A Phase IV, Multicenter, Open-Label Study of Emicizumab Prophylaxis in Persons with Hemophilia a with or without FVIII Inhibitors Undergoing Minor Surgical Procedures

Introduction: Emicizumab is a subcutaneously administered, bispecific, humanized monoclonal antibody that bridges factor (F)IXa and FX to restore the function of missing activated FVIII in persons with hemophilia A (PwHA). This study (NCT03361137) was designed to evaluate the safety and efficacy of emicizumab prophylaxis in PwHA with or without FVIII inhibitors undergoing minor surgical procedures without additional prophylaxis with bypassing agents (BPAs; for patients with FVIII inhibitors) or FVIII (for patients without FVIII inhibitors). Methods: This Phase IV, multicenter, single-arm, open-label study enrolled PwHA of any age, with or without FVIII inhibitors, who were scheduled to undergo minor surgical procedures. Patients were required to have received a minimum of four loading doses of emicizumab (3mg/kg once weekly for 4 weeks) prior to surgical procedure; subsequent maintenance doses of emicizumab were 1.5mg/kg once weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. Patients were required to be adherent to emicizumab prophylaxis. Treatment with emicizumab was scheduled to continue for at least 1 month after surgery. No other prophylactic treatment with coagulation factor was permitted. Outcome measures included incidence of excessive bleeding intra-operatively and until discharge from surgery, use of BPAs or FVIII to control bleeding (intra- and post-operatively), incidence of adverse events (AEs), and the percentage of patients with complications requiring hospitalization or return to surgery. Excessive bleeding was defined as a rating of fair to poor on the hemostatic rating scale and translates to an intra- and/or post-operative blood loss of ≥25% over expectation for a patient without hemophilia prior to discharge from surgery. Patients were followed for 28 days following discharge from surgery. Results: Between June 28, 2018 and March 13, 2020, 14 PwHA undergoing minor surgeries were enrolled (with FVIII inhibitors n=11; without FVIII inhibitors n=3); one PwHA with FVIII inhibitors enrolled but did not have surgery and discontinued prematurely, therefore the surgery analysis population comprised 13 patients (with FVIII inhibitors n=10; without FVIII inhibitors n=3). The majority (78.6%) of those enrolled were <18 years of age and all surgeries were either central venous access device (CVAD) removal (n=11) or dental procedures (n=2; Table 1). Of the 10 patients with FVIII inhibitors, one CVAD removal led to excessive bleeding during surgery with a need for BPA therapy, two patients undergoing CVAD removal received BPA therapy during surgery but had no reported excessive bleeding, three (two CVAD removals, one dental extraction) had post-operative bleeding that required use of a BPA (Table 2). Seven patients with FVIII inhibitors had zero bleeds after discharge from surgery. None of the three PwHA without FVIII inhibitors had excessive bleeding necessitating FVIII treatment during surgery or until discharge; two CVAD removals resulted in zero bleeds post-operatively and one dental extraction led to a post-operative bleed that did not require treatment. No serious AEs, thromboembolic events (TEs), thrombotic microangiopathies (TMAs) or deaths were reported during the study. Overall, 10 AEs occurred in five patients with FVIII inhibitors (headache n=3, limb injury, procedural pain, pyrexia, constipation, device occlusion, adhesiolysis, and hematoma, all n=1); no AEs were reported in patients without FVIII inhibitors. There were no AEs leading to dose modification, interruption or withdrawal of treatment, and no patient in either group had surgical complications requiring hospitalization or a return to surgery. The study was terminated early due to low enrollment and the limited variety of surgery types. Conclusions: In this study of mostly pediatric PwHA with and without FVIII inhibitors receiving emicizumab prophylaxis, minor surgeries were safely performed. The majority of surgeries were performed without additional prophylactic coagulation factor, however the small sample size should be considered here. There were no serious AEs, TEs, TMAs, or deaths. These findings are consistent with results from previous studies of patients undergoing minor surgery while receiving emicizumab prophylaxis. Disclosures Escobar: National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunn:Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Spire: Honoraria; ATHN: Research Funding; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy. Quon:Octapharma: Honoraria; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Shire/Takeda: Speakers Bureau; Orthopaedic Institute for Children: Current Employment. Trzaskoma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ko:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Carpenter:Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria.

