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Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Stephen J. Schuster, Michael R. Bishop, Constantine S. Tam, Edmund K. Waller, Peter Borchmann, Joseph P. McGuirk, Ulrich Jaeger, Samantha Jaglowski, Charalambos Andreadis, Jason R. Westin, Isabelle Fleury, Veronika Bachanova, Stephen Ronan Foley, P. Joy Ho, Stephan Mielke, John M. Magenau, Harald Holte, Koen Van Besien, Marie Jose Kersten, Takanori Teshima, Kensei Tobinai, Paolo Corradini, Oezlem Anak, Lida Bubuteishvili Pacaud, Christopher del Corral, Rakesh Awasthi, Feng Tai, Gilles Salles and Richard Thomas Maziarz

Abstract

BACKGROUND: CTL019 (tisagenlecleucel) is an investigational chimeric antigen receptor (CAR) T-cell therapy that identifies and eliminates CD19-expressing B cells. JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of CTL019 in adults with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with the best overall response (ORR) of 59% (complete response [CR], 43%; partial response [PR], 16%). Here, we report the results of the primary analysis of the JULIET study.

METHODS: Eligible patients were 18 years or older with r/r DLBCL and had progressed after receiving ≥2 lines of chemotherapy, and were ineligible for or failed autologous stem cell transplant (auto-SCT). Centrally manufactured CAR T cells were provided to patients at 27 study centers in 10 countries on 4 continents using cryopreserved apheresis, central production facilities and a global supply chain. CTL019 was manufactured at 2 sites (United States and Germany). Autologous T cells were transduced with a lentiviral vector encoding an anti-CD19 scFv-CD3ζ-4-1BB CAR, expanded ex vivo, cryopreserved, shipped, and infused at study centers. The primary endpoint was best ORR (CR + PR) per independent review committee.

RESULTS: As of data cutoff (8 March 2017), 147 patients were enrolled and 99 were infused with a single dose of CTL019 transduced cells (median, 3.1 × 108 [range, 0.1-6.0 × 108] cells). 90% of patients received bridging therapy. Prior to infusion, patients underwent restaging, and 93% received lymphodepleting chemotherapy (73% received fludarabine 25 mg/m2/cyclophosphamide 250 mg/m2/day × 3 days and 19% received bendamustine 90 mg/m2/day × 2 days). Median time from infusion to data cutoff was 5.6 months. The median age was 56 years (range, 22-76); 77% of patients had stage III or IV disease at study entry. The median number of prior lines of antineoplastic therapy was 3 (range, 1-6; 95% received ≥2 and 51% received ≥3 prior lines); 47% of patients had prior auto-SCT.

In this primary analysis of patients who received CTL019 from the US manufacturing site, among 81 infused patients with ≥3 months follow-up or earlier discontinuation the best ORR was 53.1% (95% CI, 42% to 64%; P <.0001) with 39.5% CR and 13.6% PR. At month 3, the CR rate was 32% and the PR rate 6%. Among patients evaluable at 6 months (n=46), the CR rate was 30% and PR rate was 7%. Response rates were consistent across prognostic subgroups (including those who received prior auto-SCT and those with double-hit lymphoma). Median duration of response was not reached; the 6-month probability of being relapse free was 73.5% (95% CI, 52.0% to 86.6%). Median overall survival was not reached; the 6-month probability of overall survival was 64.5% (95% CI, 51.5% to 74.8%). No patient who achieved a response (CR or PR) proceeded to allogenic- or auto-SCT. CTL019 was detected in peripheral blood by quantitative PCR for up to 367 days in responders.

Overall, 86% of patients had grade 3 or 4 adverse events (AEs). Cytokine release syndrome (CRS) occurred in 58% of infused patients, with 15% grade 3 and 8% grade 4 using the Penn grading scale and managed by a protocol-specific algorithm. 15% of patients received anti-IL6 therapy, tocilizumab, for CRS management with good response and 11% of patients received corticosteroids. Other grade 3 or 4 AEs of special interest included neurologic AEs (12%, managed with supportive care), cytopenias lasting >28 days (27%), infections (20%), and febrile neutropenia (13%). Three patients died within 30 days of infusion, all due to disease progression. No deaths were attributed to CTL019. No CRS or neurologic event associated deaths occurred.

CONCLUSIONS: CTL019 produces high response rates with 95% of CRs at 3 months being sustained at 6 months in a cohort of highly pretreated adult patients with r/r DLBCL, results which confirm the findings of our earlier interim analysis. Centralized manufacturing was feasible in the first global study of CAR T cell therapy in DLBCL. CRS and other AEs could be effectively and reproducibly managed by appropriately trained investigators without treatment-related mortality.

Disclosures Schuster: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen R&D: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy; Nordic Nanovector: Consultancy; Merck: Research Funding. Tam: Janssen Cilag: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Waller: Katz Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Cambium Medical Technologies: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Celldex: Consultancy; Helocyte: Consultancy; Coulter Foundation: Research Funding; AMGEN: Consultancy; Chimerix: Equity Ownership; Cerus: Equity Ownership; PRA: Consultancy; National Institutes of Health: Research Funding. Borchmann: Novartis Pharmaceuticals Corporation: Honoraria. Jaeger: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. Andreadis: Astellas: Honoraria; Pharmacyclics: Research Funding; Incyte Pharmaceuticals: Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria; Genentech Inc.: Employment, Equity Ownership, Honoraria; Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Gilead Sciences: Honoraria. Westin: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Fleury: Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Foley: Novartis Pharmaceuticals Corporation: Consultancy. Ho: Amgen, Bristol-Myers Squibb, Celgene, Novartis, Janssen, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mielke: KIADIS Pharma: Other: Travel grants; Jazz Pharma: Speakers Bureau; Novartis: Consultancy; Celgene: Other: Travel grants, Speakers Bureau; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Cellex GmbH: Other: Travel grants, Speakers Bureau; DGHO: Other: Travel support; ISCT: Other: Travel support. Holte: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Oslo University Hospital: Employment; Nordic Nanovector: Consultancy. Kersten: MSD: Honoraria; BMS: Honoraria; Gilead Sciences: Honoraria; Mundipharma: Honoraria; Milennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite Pharma: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Amgen: Honoraria. Teshima: Bristol-Myers Squibb: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Kyowa-Hakko Kirin: Research Funding; Pfeizer: Research Funding; Chugai: Research Funding. Tobinai: Janssen: Honoraria, Research Funding; Servier: Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; GlaxoSmithKline: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Corradini: Takeda: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Amgen: Honoraria. Anak: Novartis Pharma AG: Employment. Bubuteishvili Pacaud: Novartis Pharma AG: Employment. del Corral: Novartis Pharmaceuticals Corporation: Employment. Awasthi: Novartis Pharmaceuticals Corporation: Employment. Tai: Novartis Pharmaceuticals Corporation: Employment. Salles: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc: Patents & Royalties.

  • * Asterisk with author names denotes non-ASH members.