scholarly journals Surgeries and Diagnostic Procedures in Hemophilia Patients on Concizumab Prophylaxis: Results from the Phase 2 Explorer4 and Explorer5 Trials

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 345-345
Author(s):  
Allison P. Wheeler ◽  
Gary Benson ◽  
Hermann Eichler ◽  
Sidsel Marie Tønder ◽  
Katarina Cepo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Research Funding ◽  
Hemophilia A ◽  
Diagnostic Procedures ◽  
Concomitant Treatment ◽  
Phase 2 ◽  
Phase 3 ◽  
Time Of Surgery ◽  
Dental Procedures ◽  
Wide Range

Abstract Introduction: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in phase 3 clinical development as a once-daily, subcutaneous prophylaxis across all hemophilia subtypes. The phase 2 trials explorer4 (NCT03196284) and explorer5 (NCT03196297) investigated the efficacy and safety of daily subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors and in patients with severe hemophilia A without inhibitors, respectively. Minor surgeries and diagnostic procedures were permitted during both trials, allowing for the assessment of conducting such procedures during concizumab prophylaxis. Objective: The aim of this analysis was to describe surgeries and diagnostic procedures performed while on concizumab prophylaxis during the main and extension parts of the concizumab phase 2 trials. Methods: Both the explorer4 and explorer5 trials consisted of a main and an extension part, with patients receiving concizumab at an initial maintenance dose of 0.15 mg/kg (with an additional loading dose of 0.5 mg/kg as a first dose in explorer4) in both trials, with the option to dose escalate to 0.20 and 0.25 mg/kg in case of ≥3 spontaneous treated bleeds within the previous 12 weeks. Concomitant treatment with systemic anti-fibrinolytics was not allowed in either trial, while local/topical use was permitted. Minor surgery, defined as an invasive operative procedure in which the skin, mucous membranes, or superficial connective tissue are manipulated, such as skin biopsies, implanting of central venous access devices, or simple dental procedures, were allowed at the investigator's discretion during both trials. Major surgery was not permitted and thus constituted a protocol deviation. Only patients who had been receiving concizumab as part of explorer4 or explorer5 up until, during and immediately after surgery were included in this analysis. Results: Seven of the 25 patients treated with concizumab in explorer4 had a total of 17 surgeries while treated with concizumab during the trial. The patients who underwent surgery were aged between 24 and 45 years old. Five of these patients underwent a single procedure, 1 patient 2 procedures, and 1 patient underwent a total of 10 procedures while in the trial. At the time of surgery, with the exception of 1 patient who was receiving concizumab at 0.20 mg/kg, all patients were on 0.15 mg/kg. Additional perioperative hemostatic treatment was permitted and was given at the investigator's discretion. The majority of procedures involved dental surgery, although a venous catheter removal, hordeolum removal, and laser eye surgery were also performed (Table 1). Out of a total of 6 recorded surgery-related bleeding episodes in patients receiving concizumab in explorer4, 1 was classified as severe, while the remaining 5 as mild or moderate. In explorer5, 13 of the 36 patients treated with concizumab (26-65 years old) underwent a total of 33 surgeries while receiving concizumab prophylaxis. Seven of these patients had more than 1 surgery, ranging between 2 and 8 per person. The majority of patients (8/13) were receiving concizumab at 0.15 mg/kg, 1 patient at 0.20 mg/kg and 2 patients at 0.25 mg/kg at the time of surgery, and 2 patients were on 0.15 mg/kg concizumab for their first surgeries and switched to 0.20 mg/kg for later surgeries. Additional hemostatic treatment was given at the investigator's discretion. Dental procedures constituted most surgeries, and other procedures included vaccinations and cataract surgery, diagnostic procedures such as biopsy, endoscopy and gastroscopy, as well as a hair graft (Table 1). A total of 9 surgery-related bleeds were recorded during explorer5, all of which were classified as mild or moderate. Conclusion: Across both concizumab phase 2 trials, between 28-36% of all patients (7/25 in explorer4 and 13/36 in explorer5) receiving daily concizumab prophylaxis underwent 1 or more surgeries during the overall trial periods of 18 and 22 months, respectively. A wide range of surgeries, including invasive diagnostic procedures, were conducted while the number of surgery-related bleeds was low and classified as mild or moderate, with 1 exception. Prophylactic treatment with concizumab in patients with hemophilia is currently being investigated further in ongoing phase 3 trials. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Benson: Novo Nordisk A/S: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Sobi: Speakers Bureau. Eichler: Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Biotest: Consultancy, Honoraria. Marie Tønder: Novo Nordisk Health Care AG: Current Employment. Cepo: Novo Nordisk A/S: Current Employment. Jimenez Yuste: Novo Nordisk A/S: Consultancy, Research Funding; Bayer: Consultancy; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy. Kavakli: Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support; Takeda: Consultancy, Other: Clinical Trial Support; Roche: Consultancy, Other: Clinical Trial Support. Wong: Astellas Pharma, INc.: Research Funding. Matsushita: Baxalta/Shire/Takeda: Consultancy, Honoraria; Bayer: Consultancy; Novo Nordisk A/S: Consultancy, Honoraria, Other: educational and investigational support ; Chugai: Consultancy, Honoraria, Other: educational and investigational support ; Pfizer: Consultancy; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria; Octapharm: Honoraria; Sysmex: Honoraria.