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Multicenter, Open-Label, Single Arm, Phase II Exploratory Study to Evaluate the Effect of a One-Year Consolidation Treatment with Ponatinib 15 Mg on Treatment Free-Remission Rate in Patients with Philadelphia-Positive Chronic Myeloid Leukemia, Who Had Previously Achieved a Deep Molecular Response with Imatinib (PonaZero_study)

Blood ◽

10.1182/blood-2019-125627 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5904-5904

Author(s):

Valentin Garcia Gutierrez ◽

Luis Felipe Casado ◽

Rosa Ayala ◽

Fermin Sanchez-Guijo ◽

Juan Carlos Hernandez Boluda ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Imatinib Treatment ◽

Open Label ◽

Advisory Committees ◽

Open Label Study ◽

Free Survival ◽

Label Study ◽

Treatment Free Remission

Study Rationale The present study with ponatinib is based on previous studies on the potential role of imatinib discontinuation, to achieve a stable treatment-free remission (TFR) of patients with Philadelphia-positive Chronic Myeloid Leukemia (CML). As ponatinib has shown to induce deeper molecular responses compared with imatinib, the rationale is that ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. Purpose The purpose is to determine the successful TFR within the first 48 weeks following cessation of treatment in patients who achieved MR4 on imatinib, and maintained MR4 on ponatinib, after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (TKI) therapy, for at least 4 years, and have documented MR4 (at least 12 months) at the time of ponatinib to study entry. Objectives The Primary Objective is to evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR (do not require confirmation). The Key Secondary Objectives are: To evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR within 72 and 96 weeks following ponatinib cessation.To estimate progression-free survival (PFS) from the date of ponatinib cessation to the date of the earliest event. Treatment-free survival (TFS) defined as a lack of any of the following: loss of MMR, confirmed loss of MR4, re-start of imatinib treatment, progression of AP/BP, or death from any cause.Overall survival (OS), defined as the time from the date of cessation of ponatinib therapy to the date of death from any cause.Proportion of patients who regain MR4 within 48 weeks of imatinib treatment re-initiation, following confirmed loss of MR4 within 48 weeks subsequent to ponatinib cessation.Kinetics of BCR-ABL transcript level (IS) after re-start of imatinib therapy. Other Secondary Objectives include adverse events, laboratory data for hematology, biochemistry, and urinary test, vital signs and ECGs. Exploratory Objectives include phenotypic and genotypic biomarkers, as well as functional analysis of cytotoxic cell activation. Plasma monitoring of ponatinib levels will also be performed. Study Design This is a single-arm, open label study, open label study in 40 patients who achieved and maintained MR4, to determine the rate of successful TFR in both gender patients, treated with 15 mg/day of ponatinb for 48 weeks. Ten Spanish sites will participate. The study has two main phases: ponatinib consolidation (48 weeks) and ponatinib TFR phase (96 weeks). Inclusion criteria are patients who had received a minimum of 4 years imatinib as unique TKI therapy, have documented MR4 at least 12 months prior to study entry, and will continue with MR4 before the discontinuation of ponatinib. After stopping ponatinb (TFR phase), BCR-ABL wil be monitored every 4 weeks during the first 48 weeks, and every 12 weeks during the last period of 48 weeks. Exclusion criteria include patients with transplant, atypical transcripts, CML treatment resistant mutation, or having cardiovascular or pancreatitis diseases. Figure 1: Current State of the Study First Visit First Patient: 17 JUL 2019 Patients Enrolled: 4 Patients Recruited: 3 Screening Failure: 0 In Screening: 1 patient Figure 1 Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Steegmann:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147335 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3675-3675

