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221 Analysis of a Global Registration Trial of the Efficacy and Safety of CTL019 in Pediatric and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)Clinically Relevant Abstract

Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Advances in Immunotherapy
Saturday, December 3, 2016: 5:00 PM
Marriott Grand 11-13 (Marriott Marquis San Diego Marina)

Stephan A. Grupp, MD, PhD1,2,3,4, Theodore W Laetsch, MD5,6*, Jochen Buechner, MD, PhD7*, Henrique Bittencourt, MD, PhD8,9,10*, Shannon L Maude, MD, PhD1,4, Michael R. Verneris, MD11, Gary D Myers, MD12*, Michael W Boyer, MD13, Susana Rives, MD, PhD14*, Barbara De Moerloose, MD15,16*, Eneida R. Nemecek, MD17, Krysta Schlis, MD18*, Paul L. Martin, MD, PhD19, Muna Qayed, MD, MSc20, Peter Bader, MD21, Hidefumi Hiramatsu, MD, PhD22, Francoise Mechinaud, MD FRACP23*, Gregory A Yanik, MD24*, Christina Peters, MD25*, Andrea Biondi, MD26, Andre Baruchel, MD27,28, Nicolas Boissel, MD, PhD29, Joerg Krueger, MD30,31*, Carl H June, MD32, Kapildeb Sen, PhD33*, Yiyun Zhang, PhD33*, Karen E Thudium, PharmD, MS33*, Patricia A Wood, MD, PhD33, Tetiana Taran, MD33* and Michael A Pulsipher, MD34

1Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
2Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA
3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
4Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
5Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
6Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, TX
7Division of Paediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
8Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
9Hematology Oncology Division, CHU Sainte-Justine, Montreal, QC, Canada
10Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, QC, Canada
11Adult and Pediatric Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN
12Children’s Mercy Hospital and Clinics, Kansas City, MO
13Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City, UT
14Hospital Sant Joan de Déu, Barcelona, Spain
15Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
16Cancer Research Institute Ghent (CRIG), Ghent, Belgium
17Pediatric Hematology/Oncology & Bone Marrow Transplantation, Oregon Health & Science University, Portland, OR
18Oregon Health and Sciences University, Portland, OR
19Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, NC
20Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA
21Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
22Department of Pediatrics, Graduate School of Medicine Kyoto University, Kyoto, Japan
23Children's Cancer Centre, The Royal Children's hospital, Melbourne, Australia
24Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI
25Stem Cell Transplantation Unit, St. Anna Children’s Hospital, Vienna, Austria
26Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital/Fondazione MBBM, Monza, Italy
27Pediatric Hematology, APHP Hopital Robert Debré, Paris, France
28University Paris Diderot 7, Paris, France
29Hematology, Hôspital Saint-Louis, Paris, France
30The Hospital For Sick Children, Toronto, ON, Canada
31University of Toronto, Toronto, ON, Canada
32Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
33Cell & Gene Therapies, Novartis Pharmaceuticals Corporation, East Hanover, NJ
34Division of Hematology Oncology/Blood and Marrow Transplant, Children’s Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA

A single-center trial of CD19 directed, lentiviral transduced chimeric antigen receptor (CAR) T cells (CTL019) for relapsed and refractory (r/r) B-ALL pediatric patients showed rates of CR >90% with prolonged CAR T cell persistence/CR without further therapy in the majority of patients infused (Maude NEJM 2014).

We report here the feasibility, safety and efficacy of the first multicenter global pivotal registration CAR T cell trial. Features of this trial include: i) the first trial in which industry-manufactured cells were provided to all patients; ii) enrollment across 25 centers in the US, EU, Canada, Australia, and Japan; iii) successful transfer and manufacturing of cells in a global supply chain; and iv) successful implementation of cytokine release syndrome (CRS) management across a global trial. All patients had CD19 positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts), and were either primary refractory; chemo-refractory after first relapse, relapsed after second line therapy; or ineligible for allogeneic SCT. CTL019 was manufactured from patient PBMC under GMP conditions in the US, at a centralized “sponsor-owned” manufacturing facility, and supplied to all sites. The primary endpoint of overall remission rate (CR+CRi) within 3 months and secondary endpoints (EFS, DOR, OS and safety) were assessed by an independent review committee.

Based on preliminary data as of March 2016, 57 patients were enrolled. There were 3 manufacturing failures (5%), 5 patients were not infused due to death or adverse events (9%), and 15 patients were pending infusion at the data cut off. Following fludarabine/cyclophosphamide lymphodepleting chemotherapy in the majority of the patients, 34 patients (median age 11 [3-23], 50% with prior HSCT) were infused with a single dose of CTL019 at a median dose of 2.9 x106 transduced CTL019 cells/kg (0.2 to 4). Among 29 patients reaching D28 prior to the data cutoff, 83% (24/29) achieved CR or CRi by local investigator assessment, all of which were MRD-negative. Two early deaths occurred prior to initial disease assessment, one due to disease progression and one due to intracranial hemorrhage. Two patients did not respond. One patient was in CR by BM at D28, but CSF was not assessed, therefore this patient was classified as “incomplete” assessment.

Safety was managed by a protocol-specified CRS algorithm with no cases of refractory CRS. Using the Penn CRS grading scale, 82% of patients experienced CRS, with 7 grade 3 (21%) and 8 grade 4 (24%) events. 44% patients with CRS required anti-cytokine therapy; all received tocilizumab with or without other anti-cytokine therapy, with complete resolution of CRS. Besides CRS, the most common grade 3 and 4 non-hematologic AEs were febrile neutropenia (29%), increased bilirubin (21%), increased AST (21%), and hypotension (21%). 21% of patients experienced grade 3 or 4 neuropsychiatric events including confusion, delirium, encephalopathy, agitation and seizure; no cerebral edema was reported. CTL019 in vivo cellular kinetics by qPCR demonstrated transgene persistence in blood in responding patients at and beyond 6 months. Overall exposure (AUC 0-28d) and maximal expansion (Cmax) of CTL019 DNA measured by qPCR was higher in responding compared with non-responding patients.

In summary, this pivotal global study in pediatric and young adult patients with r/r B-ALL receiving CTL019, confirms a high level of efficacy and a similar safety profile to that shown in the prior single center experience. Safety was effectively and reproducibly managed by appropriately trained investigators. The study has completed accrual. At the meeting, updated data from a planned formal interim analysis including safety, efficacy (primary and selected secondary endpoints), cellular kinetics, and impact of anti-cytokine therapy will be presented for more than 50 patients infused at 25 global sites.

Disclosures: Grupp: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Laetsch: Novartis: Consultancy; Loxo Oncology: Consultancy. Bittencourt: Seattle Genetics: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Educational Grant. Maude: Novartis: Consultancy. Myers: Novartis Pharmaceuticals: Consultancy. Rives: Novartis: Consultancy; Jazz Pharma: Consultancy. Nemecek: Medac, GmbH: Research Funding; Novartis: Consultancy; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schlis: Novartis: Honoraria. Bader: Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Peters: Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy; Medac: Consultancy. Biondi: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees. Baruchel: Servier: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz: Consultancy; Baxalta: Research Funding. June: University of Pennsylvania: Patents & Royalties; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Tmunity: Equity Ownership, Other: Founder, stockholder . Sen: Novartis: Employment. Zhang: Novartis: Employment. Thudium: Novartis: Employment. Wood: Novartis Pharmaceuticals: Employment, Other: Stock. Taran: Novartis: Employment. Pulsipher: Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee; Medac: Other: Housing support for conference.

*signifies non-member of ASH