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 (< 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.

scholarly journals An Adaptive, Randomized, Placebo-Controlled, Double-Blind, Multi-Center Study of Oral FT-4202, a Pyruvate Kinase Activator in Patients with Sickle Cell Disease (PRAISE)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Kenneth W. Wood ◽  
James Geib ◽  
Eric Wu ◽  
Jason Berlin ◽  
Irena Webster ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Response Rate ◽  
Oxygen Affinity ◽  
Phase 2 ◽  
Advisory Committees ◽  
Double Blind ◽  
Secondary Endpoints ◽  
2,3 Dpg

The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, chronic anemia, cell adhesion, vaso-occlusion and inflammation. Exacerbating the pathogenesis of SCD, the HbS RBC has increased (↑) levels of 2,3-diphosphoglycerate (2,3-DPG), resulting in reduced (↓) Hb oxygen affinity (↑ P50), and ↓ ATP, essential for RBC homeostasis. FT-4202 is a potent, selective, and orally bioavailable allosteric activator of erythrocyte pyruvate kinase (PKR) that increases PKR activity, resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBCs. Preliminary data from the ongoing phase 1 study [NCT03815695] in healthy volunteers and patients with SCD indicate that FT-4202 is well tolerated, has no effect on steroidogenesis, and exhibits linear and time-independent pharmacokinetics (PK) and associated pharmacodynamic (PD) responses (↓ 2,3-DPG and ↑ ATP). Furthermore, in patients with SCD, a single dose of FT-4202 demonstrated favorable biologic effects, including increased Hb oxygen affinity (↓ P50), decreased point of sickling (PoS), improved RBC deformability, and improved RBC membrane function, indicative of overall improved RBC health (Estepp, J. EP1531; EHA 2020). Accordingly, we designed a phase 2/3, randomized, double-blind, placebo-controlled global study (PRAISE) to investigate the safety and efficacy of FT-4202 in patients with SCD. The PRAISE study will enroll up to 344 adult and adolescent patients with SCD, including 60 to 90 patients in the Dose Determination (DD) Group and ~ 274 patients in the Efficacy Continuation (EC) Group (see Figure). Key inclusion criteria: SCD (all genotypes), at least 2 vaso-occlusive crises (VOCs) in the past 12 mos, baseline Hb ≥ 5.5 and ≤ 10 g/dL, stable hydroxyurea (HU) therapy for the previous 90 days (if applicable). Key exclusion criteria: More than 10 VOCs in the past 12 mos, hospitalization for sickle cell crisis or other vaso-occlusive event within 14 days of consent, routine RBC transfusions, significant hepatic or renal dysfunction, history of unstable or deteriorating cardiac or pulmonary disease, or overt stroke within 2 yrs. Endpoints: The co-primary endpoints are (1) Hb response rate at Week 24 (increase of > 1 g/dL from baseline) and (2) annualized VOC rate during the blinded treatment period based on adjudicated VOC review. Secondary endpoints include measures of hemolysis, time to first VOC, and the PROMIS fatigue scale. Safety endpoints include the incidence of AEs, concomitant medications, vital signs, ECGs, clinical laboratory measurements, and physical examination. Design: The study design is a group-sequential, adaptive, phase 2/3 study (see Figure). Patients will be stratified by age, number of VOCs (2-3 vs. 4-10) in the preceding 12 mos, and prior/concomitant HU use in the preceding 12 mos. The phase 2 DD portion will assess 2 active doses and placebo with patients randomized 1:1:1. The dose will be chosen at the first interim analysis (IA1) based on safety and Hb response rate at Week 12 of the first 60 DD patients. A futility analysis will also be conducted on Hb response at that point. After dose selection, patients will be randomized 1:1 into the phase 3 EC portion to assess FT-4202 efficacy. Once 110 patients from phase 2 or 3 who have been randomized to the selected dose or placebo have completed 24 weeks of follow-up or have dropped out, a second interim analysis (IA2) will be performed to assess both efficacy and futility. IA2 will assess the co-primary endpoint of Hb response rate at Week 24 (p<0.001). The final analysis after 52 weeks of blinded treatment will test the VOC endpoint, the Hb response rate, and all secondary endpoints. Key secondary endpoints will be tested at IA2 and all will be tested at the final analysis, when there will be adequate power. Treatment: Patients will be randomized to receive FT-4202 or placebo. In the DD phase, two doses will be evaluated, and in the EC phase, the selected dose of FT-4202 from the DD phase will be evaluated in comparison to placebo. Patients in DD on the unselected dose will remain on treatment at that dose level for 52 weeks. Following completion of 52 weeks of double-blind treatment, patients may enter a 52-week open-label extension period to receive FT-4202 at the selected dose. Status: Study initiation is planned for late 2020; status will be updated at presentation. Figure Disclosures Wood: Forma Therapeutics, Inc.: Current Employment. Geib:Forma Therapeutics, Inc.: Current Employment. Wu:Forma Therapeutics, Inc.: Current Employment. Berlin:Forma Therapeutics, Inc.: Current Employment. Webster:Forma Therapeutics, Inc.: Current Employment. Ataga:Shire/Takeda: Research Funding; Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Consultancy; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Howard:Agios, Forma Therapeutics, Inc., Global Blood Therapeutics, Imara, Inc., Novo Nordisk, Novartis: Membership on an entity's Board of Directors or advisory committees; Imara, Inc., Novartis, Resonance Health: Honoraria. Estepp:ASH, NHLBI: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding. Telen:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc.: Consultancy; Forma Therapeutics: Research Funding. Brevard:Forma Therapeutics, Inc.: Current Employment.

Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo Plus Cytarabine: Results of a Phase 3 Double-Blind Randomized Controlled Multinational Study (VALOR)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Farhad Ravandi ◽  
Ellen Ritchie ◽  
Hamid Sayar ◽  
Jeffrey Lancet ◽  
Michael D. Craig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Adaptive Design ◽  
Late Relapse ◽  
Advisory Committees ◽  
Double Blind ◽  
Early Relapse ◽  
Equity Ownership ◽  
To Receive

Abstract Introduction: Despite 40 years of intense clinical research, there remain no new approved treatments or standard of care for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). New safe and effective salvage treatments are urgently needed. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML. Vosaroxin is minimally metabolized, evades P glycoprotein receptor–mediated efflux and has activity independent of p53 status. VALOR is a rigorously designed and conducted phase 3, adaptive design, randomized, double-blind, placebo-controlled trial evaluating vosaroxin plus cytarabine (vos/cyt) vs placebo plus cytarabine (pla/cyt) in patients with R/R AML (NCT01191801). Methods: Patients were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 hr, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min d 1 and 4; 70 mg/m2 in subsequent cycles) or placebo. Up to 2 induction and 2 consolidation cycles were administered. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] < 90 d) or were in first relapse (early relapse: CR1 of 90 d to 12 mo; late relapse: CR1 of 12 mo to 24 mo). Patients had received 1-2 cycles of prior induction chemotherapy including at least 1 cycle of anthracycline (or anthracenedione) and cytarabine. Randomization was stratified by disease status (refractory, early relapse, late relapse), age (< 60, ≥ 60 years), and geographic location (US, non-US). Primary efficacy and safety endpoints were overall survival (OS) and 30- and 60-day mortality; secondary endpoints were complete remission (CR) rate and incidence of adverse events (AEs). Results: Between Dec 2010 and Sept 2013, 711 patients were randomized to receive vos/cyt (n = 356) or pla/cyt (n = 355) at 124 sites; per the adaptive design, a prespecified 1-time sample size increase of 225 patients was implemented after the interim analysis. At the final analysis, median OS was 7.5 mo (95% CI: 6.4-8.5) with vos/cyt vs 6.1 mo (95% CI: 5.2-7.1) with pla/cyt (HR = 0.866 [95% CI: 0.73-1.02]; 2-sided unstratified log-rank P = 0.06) (Figure). The OS difference was statistically significant in a preplanned analysis accounting for the stratification factors at randomization (2-sided stratified log-rank P = 0.02). Overall, 29.5% of patients underwent allogeneic stem cell transplant (ASCT), including 45.8% of patients < 60 years and 20.2% of patients ≥ 60 years. Transplant rates were comparable between the 2 treatment arms (30.1% with vos/cyt and 29.0% with pla/cyt). In a predefined analysis censoring for subsequent ASCT, median OS was improved with vos/cyt (6.7 mo vs 5.3 mo with pla/cyt; HR = 0.81 [95% CI: 0.67-0.97]; P = 0.02; stratified P = 0.03) (Figure). In predefined subgroup analyses, OS benefit was greatest in patients aged ≥ 60 years (7.1 mo with vos/cyt vs 5.0 mo with pla/cyt; HR = 0.75; P = 0.003) (Figure) and those with early relapse (6.7 mo vs 5.2 mo; HR = 0.77; P = 0.04). OS with vos/cyt vs pla/cyt was 9.1 mo vs 7.9 mo in patients < 60 years (HR = 1.08; P = 0.60); 6.7 mo vs 5.0 mo in patients with refractory disease (HR = 0.87; P = 0.23); and 14.1 mo vs 12.3 mo in patients with late relapse (HR = 0.98; P = 0.96), respectively. A CR was achieved in 30.1% of patients treated with vos/cyt vs 16.3% treated with pla/cyt (P = 0.00001). Thirty-day and 60-day all-cause mortality was similar in the 2 arms (30-day: 7.9% vs 6.6%; 60-day: 19.7% vs 19.4% with vos/cyt vs pla/cyt, respectively). Most common serious AEs were febrile neutropenia (11.3% with vos/cyt vs 7.4% with pla/cyt), sepsis (8.7% vs 4.3%), pneumonia (7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%). Serious and non-serious cardiac, renal, neurologic, and hepatic AEs were comparable between treatment groups. Conclusion: Vos/cyt demonstrated improved OS and higher CR rates in patients with R/R AML without increased early mortality. In the primary OS analysis, the overall clinical benefit associated with vosaroxin may be underestimated, particularly in younger patients, due to the confounding effect of high transplant rates, a methodological limitation of AML trials. Vosaroxin-containing therapy had acceptable tolerability. VALOR results represent one of the largest datasets available in this setting, and the OS benefit was confirmed by a robust sensitivity analysis. These data support the use of this combination as a new option for salvage therapy in patients with R/R AML. Figure 1 Figure 1. Disclosures Ravandi: Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Strickland:Sunesis: Membership on an entity's Board of Directors or advisory committees. Schiller:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Pigneux:Sunesis: Consultancy. Horst:Sunesis: Research Funding. Recher:Sunesis: Consultancy; Celgene: Consultancy, Research Funding; Chugai: Research Funding. Klimek:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:Sunesis: Equity Ownership. Fox:Sunesis: Consultancy, Equity Ownership. Ward:Sunesis: Employment, Equity Ownership. Smith:Sunesis: Employment, Equity Ownership. Acton:Sunesis: Consultancy. Mehta:Sunesis: Consultancy. Stuart:Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4248-4248 ◽  
Author(s):  
Uwe Platzbecker ◽  
David P. Steensma ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
The Impact ◽  
Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

