scholarly journals Phase 3 Study of Danicopan, an Oral Complement Factor D Inhibitor, As Add-on Therapy to a C5 Inhibitor in Patients with Paroxysmal Nocturnal Hemoglobinuria with Clinically Evident Extravascular Hemolysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Austin Kulasekararaj ◽  
Antonio Risitano ◽  
Jong Wook Lee ◽  
Mingjun Huang ◽  
Jun-Ichi Nishimura ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Reticulocyte Count ◽  
Complement Factor ◽  
Publicly Traded ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Secondary Endpoints

Background: PNH is a rare, life-threatening disease caused by uncontrolled terminal pathway activation leading to intravascular hemolysis (IVH). The C5 inhibitors eculizumab (ECU) and ravulizumab (RAV) prevent IVH by inhibiting terminal complement; however, some C5 inhibitor-treated patients may experience persistent anemia due to extravascular hemolysis (EVH) caused by C3 fragment deposition and opsonization driven by constitutive activation of the alternative pathway (AP). Inhibition of factor D (FD), the rate limiting enzyme of the AP, acts on the complement cascade upstream of C3. Danicopan (ALXN2040, ACH-4471) is a first-in-class oral small molecule FD inhibitor. In vitro studies with RBCs collected from PNH patients have shown that danicopan not only inhibited hemolysis but also prevented deposition of C3 fragments on PNH RBCs. In a 24-week Phase 2 study of ECU-treated PNH patients with transfusion-dependent anemia (hemoglobin [Hgb] <10 g/dL), danicopan add-on resulted in clinically significant improvements in Hgb, near transfusion-independence, improvements in FACIT-Fatigue scores, and was generally well-tolerated; 96% of treatment-emergent adverse events were mild-to-moderate in severity and did not result in discontinuation. The purpose of this randomized, double-blind, pivotal Phase 3 trial (NCT04469465; EudraCT 2019-003829-18) is to evaluate the efficacy of oral danicopan add-on therapy in PNH patients with clinically evident EVH (CE-EVH) on an approved C5 inhibitor. Study Design and Methods: This study consists of a 12-week double-blind placebo-controlled treatment period 1 followed by a 12-week danicopan+C5 inhibitor treatment period 2 and a long-term extension up to 1-year. Patients (target enrollment, N=84) will be randomized to danicopan or matched placebo TID in a 2:1 ratio for the 12-week treatment period 1. Patients randomized to placebo for treatment period 1 will switch to danicopan at week 12 (Figure). Eligible adult patients must be receiving a stable regimen of ECU or RAV (no change in drug/dose/interval for ≥24 weeks), and have CE-EVH, defined by anemia (Hgb ≤9.5 g/dL), absolute reticulocyte count ≥120 x 109/L, and ≥1 transfusion within 6 months before study entry. The starting dose of danicopan is 150 mg TID. Patients with alanine aminotransferase (ALT) or direct bilirubin values >1.5 × upper limit of normal (ULN) will start at 100 mg TID. Doses may be escalated in 50-mg increments, with ≥4 weeks between escalations, to a maximum of 200 mg TID based on safety and clinical effect at protocol-specified time points. Exclusion criteria include major organ transplant or hematopoietic stem cell transplantation (HSCT), aplastic anemia requiring HSCT, complement deficiency, or ALT >2 × ULN. The primary efficacy endpoint is change in Hgb at week 12. Secondary endpoints are proportion of patients not requiring a transfusion through week 12, change from baseline in FACIT-Fatigue scores, and change from baseline in absolute reticulocyte count at week 12. Other secondary endpoints (at weeks 12 and 24) include RBC units transfused, Hgb stabilization, laboratory markers (including bilirubin, LDH, and PNH clone size), and patient-reported outcomes (EQ-5D-3L, EORTC-QLQ-C30, WPAI, and health resource utilization). Primary and secondary efficacy analyses will be performed on the intent-to-treat population; safety analyses will include all patients who received ≥1 dose of study drug. Danicopan has the potential to be the first oral PNH therapy, and offers an opportunity to enhance the well-characterized efficacy of C5 inhibitors without compromising safety. This Phase 3, pivotal trial will be the largest clinical evaluation of danicopan to date. More importantly, the trial has the potential to generate robust data to demonstrate the efficacy and safety of add-on, oral danicopan to C5 inhibitor therapy in PNH patients with clinically evident hemolysis. Figure Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang:Alexion: Current Employment, Current equity holder in publicly-traded company. Nishimura:Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Chugai: Consultancy. Ramirez-Santiago:Alexion: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Regis Peffault De Latour ◽  
Jeffrey Szer ◽  
Austin Kulasekararaj ◽  
Jin Seok Kim ◽  
Caroline I. Piatek ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Efficacy of Caplacizumab in Patients with aTTP in the HERCULES Study According to Initial Immunosuppression Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2365-2365
Author(s):  
Katerina Pavenski ◽  
Paul Knoebl ◽  
Marie Scully ◽  
Johanna A. Kremer Hovinga ◽  
Paul Coppo ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Immunosuppressive Therapy ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Advisory Committees ◽  
Double Blind ◽  
Improved Outcomes ◽  
Count Response ◽  
Immunosuppression Regimen

