavily pretreated NSQ NSCLC and high CEACAM5 expression (Gazzah A et al. J Clin Oncol. 2020;38[15 suppl]:9505). Herein we report results for pts treated for ≥ 12 mo with NSQ NSCLC and high or moderate CEACAM5 expression. Methods: In the Phase 1/2 study, 92 pts with heavily pretreated NSQ NSCLC and high (n = 64) or moderate (n = 28) CEACAM5 expression (≥ 2+ intensity in ≥ 50% of tumor cells or in ≥ 1% to &lt; 50% of tumor cells, respectively) were treated with tusa 100 mg/m2 Q2W. As of Jan 2020, among CEACAM5 high expressors, 13 had confirmed partial response (PR) and 28 had stable disease (SD); among moderate expressors, 2 had PR and 15 had SD. We focus here on pts treated ≥ 12 mo as of Dec 2021. Results: A total of 24 pts were treated for ≥ 6 mo, 15 pts for ≥ 9 mo, 11 pts for ≥ 12 mo, 6 pts for ≥ 24 mo, and 2 pts for ≥ 42 mo. At the data cutoff, 5 pts remained on treatment, 1 for &gt; 3.5 y. For pts treated ≥ 12 mo median (range) treatment duration was 26.6 (12.1–45.3) mo. Of 15 pts with PR in the prior analysis, as of Dec 2021 PR was still observed in 10 pts (67%) treated for ≥ 6 mo, 8 pts (53%) for ≥ 9 mo, and 7 pts (47%) for ≥ 12 mo. For the 11 pts treated ≥ 12 mo, 7 had PR and 4 had SD. Of the 11 pts treated ≥ 12 mo, 9 had high CEACAM5 expression and 2 had moderate CEACAM5 expression; most had prior treatment with an anti-PD1/PD-L1. Pts treated for ≥ 12 mo had better ECOG performance status and fewer prior treatments than the overall group. Of pts treated for ≥ 12 mo, PR occurred irrespective of CEACAM5 expression level. Only 1 pt treated for ≥ 12 mo discontinued due to a treatment emergent adverse event (TEAE) (breast cancer). Corneal events (keratitis/keratopathy) were the most frequent TEAEs, occurring in 8 pts (73%); 4 pts (36%) with Grade ≥ 3; 7 pts had subsequent treatment modification (delay or delay/reduced dose). No corneal TEAE was serious or led to treatment discontinuation. Conclusions: Almost half (47%) of pts who achieved a PR were treated for ≥ 1 y, suggesting that response to tusa in heavily pretreated pts was durable and frequently sustained. No patient discontinued long-term treatment because of drug-related toxicity. Corneal toxicity in these pts was manageable with dose modification (delay/reduction). The observed long-term clinical benefit and safety profile of tusa support its further clinical development; a Phase 3 study is ongoing to evaluate tusa monotherapy in previously treated pts with high CEACAM5 expressing NSQ NSCLC. Clinical trial information: NCT02187848.

Phase II therapeutic equivalence study of Abiraterone Acetate Tablets (I) vs. ZYTIGA® in patients with metastatic castration-resistant prostate cancer.

e17040 Background: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the originator abiraterone acetate (ZYTIGA) is observed to be with relatively low bioavailability and high pharmacokinetic variability. Abiraterone Acetate Tablets (I), in which Sodium N-[8-(2-hydroxy-benzoyl) amino] caprylate (SNAC) was added in the formulation as an absorption enhancer, was therefore developed by using nanocrystal technology to enhance the dissolution rate of pharmaceutical compounds, leading to the improvement of the low oral bioavailability and significant food effects. Methods: Patients with mCRPC were randomized (1:1) to receive either Abiraterone Acetate Tablets (I) 300 mg daily plus 5 mg prednisone orally twice daily, or ZYTIGA 1000 mg once daily plus 5 mg prednisone orally twice daily for 84 days. The primary endpoint was serum testosterone concentration (Day 9/10). Secondary endpoints included serum prostate-specific antigen (PSA), pharmacokinetics and adverse events. Results: 68 patients with a median age of 71 (52-84 yrs) (n = 34 in each group) were enrolled in the full analysis set (FAS). The least square geometric mean of Day 9/10 serum testosterone concentration (rounded-up by 1 ng/dl) in Abiraterone Acetate Tablets (I) and ZYTIGA groups was 1.053 (95% CI, 1.006-1.102) and 1.000 (95% CI, 0.956-1.046), respectively. The geometric mean ratio between two groups was 1.053 (90% CI, 0.998-1.110) and the 90% CI fell within 80.0% to 125.0% equivalence limits. The PSA-50 response rate was also similar on Days 28, 56 and 84 (46.9% vs 50.0%, 65.6% vs 57.6%, 71.9% vs 67.7%). Compared with ZYTIGAlabel, no new safety concerns were observed in Abiraterone Acetate Tablets (I). In addition, Abiraterone Acetate Tablets (I) group was observed to be with lower frequency of treatment-emergent adverse events (TEAEs) of any grade (76.5% vs 85.7%), grade ≥3 TEAEs (8.8% vs 22.9%), and grade ≥3 treatment-related adverse events (TRAEs) (5.9% vs 14.3%). Conclusions: Therapeutic equivalence between Abiraterone Acetate Tablets (I) 300 mg and ZYTIGA 1000 mg was confirmed by Day 9/10 serum testosterone concentration in mCRPC patients. Abiraterone Acetate Tablets (I) also showed a trend of improvement in safety profile. Clinical trial information: NCT04862091.