scholarly journals The Commands Trial: A Phase 3 Study of the Efficacy and Safety of Luspatercept Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low-, Low-, or Intermediate-Risk MDS in Erythropoiesis Stimulating Agent-Naive Patients Who Require RBC Transfusions

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Matteo Della Porta ◽  
Uwe Platzbecker ◽  
Valeria Santini ◽  
Guillermo Garcia-Manero ◽  
Rami S. Komrokji ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Epoetin Alfa ◽  
Phase 3 ◽  
Advisory Committees ◽  
Starting Dose ◽  
To Receive ◽  
Stimulating Factor ◽  
Rbc Transfusion

Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with &lt; 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with &lt; 5% blasts in the bone marrow, have sEPO levels &lt; 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden (&lt; 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but &lt; 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus &gt; 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO &gt; 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

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 Pharmacodynamic Effects of AG-946, a Highly Potent Next-Generation Activator of Pyruvate Kinase, in Ex Vivo Treatment of Red Blood Cells from Sickle Cell Disease Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2029-2029
Author(s):  
Minke A.E. Rab ◽  
Myrthe J. Van Dijk ◽  
Jennifer Bos ◽  
Brigitte A. van Oirschot ◽  
Johan Gerrits ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Health Research ◽  
Stock Options ◽  
Research Funding ◽  
Ex Vivo ◽  
Next Generation ◽  
Cell Disease ◽  
Advisory Committees ◽  
Glycolytic Intermediates ◽  
2,3 Dpg