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an acute, life-threatening thrombotic microangiopathy that requires urgent and specialized treatment. Prior to the introduction of caplacizumab, the treatment for aTTP was based on daily therapeutic plasma exchange (TPE; to replenish functional ADAMTS13 enzyme) plus immunosuppression (mainly corticosteroids and rituximab; to suppress anti-ADAMTS13 autoantibody production). TPE combined with immunosuppressive therapy improved outcomes in patients; however, episodes of aTTP are still associated with an acute mortality of up to 20% as these therapies do not have an immediate effect on the pathologic microvascular thrombosis. The primary results of the randomized, double-blind, placebo-controlled phase 3 HERCULES study showed that, in combination with TPE and corticosteroids, caplacizumab shortened the time to platelet count response and reduced the incidence of a composite outcome of TTP-related death, exacerbation, or major thromboembolic events, by inhibiting vWF-platelet interaction and, thereby, stopping the formation of microthrombi. As additional immunosuppression per local practice was permitted in HERCULES, the present analysis aimed to determine whether there was any difference in the efficacy of caplacizumab according to the initial immunosuppression regimen. Methods: Data of patients participating in HERCULES were stratified based on the type of first-line immunosuppression regimen (i.e. therapy started up to Day 3 of the treatment period) and analyzed descriptively. The main 2 groups analyzed were those receiving corticosteroids only and those receiving a combined regimen of corticosteroids and rituximab. Differences in dose or dosing frequency were not taken into consideration in this descriptive analysis. Results: Of the 145 randomized patients in the HERCULES study, 112 (77.2%) patients received only corticosteroids as first-line immunosuppressive therapy, while 24 (16.6%) patients received corticosteroids and rituximab (initiated within the first 3 days of the study). Three patients (2.1%) received another type of initial immunosuppression (cyclophosphamide + corticosteroids [n=1], hydroxychloroquine [n=1], and mycophenolate mofetil + corticosteroids [n=1]), 1 patient (0.7%) started immunosuppression later in the study (cyclophosphamide + corticosteroids), while 5 patients (3.4%) did not receive any immunosuppressive treatment during the study. Baseline characteristics between the main 2 subgroups were well balanced (Table 1). Immunosuppressive therapy intensification occurred in 38 patients (33.9%) initiated on corticosteroids alone (most often addition of rituximab [n=37], others included splenectomy [n=2], bortezomib [n=1], mycophenolate mofetil [n=1]), and in 3 patients (12.5%) initiated on corticosteroids with rituximab (bortezomib [n=1] and mycophenolate mofetil [n=3]). Caplacizumab treatment improved outcomes in patients with aTTP irrespective of the type of initial immunosuppression. Data on time to platelet count response and clinical outcomes are summarized in Table 2. Caplacizumab reduced the rate of the composite endpoint of TTP-related death, exacerbation, and major thromboembolic events during the double-blind treatment period irrespective of baseline immunosuppression regimen. Notably, in the placebo arm, exacerbations occurred in both subgroups to a similar extent, indicating that corticosteroids, with or without rituximab, are not immediately effective. Overall, recurrences (exacerbations or relapses) during the study were also reduced by caplacizumab in both subgroups (Table 2). Two placebo patients died during the treatment period in the corticosteroid only subgroup versus none in the corticosteroid plus rituximab subgroup (one other placebo patient died during the study drug treatment period while receiving another type of immunosuppression). Conclusion: Immunosuppressive therapy in aTTP aims to control the underlying autoimmune disease, but requires time to take effect; this exposes patients to thrombotic complications and death. Caplacizumab treatment prevents disease exacerbations and death, irrespective of the type of initial immunosuppression used, allowing time for immunosuppressive therapy to take effect. Disclosures Pavenski: Ablynx: Honoraria, Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding. Knoebl:Novo-Nordisk: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy; CSL-Behring: Consultancy; Shire/Takeda: Consultancy; Roche: Consultancy. Scully:Shire: Research Funding; Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Shire/Takeda: Consultancy; Novartis: Consultancy. Kremer Hovinga:Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Shire: Consultancy; Ablynx/Sanofi: Consultancy; Alexion: Consultancy. Peyvandi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

