Drug-related Treatment-emergent Adverse Events Research Articles

A Phase 2, Open-Label Study to Evaluate the Efficacy and Safety of Mgta-145 in Combination with Plerixafor for the Mobilization of Hematopoietic Stem Cells in Patients with Sickle Cell Anemia

Background: In sickle cell anemia (SCA), a point mutation in the β-globin gene results in abnormal hemoglobin prone to polymerization under hypoxic conditions. Erythrocytes become sickle-shaped and rigid, leading to painful vaso-occlusion, ischemic tissue damage, and endothelial dysfunction. Despite significant, life-threatening risks, allogeneic hematopoietic cell transplant (allo-HCT) is the only cure for SCA. Results of autologous HCT, using the addition of a non-sickling, post-transcriptional gene silencing or gene editing to increase fetal hemoglobin, are promising and suggest an alternative option for those who lack a suitable donor. Procuring hematopoietic stem and progenitor cells (HSPCs) is challenging in patients with SCA, as granulocyte colony-stimulating factor is contraindicated due to severe adverse effects. Peripheral blood mobilization with Plerixafor (Mozobil®, Genzyme) has recently been shown to be safe and effective in SCA. While mobilization with plerixafor allows collection of an HSPC product, many SCA patients require ≥2 cycles of multiday plerixafor doses and apheresis to collect sufficient quantities of HSCs for genetic manipulation. Reports suggest 30% of patients experience vaso-occlusive events (VOEs) of grade ≥3 during and after apheresis; therefore, a considerable unmet need exists for agents that augment stem cell (SC) yields and reduce apheresis time. MGTA-145 is an agonist of cell-surface chemokine receptor 2 (CXCR2) under development for the mobilization of CD34+ cells in combination with plerixafor. MGTA-145 binds to CXCR2, resulting in HSC release, which when given with plerixafor, increases mobilization of HSCs. Preclinical studies in animal models and clinical trials in healthy subjects and patients with multiple myeloma demonstrated that MGTA-145 with plerixafor results in more rapid and robust mobilization of CD34+ cells, including primitive HSC populations, compared to plerixafor alone. Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 1 or 2 doses of MGTA-145 combined with plerixafor for the mobilization of HSCs in individuals with SCA. Study Design and Methods: This phase 2, open-label, 2-part study (NCT05445128) will enroll approximately 10-14 adults ages 18-35 years with SCA, at 3 sites in the US. Participants must have a documented diagnosis of SCA, have a hydroxyurea washout period, and have adequate white blood cell counts and cardiopulmonary, renal, and liver function. Key exclusion criteria include history of VOE requiring a visit to a healthcare facility within 30 days of screening, poorly controlled healthcare conditions, including but not limited to cardiopulmonary or hepatorenal events ≤6 months prior to screening, and cerebrovascular accident or retinal infarct ≤2 years prior to screening. In the 1st cohort of Part A, subjects will receive a single 0.24 mg/kg subcutaneous dose of plerixafor followed by a single 0.03 mg/kg IV dose of MGTA-145, with apheresis occurring within approximately 30-45 minutes of MGTA-145 dosing. After a 1-week follow-up visit and an Independent Data Monitoring Committee (DMC) review, the 2nd cohort with additional subjects may be enrolled and given plerixafor and a 0.03 or 0.015 mg/kg or lower dose of MGTA-145 (FIGURE). Following a 1-week follow-up visit and a 2nd DMC review, patients will be enrolled in Part B and will receive, on 2 consecutive days, plerixafor and the same dose of MGTA-145 as the 2nd Part A cohort, followed by apheresis on each dosing day. The primary endpoint is total yield of CD34+ cells (CD34+ cells/kg). Safety outcomes include incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, Grade ≥3 TEAEs, treatment-emergent serious adverse events, and TEAEs leading to study drug discontinuation. Core exploratory endpoints include characterization of the phenotype and function of cells collected by apheresis and assessment of the gene-modifying potential of mobilized CD34+ cells. The results of this trial will establish if MGTA-145 with plerixafor will rapidly and safely mobilize robust numbers of high-quality SCs for HSCT in SCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Survival Outcomes in the Non-Interventional Post-Authorization Study of Patients Treated with Pomalidomide for Relapsed and Refractory Multiple Myeloma: A Sub-Analysis of Patients with Prior Triple Class Exposure