scholarly journals Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Shaji K. Kumar ◽  
Al-Ola Abdallah ◽  
Ashraf Z. Badros ◽  
Betsy Laplant ◽  
Binod Dhakal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 2 Trial ◽  
Risk Of Progression ◽  
M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

scholarly journals Clinical Trial Design Features of Myelofibrosis Trials during the Last Decade: Comprehensive Review of Clinicaltrials.Gov Data 2010-2019

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Heidi E. Kosiorek ◽  
Amylou C. Dueck ◽  
John Mascarenhas ◽  
Ruben A. Mesa ◽  
Ronald Hoffman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Trial Design ◽  
Phase 1 ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 1 Trials ◽  
Model Based ◽  
Clinical Trial Designs

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were > 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p<0.001] than non-industry sponsored trials but this is primarily due to a higher proportion of phase 3/4 trials (n=17) being conducted by industry versus non-industry (n=2) (Figure 2). Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

scholarly journals Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2395-2395
Author(s):  
Michael Callaghan ◽  
Benjamin Trzaskoma ◽  
Richard H. Ko ◽  
Lucy Lee ◽  
Anisha M. Patel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Exposure Time ◽  
Cumulative Dose ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 3 ◽  
Breakthrough Bleeding ◽  
On Demand ◽  
Equity Ownership ◽  
The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

scholarly journals A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Trine Høyer Rose ◽  
Christian Hollensen ◽  
Henrik Agersø ◽  
Rune Viig Overgaard
Keyword(s):  
Rate Constant ◽  
Drug Disposition ◽  
Hemophilia A ◽  
Phase 1 ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Publicly Traded ◽  
Phase 3 ◽  
Target Mediated Drug Disposition ◽  
Population Pk

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

SAT0149 EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY OF FILGOTINIB AND ITS METABOLITE GS-829845 IN SUBJECTS WITH RHEUMATOID ARTHRITIS BASED ON PHASE 2 AND PHASE 3 STUDIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1013-1014
Author(s):  
A. Meng ◽  
K. Anderson ◽  
C. Nelson ◽  
B. Kirby ◽  
L. Ni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Response Rates ◽  
High Response ◽  
Phase 2 ◽  
Phase 3 ◽  
Once Daily ◽  
Exposure Response ◽  
Serious Infections ◽  
Wide Range ◽  
Grade 3

