Kooperativer Bibliotheksverbund

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 3 ( 2020-03), p. S1-

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2019.12.135

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 382, No. 14 ( 2020-04-02), p. 1331-1342

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1914347

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2020

detail.hit.zdb_id: 1468837-2

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 754-754

Abstract: Background: Outcomes with salvage regimens in pts with MCL who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy are poor, with a median overall survival (OS) of 5.8 months (Martin, et al. Blood. 2016) and few pts proceeding to allogeneic stem cell transplant. ZUMA-2 is a Phase 2, registrational, multicenter, global study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL who received 1-5 prior therapies, including a BTKi. Here, we present interim efficacy and safety results from ZUMA-2. Methods: Eligible adults (aged ≥ 18 years) with R/R MCL had an ECOG score of 0 - 1 and ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi. Pts underwent leukapheresis and conditioning chemotherapy (cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days) followed by a single infusion of KTE-X19 at a target dose of 2 × 106 CAR T cells/kg. Pts could have received bridging therapy with dexamethasone, ibrutinib, or acalabrutinib after leukapheresis and before conditioning chemotherapy at the investigator's discretion. The primary endpoint was objective response rate (ORR [complete response (CR) + partial response]) assessed by an Independent Review Committee according to the Lugano Classification (Cheson, et al. J Clin Oncol. 2014). Interim efficacy endpoints were investigator-assessed using the revised IWG Response Criteria for Malignant Lymphoma (Cheson, et al. J Clin Oncol. 2007). Key secondary endpoints were duration of response (DOR), progression-free survival (PFS), OS, frequency of adverse events (AEs), levels of CAR T cells in blood, and levels of cytokines in serum. Efficacy and safety analyses included all pts who received KTE-X19. A total of 60 pts received KTE-X19; here, we present results in pts who had ≥ 1 year of follow-up. Updated safety and efficacy results in the full 60 pts, including pts who received revised AE management with the aim of decreasing toxicity, will be reported in the presentation. Results: As of May 30, 2018, 28 pts received KTE-X19 with ≥ 1 year of follow-up (median 13.2 months [range, 11.5 - 18.5]). The median age was 65 years (range, 50 - 75) and 86% of pts were male. Forty-three percent of pts had ECOG score of 1, 21% had blastoid morphology, 82% had stage IV disease, 50% had intermediate/high-risk MIPI, 86% received a median of 4 (range, 1 - 5) prior therapies, and 57% were refractory to last prior therapy. In 20/28 pts with available data, the median Ki-67 index was 38% (range, 5% - 80%). Eight pts received bridging therapy; all had disease present post-bridging. Investigator-assessed ORR was 86% (95% CI, 67% - 96%) with a CR rate of 57% (95% CI, 37% - 76%). As of May 30, 2018, 75% of responders remained in response and 64% of treated pts had ongoing responses. The 12-month estimates of DOR, PFS and OS were 83% (95% CI, 60% - 93%), 71% (95% CI, 50% - 84%), and 86% (95% CI, 66% - 94%), respectively and the medians were not reached. The most common Grade ≥ 3 AEs (≥ 20% of pts) were anemia (54%), platelet count decreased (39%), neutropenia (36%), neutrophil count decreased (32%), white blood cell count decreased (29%), encephalopathy (25%), and hypertension (21%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) was reported in 18% of pts, most commonly manifesting as hypotension (14%), hypoxia (14%), and pyrexia (11%). Grade 3/4 neurologic events (NE) were reported in 46% of pts and included encephalopathy (25%), confusional state (14%), and aphasia (11%). No Grade 5 CRS or NE occurred. All CRS events and most NE (15/17 pts) were reversible. Median time to onset and resolution of CRS was 2 days (range, 1 - 7) and 13 days (range, 4 - 60), respectively. Median time to onset of NE was 6 days (range, 1 - 15) and median time to resolution was 20 days (range, 9 - 99). There was 1 Grade 5 AE of organizing pneumonia that was considered related to conditioning chemotherapy. Median CAR T cell levels as measured by peak and area under the curve were 99 cells/µL (range, 0.4 - 2589) and 1542 cells/µL (range, 5.5 - 27239), respectively. Peak CAR T cell expansion was observed between Days 8 and 15 and declined over time. Conclusions: ZUMA-2 is the first multicenter Phase 2 study of CAR T cell therapy in pts with R/R MCL. With ≥ 1 year of follow-up, KTE-X19 demonstrated significant and durable clinical benefit, including a majority of pts achieving CR, and a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options. Disclosures Wang: VelosBio: Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding. Goy:Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Jacobson:Humanigen: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding. Hill:Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; Merck: Research Funding; ImmunGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Holmes:ADC Therapeutics: Research Funding; Kite, A Gilead Company: Consultancy, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy; Rigel: Consultancy, Speakers Bureau; Bayer: Consultancy; Novartis: Research Funding; Unum: Research Funding; Gilead: Consultancy; Juno: Consultancy; Seattle Genetics: Research Funding, Speakers Bureau. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. McSweeney:Fred Hutchinson Cancer Research Center: Patents & Royalties; Colorado Blood Cancer Institute Medical Group: Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:AlloGene: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy; Novartis: Consultancy; Miltenyi: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Pagel:Gilead Sciences: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Kersten:Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Gilead: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards. Peng:Kite, A Gilead Company: Employment. Rossi:Kite, A Gilead Company: Employment. Jain:Vida Ventures: Employment; Kite, A Gilead Company: Employment, Equity Ownership, Other: Travel support; Amgen: Equity Ownership. Rao:Kite, A Gilead Company: Employment. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. OffLabel Disclosure: ZUMA-2 is a clinical trial evaluating KTE-X19, an investigational CAR T cell therapy