Introduction When pomalidomide was first approved by the European Medicines Agency in 2013 for the treatment of relapsed/refractory multiple myeloma (RRMM), a non-interventional post-authorization registry, the MM-015 POM PASS (NCT02164955), was set up to monitor the safety of patients with longer exposure to pomalidomide treatment in routine care. With the later approval of other treatments, including the anti-CD38 monoclonal antibody daratumumab, the MM treatment pathway has been changing (Darzalex summary of product characteristics. Janssen 2022). While the first indication of pomalidomide was for the treatment of RRMM in patients previously treated with ≥ 2 prior therapies, including lenalidomide and bortezomib, patients recruited in the MM-015 POM PASS study after daratumumab approval could potentially have been treated with daratumumab prior to receiving pomalidomide (Imnovid summary of product characteristics. Celgene 2020). This specific analysis therefore assessed safety and survival outcomes in the ongoing MM-015 POM PASS study of patients exposed to all 3 classes of drugs (TCE) and those not exposed to daratumumab (non-TCE). Methods Patients receiving pomalidomide treatment were recruited into the registry from approximately 80 hematology/oncology sites in Europe. Patients should have received ≥ 1 dose of pomalidomide to be considered for the analysis. Patients who received ≥ 1 dose of lenalidomide, bortezomib, and daratumumab prior to receiving pomalidomide were classed as TCE; all other patients were classed as non-TCE. Adverse event (AE) incidence, duration of treatment (DoT), best overall response, and Kaplan-Meier estimates for overall survival (OS) were analyzed. A multivariate Cox regression was used to estimate adjusted hazard ratio (HR) for survival time between TCE and non-TCE subgroups. Results The safety population had 761 patients; 85 were classed as TCE and 676 as non-TCE. At the data cutoff for this analysis (December 31, 2021), 2 TCE and 9 non-TCE patients remained on treatment. Patients in this study had a median age (range) of 71 (36-92) years, 53.6% were male, and 47.4% had an Eastern Cooperative Oncology Group performance status of 1. Baseline characteristics between TCE and non-TCE groups were broadly comparable; TCE patients had a higher median number of prior treatment lines (4.0 vs 3.0) and were more likely to have a high-risk cytogenetic abnormality (22.4% vs 9.8%) than non-TCE patients. Most patients had ≥ 1 treatment-emergent AE (TEAE). TCE patients had higher rates of grade 3/4 TEAEs (95.3% vs 80.5%, respectively), serious TEAEs (75.3% vs 67.0%, respectively), and TEAEs leading to death (30.6% vs 22.9%, respectively) compared with non-TCE patients. Rates of drug-related TEAEs and TEAEs leading to dose reduction, interruption, or discontinuation were similar between TCE and non-TCE patients. Blood and lymphatic system disorders were the most common TEAEs for TCE and non-TCE patients at any grade (76.5% and 74.0%) or grade 3/4 (TCE, 64.7%; non-TCE, 57.4%) (Table). The main reasons for treatment discontinuation were progressive disease (TCE, 49.4% [n = 42]; non-TCE, 53.6% [n = 362]), AEs (TCE, 20.0% [n = 17]; non-TCE, 19.5% [n = 132]), and death (TCE, 16.5% [n = 14]; non-TCE, 10.4% [n = 70]). The death rate was higher in the TCE group, with 84.7% (n = 72) of the TCE group and 71.7% (n = 485) of the non-TCE group having died. TCE and non-TCE patients had a similar median DoT [range] (5.2 [0.3-43.0] vs 5.1 [0.2-74.6] months) and overall response rate (35.3% [n = 30] vs 36.7% [n = 248]). OS was lower in TCE patients compared with non-TCE patients (9.8 vs 15.6 months; HR, 1.73; 95% confidence interval [CI], 1.33-2.23; P < 0.0001). Conclusions Updated results of this ongoing non-interventional study continue to show that the safety profile of pomalidomide-based treatment in patients with RRMM in the real world is consistent with that from randomized controlled trials. No new safety signals were identified for patients treated with pomalidomide even when being exposed to bortezomib, lenalidomide, and daratumumab. TCE patients in the study had a higher risk of death compared with those who were non-TCE (HR, 1.73; 95% CI, 1.33-2.23). Study support The study was supported by Celgene, a Bristol-Myers Squibb Company. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

IntroductionClinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment.MethodsIn this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety.ResultsIn total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (− 11.6/− 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (− 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was − 4.8 mL/min/1.73 m2.ConclusionEsaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction.Clinical Trial RegistrationjRCTs06119002.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02294-z.