Background:Filgotinib is an orally administered small molecule that provides selective inhibition of JAK1, a signaling molecule that helps drive inflammatory pathways underlying rheumatoid arthritis (RA).Objectives:Exposure-response (ER) analyses were performed for efficacy following completion of Phase 2 studies over a wide range of doses to support evaluation of 200mg and 100 mg once daily in Phase 3 studies. ER analyses were subsequently performed by using Phase 3 efficacy data to support selection of the proposed registrational dose. ER analyses for safety based on pooled Phase 2 and Phase 3 studies were conducted to examine the safety of evaluated doses.Methods:Population PK analyses were conducted to estimate plasma exposures of filgotinib and GS-829845 (major circulating active metabolite of filgotinib) in both Phase 2 (DARWIN 1 and DARWIN 2) and Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) encompassing a dose range of 25 to 100 mg twice daily and 50 to 200 mg once daily. As both filgotinib and GS-829845 contribute to efficacy via JAK1 inhibition, their exposures were combined into single parameters, AUCeff and Ctau-eff (effective area under the curve and effective concentration at trough, by accounting for relative inhibition potency and molecular weight) in the ER analyses for various efficacy endpoints (e.g ACR20/50/70 responses) at Week 12 and Week 24. The ER analyses for safety endpoints (the 5 most frequent treatment-emergent adverse events [TEAEs] and Grade 3 or 4 laboratory abnormalities, serious TEAEs, and serious infections) were performed separately for filgotinib and GS-829845 exposures to characterize the individual safety profile of each analyte. The 5 evaluated TEAEs were nausea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension; the 5 Grade 3/4 laboratory abnormalities included lymphocytes decrease, glucose increase, phosphate decrease, triacylglycerol lipase increase, and creatine kinase increase.Results:In the ER analyses for efficacy based on Phase 2 studies, high response rates were demonstrated in ACR20/50/70 across all octile groups in subjects with RA receiving filgotinib and the ER supported further evaluation of both 200 mg and 100 mg once daily doses in Phase 3 clinical studies. Similarly, ER relationships based on pooled Phase 3 studies across various endpoints (e.g ACR20/50/70) consistently revealed high response rates across the exposure range for both the filgotinib 200 mg and 100 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50 and ACR70 with the effective exposures at filgotinib 200 mg primarily residing on the plateau of the ER curves.Filgotinib was generally well-tolerated with no individual TEAE or Grade 3 or 4 laboratory abnormality > 5% in the filgotinib 200 mg once daily group up to Week 12. No relationships were observed between filgotinib and GS-829845 exposures (AUC0-24 and Cmax) and the most frequent TEAEs, Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections up to Week 52.Conclusion:ER analyses demonstrate that both the 200 mg and 100 mg once daily filgotinib doses are efficacious in subjects with moderately to severely active RA without clear dose-dependent effects on safety. The trend towards greater efficacy with higher exposures for some secondary endpoints (ACR50 and ACR70) and a lack of exposure-safety relationship supports a dose of 200 mg once daily over 100 mg once daily since it presents the best benefit/risk ratio among the doses tested.Disclosure of Interests: :Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Sciences, Cara Nelson Shareholder of: Gilead, Employee of: Gilead, Brian Kirby Shareholder of: Gilead, Employee of: Gilead, Liyun Ni Shareholder of: Gilead, Employee of: Gilead, Shu-Min Chuang Shareholder of: Gilead, Employee of: Gilead, Brian Kearney Shareholder of: Gilead, Employee of: Gilead, Anita Mathias Shareholder of: Gilead, Employee of: Gilead

scholarly journals P011 Sharing is caring: a regional service development project exploring secondary immunosuppression in children

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Joshua L Bennett ◽  
Christo Tsilifis ◽  
Aisling Flinn ◽  
Thomas Altmann ◽  
Nathaniel Jansen ◽  
...  
Keyword(s):  
Information Sharing ◽  
Phase 1 ◽  
Development Project ◽  
Service Development ◽  
Phase 2 ◽  
Phase 3 ◽  
Immunomodulatory Agents ◽  
Immunomodulatory Agent ◽  
Children's Hospital ◽  
Wide Range