P.020 Long-term safety and tolerability of atogepant 60mg once daily for preventive treatment of migraine: a phase 3, 40-week, multicenter extension to the advance trial

Background: A phase 3 trial, ADVANCE (NCT03777059), demonstrated that atogepant, an oral, CGRP receptor antagonist dosed once daily, results in clinically meaningful reductions in mean monthly migraine days. This open-label extension for ADVANCE trial completers evaluated long-term safety and tolerability of atogepant over 40-weeks. Methods: Participants in this trial (NCT03939312), rolled over from the ADVANCE trial, were treated with atogepant 60mg once daily for 40-weeks, with a 4-week safety follow-up. Only safety data were collected. Results: 685 participants took at least one dose of study drug, 74.6% completed the 40-week treatment period; mean age of 41.8 years, 88.2% female, 84.4% white, and mean BMI of 30.58 kg/m2. Mean (SD) treatment duration was 233.6 (89.32) days. 62.5% of participants experienced a treatment-emergent adverse event (TEAE), with 8.8% considered treatment-related by the investigator; serious adverse events (SAEs) occurred in 3.4% of participants, none were treatment-related. The most frequent AEs leading to discontinuation was nausea (0.4%, n=3); the most frequent TEAEs observed included upper respiratory tract infection (5.5%, n=38) and urinary tract infection (5.3%, n=36). No deaths or hepatic safety issues were observed. Conclusions: Safety results are consistent with known safety profile of atogepant and support long-term safety and tolerability of once daily dosing of atogepant 60mg.

Efficacy and Safety of AbobotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity Incontinence Performing Regular Clean Intermittent Catheterization: Pooled Results from Two Phase 3 Randomized Studies (CONTENT1 and CONTENT2)

BackgroundFor patients with neurogenic detrusor overactivity incontinence (NDOI), treatment with oral medications is often unsatisfactory. ObjectiveTo assess the efficacy and safety of abobotulinumtoxinA (aboBoNT-A) for NDOI. Design, setting, and participantsTwo randomized, double-blind phase 3 studies (CONTENT1, NCT02660138; CONTENT2, NCT02660359) enrolled patients with NDOI who were regularly performing clean intermittent catheterization (CIC) and were inadequately managed with oral therapy. Pooled results from the first placebo-controlled treatment cycle are reported. InterventionPatients received injections of aboBoNT-A 600 U (n = 162) or 800 U (n = 161) or placebo (n = 162) into the detrusor muscle. Outcome measurements and statistical analysisThe primary endpoint was the mean change from baseline in NDOI episodes per week at week 6. Secondary endpoints reported are the proportion of patients with no NDOI episodes, the volume per void, urodynamic parameters, and quality of life (QoL). Safety was also assessed. Statistical analyses were conducted for the pooled study populations (each aboBoNT-A dose vs placebo). Results and limitationsAt week 6, NDOI episodes per week were significantly reduced in each aboBoNT-A group versus placebo (both p < 0.001) and the volume per void had significantly increased. Approximately one-third of patients in each aboBoNT-A dose group reported no NDOI episodes versus 3% of patients in the placebo group. Reductions in urinary incontinence (UI) were reflected in significantly greater improvements in UI-related QoL in the aboBoNT-A groups versus placebo. Urodynamic parameters (bladder capacity and detrusor pressure) were significantly improved with each aboBoNT-A dose versus placebo. Each aboBoNT-A dose was well tolerated. Symptomatic urinary tract infection was the most frequent treatment-emergent adverse event, with incidence comparable across the aboBoNT-A and placebo groups. The studies were terminated prematurely owing to slow recruitment and were not designed for statistical comparison between the two aboBoNT-A doses. ConclusionsIntradetrusor aboBoNT-A is an effective treatment and alternative option for patients with NDOI who have an inadequate response to oral anticholinergics and are already performing CIC. Patient summaryIn patients with bladder muscle overactivity caused by neurological conditions (multiple sclerosis or spinal cord injury) and resulting in urinary incontinence, abobotulinumtoxinA injections improved their symptoms and bladder function, with no unexpected effects.