976P Phase II trial of trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC): Registrational data from DESTINY-Lung01

In the primary analysis of DESTINY-Lung01 (NCT03505710; data cutoff May 3, 2021), T-DXd (a HER2-targeting antibody–drug conjugate) in pts with previously treated HER2m NSCLC had a confirmed objective response rate (ORR) of 55% (95% CI, 44-65) and a safety profile generally consistent with previous reports (Li N Engl J Med 2021). This update provides additional subgroup analyses and longer follow-up in all pts. Pts with HER2m NSCLC refractory to standard therapy received T-DXd 6.4 mg/kg IV Q3W. Primary endpoint was ORR per RECIST v1.1 by independent central review (ICR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. At data cutoff (December 3, 2021), 91 pts with HER2m NSCLC were assessed. At baseline, 36.3% had asymptomatic central nervous system metastasis (CNS met); 33.0% had >2 prior therapies; 94.5% had prior platinum-based chemotherapy (CT). Median follow-up and treatment duration were 16.7 and 6.9 mo, respectively. The table shows primary endpoint for the overall and subgroup populations, including pts with CNS met. In the overall population, median PFS was 8.2 mo (95% CI, 6.0-11.9); median OS was 18.6 mo (95% CI, 13.8-25.8); median DOR was 10.6 mo (5.8-17.7); DCR was 92.3% (95% CI, 84.8-96.9). Drug-related treatment-emergent adverse events (TEAEs) occurred in 88 (96.7%) pts. The most common TEAEs were nausea (76.9%), vomiting (47.3%), and alopecia (46.2%). Adjudicated drug-related interstitial lung disease occurred in 25 (27.5%) pts (3 grade [G] 1, 16 G 2, 4 G 3, 2 G 5).Table: 976PT-DXd efficacy in HER2m NSCLCOverall N = 91Prior therapyCT n = 86CT and anti–PD-(L)1 n = 57CNS metHER2 KD mut n = 85≤2 lines n = 61>2 lines n = 30Yes n = 33No n = 58ORR by ICR, n (%) 95% CI50 (54.9) 44.2-65.434 (55.7) 42.5-68.516 (53.3)34.3-71.746 (53.5) 42.4-64.337 (64.9) 51.1-77.118 (54.5) 36.4-71.932 (55.2) 41.5-68.349 (57.6) 46.5-68.3Complete response1 (1.1)NA1 (1.2)001 (1.7)NAPartial response49 (53.8)45 (52.3)37 (64.9)18 (54.5)31 (53.4)Stable disease34 (37.4)34 (39.5)16 (28.1)14 (42.4)20 (34.5)Progressive disease3 (3.3)2 (2.3)1 (1.8)03 (5.2)Nonevaluable4 (4.4)4 (4.7)3 (5.3)1 (3.0)3 (5.2)DOR, median, mo 95% CI10.6 5.8-17.712.0 5.7-18.310.6 5.6-18.3NANA, not available. Open table in a new tab NA, not available. T-DXd showed durable anticancer activity that was consistent across subgroups including pts with >2 prior therapies and pts with CNS met. The updated results show no new safety signals and provide further evidence supporting T-DXd as a new treatment standard in pts with previously treated HER2m NSCLC.

730MO First-in-human phase I study of INCAGN02390, a TIM-3 monoclonal antibody antagonist in patients with advanced malignancies

TIM-3 is a transmembrane checkpoint receptor expressed on multiple immune cells that promotes an inhibitory tumor microenvironment. INCAGN02390 is a fully human Fc-engineered IgG1κ monoclonal antibody that selectively inhibits TIM-3 ligand interactions. This study is primarily aimed to determine the safety and tolerability and define the MTD or PAD of INCAGN02390 monotherapy. This is a phase 1, multicenter, open-label, dose-escalation study that enrolled pts with locally advanced or metastatic solid tumors that failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02390 Q2W in 7 dose levels (DLs): 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. The primary endpoint was safety and tolerability. Other endpoints were PK, PD and preliminary efficacy per RECIST v1.1. Forty pts (median age, 63 y) were enrolled; 53% were male and 83% had ECOG PS 1. Lead cancer types were breast (15%), lung (13%), and colorectal (10%). 98% received prior systemic therapy (58% had prior immunotherapy). No DLT was observed and MTD was not reached. Most frequent treatment-emergent adverse events (TEAEs) were anemia (35%), back pain (30%), and fatigue (28%). Drug-related grade ≥3 TEAEs were observed in 7.5% of pts (anemia, adrenal insufficiency, and amylase increased [n=1 each]; all Gr3). One drug-related serious TEAE (adrenal insufficiency) occurred at the 1600 mg DL. One drug-unrelated fatal TEAE (multi-organ failure) occurred in the 800-mg DL. INCAGN02390 trough serum concentrations achieved steady state around Cycles 4 to 6. Maximum concentration and area under the serum concentration-time curve were linear across most DLs. Doses ≥400 mg led to trough TIM-3 receptor occupancy levels of ≥90% in peripheral blood. Disease control rate was 17.5%, with 1 confirmed partial response in a pt with an adenoid cystic carcinoma in lung. INCAGN02390 monotherapy was generally well tolerated, with linear PK. The 400 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).