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126064

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 20-22

Abstract: Background: KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is currently being evaluated in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who received 1 - 5 prior therapies (including a Bruton tyrosine kinase inhibitor) in the Phase 2, registrational, multicenter ZUMA-2 study. With a median follow-up of 12.3 months, we previously reported an objective response rate (ORR) of 93% (67% complete response [CR] rate) with KTE-X19 treatment in the 60 efficacy-evaluable patients in ZUMA-2 (Wang et al. N Engl J Med. 2020;382:1331). Here, we present an updated analysis of efficacy, safety, and pharmacology for all patients with a minimum follow-up of 1 year. Methods: Eligible patients with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19 (2 × 106 CAR T cells/kg; Wang et al. N Engl J Med. 2020;382:1331). The primary endpoint was ORR (CR + partial response) as assessed by an Independent Review Committee according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014;32:3059). Efficacy data are reported for the 60 treated patients with ≥ 1 year of follow-up; safety data are presented for all 68 treated patients. Results: As of December 31, 2019, the median follow-up was 17.5 months (range, 12.3 - 37.6). The ORR was 92% (95% CI, 81.6 - 97.2), with a CR rate of 67% (95% CI, 53.3 - 78.3). Of all efficacy-evaluable patients, 48% had ongoing responses at the data cutoff. Medians were not reached for duration of response, progression-free survival (PFS), or overall survival; 15-month estimates were 58.6% (95% CI, 42.5 - 71.7), 59.2% (95% CI, 44.6 - 71.2), or 76.0% (95% CI, 62.8 - 85.1), respectively. In patients who achieved a CR, the median PFS was not reached (15-month rate, 75.1% [95% CI, 56.8 - 86.5]); in those who achieved a partial response, the median PFS was 3.1 months (95% CI, 2.3 - 5.2). Median PFS was 1.1 months (95% CI, 0.9 - 3.0) in nonresponding patients. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6 - 37.6); 39.3% of these patients remain in remission with no further therapy. Common grade ≥ 3 adverse events were neutropenia (85%), thrombocytopenia (53%), anemia (53%), and infections (34%). Grade ≥ 3 cytopenias were reported in 60% of patients ≥ 30 days post-infusion. Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al. [Blood. 2014;124:188]) occurred in 15% of patients; 59% received tocilizumab for management of CRS. Grade ≥ 3 neurologic events (NEs) were reported in 31% of patients, and 38% received steroids for NE management. All CRS events and most NEs (37/43) resolved, as previously reported. There were no Grade 5 CRS events or NEs, and no new Grade 5 events occurred with additional follow-up. As previously reported, there were 2 cases of Grade 2 cytomegalovirus infection, 1 case each of Grade ≥ 3 hypogammaglobulinemia and Grade ≥ 3 tumor lysis syndrome, and no cases of Epstein-Barr virus-associated lymphoproliferation, replication-competent retrovirus, hemophagocytic lymphohistiocytosis, or KTE-X19-related secondary cancers. Median peak CAR T cell levels and median area under the curve (Days 0 - 28) were 98.9 cells/µL (range, 0.2 - 2565.8) and 1394.9 cells/µL (range, 3.8 - 27,700) in patients with ongoing responses at 12 months, 202.6 cells/µL (range, 1.6 - 2589.5) and 2312.3 cells/µL (range, 19.0 - 27,200) in patients who were relapsed at 12 months, and 0.4 cells/µL (range, 0.2 - 95.9) and 5.5 cells/µL (range, 1.8 - 1089.1) in nonresponders. Of the 57 efficacy-evaluable patients with data available, 