Efficacy and Safety of Pegcetacoplan Treatment in Complement-Inhibitor Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Phase 3 Prince Study

Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease characterized by hemolysis and thrombosis. Many patients with PNH use C5-inhibitors (i.e., eculizumab/ravulizumab) to control their symptoms. Although C5-inhibition prevents intravascular hemolysis (IVH), it fails to prevent extravascular hemolysis (EVH). Because of persistent EVH, up to 72% of eculizumab-treated patients remain anemic, and up to 36% require at least one transfusion per year. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the US FDA to treat adults with PNH, controls IVH and prevents EVH. Studies of PEG treatment in patients with PNH that remained anemic despite eculizumab treatment demonstrated that PEG was superior to eculizumab in achieving improvements in hemoglobin (Hb) levels (Hillmen P, et al., N Engl J Med, 2021 384 (11):1028-1037). Additionally, two early phase open-label trials demonstrated the efficacy of PEG in complement-inhibitor naïve patients with PNH (Wong RS, et al., Blood, 2020 136 [Supplement 1]). Aims: To present results from the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to standard of care (SOC; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: Fifty-three adult (≥18 years old), complement-inhibitor naïve (no complement-inhibitor treatment [i.e., eculizumab/ravulizumab] within 3 months prior to screening) patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6 g/dL; females: ≤12.0 g/dL), and lactate dehydrogenase (LDH) levels ≥1.5 times the upper limit of normal (1.5x ULN; ≥339 U/L) were enrolled. Patients were randomized 2:1 to receive PEG (1080 mg subcutaneously twice weekly [n=35]) or SOC (excluding complement-inhibitors eculizumab/ravulizumab [n=18]) through Week 26. Patients on SOC had the option to switch to the PEG group if their Hb decreased by ≥2 g/dL from baseline. Co-primary endpoints were Hb stabilization (avoidance of a >1 g/dL decrease in Hb levels in the absence of transfusions) and change from baseline (CFB) in LDH level from baseline to Week 26. Secondary endpoints included CFB in Hb levels, transfusion avoidance (defined as the proportion of subjects who did not require a transfusion through Week 26), and the incidence of adverse events (AEs). Statistical analyses were performed using the Cochran-Mantel-Haenszel test and ANCOVA model. Results: PEG was superior to SOC in both co-primary endpoints. Hb stabilization was achieved by 85.7% (n=30) of PEG-treated patients and 0.0% of SOC patients through Week 26 (p<0.0001). PEG-treated patients demonstrated superior reductions in mean LDH levels from baseline to Week 26 compared to SOC patients (least-squares mean CFB: PEG, -1870.5 U/L; SOC, -400.1 U/L; p<0.0001), and mean LDH levels in PEG-treated patients at Week 26 (mean level: 204.6 U/L) were below the ULN for LDH (226.0 U/L). PEG was also superior to SOC in the secondary endpoints: mean CFB in Hb levels (least-squares mean CFB: PEG, 2.9 g/dL; SOC, 0.3 g/dL; p=0.0019; Week 26 mean Hb: PEG, 12.8 g/dL; SOC, 9.8 g/dL) (Figure) and transfusion avoidance (PEG, 91.4%, n=32; SOC, 5.6%, n=1; p<0.0001). Serious AEs were reported by 8.7% (n=4) of PEG-treated patients and 16.7% (n=3) of SOC patients through Week 26. Two deaths (PEG, 2.9%, n=1, septic shock related to medullary aplasia; SOC, 5.6%, n=1, respiratory failure), both deemed unrelated to treatment, occurred. No events of meningitis or thrombosis were reported in either group. The most common AEs reported during the study were injection site reaction (PEG, 30.4%, n=14; SOC, 0.0%), hypokalemia (PEG, 13.0%, n=6; SOC, 11.1%, n=2), and fever (PEG, 8.7%, n=4; SOC, 0.0%). There were no AEs leading to discontinuation of PEG. Conclusions: Patients with PNH that were naïve to complement-inhibitor treatment demonstrated meaningful hematological and clinical improvements following 26 weeks of PEG treatment. The safety profile of PEG was similar to previous study results and represent a favorable risk-benefit profile. These results provide evidence for the safety and efficacy of PEG treatment in complement-inhibitor naïve patients with PNH. Figure 1 Figure 1. Disclosures Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Ajayi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Alvarenga: Apellis Pharmaceuticals: Consultancy. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Francois: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

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

Blood ◽

10.1182/blood-2020-140777 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Regis Peffault De Latour ◽

Jeffrey Szer ◽

Austin Kulasekararaj ◽

Jin Seok Kim ◽

Caroline I. Piatek ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Naïve ◽

Secondary Endpoints

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

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Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Blood ◽