Efficacy and Safety of Oteseconazole in Recurrent Vulvovaginal Candidiasis

BackgroundManagement of recurrent vulvovaginal candidiasis (RVVC) is an unmet clinical challenge without approved treatment in the United States. Oteseconazole is a novel oral selective inhibitor of fungal CYP51, designed to treat RVVC without off-target toxicities. VIOLET comprised two global, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (CL-011 and CL-012). The primary objective was to evaluate oteseconazole efficacy through week 48. Key secondary objectives evaluated time to first recurrence, safety, and patient-reported outcomes.MethodsWomen with three or more symptomatic acute vulvovaginal candidiasis (VVC) episodes within the previous 12-month period, including the screening episode (in which the VVC episode cleared with fluconazole induction therapy), were randomly assigned 2:1 at baseline (maintenance phase) to 150 mg of oral oteseconazole daily for 7days and then once weekly for 11 weeks or to matching placebo for 12 weeks. Time-to-first-recurrence data were collected during the maintenance phase. Posttreatment follow-up was 36 weeks.ResultsAmong 656 women (326 in CL-011 and 330 in CL-012), the averaged percentage of participants with one or more RVVC episodes through week 48 was 6.7% (range, 6.5 to 7.4%) in CL-011 and 3.9% (3.7 to 4.6%) in CL-012 in the oteseconazole groups versus 42.8% (41.3 to 45.0%) and 39.4% (38.0 to 42.6%) in the corresponding placebo groups (P<0.001). Among oteseconazole-treated participants in CL-011 and CL-012 who experienced an RVVC episode (n=22), the mean time to recurrence was 45.7 and 47.2 weeks versus 27.8 and 33.1 weeks for placebo-treated participants (n=84), respectively (hazard ratio [95% confidence interval], 0.11 [0.06 to 0.21] for CL-011 and 0.08 [0.04 to 0.17] for CL-012; P<0.001). Types and frequencies of treatment-emergent adverse events (TEAEs) were similar between groups in both trials, with no drug-related serious TEAEs or adverse effects on pregnancy outcomes, liver function, or QT interval.ConclusionsOral oteseconazole was effective in preventing acute VVC recurrence and treating RVVC through week 48 in the CL-011 and CL-012 trials, with mostly mild TEAEs. (Funded by Mycovia Pharmaceuticals, Inc., ClinicalTrials.gov numbers, NCT03562156 for CL-011 and NCT03561701 for CL-012.)

Safety, tolerability and pharmacokinetics of a Class I natural medicine with therapeutic potential for vascular dementia: Naoqingzhiming tablet

Naoqingzhiming, whose active ingredient is echinacoside, is the first new Class I natural medicine approved for clinical trials for the therapeutic potential of vascular dementia in China. We report randomized, double-blind, placebo-controlled trials to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of Naoqingzhiming tablet after oral administration in healthy Chinese subjects. The single ascending dose of Naoqingzhiming tablet (180–2160 mg) were well tolerated in all enrolled subjects, without serious adverse events and adverse events leading to withdrawal from the study. The most common drug-related treatment-emergent adverse events were elevated blood bilirubin and serum uric acid. No clinically significant findings were found in the physical examinations, vital signs or electrocardiograms. After single-dose administration of Naoqingzhiming tablet, echinacoside was absorbed with a Tmax at 1.25–1.75 h and declined with a t1/2 of 2.42–3.33 h. However, the proportionality coefficients for Cmax, AUC0−t and AUC0-∞ of echinacoside were not fully contained in the pre-defined 90 % CI criterion (0.91–1.09). As a result, the dose proportionality could not be concluded statistically within the dosage range of this study. Overall, the safety profile and PK properties support further development and use of Naoqingzhiming in vascular dementia.