Author(s):

David M Ross ◽

Alejandro Arbelaez ◽

Lynette C.Y. Chee ◽

Chun Yew Fong ◽

Devendra Hiwase ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Maximum Increase ◽

Phase 2 Study ◽

Dose Levels

Abstract Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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Trial in Progress: The Phase III, Randomized, Open-Label, Multicenter COMMODORE 2 Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria Not Previously Treated with Complement Inhibitors

Blood ◽

10.1182/blood-2020-136647 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Austin Kulasekararaj ◽

Guangsheng He ◽

Talha Munir ◽

Jeffrey Pu ◽

Antonio Risitano ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Medical Writing ◽

Third Party ◽

Phase Iii ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Complement Inhibitors ◽

Previously Treated

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody engineered to significantly extend half-life and enable subcutaneous (SC) administration once every 4 weeks in C5-mediated diseases. Based on the promising results of the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab is currently under investigation as a potential therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations include breakthrough hemolysis due to unsustained C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the treatment burden of regular intravenous (IV) infusions. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 2 study (NCT04434092) is evaluating the efficacy and safety of crovalimab compared with eculizumab in patients aged ≥ 12 years with PNH not previously treated with complement inhibitors. Patients are randomized 2:1 to receive crovalimab or eculizumab (Figure 1). Two hundred patients in the crovalimab arm will receive a loading series of crovalimab (IV dose on Day 1, followed by weekly SC doses for 4 weeks starting on Day 2). This is followed by SC maintenance dosing every 4 weeks starting at Week 5. Patients in the eculizumab arm receive a weekly IV loading dose of eculizumab for the first 4 weeks, followed by IV maintenance dosing starting at Week 5 and then once every 2 weeks for 24 weeks. After 24 weeks of treatment, patients can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective of COMMODORE 2 is to evaluate the noninferiority of crovalimab compared with eculizumab based on the co-primary endpoints of (1) the proportion of patients who achieve transfusion avoidance and (2) the proportion of patients with hemolysis control. Secondary efficacy objectives are to evaluate the noninferiority of crovalimab compared with eculizumab in regard to the (1) proportion of patients who experience breakthrough hemolysis, (2) proportion of patients who achieve stabilization of hemoglobin, and (3) mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, and adverse events leading to study drug discontinuation. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pu:SUNY Upstate Medical University: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. 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; Biocryst: 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; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: 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; Pfizer: Speakers Bureau; RA pharma: Research Funding. Röth:Roche: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Sima:F. Hoffmann-La Roche Ltd/Genentech: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

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Mitapivat (AG-348), an Oral PK-R Activator, in Adults with Non-Transfusion Dependent Thalassemia: A Phase 2, Open-Label, Multicenter Study in Progress

Blood ◽

10.1182/blood-2019-123113 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2249-2249

Author(s):

Kevin H. M. Kuo ◽

D. Mark Layton ◽

Katrin Uhlig ◽

Megan Lynch ◽

Li Liu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Ineffective Erythropoiesis ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Open Label Study ◽