84% had B cells detectable by flow cytometry at baseline. Of those in ongoing responses at 12 months, 10 of 26 patients (38%) with evaluable samples had B cells detectable at 3 months, and 10 of 18 (56%) had detectable B cells at 12 months; gene-marked CAR T cells were no longer detectable at 12 months in 5 of 28 evaluable patients (17%). Conclusions: The ZUMA-2 study continues to demonstrate substantial and durable clinical benefit of KTE-X19 therapy with manageable safety in patients with R/R MCL. Within this patient population, which lacks curative treatment options, most patients achieved durable CR, and no new safety signals were reported. Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL. Disclosures Wang: Verastem: Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Targeted Oncology: Honoraria; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Guidepoint Global: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; InnoCare: Consultancy; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria. Munoz:Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Innovent: Consultancy; Fosunkite: Consultancy; Beigene: Consultancy, Speakers Bureau; Alexion: Consultancy; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Millenium: Research Funding. Goy:MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Xcenda: Consultancy; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity Verastem: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment. Locke:Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options. Hill:Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Timmerman:Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Merck: Research Funding; Valor: Research Funding; Genmab: Current equity holder in publicly-traded company. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Flinn:Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Agios: Research Funding; ArQule: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Great Point Partners: Consultancy; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; Nurix Therapeutics: Consultancy; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Curio Science: Consultancy. McSweeney:Fred Hutchinson: Patents & Royalties; Colorado Blood Cancer Institute: Current Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Miltenyi Biotec: Research Funding. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy. Kersten:Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Research Funding; Roche: Research Funding; Takeda: Research Funding; Miltenyi: Consultancy, Honoraria, Other: travel support. Milpied:Celgene: Other: Travel support; Gilead Sciences: Other: consultancy or advisory role; Janssen: Honoraria; Sandoz: Honoraria, Other: consultancy or advisory role; Astellas: Honoraria; Roche: Honoraria, Other: Travel support. Fung:Takeda: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Houot:Janssen: Honoraria; Gilead: Other: Personal fees; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Beitinjaneh:Jazz: Other: speaker's bureau; Kite, a Gilead Company: Honoraria, Other: consulting or advisory role, speaker's bureau, ; ATARA: Research Funding; Gilead: Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Murugappan:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kloos:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Reagan:Curis: Consultancy; Seattle Genetics: Research Funding; Kite, a Gilead Company: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136382

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Transplantation and Cellular Therapy, Elsevier BV, Vol. 27, No. 3 ( 2021-03), p. S342-