P682: NEMTABRUTINIB (MK-1026), A NON-COVALENT INHIBITOR OF WILD-TYPE AND C481S MUTATED BRUTON TYROSINE KINASE FOR B-CELL MALIGNANCIES: EFFICACY AND SAFETY OF THE PHASE 2 DOSE-EXPANSION BELLWAVE-001 STUDY

Background: For patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms, resistance to Bruton tyrosine kinase inhibitors (BTKi) develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. Nemtabrutinib (MK-1026, formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481-mutated BTK. Aims: In the phase 1/2 dose-escalation and dose-expansion BELLWAVE-001 study (NCT03162536), the preliminary recommended phase 2 dose (RP2D) of nemtabrutinib was determined to be 65 mg once daily. The efficacy and safety of nemtabrutinib in patients (pts) with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose-expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary nemtabrutinib RP2D. Approximately 10-25 eligible pts were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (Richter transformation with ≥1 prior therapy), Cohort D-H (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, high-grade B cell lymphoma with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia [WM], respectively, who received ≥2 prior therapies), Cohort I (food-effect cohort including pts with B-cell NHL, CLL/SLL, and WM). Primary end point was ORR (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary end points included DOR and safety and tolerability. Results: Among 118 pts enrolled, 44 had B-cell NHL, 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Pts with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 30 (59%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off (April 7, 2021), median (range) follow-up was 4.6 mo (0.1-26.7) for all treated pts. ORR was 57.9% (22/38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy-evaluable population of pts with CLL/SLL treated at preliminary RP2D. Median duration of response was not estimable [NE] (range, 8.3 mo-NE). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), diarrhea (21%), and arthralgia (20%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%). Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Summary/Conclusion: Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing.

P822: A PHASE 1 SINGLE ASCENDING DOSE STUDY OF CAN106, A LONG-ACTING ANTI-C5 COMPLEMENT MONOCLONAL ANTIBODY IN CLINICAL DEVELOPMENT FOR PNH AND OTHER COMPLEMENT-MEDIATED DISEASES

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired genetic disorder caused by clonal mutations in the PIGA gene. Deficiency of PIGA protein renders erythrocytes susceptible to complement-mediated destruction, causing intravascular and extravascular hemolysis, which can lead to anemia, fatigue, thromboembolism, major organ damage, and death. Despite the approval of one anti-C3 and two anti-C5 therapies for PNH, high treatment costs limit market access in many countries. CAN106 is a novel anti-C5 monoclonal antibody designed for optimal pH-dependent binding to C5 and enhanced binding to FcRN to increase intracellular recycling and prolong its half-life. Aims: This first-in-human Phase 1 study aimed to evaluate the single-dose safety and tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of CAN106. Methods: This was a randomized, double-blind, placebo-controlled, single-ascending-dose study. We enrolled 31 healthy adult subjects at a single site in Singapore who received CAN106 (mg/kg) or placebo at one of the following 6 doses (mg/kg) and ratios: (0.25, n=1:0; 0.75, n=1:0; 2, n=3:2; 4, n=6:2; 8, n=6:2 or 12, n=6:2). The primary endpoint was the incidence of adverse events overall and by intensity, seriousness, type, and relatedness to study drug. Secondary endpoints were the pharmacokinetic characterization of CAN106, the pharmacodynamic effects on free C5 (target engagement) and CH50 (serum hemolytic activity), and the incidence of anti-drug antibodies. The original study duration of 196 days was shortened to 112 days based upon the observed half-life of CAN106 and the return of CH50 to normal values. Results: The mean age of subjects was 34 years, and 97% were male. All 31 subjects completed the study. Seven CAN106 subjects experienced 20 treatment-emergent adverse events (TEAEs), and three placebo subjects experienced five TEAEs. Most TEAEs were mild and not related to CAN106, and all resolved without any sequelae. Three CAN106 subjects experienced seven drug-related TEAEs at the two highest doses. Most were mild, none was serious, and all resolved without any sequelae. These events included a moderate infusion-related reaction that resolved upon discontinuing treatment; mild dizziness; and mild elevations in ALT, AST, hemoglobin, hematocrit, and RBC. CAN106 exposure (Cmax and AUC) was dose-proportional, linear, and had low inter-subject variability (<20% CV). The terminal elimination half-life was approximately 32 days. CAN106 led to dose-dependent reductions in free C5 and CH50 within 24 hours. At the 8 and 12 mg/kg doses, all subjects showed >99% reduction in free C5 and >90% inhibition of CH50, with the latter sustained for 2 to 4 weeks. Two subjects in the 4 mg/kg cohort tested positive for anti-drug antibodies at single time points (pre-dose and Day 28). Summary/Conclusion: CAN106 was safe and well-tolerated at single doses up to 12 mg/kg in healthy adult subjects. The dose-exposure relationship was linear, and the 32-day half-life in healthy subjects was similar to that of ravulizumab, which is dosed every 8 weeks in patients, suggesting the potential for an extended dosing interval. CAN106 led to rapid, dose-dependent reductions in free C5 and CH50, and at the two highest doses, achieved complete and sustained complement blockade (>90% inhibition of CH50) for up to 4 weeks. These promising results support further clinical development of CAN106 in PNH and other complement-mediated diseases.