Abstract Background/Aims  The range of approved immunosuppressive and immunomodulatory (IM) agents has grown considerably with an increasing list of indications across paediatric specialties. At present, there is limited evidence supporting best practice for prescribing and monitoring of IM agents in children and young people (CYP). We present a staged service development project exploring cross-specialty prescribing and monitoring of IM agents at a tertiary children’s hospital (Great North Children’s Hospital, GNCH) and data sharing with local hospitals across northeast England. Methods  In Phase 1, we searched pharmacy databases and surveyed specialty teams in GNCH to identify clinicians regularly prescribing IM agents to CYP over a twelve-month period. Phase 2 was a cross-specialty retrospective case-notes review of prescribing, monitoring and infection surveillance in a representative sample of CYP on IM agents. Phase 3 explored information sharing with six other hospitals in the region and acute presentations to these sites involving CYP on IM agents. Results  Phase 1 identified 9 paediatric and 2 adult specialties prescribing IM agents to 416 CYP. 32 discrete IM therapies were prescribed with significant between-specialty overlap in drugs prescribed but a wide range of prescribing and monitoring practices. Phase 2 assessed 77 CYP on IM agents in detail - 57% were prescribed &gt;1 IM agent, 100% had FBC measured at least once (range once only to weekly), 18% developed lymphopenia at least once and 40% were prescribed prophylactic antibiotics. Previous varicella exposure had been assessed in 70%. Phase 3 data are summarised in Table 1. P011 Table 1:Information sharing and acute presentations to regional hospitals local to immunosuppressed patientsTotal number of patients141Mean age in years (range)11 (2 - 17)NDiagnosisJIA without uveitis108JIA with uveitis9Uveitis alone8Systemic JIA4Period fever4Behçet’s disease2Juvenile dermatomyositis2Scleroderma1Juvenile systemic lupus erythematosus1Mixed connective tissue disease1Granulomatosis with polyangiitis1Immunosuppressive or immunomodulatory agent usedAdalimumab65Methotrexate42Tocilizumab22Mycophenolate mofetil10Etanercept10Infliximab5Sulfasalazine5Prednisolone4Abatacept4Leflunomide4Canakinumab2Colchicine2Anakinra2Rituximab2Cyclophosphamide1Number of immunosuppressive or immunomodulatory agents per patient3 agents52 agents441 agent92Number of acute presentations by diagnosis or presenting complaint (n = 19)Fever4Chickenpox4Viral upper respiratory tract infection2Joint pain2Abdominal pain2Rash2Eye infection1Tonsilitis1Wheeze1Yes (%)No (%)Named local consultant (n = 129)3763Correct diagnosis recorded locally (n = 130)8020Correct immunosuppressive or immunomodulatory agent recorded locally (n = 130)5050Open access for febrile illness (n = 116)4159Reviewed in past 2 years for acute illness (n = 109)1783Note: presented numbers for immunosuppressive or immunomodulatory agents are not mutually exclusive. JIA, juvenile idiopathic arthritis Conclusion  IM agents are central to modern paediatric clinical care across a wide range of diseases. This staged project identified significant variation in IM prescribing and monitoring practice between specialties at GNCH. Communication between specialty and local teams is inadequate. Particular areas of concern include limited diagnostic, blood monitoring and medication information sharing and limited local information governing management of intercurrent illness and vaccination. Although different disease processes can necessitate different advice and prescribing practices, sharing examples of good practice will minimise unnecessary variation. We propose the development of a regional immunosuppression working group to improve quality and safety across our region. Disclosure  J.L. Bennett: None. C. Tsilifis: None. A. Flinn: None. T. Altmann: None. N. Jansen: None. H. Tumelty: None. K. Aitken: None. S. Bhopal: None. E. Harrison: None. S. Ravenscroft: None. E. Sen: None. E. Williams: None. T. Flood: None. S. Sampath: None. A. Battersby: None. F. McErlane: None.

A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4086-4086
Author(s):  
Chul Won Jung ◽  
Lee-Yung Shih ◽  
Zhijian Xiao ◽  
Jie Jin ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Open Label ◽  
Phase 3 ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Large Phase ◽  
Grade 3

Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1625-1625
Author(s):  
Keita Kirito ◽  
Norio Komatsu ◽  
Kazuya Shimoda ◽  
Hikaru Okada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Spleen Size ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Starting Dose ◽  
Grade 3 ◽  
Eortc Qlq

Abstract BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study. METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued. RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid. Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study. At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure). CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L. Disclosures Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

Efficacy and Safety of Eltrombopag for Treatment of Patients with Myelodysplastic Syndromes after Hypomethylating-Agent Failure: A Phase 2 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1691-1691 ◽  
Author(s):  
Maliha Khan ◽  
Bodden Kristy ◽  
Tapan Kadia ◽  
Alessandra Ferrajoli ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Open Label ◽  
Bone Marrow Fibrosis ◽  
First Response ◽  
Transfusion Requirements ◽  
Marrow Fibrosis

Abstract Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x10⁹/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings. Disclosures Off Label Use: Eltrombopag for the treatment of MDS-related cytopenias". Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding.

Bleeding Events and Safety Outcomes in Patients with Hemophilia a with Inhibitors: A Prospective, Multicenter, Non-Interventional Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3800-3800 ◽  
Author(s):  
Johnny Mahlangu ◽  
Johannes Oldenburg ◽  
Michael U Callaghan ◽  
Midori Shima ◽  
Elena Santagostino ◽  
...  
Keyword(s):  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Interventional Study ◽  
Bleeding Events ◽  
Legal Guardian ◽  
Phase 3 ◽  
Advisory Committees ◽  
Safety Outcomes ◽  
Bypassing Agents