Type of Medium: Online Resource

ISSN: 2666-6367

URL: Article

DOI: 10.1016/S2666-6367(21)00440-1

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 3056525-X

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3726-3726

Abstract: Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. The primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) demonstrated that the umbralisib+ublituximab (U2) combination prolonged progression-free survival (PFS) compared to chemoimmunotherapy in both treatment-naïve (TN) and previously treated (PT) populations (Gribben et al. 2020). Herein, results are presented for patients treated with U2 by treatment status. Methods: Patients ≥18 years of age with TN or PT CLL requiring treatment, per iwCLL criteria with adequate organ function and ECOG PS ≤2, were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (treatment-naïve vs. previously treated) and deletion 17p status. Umbralisib was administered orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. While the primary analysis reported results for the pooled intent-to-treat population, the current analysis focuses on outcomes in patients treated with U2 by treatment status. Results: At data cut-off date of May 1, 2020, U2-treated patients had a median follow-up of 35.27 months. Of the 210 patients treated with U2, 119 were TN and 91 were PT. TN patients had a median age of 68 years (39 - 88 years) and 63% were male. Median PFS for U2 in TN patients was 38.5 mos (95% CI, 33.2, NE) with an estimated 24-mo PFS rate of 76.6%. IRC-assessed ORR was 84.0% (95% CI, 77.5%-90.6%). The median duration of exposure to umbralisib and ublituximab was 26.5 and 29.5 mos, respectively. In TN patients, AEs of special interest (AESI) of grade ≥3 included: neutropenia (24.1%), diarrhea (13.8%), ALT increased (12.1%), AST increased (7.8%), non-infectious colitis (2.6%), infusion-related reaction (IRR, 0.9%), and pneumonitis (0.9%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 5.2% (neutropenia), 2.6% (diarrhea), 3.4% (ALT increase), 1.7% (AST increase), 1.7% (colitis), 0.9% (IRR), and 0.9% (pneumonitis) of patients. PT patients had a median of 2 prior (1 - 9) lines of therapy, the median age was 65 years (43 - 87 years) and 65.9% were male. Median PFS was 19.5 mos (95% CI, 14.6-27.7) with an estimated 24-mo PFS rate of 41.3%. The IRC-assessed ORR was 82.4% (95% CI, 74.6%-90.2%). Among 14 patients previously treated with ibrutinib, the ORR was 57%. The median duration of exposure to umbralisib and ublituximab were 15.6 mos and 14.6 mos, respectively. In PT patients, AESI of grade ≥3 included: neutropenia (40.0%), diarrhea (10.0%), IRR (3.3%), ALT increase (3.3%), AST increase (2.2%), and non-infectious colitis (2.2%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 1.1% (ALT increase), 1.1% (AST increase), and 1.1% (colitis) of patients. Conclusions: U2 demonstrated a tolerable safety profile in both the TN and PT populations. These results mark the first randomized Phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting. Disclosures Jacobs: Genentech: Consultancy; Jannsen: Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Verastem: Consultancy; AbbVie: Consultancy, Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau; TeneoBio: Research Funding; MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Giannopoulos: Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Wróbel: Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria. Cultrera: Beigene: Research Funding. Danilov: Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Burke: Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; Epizyme: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Roche/Genentech: Consultancy; AstraZeneca: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Beach: TG Therapeutics: Speakers Bureau. Huntington: TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria; Flatiron Health Inc.: Consultancy; Bayer: Honoraria; Servier: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Thyme Inc: Consultancy; SeaGen: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sharman: TG Therapeutics: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Lilly: Consultancy; AbbVie: Consultancy. Siddiqi: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: 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; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; DTRM: Research Funding; Ascentage: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; MEI Pharma: Research Funding; LOXO: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; BeiGene: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Pagel: AstraZeneca: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Dlugosz-Danecka: Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; AbbVie: Research Funding; Macrogenics: Research Funding; Beigene: Research Funding; MEI Pharma: Research Funding; Incyte Corp.: Research Funding; Takeda: Research Funding. Ghosh: Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Weiss: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gribben: Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Gilead/Kite: Honoraria; BMS: Honoraria; Abbvie: Honoraria; AZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147460