Abstract CT537: A phase 2, multicenter, randomized, double-blind trial of maintenance therapy with FLT3 inhibitor gilteritinib (ASP2215) in patients with FLT3/ITD AML (GOSSAMER study)

Abstract Background: Patients with acute myeloid leukemia (AML) in remission are at high risk of relapse, warranting remission-prolonging therapy. Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) inhibitor approved as monotherapy in FLT3-mutated relapsed/refractory AML. The aim of the study was to compare relapse-free survival (RFS) in patients with FLT3/internal tandem duplication AML in first complete remission who received gilteritinib or placebo. Method: In this phase 2, double-blind trial, patients were randomized 2:1 to gilteritinib (120 mg) or placebo once daily for up to 2 years, beginning after completion of induction/consolidation (I/C) therapy. RFS, defined as time from randomization date until the date of documented relapse or death from any cause was assessed via independent review committee adjudication (primary efficacy endpoint). Overall survival (OS) was defined as the time from date of randomization until date of death from any cause. Survival and treatment-emergent adverse events (TEAEs) were assessed 30 days after treatment discontinuation, and every 3 months thereafter. Due to a slow accrual rate, this trial (NCT02927262) was changed from a planned phase 3 to phase 2 based on the reduction in sample size. Results: 124 patients were screened and 98 were randomized (gilteritinib 63, placebo 35) and are included in the full analysis set (FAS), of whom 32 (gilteritinib 20, placebo 12) completed 2 years of treatment. The safety analysis set (SAF) comprised 97 patients (gilteritinib 62, placebo 35) who had received ≥1 dose of study drug. In the FAS, relapse occurred in 31/63 (49.2%) gilteritinib- and 20/35 (57.1%) placebo-treated patients; 3/63 (4.8%) gilteritinib-treated patients died without relapse. RFS was not significantly improved with gilteritinib vs placebo (hazard ratio [HR] 0.738, 95% confidence interval [CI] 0.407-1.336; 1-sided stratified log-rank p-value 0.163). Median RFS was 24.02 months for gilteritinib and 15.84 months for placebo. OS in the FAS was not significantly different between treatments (gilteritinib 21/63, [33.3%], placebo 11/35 [31.4%]; HR 1.130, 95% CI 0.540-2.364; 1-sided stratified log-rank p-value 0.627). Median OS was not reached in either arm. TEAEs in the SAF occurred in 58/62 (93.5%) gilteritinib- and 33/35 (94.3%) placebo-treated patients including, respectively, 51/62 (82.3%) and 20/35 (57.1%) drug-related TEAEs and 10/62 (16.1%) and 3/35 (8.6%) serious drug-related TEAEs. The most common TEAEs were increased blood creatine phosphokinase (gilteritinib 18/62 [29.0%], placebo 1/35 [2.9%]) and thrombocytopenia (gilteritinib 12/62 [19.4%], placebo 4/35 [11.4%]). Conclusion: Gilteritinib showed improved RFS versus placebo, but the difference was not statistically significant. There were no new safety findings in the gilteritinib arm. Citation Format: Mark D. Minden, Jacob M. Rowe, Emmanuel Gyan, Kohmei Kubo, Nahla Hasabou, David Delgado, Wensheng He, Stanley C. Gill, Jason E. Hill, Ramon Tiu. A phase 2, multicenter, randomized, double-blind trial of maintenance therapy with FLT3 inhibitor gilteritinib (ASP2215) in patients with FLT3/ITD AML (GOSSAMER study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT537.

Early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer.

1038 Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses &lt; 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was &gt; 3 months. In all cohorts, the most common (&gt; 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses &lt; 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, Kpuu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596. [Table: see text]

A multicenter, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.

3011 Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of &gt; 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.

Clinical efficacy and safety of the BAT1706 (proposed bevacizumab biosimilar) compared with reference bevacizumab in patients with advanced nonsquamous NSCLC: A randomized, double-blind, phase III study.