10.1182/blood-2020-140469 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-3

Author(s):

Nichola Cooper ◽

Robert P. Numerof ◽

Sandra Tong ◽

David J. Kuter

Keyword(s):

Research Funding ◽

Rescue Therapy ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Phase 2 Study ◽

Syk Inhibitor

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: Age ≥18;Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);failure of ≥1 prior treatment for wAIHA;Haptoglobin <LLN (lower limit of normal) or total bilirubin >ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: Presence of other forms of AIHA;Uncontrolled or insufficiently controlled hypertension;Neutrophil count <1,000/µL,Platelet count <30,000/μL (unless patient has Evans syndrome);Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy; duration of hemoglobin response; and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patients have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. Figure Disclosures Cooper: Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Tong:Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter:Incyte: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria.

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

Blood ◽

10.1182/blood.v128.22.470.470 ◽

2016 ◽

Vol 128 (22) ◽

pp. 470-470 ◽

Cited By ~ 20

Author(s):

Umberto Vitolo ◽

Marek Trněný ◽

David Belada ◽

Angelo M Carella ◽

Neil Chua ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

B Cell Lymphoma ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Secondary Endpoints ◽

Grade 3

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

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BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽

10.1182/blood-2021-145936 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3742-3742

Author(s):

Anthony R. Mato ◽

William G. Wierda ◽

John M. Pagel ◽

Matthew S. Davids ◽

Pier Luigi Zinzani ◽

...

Keyword(s):

Research Funding ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Fixed Duration ◽

Small Lymphocytic Lymphoma ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Free Survival ◽

Prior Therapy

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. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today's standard of care. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, 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). Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population. Study Design and Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure). Eligible patients are adults with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Disclosures Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Genmab: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding. Wierda: GSK/Novartis: Research Funding; Xencor: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Gilead Sciences: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy. Davids: Astra-Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding. Zinzani: ROCHE: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; MSD: Consultancy, Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau. Lu: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Liu: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. 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. Tam: Beigene: Honoraria; Loxo: Honoraria; Abbvie: Research Funding; Janssen: Research Funding; Beigene: Research Funding; Janssen: Honoraria; Abbvie: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Eyre: Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding.

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

Blood ◽

10.1182/blood-2020-134388 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Austin Kulasekararaj ◽

Antonio Risitano ◽

Jong Wook Lee ◽

Mingjun Huang ◽

Jun-Ichi Nishimura ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Reticulocyte Count ◽

Complement Factor ◽

Publicly Traded ◽

Phase 3 ◽

Advisory Committees ◽

Double Blind ◽

Secondary Endpoints

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

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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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Majic: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood-2021-148155 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1553-1553

Author(s):

Matthew S. Davids ◽

Anthony R. Mato ◽

Juliette Hum ◽

Susana Wargo ◽

Ugochinyere Emeribe ◽

...

Keyword(s):

Research Funding ◽

Lymphocytic Leukemia ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Free Survival ◽