Label Study ◽

Equity Ownership

Background: Thalassemia is a group of inherited blood disorders in which genetic mutation(s) in the α- and/or β-globin locus lead to excess precipitation of β- or α-globin, respectively, and compromised red blood cell (RBC) survival. The condition is characterized by ineffective erythropoiesis and peripheral hemolysis, with resultant anemia. Adenosine triphosphate (ATP) supply appears to be insufficient in thalassemic RBCs to maintain RBC membrane fitness and clearance of globin precipitates. Mitapivat (AG-348) is an oral, small-molecule, allosteric activator of the RBC-specific form of pyruvate kinase (PK-R). PK-R is a key enzyme for maintaining energy homeostasis in RBCs, as they rely almost exclusively on the process of glycolysis to generate ATP. In healthy adults, mitapivat activates wild-type PK-R and increases ATP levels in RBCs. In adults with PK deficiency who were not regularly transfused, oral mitapivat was well tolerated and induced rapid, durable hemoglobin (Hb) increases (NCT02476916). In the Hbbth/3+ mouse model of β-thalassemia, mitapivat increased ATP levels; reduced markers of ineffective erythropoiesis; and improved anemia, RBC survival, and indices of iron overload. These data support the hypothesis that increased ATP synthesis mediated via PK-R activation by mitapivat may improve the survival of thalassemic RBCs in the bone marrow and/or peripheral circulation, and thus represents a novel mechanism to treat patients with thalassemia. Here we present the design of a phase 2, open-label study designed to test this hypothesis and assess the proof of concept of mitapivat in patients with thalassemia. Methods: This phase 2, multicenter, open-label study (NCT03692052) is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT). Four sites in North America and the United Kingdom are enrolling patients. The study consists of a 24-week core period followed by a 2-year extension period (Figure). Approximately 17 subjects with NTDT, i.e., β-thalassemia with or without α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease), will be enrolled. Non-transfusion dependence is defined as ≤5 units of RBCs transfused in the preceding 24 weeks and no transfusions in the 8 weeks prior to the first day of study drug. The hemoglobin inclusion criterion is ≤10.0 g/dL, which was increased from ≤9.0 g/dL in a recent protocol amendment to better reflect the clinical representation in the NTDT patient population. All eligible patients will receive an initial mitapivat dose of 50 mg twice daily (BID). At the week 6 visit the dose may be increased to 100 mg BID, depending on safety and Hb response. The primary endpoint is the proportion of subjects who achieve an Hb response, defined as an increase in Hb of ≥1.0 g/dL from baseline at any time between week 4 and week 12 (inclusive). Key secondary and exploratory endpoints include changes in Hb and markers of hemolysis; hematopoietic activity; iron metabolism and iron overload; and assessments of safety and pharmacokinetics. The study is currently enrolling. Figure Disclosures Kuo: Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Layton:Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Uhlig:Agios: Employment, Equity Ownership. Lynch:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Vichinsky:GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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Preliminary Results of a Phase 2, Open-Label Study of Venetoclax (ABT-199/GDC-0199) Monotherapy in Patients with Chronic Lymphocytic Leukemia Relapsed after or Refractory to Ibrutinib or Idelalisib Therapy

Blood ◽

10.1182/blood.v126.23.715.715 ◽

2015 ◽

Vol 126 (23) ◽

pp. 715-715 ◽

Cited By ~ 21

Author(s):

Jeffrey Jones ◽

Anthony R. Mato ◽

Steven Coutre ◽

William Wierda ◽

Michael Y. Choi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Assessment ◽

Lymphocytic Leukemia ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Open Label Study ◽