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 37-39

Abstract: Background: Umbralisib is an oral, once-daily, novel, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. U2 has been well-tolerated and demonstrated promising activity in heavily pre-treated CLL patients. Herein, results are presented for the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311), which evaluated U2 vs O+Chl in patients with TN and R/R CLL. Methods: Patients ≥18 years of age with treatment-naïve (TN) or relapsed/refractory (R/R) CLL requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Stratification factors included treatment status (TN vs R/R) and del(17p) status. Patients were initially randomized 1:1:1:1 to receive U2, O+Chl, umbralisib monotherapy, or ublituximab monotherapy. Following establishment of contribution comparing U2 to the single agents, patients were randomized 1:1 to U2 or O+Chl. Umbralisib was given orally at 800 mg once-daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. O was given intravenously at 1000 mg on Days 1/2 [split 100/900] , 8, and 15 of Cycle 1, and Day 1 of Cycles 2 - 6. Chl was given orally at 0.5 mg/kg on Day 1 and 15 of Cycles 1 - 6. Each cycle was 28 days. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) of U2 vs O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety (assessed from the first dose until 30 days after the last dose of study medication in each arm) as well as contribution of umbralisib and ublituximab to the U2 combination. Results: From Feb 2016 - Oct 2017, 421 pts were randomized to the U2 (n=210) or O+Chl (n=211) arms. The median age was 67 y (range, 36-91); 57% of patients (n=240) were treatment-naïve; 43% (n=181) had R/R CLL (median number of prior treatments = 1); 10% had del(17p), 20% del(11q), and 56% were IgHV unmutated. 66% were male. Demographics were well-balanced between treatment arms. At a median follow-up of 36.2 mos, U2 significantly prolonged PFS vs O+Chl (median 31.9 mos vs 17.9 mos; HR 0.546, 95% CI 0.413-0.720, P & lt;0.0001; Figure 1). Estimated 24-mo PFS rates with U2 and O+Chl were 60.8% and 40.4%, respectively. PFS improvement with U2 vs O+Chl was consistent across all subgroups examined including treatment naïve patients (median 38.5 mos vs 26.1 mos; HR [95% CI]; 0.482 [0.316-0.736] ); and relapsed/refractory patients (median 19.5 mos vs 12.9 mos; HR [95% CI]; 0.601 [0.415-0.869] ). IRC-assessed ORR was higher with U2 (83.3%; 95% CI, 78.1%-88.6%) vs O+Chl (68.7%; 95% CI, 62.2%-75.2%; P & lt;0.001). Among previously treated subjects, twenty-six (6%) received prior ibrutinib (14 on U2, 12 on O+Chl), with an ORR of 57% observed for U2 compared to 25% for O+Chl in this population. MRD data is currently being analyzed. The median treatment duration was 23 mos for U2 (range, 0.1 - 49 mos) and 5 mos (range, 0.1 - 7 mos) for O+Chl. G3/4 AEs of interest regardless of causality (U2 vs O+Chl) included neutropenia (30.6% vs 34.7%), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion related reaction (1.9% vs 3.5%), elevated AST/ALTs (8.3% vs 2%), colitis (3.4% vs 0%) and pneumonitis (2.9% vs 0%). AEs led to treatment discontinuation in 34 patients (16.5%) on U2 and 16 patients (7.6%) on O+Chl. Conclusions: UNITY-CLL is the first randomized Phase 3 study in CLL of a PI3Ki vs. chemoimmunotherapy, and the first randomized study of a PI3Ki in treatment-naive CLL. U2 exhibited a well-tolerated safety profile, and significantly improved PFS vs. standard of care chemoimmunotherapy in patients with treatment-naive and relapsed/refractory CLL. Figure Disclosures Gribben: Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Honoraria. Jurczak:Celgene: Research Funding; Afimed: Research Funding; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Janssen China R & D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Acerta: Consultancy, Research Funding; Pharmacyclics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; MEI Pharma: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding; Epizyme: Consultancy; Roche: Research Funding; MorphoSys: Research Funding; TG Therapeutics, Inc.: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months. Jacobs:Sanofi Genzyme: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Verastem: Consultancy; Seattle Genetics: Consultancy; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding. Giannopoulos:BMS-Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Florida Cancer Specialists and Research Institute: Current Employment; Sarah Canon Research Institute: Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Danilov:Nurix: Consultancy; Celgene: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Gilead Sciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; BeiGene: Consultancy; Takeda Oncology: Research Funding; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Research Funding; Bayer Oncology: Consultancy, Research Funding. Burke:Gilead: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Kura: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Roche: Consultancy; Seattle Genetics: Speakers Bureau; Celgene: Consultancy. Goldschmidt:Bristol-Myers Squibb: Speakers Bureau; Amgen: Consultancy; Blue Ridge Cancer Care: Current Employment. Huntington:Genentech: Consultancy; Astrazeneca: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; DTRM: Research Funding. Pinilla Ibarz:AstraZeneca: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Sunesis Pharmaceuticals: Consultancy; TG Therapeutics: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding. Siddiqi:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Brander:MEI Pharma: Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding. Kolibaba:TG Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other; Verastem: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; McKesson Life Sciences: Consultancy; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Therapeutics: Research Funding; Compass Oncology: Ended employment in the past 24 months. Ghosh:Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol-Myers Squibb: Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding. Sportelli:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor:Astex Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nomocan: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Other: Consulting; Servier: Consultancy. Weiss:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Flinn:Iksuda Therapeutics: Consultancy; Curis: Research Funding; Infinity Pharmaceuticals: Research Funding; F. Hoffmann-La Roche: Research Funding; Vincera Pharma: Consultancy; Karyopharm Therapeutics: Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; ArQule: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Great Point Partners: Consultancy; IGM Biosciences: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Johnson & Johnson: Other; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Curio Science: Consultancy; Nurix Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Agios: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134783