scholarly journals Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Antonio Risitano ◽  
Ilene C. Weitz ◽  
Carlos M. de Castro ◽  
Jean-Jacques Kiladjian ◽  
Morag Griffin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Response To Treatment ◽  
Publicly Traded ◽  
Phase 3 ◽  
Advisory Committees ◽  
Post Hoc Analysis ◽  
Hematologic Response ◽  
Post Hoc

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin <10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH >1.5× upper limit of normal and/or ARC >150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (<3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (>6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 409-409 ◽  
Author(s):  
Valeria Santini ◽  
Antonio Almeida ◽  
Aristoteles Giagounidis ◽  
Stephanie Gröpper ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

scholarly journals Improvements in Fatigue Correlate with Changes in Clinical and Hematological Outcomes: Post Hoc Analyses from the Pegasus Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
David Cella ◽  
William R. Lenderking ◽  
Sujata P. Sarda ◽  
Scott B. Baver ◽  
Mohamed Hamdani ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Physical Functioning ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Reticulocyte Count ◽  
Hemoglobin Level ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Indirect Bilirubin ◽  
Post Hoc

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease characterized by complement-mediated hemolysis resulting in anemia, thrombosis, and bone marrow failure. The PEGASUS phase 3 randomized study demonstrated superiority of pegcetacoplan vs. eculizumab on improvements in hemoglobin, and pegcetacoplan improved clinical and hematological outcomes such as fatigue in patients with partial response to eculizumab after treatment for at least 3 months (Hb &lt;10.5 g/dL). The objectives of these post-hoc analyses were to explore relationships among effect modifiers, including fatigue and hemoglobin, reticulocyte count, indirect bilirubin, and physical functioning. Also, this study assessed further detail on the treatment effects of pegcetacoplan on fatigue in patients. METHODS Patients ≥18 years of age with PNH and hemoglobin concentration &lt;10.5 g/dL despite receiving treatment with eculizumab for ≥3 months were eligible for inclusion. Patients entered a 4-week run-in period in which they received eculizumab plus twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously) and were then randomized 1:1 to monotherapy with pegcetacoplan or eculizumab for 16 weeks. Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue scale, and a variety of symptoms (including fatigue and physical functioning) were evaluated with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) scale. Convergent validity was assessed using Spearman correlations and known groups validity was assessed using analysis of covariance (ANCOVA), as suggested by the FDA Guidance on patient-reported outcomes (US Food Drug Administration.Fed Regist. 