Equity Ownership

Abstract Introduction: The overall outcome of patients (pts) with chronic lymphocytic leukemia (CLL) who relapse after or become refractory to treatment with B-cell receptor (BCR) signaling antagonists, including ibrutinib (IBR) or idelalisib (IDE), is recently being appreciated and appears quite poor. To date, no phase 2 studies have reported efficacy in this population. Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor with a BCR-independent mechanism of action and substantial activity in pts with heavily pretreated relapsed or refractory CLL. We report preliminary results from an ongoing phase 2, open-label study evaluating venetoclax monotherapy in CLL pts relapsed after or refractory to IBR or IDE (NCT02141282). Methods: Pts with CLL relapsed after or refractory to IBR (Arm A) or IDE (Arm B) receive venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of 400 mg. Pts with Richter's transformation (RT) suspected by screening PET CT or confirmed by lymph node biopsy are ineligible. The primary objectives are to assess the efficacy (investigator assessed overall response rate, ORR) and safety of venetoclax. Disease and response assessment was performed using iwCLL criteria at weeks 8, 24 and every 12 weeks thereafter. Adverse events (AEs) are monitored throughout the study. Results: As of April 30, 2015, 28 pts were enrolled in the study. Three screened pts were ineligible due to RT. Pt demographics are summarized by treatment arm in the table. Twenty-two entered into Arm A after a median duration on IBR of 15.5 months (range: 1-56). Investigator-reported best responses while on IBR prior to starting venetoclax were 14 partial response (PR), 4 stable disease (SD) and 3 progressive disease (PD); best response for 1 pt is unknown. Six entered into Arm B after a median duration on IDE of 9.7 months (range: 1-34). Investigator-reported best responses while on IDE prior to starting venetoclax were 1 complete response (CR), 3 PR and 2 SD. At last follow-up, the median time on venetoclax was 2.4 months (range: 0.1- 7) for Arm A and 1.7 months (range: 1.2-4.5) for Arm B. Venetoclax discontinuation occurred in 4 pts in Arm A (1 each due to respiratory failure, multi-organ failure, PD of RT, death of unknown cause) and in 1 pt in Arm B (PD prior to first assessment). Fifteen pts in Arm A and 3 in Arm B underwent Week 8 response assessment. In Arm A, 8/15 (53%) achieved a PR, 6/15 (40%) had SD, and 1/15 was inevaluable. In Arm B, 2/4 achieved a PR, 1/4 had SD, and 1/4 had PD prior to first assessment. Pts with SD had evidence of ongoing disease reduction, measured by decreasing circulating lymphocytes and lymph nodes. As of the cutoff date, 23 pts remain on venetoclax therapy. Compared to prior venetoclax monotherapy studies, no new safety signals for venetoclax were observed in either treatment arm. Treatment-emergent AEs (all grades) in >25% of the overall population were neutropenia (57%), anemia (35%), diarrhea (32%) and nausea (32%). Treatment-emergent grade 3/4 AEs in >10% of the overall population were neutropenia (43%; 3/12 of the neutropenic pts developed febrile neutropenia), anemia (29%), thrombocytopenia (18%), hypophosphatemia, hypoxia, leukopenia, and pneumonia (each 11%). Serious AEs in ≥2 pts overall were febrile neutropenia, increased blood potassium, multi-organ failure, and pneumonia (each 7%). Prior to study entry, 7/22 (32%) in Arm A received G-CSF support. One pt with high disease burden developed laboratory TLS in week 4, upon escalating to the 200 mg daily venetoclax dose, evident by hyperuricemia and hyperphosphatemia. Electrolytes returned to normal levels after a dose interruption and intervention. No pts experienced clinical TLS; laboratory changes were not clinically significant. Conclusions: In this group of pts with aggressive disease relapsed after or refractory to BCR-targeted agents, venetoclax monotherapy demonstrated early activity at the 8 week assessment, which occurred within 3 weeks of reaching the target 400 mg daily dose. The majority of evaluable pts achieved PR or SD. Venetoclax monotherapy exhibited a tolerable safety profile without events of clinical TLS. This is the first phase 2 study to show activity in a relatively uniform population of pts previously treated with BCR kinase inhibitors; the data suggests that venetoclax is active in these pts. Enrollment in both arms was ongoing as of the data cut. Figure 1. Figure 1. Disclosures Jones: Genentech, Pharmacyclics; institutional research funding from Abbvie, Pharmacyclics, Genentech, and Gilead: Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Mato:AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Coutre:AbbVie: Research Funding. Wierda:Genentech: Consultancy; AbbVie and Genentech: Research Funding. Choi:AbbVie and Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; AbbVie: Research Funding. Davids:AbbVie and Janssen: Consultancy; Genentech and Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, TG Therapeutics, and Infinity: Research Funding. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barr:Pharmacyclics: Research Funding; AbbVie and Pharmacyclics: Consultancy. Burns:AbbVie: Employment, Equity Ownership. Montalvo:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Busman:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Byrd:Pharmacyclics: Research Funding; Genenttech, AbbVie, Acerta, Pharmacyclics: Other: Unpaid consultant.