Comparative Efficacy and Safety of Lacosamide and Oxcarbazepine for Seizure Control in Children with Newly Diagnosed Solitary Neurocysticercosis.

In newly diagnosed neurocysticercosis (NCC) with seizures, the choice of anti-seizure medication (ASM) seems to be arbitrary due to a lack of comparative studies. Although oxcarbazepine (OXC) is often considered efficacious for focal seizures in NCC, due to adverse effects, newer ASMs like levetiracetam (LCM) and lacosamide are also being explored. This study was performed by case record review of children with newly diagnosed solitary viable parenchymal NCC aged 4-18years who received lacosamide and OXC at least for 12 weeks between August 2019 and April 2021, from a prospective registry of a tertiary care teaching hospital in north India. Seizure control, electroencephalographic abnormalities, resolution of inflammatory granulomas and adverse effects were compared between two arms at 12 and 24 weeks. Total 31 (8.3 ± 4.7 years, 19 boys) and 72 (8.6 ± 4.2 years, 43 boys) completed at least 12 weeks follow-up in LCM and OXC groups, out of which 2 and 51 completed at least 24 weeks follow-up in LCM and OXC groups, respectively. The occurrence of breakthrough seizure was comparable in both arms at 12 and 24 weeks (1/31 and 2/22 in lacosamide group vs. 2/72 and 4/51 in OXC group, p = 0.66 and 0.59, respectively). Patients receiving OXC had more frequent treatment-emergent adverse events (p = 0.0001) and four patients required discontinuation due to severe adverse events (SAEs), while none in the lacosamide group had SAEs. Lacosamide appears to be efficacious and safe for achieving seizure freedom in patients with solitary viable parenchymal neurocysticercosis.

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy

BackgroundThe INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies.Patients and methodsA multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate.ResultsTwenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar–plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib.ConclusionAlthough the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

89 Pooled Safety Analysis Evaluating Bioengineered Allogeneic Cellularized Construct in Patients with Deep Partial-thickness Thermal Burns

IntroductionAutograft (AG) is the standard of care treatment for deep burns but requires creation of a donor site wound prone to pain and scarring. Treatment with a bioengineered allogeneic cellularized construct (BACC) is an alternative approach that can reduce or eliminate the need for autografting. The BACC is a bilayer construct that was recently approved in the US for the treatment of adult deep partial-thickness (DPT) burns. Here, we report the analysis of pooled safety data from two open-label, randomized, controlled trials (STRATA2011 [NCT01437852] and STRATA2016 [NCT03005106]) that evaluated efficacy and safety of BACC versus autografting in patients with DPT burns.MethodsThe trials enrolled 101 patients aged ≥18 years with 3–49% total body surface area (TBSA) thermal burns. In each patient, two DPT areas on the torso or extremities were randomized to receive BACC or AG, where the mean total BACC dosage was 234.8 cm2 (range: 12.0–960.0 cm2). The safety endpoints assessed at each visit included: 1) treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious AEs (SAEs); 2) changes in immunologic responses (panel reactive antibodies [PRA], anti-bovine serum albumin [BSA] antibody response [STRATA2016 only]); 3) persistence of allogeneic DNA; and 4) laboratory exam and vital signs.ResultsEighty-seven patients (86.1%) experienced TEAEs, 30 patients (29.7%) experienced TRAEs, and 16 patients (15.8%) experienced SAEs. The most frequent TEAEs reported by ≥10% of patients in the pooled analysis were pruritus (n=31, 30.7%) and blister, hypertension, and hypertrophic scar (n=11, 10.9% each). The most frequent TRAEs (≥5% of patients) were pruritus (n=13, 12.9%) and blister (n=5, 5%). The most common SAEs were transplant (BACC or AG) failure, pneumonia, and deep vein thrombosis (n=2, 2% each), where only one SAE (impaired healing of moderate severity) was possibly related to BACC. One patient (1%) discontinued the trial due to a TEAE (traumatic brain injury). Two patients (2%) experienced SAEs that led to death, neither related to BACC. The number of patients with positive PRA values that were negative at baseline were 36 (38.7%) at Day 28 and 20 (22%) at Month 3. The number of patients with reactivity to HLA I class alleles found in the BACC increased from 4 (4%) at baseline to 39 (40.9%) at Day 28, then decreased to 22 (24.2%) at Month 3. No persistence of allogeneic DNA from the BACC was detected.ConclusionsBACC is well tolerated and is not associated with any unexpected SAEs or TEAEs. The safety profile at BACC treatment sites is similar to that at AG treatment sites. Thus, BACC may offer a safe alternative to autografting for the treatment of DPT burns.