2009;74(235):65132-65133). Subjects were grouped based on hemoglobin level (&lt;10 g/dL, 10 to ≤12 g/dL, &gt;12 g/dL), and by degree of hemoglobin improvement: &lt;1 g/dL, ≥1 to &lt;2 g/dL, and ≥2 g/dL. RESULTS At Week 16, in the overall sample (n = 80; intent-to-treat), the FACIT-Fatigue total score was significantly correlated with hemoglobin (r = 0.47, p &lt; 0.0001; Figure 1), reticulocyte count (r = -0.37, p &lt; 0.01), indirect bilirubin (r = -0.25, p &lt; 0.05), and with multiple EORTC domains including fatigue and physical function (r = -0.88, p &lt; 0.0001 and r = 0.82, p &lt; 0.0001 respectively). In a responsiveness analysis, groups with greater improvement in hemoglobin over 16 weeks showed the most improvement in fatigue (F = 9.03, p &lt; 0.0001), with the largest reduction in fatigue in the group with an increase in hemoglobin of ≥2 g/dL (11.3-point improvement in FACIT-F total score). In contrast, individuals with little to no hemoglobin improvement (&lt;1 g/dL) reported slightly more fatigue (-1.2 worsening in FACIT-F total score). The FACIT-F also distinguished between groups with different levels of hemoglobin (&lt;10 g/dL, 10 to ≤12 g/dL, &gt;12 g/dL) at Week 16 (F = 4.78, p = 0.0019). An analysis of the correlation of change scores indicates a clear separation between pegcetacoplan and eculizumab, showing a greater effect of pegcetacoplan on change in hemoglobin and improvement in fatigue (Figure 2). CONCLUSION In PNH, hemoglobin level and positive change in hemoglobin were significantly related to reduced fatigue. Pegcetacoplan resulted in significantly lower fatigue and hemoglobin scores at Week 16 compared to eculizumab. Disclosures Cella: Novartis:Consultancy;Kiniksa:Consultancy;IDDI:Consultancy;BMS:Consultancy, Research Funding;Oncoquest:Consultancy;ASAHI KASEI PHARMA CORP.:Consultancy;Mei Pharma:Consultancy;Ipsen:Consultancy, Research Funding;Evidera:Consultancy;DSI:Consultancy, Research Funding;BlueNote:Consultancy;Abbvie:Consultancy, Research Funding;Astellas:Consultancy, Honoraria;FACIT.org:Membership on an entity's Board of Directors or advisory committees, Other: President;PROMIS Health Org:Membership on an entity's Board of Directors or advisory committees, Other;Pled Pharma:Research Funding;Janssen:Research Funding;Clovis:Research Funding;Alexion:Research Funding;Apellis:Consultancy;Pfizer:Consultancy, Research Funding.Lenderking:Evidera:Current Employment.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Hamdani:Apellis Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Hsieh:Evidera/PPD:Current Employment.Shaffer:Evidera:Current Employment.Röth:Sanofi:Consultancy, Honoraria;Roche:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Biocryst:Consultancy, Honoraria;Apellis:Consultancy, Honoraria;Alexion Pharmaceuticals Inc.:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

scholarly journals A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1504-1504
Author(s):  
Srdan Verstovsek ◽  
Andrew T. Kuykendall ◽  
Ronald Hoffman ◽  
Yelena Ginzburg ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Data Safety Monitoring Board ◽  
Publicly Traded ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit &lt;45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed N ucleophosmin 1-mutated Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1282-1282
Author(s):  
John C. Byrd ◽  
Jorge E. Cortes ◽  
Mark D. Minden ◽  
Thomas Oellerich ◽  
Eytan M. Stein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Acute Myeloid