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 5, No. 23 ( 2021-12-14), p. 5332-5343

Abstract: Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82] ; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43] ; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%] ), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%] ). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2021005132

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 2876449-3

In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 4, No. 1 ( 2016-12)

Type of Medium: Online Resource

ISSN: 2051-1426

URL: Article

DOI: 10.1186/s40425-016-0188-z

Language: English

Publisher: BMJ

Publication Date: 2016

detail.hit.zdb_id: 2719863-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2577-2577

Abstract: Interleukin-21 (IL-21) is a member of the common gamma chain cytokine family, which includes IL-2, IL-7 and IL-15, and serves to activate NK cells and CD8+ T cells, as well as modulate B cell functions. Like IL-2, IL-21 can enhance antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, unlike IL-2, IL-21 can render effector T cells resistant to suppression by T reg cells, and can have direct anti-tumor effects against malignant B cells. IL-21 has been shown to promote apoptosis in follicular lymphoma cells, and to induce granzyme B expression in chronic lymphocytic leukemia cells and sensitize them to apoptosis. In a human lymphoma xenograft model, combination treatment with rituximab plus recombinant IL-21 (rIL-21) led to increased survival compared to either agent alone. To further evaluate the potential safety, pharmacokinetics, and anti-tumor effects of combining rIL-21 with rituximab, a phase 1, two-part dose-escalation study was initiated in patients with relapsed CD20+ B cell lymphomas. For dose escalation, cohorts of 3 patients each received weekly rituximab (375 mg/m2) on days -7, 0, 7, 14, and 21, and rIL-21 at 1 of 3 dose levels (30, 100, or 150 g/kg) on days 0, 7, 14, and 21. Patients without disease progression at day 36 were eligible to receive a second cycle beginning 2 weeks later, and CT scan assessments were repeated at day 50 of cycle 2. Enrollment to an expansion cohort of up to 12 additional patients for treatment at the maximum tolerated dose was initiated. A total of 15 patients have been enrolled to date, including 9 dose-escalation patients, all of whom are evaluable for clinical response. The latter include 4 with follicular lymphoma, 4 with small lymphocytic leukemia (SLL), and 1 with marginal zone lymphoma. The median number of prior regimens was 3 (range 1–8), with 8/9 patients having had prior rituximab (1–3 cycles). No patient receiving 100 g/kg or higher of rIL-21 had disease progression, and 7 of 9 patients completed 2 treatment cycles. Overall best responses included 2 CR, 3 PR (including 2 patients whose last response to rituximab lasted & lt; 6 months), and 3 SD by Cheson criteria, for an overall response rate of 56%. No dose limiting toxicities occurred in the first cycle at any dose. Most adverse events were grade 1–2 and included flu-like symptoms, fatigue, pruritus, insomnia, and diarrhea. Laboratory abnormalities were generally mild to moderate and included lymphopenia, transaminase elevations, thrombocytopenia in one patient and hypophosphatemia. Retreatment at 150 g/kg was associated with transient grade 3 nausea, vomiting, and diarrhea in one patient, while a second patient had grade 2 lower extremity edema. Thus, the 100 g/kg dose was chosen for cohort expansion. Combination treatment with interleukin-21 plus rituximab for up to two 4-week cycles is generally well-tolerated and associated with clinical responses, even in subjects heavily pre-treated with rituximab. Enrollment in the 100 g/kg expansion cohort is ongoing. These encouraging results support further evaluation of this combination in phase 2 trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.2577.2577

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7