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BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽

10.1182/blood-2021-145938 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3732-3732

Author(s):

Wojciech Jurczak ◽

Caroline Dartigeas ◽

Marta Coscia ◽

Peter S. Ganly ◽

Ghassan Al-Jazayrly ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Small Lymphocytic Lymphoma ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Mutation Status

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In a phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397, 10277:892-901). Study Design and Methods: BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC). Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients. Disclosures Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Coscia: Gilead: Honoraria; AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Bao: Loxo Oncology at Lilly: Current Employment; Genentech: Ended employment in the past 24 months. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zinzani: Eusapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Celtrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

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Long-Term Follow-up of Ibrutinib Treatment for Rituximab-Refractory Waldenström's Macroglobulinemia: Final Analysis of the Open-Label Substudy of the Phase 3 iNNOVATETM Trial

Blood ◽

10.1182/blood-2020-133916 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39

Author(s):

Judith Trotman ◽

Christian Buske ◽

Alessandra Tedeschi ◽

Jeffrey V. Matous ◽

David MacDonald ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Final Analysis ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Heavily Pretreated ◽

Travel Grant

Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor approved in the US and EU either as single-agent therapy or in combination with rituximab for treatment of patients with Waldenström's macroglobulinemia (WM) across all lines of therapy. The open-label substudy of the phase 3 iNNOVATE trial (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was highly efficacious (90% overall response rate [ORR] per investigator) with improved responses over time in heavily pretreated, rituximab-refractory patients with WM (Buske Blood 2018). Here, we present results from the final analysis of the iNNOVATE open-label substudy. Methods : Patients with WM who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy received once-daily ibrutinib 420 mg. Endpoints included progression-free survival (PFS) and ORR (≥MR) per Independent Review Committee (IRC), overall survival (OS), hemoglobin (Hgb) improvement, and safety; serum immunoglobulin M (IgM) reduction was also assessed. Results : Thirty-one patients with rituximab-refractory disease were enrolled; median age was 67 years (range 47-90), and median number of prior therapies was 4 (range 1-7). Median baseline Hgb was 103 g/L (range 64-146). Median baseline IgM was 39 g/L (range 9-107). Median follow-up was 58 months (range 9-61). Median PFS was 39 months (95% CI 25-NE); the PFS rate at 60 months was 40%. Median PFS was not reached (95% CI 27-NE) in patients with the MYD88L265P/CXCR4WT genotype and was 18 months (95% CI 3-28) in patients with the MYD88L265P/CXCR4WHIM genotype. ORR was 87%, with similar ORR observed across genetic subtypes (MYD88L265P/CXCR4WT, 88% [15/17]; MYD88L265P/CXCR4WHIM, 86% [6/7]); major response rates (≥PR) among these genotypes were 88% (15/17) and 71% (5/7), respectively (Figure 1A). Median OS was not reached in the full cohort of patients, regardless of number of prior therapies (1-2 vs ≥3). Improvements in IgM and Hgb were generally rapid and sustained (Figure 1B). Twenty-two patients (71%) had sustained improvement in Hgb, including 17/21 (81%) with baseline Hgb ≤110 g/L. Median change in IgM from baseline to nadir (month 54) was -37 g/L (range -75 to -5). Median duration of ibrutinib treatment was 41 months. The most common reason for discontinuing ibrutinib while on study was progressive disease (42%). At time of study closure, 14 patients (45%) remained on treatment; of these, 6 went on to receive ibrutinib in the commercial setting and 8 enrolled in a treatment extension study. Overall, 97% of patients experienced a treatment-emergent adverse event (TEAE), most commonly diarrhea (48%; grade ≥2, 13%) and pyrexia (35%; grade ≥2, 6%). Grade 3/4 TEAEs occurred in 81% of patients; the most common were neutropenia (16%), hypertension (10%), and anemia (10%). No deaths occurred due to AEs, and no patients died while on treatment. Ibrutinib dose was reduced in 5 patients (16%) due to an AE, and 2 patients (6%) discontinued treatment because of an AE. No patients experienced major hemorrhage or atrial fibrillation. Conclusions : In this final analysis of the open-label substudy of the iNNOVATE trial, single-agent ibrutinib continued to show sustained efficacy in patients who had heavily pretreated, rituximab-refractory WM. Responses to ibrutinib were consistent across genotypes, although subgroup numbers were small. Ibrutinib maintained a manageable safety profile, and no new safety signals were identified with over 5 years of overall follow-up. Disclosures Trotman: Celgene: Research Funding; PCYC: Research Funding; Takeda: Research Funding; BeiGene: Research Funding; F. Hoffmann-La Roche: Research Funding. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matous:Celgene: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. MacDonald:Roche Canada: Consultancy, Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria. Tam:BeiGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tournilhac:INNATE Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant. Ma:Genentech: Consultancy, Honoraria; Novartis: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Bioverativ: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Juno: Research Funding. Treon:Janssen: Consultancy, Other: Travel/accommodations/expenses; BeiGene: Consultancy; Bristol-Myers Squibb: Research Funding; BioGene: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel/accommodations/expenses, Research Funding. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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, Speakers Bureau. Ping:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Briso:Pharmacyclics GmbH, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Arango-Hisijara:Pharmacyclics LLC, an AbbVie Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Dimopoulos:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy.