Abstract Background: Spleen tyrosine kinase (SYK) is a component of both lymphoid and myeloid cell signaling pathways and has been implicated in the pathogenesis of a subset of acute myeloid leukemia (AML) defined by dysregulated expression of the HOXA9 and MEIS1 transcription factors. Entospletinib (ENTO) is an oral, selective SYK inhibitor that is acceptably tolerated when administered with intensive induction and consolidation in newly diagnosed AML patients. In a phase 2 study, following induction with cytarabine and daunorubicin (7+3) plus ENTO, higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) were observed in patients with rearrangements of the KMT2A (MLL) gene (MLL-r) and mutations of the nucleophosmin 1 (NPM1) gene, both of which are associated with aberrant expression of HOXA9 and MEIS1, as compared to patients without these mutations. In an exploratory analysis, patients with HOXA9/MEIS1 expression levels above the median experienced superior overall survival (OS) as compared to patients with expression levels below the median. In the AGILITY trial, we hypothesize that the addition of ENTO to intensive induction/consolidation in newly diagnosed patients with NPM1-mutated AML will improve the rate of CR without evidence of measurable residual disease (MRD-negative CR) post-induction and duration of event-free survival (EFS). Methods: AGILITY will be a global, multi-center, double-blind, placebo-controlled trial of ENTO in combination with cytarabine plus daunorubicin or idarubicin induction (7+3) and age-adjusted high-dose cytarabine (HiDAC) consolidation in newly diagnosed AML patients aged 18-75 years who are candidates for intensive induction and harbor a documented NPM1 mutation based on local or central mutation testing. Patients with co-mutated FLT3 (internal tandem duplication or tyrosine kinase domain) and for whom midostaurin with 7+3 is indicated are excluded. Patients will be stratified based on age (&lt;60 vs ≥60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). Approximately 180 patients will be randomized to receive 7+3 induction and HiDAC consolidation with ENTO (400 mg orally twice daily) versus 7+3 induction and HiDAC with placebo. Patients with &lt;5% leukemic blasts after 1 cycle of induction will proceed to the first cycle of HiDAC consolidation while patients with ≥5% residual blasts will undergo a second induction cycle. Patients who do not achieve CR after 2 cycles of chemotherapy (either 2 induction cycles or 1 induction and 1 consolidation cycle) plus ENTO or placebo will be designated as induction treatment failures (ITF). Patients who achieve or remain in CR after 2 chemotherapy cycles will be evaluated for MRD in bone marrow based on enumeration of mutant NPM1 alleles using a molecular assay. Patients may receive up to 3 cycles of consolidation with HiDAC and ENTO or placebo beyond chemotherapy cycle 2 per their original randomized treatment assignment. The number of consolidation cycles and timing of hematopoietic stem cell transplant (HSCT) or other post-consolidation therapy (if any) is at the discretion of the investigator. All patients will be followed for relapse and survival. The primary endpoint will be the rate of MRD-negative CR (&lt;0.01% mutant NPM1 alleles). Patients without an evaluation of response and MRD after chemotherapy cycle 2 will be imputed as treatment failures for the analysis. A key secondary endpoint will be EFS, defined as time from randomization to the earliest occurrence of ITF, relapse from CR, or death from any cause. Patients without an event at the time of the EFS analysis will be censored at the last study evaluation they were event-free. EFS will be estimated using the Kaplan-Meier method and summarized by treatment group. Differences between treatment groups will be assessed with the log-rank test stratified by age (&lt;60 vs ≥60 years) and choice of anthracycline in induction (daunorubicin vs idarubicin). OS will be analyzed in a similar manner. Key exploratory endpoints will be the correlation between recurring genomic mutations and response or progression and longitudinal assessment of peripheral blood for detection of NPM1-m alleles among patients who achieve MRD-negative CR post-induction. An independent data-monitoring committee will monitor emerging safety and efficacy data from this trial on an ongoing basis. Disclosures Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Minden: Astellas: Consultancy. Oellerich: Roche: Consultancy; Gilead: Research Funding; Kronos Bio, Inc.: Consultancy; Merck KGaA: Consultancy, Research Funding. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Syndax Pharmaceuticals: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy. Elder: PharPoint Research, Inc.: Current Employment. Kumar: Kronos Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Bray: Kronos Bio, Inc.: Consultancy. DiMartino: Kronos Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. OffLabel Disclosure: Entospletinib is an investigational therapy

scholarly journals Dynamic and Time-to-Event Analyses Demonstrate Marked Reduction in Transfusion Requirements for Janus Kinase Inhibitor-Naïve Myelofibrosis Patients Treated with Momelotinib Compared Head to Head with Ruxolitinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1663-1663 ◽  
Author(s):  
Ruben A Mesa ◽  
John Catalano ◽  
Francisco Cervantes ◽  
Timothy Devos ◽  
Jason Gotlib ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Recurrent Events ◽  
Iron Homeostasis ◽  
Janus Kinase ◽  
Time To Event ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Baseline Characteristics