Exposure-adjusted safety analyses of the VISION phase 3 trial of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

85 Background: In the VISION trial, targeted radioligand therapy with 177Lu-PSMA-617 significantly prolonged radiographic progression free survival (rPFS) and overall survival when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA)-PET-positive metastatic castration-resistant prostate cancer. There was a higher incidence of treatment-emergent adverse events (TEAEs) with 177Lu-PSMA-617 + SoC vs SoC. However, treatment exposure was more than three times longer in the 177Lu-PSMA-617 + SoC arm and thus relative toxicity may have been overestimated. A post hoc analysis of the relationship between exposure and frequency of TEAEs was performed to facilitate comparison of rates between arms. Methods: In this international, open-label study, adult patients previously treated with ≥ 1 androgen receptor pathway inhibitors and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, ≤ 6 cycles) + SoC or SoC. Safety was a secondary endpoint. TEAEs (regardless of causality) were reported from start of randomized treatment for up to 30 days after last treatment administration (including SoC) or 1 day before subsequent anticancer treatment, whichever occurred first. Overall TEAE incidence was adjusted for treatment exposure by calculating incidence per 100 patient treatment-years (PTY). The analysis was performed for the first occurrence of TEAEs. Results: Exposure-adjusted incidence of any grade, grade ≥ 3 and selected TEAEs are listed in the table. There was similar exposure-adjusted incidence of gastrointestinal events and fatigue and higher exposure-adjusted incidence of musculoskeletal and renal events with SoC compared with 177Lu-PSMA-617 + SoC suggesting an association with treatment exposure rather than 177Lu-PSMA-617. Dry mouth, dry eye and acute myelosuppression maintained a higher incidence, confirming relationship with 177Lu-PSMA-617 treatment. Conclusions: The adjusted safety analysis, accounting for a longer safety observation due to longer rPFS in patients receiving 177Lu-PSMA-617, reveals a comparable incidence of TEAEs between arms. This confirms a favorable risk/benefit profile of 177Lu-PSMA-617 added to SoC in this patient population. Clinical trial information: NCT03511664. [Table: see text]

Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial.

ObjectiveBurosumab, an anti-fibroblast growth factor 23 antibody, was recently approved for the treatment of X-linked hypophosphatemia (XLH).We evaluated the safety and efficacy of burosumab in pediatric XLH patients.MethodsThis open-label, phase 3/4 trial of ≤ 124 weeks’ duration was conducted at 4 Japanese medical centers. Fifteen children aged 1 to 12 years with XLH were included. All had previously been treated with phosphorus or vitamin D. Subcutaneous burosumab was administered every 2 weeks, starting with 0.8 mg/kg, and adjusted based on serum phosphorus levels and any safety concerns (maximum 2 mg/kg). Safety assessments included the frequency of treatment-emergent adverse events (TEAEs). Efficacy of burosumab on biochemical markers, clinical markers of rickets, motor function, and growth was also evaluated.ResultsThe average treatment duration was 121.7 weeks. Frequently reported TEAEs were nasopharyngitis (46.7%), dental caries (40.0%), and influenza (33.3%). At baseline, patients had low serum phosphorus concentrations (2.6 ± 0.3 mg/dL) and low-to-normal 1,25-dihydroxyvitamin D concentrations (24.7 ± 12.7 pg/mL), which increased with burosumab treatment and were maintained during the study period. Alkaline phosphatase decreased continuously. At baseline, the mean ± SD total Thacher Rickets Severity Score (RSS) was 1.3 ± 1.2, and 4 patients (26.7%) had an RSS ≥ 2.0. Mean Radiographic Global Impression of Change and RSS tended to improve, particularly in patients with higher baseline RSS. There was a trend toward increased 6-minute walk test distance. No apparent changes in growth rate were observed.ConclusionBurosumab has a good safety profile and is effective in pediatric patients with XLH.