Abstract Background: Sickle cell disease (SCD) is a monogenetic red blood disorder that is characterized by hemolytic anemia and vaso-occlusive crises. Among the many factors that contribute to disease pathophysiology is stiffening and sickling of red blood cells (RBC), which is the direct result of the formation of abnormal hemoglobin S. Sickling is one of the core factors that cause vaso-occlusion and sickling is modulated by glycolytic intermediates such as 2,3-diphosphoglycerate (2,3-DPG) and ATP. Previously we showed that red blood cell pyruvate kinase (PKR), the key regulatory enzyme of glycolysis, is impaired in SCD and that ex vivo treatment with mitapivat, an allosteric activator of PKR, increased enzymatic activity and thermostability, reduced 2,3-DPG levels, decreased p50, and subsequently reduced sickling (Rab et al, Blood 2021). Currently, mitapivat is in phase 1 and phase 2 trials for SCD (#NCT04000165 and EudraCT#2019-003438). Aims: Recently, AG-946, a next-generation activator of PKR has been developed. Here we investigate the pharmacodynamic effects of AG-946 in ex vivo treatment of RBC from SCD patients in comparison with mitapivat. Methods: Buffy coat depleted whole blood obtained from five patients with SCD was incubated for 20-24 hrs in absence or presence of mitapivat (100 mM) or AG-946 (1 mM, 5 mM, 50 mM). After ex vivo treatment, enzymatic activities of PKR and PK-thermostability was measured. Glycolytic intermediates ATP and 2,3-DPG were measured using LC-MS/MS. Hemoglobin oxygen affinity (p50) was measured with the Hemox Analyzer. RBC sickling was analyzed with the oxygenscan, a newly developed method that characterizes individual sickling behavior by oxygen gradient ektacytometry. Individual tendency to sickle is reflected by Point-of-Sickling (PoS) that indicates the specific pO 2 at which RBCs start to sickle during deoxygenation under shear stress. Results: PKR activity was increased compared to vehicle (DMSO) to a similar extent in presence of both mitapivat and AG-946 (Figure 1A). In addition, PKR thermostability was significantly increased compared to vehicle (mean 22%, SD 6%) in samples treated with mitapivat 100 mM (mean 78%, SD 11%), as well as AG-946 5 mM (mean 66%, SD 23%), and AG-946 50 mM (mean 95%, SD 17%, Figure 1B). The glycolytic intermediate 2,3-DPG decreased after incubation with both mitapivat and AG-946 (Figure 1C), which was further illustrated by the improved ATP/2,3-DPG ratio (Figure 1D). In line with these latter results p50 decreased significantly after incubation with mitapivat 100 mM (mean 95%, SD 2%), as well as AG-946 1 mM (mean 96%, SD 2%), AG-946 5 mM (mean 94%, SD 2%), and AG-946 50 mM (mean 95%, SD 3%, Figure 1E). The improved metabolic status and p50 was accompanied by a decreased PoS compared to vehicle in RBCs treated with mitapivat or AG-946, indicating reduced RBC sickling tendency in vitro (Figure 1F). Conclusion: Ex vivo treatment of SCD RBCs with the next-generation PKR activator AG-946 activates and stabilizes PK, decreases 2,3-DPG levels, improves the ATP/2,3-DPG ratio, improves p50 and lowers the PoS. These beneficial effects are similar to ex vivo treatment with mitapivat but, importantly, are obtained at much lower concentrations. Therefore, AG-946 may be a potent activator of PKR in SCD. Taken together, these results are the first in an ex vivo model to demonstrate that the next-generation PK activator AG-946 has a similar favorable pharmacodynamic profile to mitapivat with enhanced PK-stabilizing properties and, hence, represents a potential novel therapeutic option in addition to mitapivat for the treatment of SCD and other hemolytic anemias. Figure 1 Figure 1. Disclosures Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Van Dijk: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kung: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Van Beers: Pfizer: Research Funding; RR Mechatronics: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dang: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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 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.

A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 202-202 ◽  
Author(s):  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
Philippe Moreau ◽  
Andrzej Jakubowiak ◽  
Marc S Raab ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Phase 2 ◽  
Phase 3 ◽  
Advisory Committees ◽  
Infusion Reactions ◽  
Grade 3