Momelotinib (MMB) is a potent, selective, orally-bioavailable, small-molecule inhibitor of JAK1, JAK2 and ACVR1 being developed for the treatment of intermediate and high risk myelofibrosis (MF). Systemic inflammation integral to the pathogenesis of MF leads to increased ACVR1 activity which in turn increases secretion of hepcidin, resulting in perturbed iron homeostasis and an iron-restricted anemia (Physiol Rev. 2013;93:1721-41, Am J Hematol. 2014;89:470-9). MMB's inhibition of ACVR1, unique amongst the JAK inhibitor (JAKi) class, leads to a reduction of hepcidin, restoring iron homeostasis and RBC production and alleviating anemia and transfusion dependency (TD). Chronic, progressive anemia is the key hallmark feature of MF; anemia and TD are strongly predictive of reduced survival (Am J Hematol. 2013;88:312-6). MMB is the only clinical stage JAKi to possess potent ACVR1 inhibitory activity, resulting in improvement of anemia in contrast to ruxolitinib (RUX) which results in worsening. The SIMPLIFY-1 (S1) trial, a double-blind, active-controlled Phase 3 study in which 432 patients received randomized treatment with MMB or RUX for 24 weeks was previously reported (JCO. 2017;35:3844-50). In addition to a significant reduction in splenomegaly and improvement in constitutional symptoms, the study demonstrated that patients in the MMB arm achieved nominal-statistical significance for all anemia endpoints tested, including a higher rate of transfusion independence (p<0.001) and lower rates of TD (p=0.019) at Week 24, compared to patients on RUX, consistent with MMB's pro-erythropoietic effect. Overall, a demonstrably decreased transfusion requirement was noted in patients who received MMB vs RUX. Since transfusion burden is of significant concern to clinicians and patients, to better understand the dynamics of RBC transfusions we further examined the S1 data through statistical models utilizing a variety of novel anemia benefit endpoints including time until transfusion and overall intensity of transfusions across time. The proportions of patients with 0 and 4 transfusions were calculated and time-to-event analyses examining time-to-first and time-to-fifth units transfused also conducted. Since transfusions typically comprise 2 units, the fifth unit transfused represents a de facto third transfusion event. The number of units transfused were also considered to be recurrent events and examined with and without patients' baseline characteristics as covariates. Finally, a mixture model, based on a zero-inflated negative binomial (ZINB) distribution fit to the transfusion data, was employed to compare between the treatment groups the proportions of subjects with zero transfusion burden and the mean transfusion rates. Kaplan-Meier estimates of the proportion of patients who did not require any units transfused during the 24 week randomized treatment period were 73% and 46% for MMB and RUX respectively (p<0.0001; Figure 1), while the proportion of patients requiring 4 or fewer units were 83% and 62% (p<0.0001). When examining units transfused as recurrent events, patients receiving MMB possessed a hazard ratio of approximately one-half that for patients on RUX (HR 0.522; p<0.0001) for models both with and without patients' baseline characteristics as covariates. The ZINB covariate model demonstrated that MMB increased the odds of having zero units transfused in the first 24 weeks by a factor of 9.3 (p<0.0001) vs RUX. Taken together, the novel dynamic and time-to-event analysis methods described are relevant and informative additions to standard measures of transfusion burden in patients with MF. The results of these analyses allow more detailed description of MMB's differentiated anemia benefit as compared to RUX in a double-blind study of JAKi-naïve patients. These results when combined with additional data from the SIMPLIFY studies demonstrate that MMB is able to address the three hallmark features of MF, namely anemia, constitutional symptoms and splenomegaly, differentiating it from other JAK inhibitors. The benefit of MMB in reducing transfusion burden will be further evaluated in MOMENTUM, a future Phase 3 study of MMB in MF patients. In addition to assessment of constitutional symptoms, anemia and splenomegaly, MOMENTUM will provide opportunity to further evaluate associations between anemia benefit and patient reported measures of clinical benefit. Disclosures Mesa: Promedior: Research Funding; Gilead Sciences: Research Funding; Galena Biopharma: Consultancy; AbbVie: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; Genotech: Research Funding; CTI: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; NS Pharma: Research Funding; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; Samus: Research Funding; Shire: Honoraria; Baxalta: Consultancy. Catalano:Celgene: Other: Travel support (ASH 2018). Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Gotlib:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Coart:IDDI: Consultancy, Employment. D'Hollander:IDDI: Consultancy, Employment. Donahue:Sierra Oncology Inc.: Employment. Kowalski:Sierra Oncology Inc.: Employment.

scholarly journals A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3109-3109
Author(s):  
Joanna Howard ◽  
Kevin H.M. Kuo ◽  
Abdulafeez Oluyadi ◽  
Hui Shao ◽  
Susan Morris ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Phase 2 ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Hb Concentration ◽  
To Receive ◽  
2,3 Dpg