9041 Background: A Randomized, Double-blind, Phase III Study was conducted to confirm clinical similarity between BAT1706, a proposed biosimilar to reference bevacizumab, and EU-bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Patients were randomized 1:1 to BAT1706 plus paclitaxel and carboplatin (Arm A) or EU-bevacizumab plus paclitaxel and carboplatin (Arm B) given three weeks for 6 cycles, followed by maintenance therapy with BAT1706 or EU- bevacizumab. The primary endpoint was overall response rate at Week 18 (ORR18). Secondary endpoints included ORR at Week 6 and 12, best ORR, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: A total of 651 patients were randomized: BAT1706 (n = 325) or EU- bevacizumab (n = 326). In total, 649 randomized patients (BAT1706 (n = 325) or EU- bevacizumab (n = 324)) received at least one cycle of combination treatment. The median duration of therapy was 29.1 weeks (ranging from 3.0 to 62.1 weeks) in the Arm A and 27.0 weeks (ranging from 3.0 to 53.9 weeks) in the Arm B. The extent of exposure to BAT1706 and EU- bevacizumab was similar between these two arms. Overall, the proportion of patients achieving an ORR by Week 18 was comparable across Arm A and B (48.0% and 44.5%). The ORR risk ratio of 1.08 with 90% CI (0.94, 1.24) and the ORR risk difference of 0.03, with 95% CI (-0.04, 0.11) were within pre-specified equivalence margin. In addition, the multivariate-adjusted risk ratio was 1.07, with a 90% CI (0.93, 1.22). The ORR18 risk difference between BAT1706 and EU- bevacizumab was 0.03, with the 2-sided 95% CI (-0.04, 0.11) that fell entirely within pre-specified equivalence margin. In addition, the multivariate-adjusted risk difference was 0.03, with a 95% CI (-0.04, 0.11). The hazard ratio stratified for time to PFS was 0.915 and the PFS rate at 12 months was 20.7% versus 21.8%. At the end of the study, there were no significant differences between both the treatments. The incidence of treatment-emergent adverse events (TEAEs) and study drug-related TEAEs was similar between these two arms. Overall, the safety profiles of BAT1706 were consistent with that of EU- bevacizumab, no new safety signals or noticeable trends were observed. The mean serum concentrations were comparable between BAT1706 and EU- bevacizumab over the entire sampling interval both in pre-dose and post-dose. The incidence of positive anti-drug antibodies results was low (≤5%) and decreased over time in both treatment arms. No patient was detected to have positive neutralizing anti-drug antibody result during the study. Conclusions: BAT1706 demonstrated clinical equivalence to reference EU-bevacizumab in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT03329911.

Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects.

ObjectiveTo investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses.MethodsThis open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated.ResultsThirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0–1.5h and mean t1/2 was 7.4–13.0h for all doses. In the multiple-dose period, median tmax was 1.5–2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death.ConclusionFollowing single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses.Clinicaltrials.gov IdentifierNCT04143477.

Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis

Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking. To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China. This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020. Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone. Complete or partial response rate at week 24 (prespecified). A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs. In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN. ClinicalTrials.gov Identifier: NCT02457221.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside.

BackgroundTo accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients.Methodology / Principal findingsPlasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest.Conclusions/SignificancePharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins.

A Randomised Controlled Trial Comparing the Pharmacokinetics and Tolerability of the Proposed Adalimumab Biosimilar MSB11022 Delivered via Autoinjector and Pre-filled Syringe in Healthy Subjects.

IntroductionThe aim of the study was to demonstrate the bioequivalence, and compare the safety and tolerability of MSB11022, a proposed biosimilar of adalimumab, when delivered by either an autoinjector (AI) or a pre-filled syringe (PFS).MethodsIn this pharmacokinetic (PK), parallel group, open-label study, 216 healthy volunteers were randomised 1:1 to receive a single subcutaneous injection of a 40 mg/0.8 mL dose of MSB11022 administered via AI or PFS. Coprimary PK endpoints were maximum observed concentration (Cmax), area under the concentration–time curve (AUC) from time 0 to the last quantifiable concentration (AUC0–t), and AUC from time 0 extrapolated to infinity (AUC0–inf). PK equivalence between the AI and PFS administration methods was declared if the 90% confidence intervals (CIs) for the ratio of geometric least square means was entirely contained within the 80–125% equivalence margin for all coprimary endpoints. Safety and tolerability were also evaluated.ResultsThe 90% CI for the three coprimary PK endpoints (Cmax, AUC0–t and AUC0–inf) were entirely contained within the predefined equivalence margins of 80–125%. Mean serum concentration–time profiles were similar following injection via AI or PFS. Treatment-emergent adverse events (TEAEs) were comparable across both treatment groups. Study device-related TEAEs were reported by 11.3% and 13.1% of subjects in the AI and PFS treatment groups, respectively. Study drug-related TEAEs were reported by 28.3% and 34.6% of subjects in the AI and PFS treatment groups, respectively. Few subjects experienced injection-site reactions, mainly pain and erythema, regardless of the administration method.ConclusionDelivery of MSB11022 via an AI is bioequivalent to delivery via a PFS. The safety and tolerability profile of MSB11022 was comparable across administration methods. The development of an AI for MSB11022 provides a choice of self-injection devices available to patients, potentially improving treatment compliance.Trial RegistrationClinicalTrials.gov trial identifier: NCT04018599.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00432-1.

Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial.

ObjectiveTo evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15‐min intravenous (IV) infusion and bolus (≤2‐min injection).MethodsEP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open‐label trial in patients ≥1 month to <16 years of age with epilepsy. Patients received up to 5 mg/kg/day BRV (not exceeding 200 mg/day). Enrollment was sequential by descending age, depending on safety review. Outcomes included BRV plasma concentrations before and after IV administration, treatment‐emergent adverse events (TEAEs), and discontinuations due to TEAEs.ResultsFifty patients were enrolled, received BRV, and completed the trial. Twenty‐six patients (52.0%) received 15‐min infusions and 24 (48.0%) received bolus injections. Most patients (80.0%) received one IV dose. In the 15‐min infusion group, geometric mean (GeoMean) BRV concentrations 15 (±2) min (n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15‐min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug‐related TEAEs (15‐min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred.SignificanceIV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15‐min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15‐min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

A randomized, double-blind, placebo (PBO)-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide (ENZA) in chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with docetaxel (DOC) plus prednisolone (PDN) who have progressed on ENZA: PRESIDE.

15 Background: PRESIDE (NCT02288247) evaluated the benefit of continued ENZA + androgen deprivation therapy (ADT) with DOC + PDN in men with mCRPC who progressed on ENZA + ADT. Methods: PRESIDE (Dec 2014–Apr 2020) enrolled chemotherapy-naïve men with mCRPC and disease progression while on a luteinizing hormone-releasing hormone (LHRH) agonist/antagonist (ADT) or after bilateral orchiectomy. Pts received open-label ENZA (160 mg) + ADT in Period 1 (P1). Those with a prostate-specific antigen (PSA) response of ≥50% change from baseline to week (wk) 13 and later progression were eligible for Period 2 (P2). P2 pts received DOC (75 mg/m2), PDN (10 mg), and ADT, and were randomized to ENZA (160 mg) or PBO. The primary endpoint was progression-free survival (PFS) in P2 (from randomization to radiographic/clinical progression or death). Secondary endpoints included time to PSA progression (TTPP) [≥25% increase; absolute increase ≥2 ng/mL] and PSA response in P2. Hazard ratios (HRs) were from a Cox proportional hazards model with covariates for treatment and P1 progression. Adverse events (AEs) were recorded to assess safety. Results: 687 pts received ENZA in P1; 273 pts were randomized and 271 were treated in P2. Baseline demographics and characteristics were balanced between P2 arms. Median ENZA exposure was 62.6 wks in P1 and 36.1 and 30.1 wks in P2 with ENZA and PBO, respectively. At P2 data cut-off (Apr 30, 2020), 269 (99.3%) pts had discontinued therapy; 93 pts in each arm (ENZA, 74.4%; PBO, 75.6%) had progression. PFS was significantly improved with ENZA (HR 0.72; 95% confidence interval [CI] 0.53, 0.96; p = 0.027), with a higher median PFS with ENZA (9.53 months; 95% CI 8.25, 10.87) than with PBO (8.28 months; 95% CI 6.28, 8.71). ENZA also significantly delayed TTPP (8.44 vs. 6.24 months with PBO; HR 0.58; 95% CI 0.41, 0.82; p = 0.002) and improved PSA response at any time (ENZA, n = 76 [55.9%]; PBO, n = 50 [37.0%]). There were 46 (6.7%) deaths in P1 and 20 (ENZA, n = 13 [9.6%]; PBO, n = 7 [5.2%]) in P2. In P2, 264 (97.4%) pts had a treatment-emergent AE (TEAE) [ENZA, n = 133 (97.8%); PBO, n = 131 (97.0%)]. Grade 3/4 TEAEs were reported by 84 (61.8%) pts on ENZA and 84 (62.2%) on PBO, and 12 (8.8%) and 9 (6.7%) pts, respectively, had TEAEs leading to discontinuation. Neutropenia (ENZA, 16.9%; PBO, 20.7%) was the most common grade 4 TEAE. Drug-related TEAEs (ENZA, 46.3%; PBO, 41.5%) were similar, and 90.4% of pts in each arm reported DOC-related TEAEs. Conclusions: Continued ENZA therapy in men with mCRPC who progressed on ENZA + ADT and received post-progression DOC + PDN significantly improved PFS compared to PBO. Treatment was well tolerated and ENZA AEs were consistent with its known safety profile. Clinical trial information: NCT02288247.