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Early-Onset Osteopenia and Osteoporosis in Patients with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2020-136598 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-32

Author(s):

Hanny Al-Samkari ◽

Rachael F. Grace ◽

Andreas Glenthoej ◽

Oliver Andres ◽

Wilma Barcellini ◽

...

Keyword(s):

Medical History ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Open Label ◽

Private Company ◽

Advisory Committees ◽

T Score ◽

History Of ◽

La Jolla

Background: Hereditary pyruvate kinase (PK) deficiency results in lifelong hemolytic anemia and several significant comorbidities, the epidemiology of which are not well characterized. Among these is reduced bone mineral density (BMD), which can result in premature osteopenia, osteoporosis, and fractures. To better characterize the bone density abnormalities in patients with PK deficiency, this study evaluated pooled pre-treatment baseline data from 3 clinical trials involving patients with PK deficiency investigating mitapivat, an allosteric activator of PK: DRIVE-PK (NCT02476916), ACTIVATE (NCT03548220), and ACTIVATE-T (NCT03559699). This is the first large PK deficiency cohort in which dual-energy x-ray absorptiometry (DXA) scores were systematically and consistently assessed. Methods: DRIVE-PK is a completed phase 2, global, randomized, open-label study. ACTIVATE is an ongoing phase 3, global, randomized, double-blind, placebo-controlled study. ACTIVATE-T is an ongoing phase 3, global, open-label, single-arm study. In all 3 studies, patients ≥ 18 years of age with a confirmed diagnosis of PK deficiency were eligible to participate. Patients were eligible to participate in DRIVE-PK and in ACTIVATE if they were not regularly transfused (DRIVE-PK: ≤ 3 units of red blood cells in the prior 12 months; no transfusions in the prior 4 months; ACTIVATE: ≤ 4 transfusion episodes in the previous year; no transfusions in the prior 3 months) and in ACTIVATE-T if they were regularly transfused (≥ 6 transfusion episodes in the previous year). BMD was measured using DXA scans at baseline; scans were obtained locally for all 3 studies. Scans were interpreted locally for DRIVE-PK and centrally for ACTIVATE and ACTIVATE-T. Osteopenia and osteoporosis were identified on DXA scanning according to standard definitions, and the prevalence of each was compared to the prevalence ascertained via medical history. Results: Full demographics and characteristics of patients at baseline are shown in the Table. Of 159 patients evaluated (DRIVE-PK, n = 52; ACTIVATE, n = 80; ACTIVATE-T, n = 27), the median age was 34 years (range, 18-78) and the majority were female (n = 88; 55.3%). Of 155 patients who had baseline T-scores for total femur, spine, and femoral neck, 38 (24.5%) had a T-score of ≥ -1.0 at all locations, indicating normal BMD; 91 (58.7%) had a T-score of < -1.0 to > -2.5 at 1 or more locations, indicating osteopenia; and 26 (16.8%) had a T-score of ≤ -2.5 at 1 or more locations, indicating osteoporosis. The proportion of patients in each T-score range for each of the 3 locations is shown in the Figure. In contrast to the DXA scan findings, only 28 (17.6%) patients had a known medical history of osteopenia and 23 (14.5%) had a known medical history of osteoporosis. Taking together DXA scan results and medical history for all 159 patients, 85 patients (53.5%) had osteopenia and 33 patients (20.8%) had osteoporosis. The median age for patients with either osteopenia or osteoporosis (n = 118) was 36 years (range, 18-78). Of these, 20 patients (16.9%) were regularly transfused and 98 patients (83.1%) were not regularly transfused. Conclusions: In this large cohort, universal DXA scanning revealed that over three-quarters of adults with PK deficiency had osteopenia or osteoporosis, irrespective of transfusion requirements. Given the young median age of the cohort (34 years), these findings