Safety and dose-escalation study of a targeted oncolytic adenovirus, suratadenoturev (OBP-301), in patients with refractory advanced liver cancer: Phase I clinical trial.

459 Background: Suratadenoturev (OBP-301) is an oncolytic adenovirus that harbors a promoter of human telomerase reverse transcriptase ( hTERT) and is genetically modified to selectively replicate within and then lyse cancer cells. The aim of this study was to assess the safety and optimal dosage for intratumoral (IT) injection of OBP-301 in patients with advanced hepatocellular carcinoma (HCC). Methods: An open-label, non-comparative, phase I dose-escalation trial was performed in 20 patients who had refractory advanced HCC. OBP-301 was administered to the primary tumor using ultrasound guidance. A single IT injection of 1010 virus particles (VP) was administered to patients in the initial cohort (Cohort-1), and the subsequent single-dose cohorts received 1011 VP (Cohort-2), 1012 VP (Cohort-3), and 3×1012 VP (Cohort-4). A multiple dose cohort (Cohort-5) received 2×1012 VP × 3 times every 2 weeks. Each of the single-dose cohorts had 3 patients and there was a single escalating dose of OBP-301 from 1010 to 3×1012 VP. The multiple-dose cohort had 8 patients, and 6 of them received multiple escalating doses of 2×1012 VP ×3 times every 2 weeks. Results: There were 18 males and 2 females, and the median age was 59.39 years (range: 48.4–65.9). Patients had good tolerance of the single dose and multiple-dose regimens, and the maximum tolerated dose (MTD) was more than 6×1012 VP/patient. There was no evidence of toxicity with increasing dose, but there was a greater frequency of treatment-emergent adverse events (TEAEs) in Cohorts 4–5 than in Cohorts 1–3. The most common TEAEs related to OBP-301 were influenza-like illness (30%), pyrexia (15%), and fatigue, decreased platelet count, abdominal distension, and anemia (10% each). The overall intrahepatic mRECIST response occurred in 7 patients (39%) with confirmed stable disease (SD) and 11 (61%) with progressive disease (PD). The best target response occurred in 14 patients (78%) and 4 (22%) of them had PD. There was evidence of OBP-301 replication-dependent dissemination in the blood. Cohorts 4–5 had about 50% greater levels of CD8+ T cells in peripheral blood after OBP-301 injection. Conclusions: Multiple IT injections of OBP-301 are well-tolerated in advanced HCC. Although antitumor activity of the study medication alone would not be demonstrated obviously, SD observed as best local response was higher than as overall response. Improved anti-tumor efficacy can be achieved with adjusting viral injection volume to the target sites as well as with adopting the combination therapy with another immunothrapeutics in further study (JRCT ID: jRCT2033200223). Clinical trial information: NCT02293850.

Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial

IntroductionTrifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted.MethodsIn this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety.ResultsOf 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%.ConclusionsTreatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL.

Preliminary results of a phase 1 study of sea-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

559 Background: SEA-CD40 is an investigational nonfucosylated IgG1 monoclonal agonistic antibody targeted to CD40, expressed on antigen-presenting cells. SEA-CD40 binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. PDAC can be treated with gemcitabine + nab-paclitaxel (GnP), often with poor survival. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation to CD8+ T cells. In preclinical models, the combination of SEA-CD40 and chemotherapy resulted in significant antitumor activity which is further enhanced with anti-PD1 treatment. We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). Methods: Patients (pts) ≥18 years old with untreated metastatic PDAC and Eastern Cooperative Oncology Group performance scores of 0 or 1 were enrolled. GnP were administered on Days 1, 8, and 15 of each 28-day cycle with 10 or 30 μg/kg SEA-CD40 IV on Day 3. Pembro was administered every 42 days starting on Day 8. Results: As of July 9, 2021, 61 pts were treated: 40 and 21 pts at 10 and 30 μg/kg SEA-CD40, respectively. Minimum follow-up was 5 months. The most frequent treatment-emergent adverse events (TEAEs) are shown in Table. 5 (8%) pts experienced an AE leading to treatment (tx) discontinuation (3 and 2 in 10 and 30 μg/kg SEA-CD40 dose, respectively), 35 (57%) pts experienced a serious TEAE (22 and 13 pts in 10 and 30 μg/kg, respectively). Two tx-related deaths occurred: colitis attributed to pembro, and septic shock attributed to GnP. Pts had transient increases in circulating cytokines and chemokines associated with immune activation and trafficking as well as increases in markers of activation on peripheral NK cells and T cells. Conclusions: The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing. Clinical trial information: NCT02376699. [Table: see text]

OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study

Abstract Background Anti-IL23p19 inhibitors are emerging as promising treatment options for ulcerative colitis (UC). Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of inflammatory bowel diseases. We assessed the induction efficacy and safety of miri with a Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo (PBO)-controlled trial (LUCENT 1; NCT03518086) in patients with moderately to severely active UC (Modified Mayo Score 4–9 points and centrally read Mayo endoscopic subscore ≥2) who had inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib. Methods Adult patients (N=1281) were randomized in a 3:1 ratio to receive blinded intravenous administration of 300 mg miri or PBO every 4 weeks for 12 weeks. Randomization was stratified by biologic failure status, baseline (BL) corticosteroid use, BL disease activity as measured by modified Mayo score, and world region. The primary objective was to test the hypothesis that miri was superior to PBO in inducing clinical remission at Week 12. Key secondary objectives were clinical response, endoscopic remission, symptomatic remission, clinical response in biologic-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Week 12 (see Figure for endpoint definitions). Mixed Model for Repeated Measures was used to assess urgency; the Cochran-Mantel-Haenszel test, with missing data imputed as nonresponse, was used to assess all other outcomes. Results BL characteristics were balanced across the two treatment groups. A significantly greater proportion of patients treated with miri achieved clinical remission at Week 12 (Miri: 24.2%; PBO: 13.3%; Δ=11.1 [99.875%CI: 3.2, 19.1]; p=0.00006). Miri-treated patients achieved all key secondary endpoints, including a significantly greater average reduction in bowel urgency severity compared to PBO (p&amp;lt;0.00001). The frequencies of treatment-emergent adverse events in miri-treated patients were similar to PBO. There were numerically fewer serious adverse events (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to adverse events (Miri: 15 [1.6%], PBO: 23 [7.2%]) in miri-treated patients compared to PBO. There were 2 colon malignancies in the miri arm (0.2%) and no deaths during the treatment period. Conclusion In this phase 3 UC study, 300mg miri IV demonstrated statistically significant and clinically meaningful improvements vs PBO in all primary and key secondary endpoints across clinical, endoscopic, histologic, and symptomatic measures, with an acceptable safety profile.

A Prospective Study of Azilsartan Medoxomil in the Treatment of Patients with Essential Hypertension and Type 2 Diabetes in Asia.

This phase 4 study evaluated the efficacy and safety of azilsartan medoxomil (AZL-M) in patients with essential hypertension and type 2 diabetes mellitus (T2DM) in Hong Kong, Taiwan, and Thailand. This was a prospective, multicenter, single-arm, open-label study with patients aged 18–75 years with T2DM and essential hypertension and on stable treatment for T2DM. Patients with uncontrolled hypertension were treated with AZL-M 40 mg daily, with the option to uptitrate to 80 mg at 6 weeks. In all, 380 of the 478 patients screened in Hong Kong, Taiwan, and Thailand were enrolled. At week 6, 97 patients (25.5%) were titrated up to AZL-M 80 mg based on BP readings. At 12 weeks, 54.8% of patients reached the blood pressure (BP) goal of <140/85 mm Hg by trough sitting clinic BP (primary endpoint), and 62.8% and 27.0% achieved a BP of <140/90 mm Hg and <130/80 mm Hg, respectively. The efficacy of AZL-M over 12 weeks was also seen in different age and body mass index groups. The incidence of treatment emergent adverse events (TEAEs) was 12.9% before 6 weeks and 16.1% after 6 weeks, and they were mostly mild in severity. The most frequent TEAE was dizziness (4.7%). The incidence of TEAEs leading to study drug discontinuation (4.5%) and drug-related TEAEs (5.0% before 6 weeks; 3.9% after 6 weeks) was low. In patients with essential hypertension and T2DM in Asia, treatment with AZL-M indicated a favorable efficacy and safety profile in achieving target BP.