Abstract Introduction: Coagulation factor VIII (FVIII) deficiency in hemophilia A (HA) patients (pts) results in spontaneous bleeding events, secondary arthropathy and diminished quality of life (QoL). FVIII replacement agents, the current standard of care, may require several infusions to treat bleeding events and infusions 2-3 times a week are needed for prevention of bleeding events due to relatively short half-lives. A major challenge of current therapies is development of anti-FVIII alloantibodies (inhibitors), which occur in 15-30% of HA pts, diminish effectiveness of FVIII replacement and are associated with significant morbidity and reduced QoL. Options for pts with inhibitors are limited. Bypassing agents to prevent/treat bleeding events, and immune tolerance induction to eliminate inhibitors, require frequent dosing, are not available in all countries, and have suboptimal efficacy. Thus, a high unmet need exists for safe, more effective and less burdensome options for pts with inhibitors. Emicizumab (ACE910), a bispecific monoclonal antibody in development for the management of HA, binds to FIXa and FX to mimic FVIII cofactor function and may be able to address current treatment needs. Real world data (RWD) collected from HA pts are considered of high importance for the emicizumab clinical development program, providing the possibility of intra-patient comparison for those who may be subsequently eligible to participate in a pivotal emicizumab Phase 3 study (NCT02622321). This non-interventional study (NIS) aims to prospectively collect detailed, high-quality data on bleeding events and safety outcomes in HA pts treated according to local routine clinical practice. In the first cohort (Cohort A), data from adult/adolescents with inhibitors were collected. Methods: This prospective NIS (NCT02476942) was approved by local Ethics review groups, and all pts and/or legal guardians signed informed consent/assent prior to study entry. In Cohort A, eligible pts were ≥12 years old and had congenital HA of any severity; documented history of high-titer FVIII inhibitors (≥5 Bethesda Units/mL); documented treatment with bypassing agents for ≥6 months; and, ≥6 or ≥2 bleeds in the last 6 months on episodic or prophylactic treatment, respectively. Primary objective was to characterize the number of bleeding events over time. Bleeding/bypassing agent data were collected through a bleed and medication questionnaire (BMQ) developed by the Sponsor, as no standard questionnaire is available. BMQ was completed by the pt/legal guardian via an electronic handheld device. Demographic data and medical history were collected from pts' medical records on an electronic Case Report Form. Throughout the study, investigators recorded adverse events (AEs), concomitant medication, and routine laboratory assessment data. At least monthly interactions of pts/legal guardian with a professional from their treatment center were requested to confirm self-reported bleed/medication information. Results: 103 HA pts with inhibitors (75 on episodic and 28 on prophylactic regimens with bypassing agents) from 33 centers and 12 countries were enrolled in Cohort A. As of 7/21/16, 54 pts had rolled over to the emicizumab Phase 3 study in adults/adolescents with inhibitors. The following Cohort A data will be presented: pt demographics/characteristics; global distribution of pts by country; summary of hemophilia medical history, concomitant medications and surgeries; pts' self-reported information on bleeding events and treatment (all, and by episodic and prophylactic treatment), including bleeding rates, types and locations, reason for coagulation product use, product type used, dose; and, safety. Conclusion: The NIS will provide high quality documentation of bleeding events and safety outcomes in adult/adolescent HA pts with inhibitors treated with bypassing agents according to local clinical practice. For those participating in the ongoing Phase 3 emicizumab study, these data will provide the opportunity to perform robust intra-patient comparisons of prospectively collected bleeding event/medication data before and during emicizumab treatment. This is the first report of prospective RWD being collected for use as a valid historical control for a pivotal Phase 3 study in HA pts with inhibitors, and a novel and unique approach to bolster data reported in the clinical development of emicizumab. Disclosures Mahlangu: Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy. Callaghan:Grifols: Honoraria; Bayer: Honoraria; Baxalta: Honoraria, Research Funding; Roche: Honoraria, Research Funding; CSL Behring: Honoraria; Biogen: Honoraria. Shima:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sysmex Corporation: Patents & Royalties, Research Funding. Santagostino:Bayer: Consultancy; Grifols: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; CSL Behring: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy; Biogen Idec: Consultancy; Sobi: Consultancy; Roche: Consultancy. Lehle:Roche: Employment. Uguen:Roche: Employment. Hirst:F. Hoffmann La-Roche Ltd: Employment; AstraZeneca: Other: Previous employment . Recht:Novo Nordisk: Consultancy, Research Funding; Biogen Idec: Research Funding; Baxalta: Research Funding; Kedrion: Consultancy. Kruse-Jarres:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.

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