The Past ◽

History Of ◽

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Privately Held

Abstract Background: Novel targeted agents, namely Bruton tyrosine kinase inhibitors (BTKis), B-cell leukemia/lymphoma-2 inhibitors (BCL-2is), and anti-CD20 monoclonal antibodies, have advanced chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treatment beyond traditional chemoimmunotherapy. While 1-year fixed-duration venetoclax-obinutuzumab (VO) is effective, about 25% of patients do not achieve peripheral blood (PB) undetectable minimal residual disease (uMRD). This regimen contains intravenous therapy with obinutuzumab, which presents potential additional toxicities such as infusion reactions and tumor lysis syndrome as well as the potential inconvenience of an intravenous drug. Moreover, patients with higher-risk genomic features such as TP53-aberrant disease or unmutated IGHV have shorter progression-free survival (PFS) than lower-risk cohorts. Whether extending the course of venetoclax beyond 1 year in patients with detectable MRD improves PFS remains unknown. Preclinical data support combining BTKi and BCL-2i, and recent studies with the first-generation BTKi ibrutinib plus venetoclax (IV) have demonstrated deep/durable responses with uMRD rates similar to VO in previously untreated patients with CLL; however, toxicities of this regimen (e.g., cardiac events, neutropenia, etc.) may be challenging, particularly in older patients and those with comorbidities. Acalabrutinib, a highly selective next-generation BTKi, showed an improved safety profile versus ibrutinib in a phase 3 head-to-head trial in relapsed/refractory CLL, and was very effective and well tolerated in a phase 2 study combined with VO. We hypothesize that time-limited doublet therapy with acalabrutinib plus venetoclax (AV) would induce PFS and levels of uMRD similar to those of VO in treatment-naïve (TN) CLL/SLL irrespective of genomic risk features and offer the convenience and favorable tolerability of an all-oral regimen. Moreover, we hypothesize that MRD-guided therapy duration approach will help to define the optimal duration of therapy for both VO and AV. Methods: MAJIC is a phase 3, open-label, randomized, multicenter, global study evaluating AV vs VO in patients aged ≥18 years with TN CLL/SLL. The primary objective of the MAJIC trial is to evaluate investigator-assessed PFS of MRD-guided AV vs MRD-guided VO in a noninferiority design. Key secondary endpoints include uMRD rates at sequential time points, complete and overall response rate, event-free survival, overall survival, quality of life/patient-reported outcomes, and safety. After the screening period, approximately 600 patients will be randomized (1:1, with stratification by age, TP53, and IGHV status) to receive either AV: acalabrutinib (100 mg twice daily with 2 lead-in cycles) then combined with venetoclax introduced at cycle 3 (including dose ramp-up) for 12 cycles, or VO: intravenous obinutuzumab at standard dosing with venetoclax initiated per standard dosing at day 22 cycle 1 (including dose ramp-up) for 6 cycles, followed by 6 cycles of venetoclax monotherapy, for a total of 12 cycles of venetoclax therapy in both arms. Patients with detectable MRD (10 -5 sensitivity by clonoSEQ ® next-generation sequencing) at that time will continue therapy for an additional 12 cycles with either AV (acalabrutinib-containing cohort) or venetoclax monotherapy (for the VO cohort) for a total of 24 months of therapy in both arms, unless they experience progressive disease or unacceptable toxicity. All patients will discontinue study therapy after 24 months, regardless of MRD status at that time point. Response assessments including MRD will occur at the end of 12 months of venetoclax (and 24 months if receiving a second year of therapy) in both arms, and patients with PB uMRD by clonoSEQ at 10 -5 sensitivity at that time point will discontinue therapy. Further correlative studies such as association of baseline genetic markers with clinical outcomes and MRD kinetics will be conducted. Key exclusion criteria are clinically significant cardiovascular disease, history of bleeding diathesis, and history of significant cerebrovascular disease/event. Patient enrollment is to begin at the end of 2021. Summary: This trial in progress is to inform the choice of which of these doublet therapy approaches might be most appropriate for patients with previously untreated CLL/SLL without restriction by genetic background or age. Disclosures Davids: Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Research to Practice: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; BeiGene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mato: DTRM BioPharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genmab: Research Funding; Nurix: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; MSKCC: Current Employment; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Hum: AstraZeneca: Current Employment. Wargo: AstraZeneca: Current Employment. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Shahkarami: Astrazeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Sokolowski: AbbVie: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Abhyankar: Genentech, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Hermann: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; BMS: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Investigational study

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Impact of Platelet Transfusion on Pulmonary Function of Hematology Oncology Patients: The Piper Study

Blood ◽

10.1182/blood-2021-146916 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1077-1077

Author(s):

Allison P. Wheeler ◽

Edward L. Snyder ◽

Majed A. Refaai ◽

Claudia S. Cohn ◽

Jessica Poisson ◽

...

Keyword(s):

Pulmonary Disease ◽

Primary Endpoint ◽

Cardiac Disease ◽

Research Funding ◽

Platelet Transfusion ◽

Pulmonary Injury ◽

Publicly Traded ◽

Oncology Patients ◽

History Of ◽

Secondary Endpoints

Abstract Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p<0.05) decreased RR of PRPC respectively for baseline covariates: age < 65 (0.53), male (0.54), non-white (0.32), chemotherapy (0.40), prior pulmonary disease (0.55), and prior cardiac disease (0.58). Least squares (LS) mean days to initiation of TEAMV for patients with PD were longer for PRPC recipients. PEP adjudicated incidence of ARDS was not significantly different between cohorts (Table). Total and serious CSPAE were not different between the cohorts. There were no significant differences between cohorts in Respiratory, Thoracic, and Mediastinal Disorders, the most frequent system organ class event. Mortality was not different between cohorts. Multivariate analysis (mITT) for the probability of CSPAE or transfusion associated cardiac overload (TACO) showed PC type had no effect. The odds ratio (OR) of CSPAE or TACO during PC support was significantly increased (p< 0.05) in both cohorts for history of cardiac disease (1.35), history of pulmonary disease (2.57), diagnosis of Myelodysplasia (1.88), and diagnosis of Myelodysplasia/Myeloproliferative disease (2.27). There was a significant treatment interaction (p= 0.043) between PC type and acute myelogenous leukemia (AML), increased OR = 1.49 for CPC versus PRPC. Conclusions. PRPC did not potentiate pulmonary injury during PC support; and their use may decrease TEAMV risk with benefit of reduced TTI risk. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

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