have considerable significance and implications for the screening and care of patients with PK deficiency throughout their adult lives. Early monitoring of these patients with DXA scans in order to ensure a prompt diagnosis of bone density abnormalities and indicated treatment may be warranted. Disclosures Al-Samkari: Argenx: Consultancy; Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy; Amgen: Research Funding. Grace:Novartis: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Glenthoej:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexicon: Research Funding; Novo Nordisk: Honoraria. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Kuo:Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morado:Sanofi Genzyme: Honoraria, Other: Grants. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Dong:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Tai:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Hawkins:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Gheuens:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; BMS: Consultancy, Honoraria. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Magnetismm-3: An Open-Label, Multicenter, Non-Randomized Phase 2 Study of Elranatamab (PF-06863135) in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-152984 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1674-1674

Author(s):

Alexander Lesokhin ◽

Shinsuke Iida ◽

Don Stevens ◽

Afshin Eli Gabayan ◽

Wei Dong Ma ◽

...

Keyword(s):

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Phase 2 Study ◽

Immunomodulatory Drug ◽

Randomized Phase 2

Abstract Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing. Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab. Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. Disclosures Lesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

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BRUIN CLL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽

10.1182/blood-2021-145926 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3736-3736

Author(s):

Jeff P. Sharman ◽

Wojciech Jurczak ◽

Catherine C. Coombs ◽

Marisa Hill ◽

Denise Wang ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Small Lymphocytic Lymphoma ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Prior Therapy

Abstract Background: Covalent Bruton Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and many patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized phase 3 study is to demonstrate the superiority of continued BTK pathway inhibition with pirtobrutinib compared to other available therapies in patients with BTKi-treated CLL/SLL. Study Design and Methods: BRUIN CLL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL/SLL who have been treated with a prior covalent BTKi. Prior therapy with venetoclax is permitted. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior venetoclax (yes/no). Patients receiving investigator's choice are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 (determined by IRC). Eligible patients are adults aged ≥18 years with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who have received prior covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation any time pre-enrollment, a major bleeding event on prior covalent BTKi and history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients (NCT04666038). Disclosures Sharman: BeiGene: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Hill: Loxo Oncology at Lilly: Current Employment. Wang: Loxo Oncology at Lilly: Current Employment. Ku: Loxo Oncology at Lilly: Current Employment, Current holder of stock options in a privately-held company. Guntur: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Ghia: Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Mato: Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Nurix: Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding.

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