Abstract Abstract 202 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of MM cells, with lower expression on natural killer (NK) cells and little to no expression on normal tissues. The mechanism of action of Elo is primarily NK cell-mediated antibody-dependent cellular cytotoxicity against MM cells. In the Phase 1 portion of this 1703 study, Elo escalated from 5 to 20 mg/kg intravenously (IV) plus Ld resulted in an 82% objective response rate (ORR) in pts with R/R MM (Lonial, J Clin Oncol 2012). Historically, lenalidomide plus high dose dexamethasone provided a 61% ORR and a median 11.1 months (mos) progression free survival (PFS) in a similar pt population (Dimopoulos, Weber, N Engl J Med 2007). At the time of previous presentation (Moreau, ASCO 2012), median PFS in the Phase 2 portion the 1703 study of Elo + Ld was not reached (NR) with 10 mg/kg after a median follow-up of 17.2 mo and was 18.6 mo with 20 mg/kg. Methods: Pts with R/R MM previously treated with 1–3 prior therapies were randomized to Elo 10 or 20 mg/kg IV (days 1, 8, 15, 22 every 28 days in cycles 1–2 and days 1, 15 in cycles ≥3) plus lenalidomide 25 mg (PO) (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on Elo dosing days. All pts received a premedication regimen of methylprednisolone or dexamethasone, diphenhydramine, ranitidine, and acetaminophen prior to elo dosing to minimize infusion reactions. Treatment continued until disease progression, unacceptable toxicity, or death. Pts were monitored for PFS until 60 days post-treatment follow-up. The primary objective was efficacy (ORR ≥partial response) according to the International Myeloma Working Group criteria. Results: 73 pts were treated (10 mg/kg, n=36; 20 mg/kg, n=37). Median age was 63 (range, 39–82) years, 55% received ≥2 prior therapies, 60% prior bortezomib, and 62% prior thalidomide. Median (range) duration of treatment was 20.5 (3.0–31.0) and 16.0 (1.0–32.0) cycles with 10 and 20 mg/kg, respectively. At the data cutoff (July 10 2012), 27 pts (10 mg/kg, n=15; 20 mg/kg, n=12) were ongoing and 46 pts discontinued (disease progression, n=26; adverse events, n=11; investigator/pt decision, n=9). ORR was 84% overall; 92% with 10 mg/kg (chosen as the Phase 3 dose) and 76% with 20 mg/kg (see Table). Overall median time to objective response was 1 month (range, 0.7–19.2). After a median follow-up of 18.1 mos, median PFS in the 10 mg/kg cohort was 26.9 mos (95% confidence interval [CI]: 14.9–NR); however, 15 pts are still ongoing with a median follow-up of 23.9 mos, and the PFS data will likely mature further with longer follow up. Median PFS in the 20 mg/kg cohort was 18.6 mos (95% CI: 12.9–NR). In subgroup analyses combining 10 and 20 mg/kg cohorts, ORRs for pts with 1 (n=33) or ≥2 prior therapies (n=40) were 91% and 78%, respectively, and overall median PFS were 25.0 (95% CI: 15.7–NR) and 21.3 mos (95% CI: 14.0–NR), respectively. Pts with prior thalidomide (n=45) had an ORR of 82% and median PFS of 26.9 mos (95% CI: 14.9–NR). Fifty-six (78%) pts experienced ≥1 treatment emergent grade ≥3 event. Most common were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), anemia (12%), leukopenia (10%), hyperglycemia (10%), pneumonia (7%), diarrhea (7%), fatigue (7%), and hypokalemia (6%). Two deaths occurred on study (multiple adverse events [n=1; pneumonia, multiple organ failure and sepsis]; disease progression [n=1]). Investigator-designated (any grade) infusion reactions were reported in 12% of pts; 1 pt had a grade 3 event (rash). There were 4 cases of second primary malignancies (prostate; bladder; myelodysplastic syndrome; nasal squamous cell); all were deemed unrelated to Elo. Conclusions: In pts with R/R MM, Elo + Ld was generally well tolerated. Elo at 10mg/kg (the phase 3 dose) + Ld resulted in a high ORR and an encouraging median PFS of 26.9 mos after 18.1 mos of median follow-up. Phase 3 trials of Elo 10 mg/kg ± Ld are ongoing in newly diagnosed MM (ELOQUENT-1; CA204-006; NCT01335399) and R/R MM (ELOQUENT-2; CA204-004; NCT01239797). Disclosures: Richardson: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Elotuzumab is not currently approved for any indication. Jagannath:Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Facon:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Celgene: Honoraria, Research Funding. Reece:Johnson & Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Deng:Abbott Biotherapeutics Corp: Employment. Kroog:BMS: Employment. Singhal:Abbott Biotherapeutics: Employment, Equity Ownership. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy.

scholarly journals Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Norbert Vey ◽  
Corentin Orvain ◽  
Christian Recher ◽  
Arnaud Pigneux ◽  
Marc Bernard ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Risk Groups ◽  
Advisory Board ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
Consolidation Phase

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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