Abstract Background: Sickle cell disease (SCD) is a life-threatening, hereditary hemoglobin (Hb) disorder characterized by chronic hemolytic anemia, pain, end-organ damage, and poor quality of life. The key pathology is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP. Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis. SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an investigational, first-in-class, oral, small-molecule allosteric activator of the RBC-specific form of pyruvate kinase (PKR), a key enzyme in glycolysis. Activation of wild-type PKR decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD. Data from the Phase 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, and was associated with a dose-dependent increase in ATP and decrease in 2,3-DPG, in addition to improvements in anemia and hemolytic markers. Based on these results, a Phase 2/3 study investigating the safety and efficacy of mitapivat in patients (pts) with SCD is planned. Methods: This Phase 2/3, double-blind, randomized, placebo-controlled, multicenter study aims to evaluate the efficacy and safety of mitapivat in pts with SCD. Eligible: pts ≥ 16 years of age with documented SCD (HbSS, HbSC, HbSβ 0/HbSβ + thalassemia, other SCD variants), 2-10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and an Hb level of 5.5-10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥ 90 days before starting study drug. Not eligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving treatment with SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation. In the double-blind Phase 2 part of the study, 69 pts will be randomized (1:1:1) to receive 50 mg mitapivat, 100 mg mitapivat, or placebo BID for 12 weeks. The primary objective of the Phase 2 part of the study is to determine the recommended Phase 3 dose of mitapivat by evaluating anemia and safety vs placebo via the following endpoints: Hb response, defined as a ≥ 1.0 g/dL increase in average Hb concentration over Weeks 10-12 compared with baseline; and type, severity, and relationship of adverse events (AEs) and serious AEs (SAEs). In the double-blind Phase 3 part of the study, 198 pts who did not participate in the Phase 2 study will be randomized (2:1) to receive the selected Phase 3 dose of mitapivat or placebo, BID, for 52 weeks, stratified by the number of SCPCs in the prior year (&lt; 5, ≥ 5) and by HU use. The primary objectives of the Phase 3 study are to determine the effect of mitapivat vs placebo on anemia in pts with SCD, measured by Hb response, defined as a ≥ 1.0 g/dL increase in average Hb concentration over Weeks 24-52 compared with baseline, and to determine the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include change over Weeks 24-52 compared with baseline in the following: average Hb concentration, indirect bilirubin, percent reticulocyte, and Patient-Reported Outcomes Measurement Information System ® (PROMIS) fatigue 13a Short Form scores; annualized frequency of hospitalizations for SCPC. Other secondary objectives include evaluation of effect on additional markers of hemolysis and erythropoiesis, additional clinical efficacy measures related to SCPC, additional patient-reported measures of fatigue and pain, physical activity, safety, and pharmacokinetics/pharmacodynamics of mitapivat. Pts who complete the double-blind period of either the Phase 2 or Phase 3 part of the study will be eligible to receive mitapivat for an additional 216 weeks in the open-label extension period. Results: Not yet available Conclusion: This Phase 2/3 study will investigate the efficacy and safety of the pyruvate kinase activator mitapivat in pts ≥ 16 years of age with SCD and enrollment will begin in 2021. Figure 1 Figure 1. Disclosures Howard: Resonance Health: Honoraria; Novartis: Consultancy, Honoraria; Bluebird Bio: Research Funding; Forma Therapeutics: Consultancy; Agios Pharmaceuticals: Consultancy; Novo Nordisk: Consultancy; Global Blood Therapeutics: Consultancy; Imara: Consultancy, Honoraria. Kuo: Bluebird Bio: Consultancy; Apellis: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Oluyadi: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Shao: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Morris: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Zaidi: Agios Pharmaceuticals: Current Employment. Van Beers: RR Mechatronics: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

Obinutuzumab or Rituximab Plus CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma: Final Results from an Open-Label, Randomized Phase 3 Study (GOYA)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 470-470 ◽  
Author(s):  
Umberto Vitolo ◽  
Marek Trněný ◽  
David Belada ◽  
Angelo M Carella ◽  
Neil Chua ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Secondary Endpoints ◽  
Grade 3

Abstract Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

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