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976 HESTER: A Phase II Study Evaluating Efficacy and Safety of Tisagenlecleucel Reinfusion in Pediatric and Young Adult Patients with Acute Lymphoblastic Leukemia Experiencing Loss of B-Cell Aplasia

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, Lymphoid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Michael W Boyer, MD1, Sonali Chaudhury, MBBS, MD2*, Kara L Davis, DO3, Timothy Alan Driscoll, MD4*, Stephan A Grupp, MD, PhD5, Michelle Hermiston, MD, PhD6, Samuel John, MD7*, Amy K Keating, MD, PhD8*, Christina Kovacs, BS, JD9*, Andrea Magley, BS9*, Gary Douglas Myers, MD10*, Christine L Phillips, MD11, Michael A Pulsipher, MD12, Das Purkayastha, PhD9*, Julie-An Talano, MD13 and Jennifer Willert, MD9*

1University of Utah School of Medicine, Salt Lake City, UT
2Northwestern University Feinberg School of Medicine, Chicago, IL
3Division of Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
4Pediatric Transplant and Cellular Therapy, Duke University Medical Center, Durham, NC
5Children's Hospital of Philadelphia, Philadelphia, PA
6Department of Pediatrics (Pediatric Hematology/Oncology), University of California San Francisco, San Francisco, CA
7Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX
8Children's Hospital Colorado and University of Colorado, Aurora, CO
9Novartis Pharmaceuticals Corporation, East Hanover, NJ
10Children's Mercy Hospital, Kansas City, MO
11University of Cincinnati College of Medicine, Cincinnati, OH
12Children’s Hospital Los Angeles Cancer and Blood Disease Institute, Los Angeles, CA
13Medical College of Wisconsin, Milwaukee, WI

Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy approved for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma. The ELIANA trial showed efficacy (81% overall remission rate [ORR]; 60% complete remission [CR]) and safety of tisagenlecleucel in r/r B-ALL (Maude et al. N Engl J Med. 2018). In the ELIANA trial, sustained remissions were associated with B-cell aplasia, an expected on-target effect of tisagenlecleucel and a pharmacodynamic marker for tisagenlecleucel persistence. In some patients who demonstrated short CAR-T cell persistence, reinfusion with 1 or more additional doses of tisagenlecleucel has restored B-cell aplasia and produced a 60% CR rate in patients who were reinfused with humanized CD19-targeted CAR-T cell therapy (Maude et al. J Clin Oncol. 2016). This prolongs the period of tisagenlecleucel activity and immunosurveillance and may therefore prolong durable remission. We introduce a trial in progress investigating the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing a loss of B-cell aplasia.

Study Design and Methods: HESTER (NCT04225676) is a phase II, open-label, multicenter trial to determine the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing loss of B-cell aplasia. Eligible patients must be ≤25 years of age with a confirmed diagnosis of CD19(+) leukemia. Patients must have been previously infused with commercial tisagenlecleucel and have at least 1 additional dose of commercial tisagenlecleucel prescribed to them in the course of medical practice. Commercial tisagenlecleucel must be given for reinfusion within 9 months of the initial manufacturing date. Patients must have loss of B-cell aplasia defined as peripheral blood (PB) absolute B lymphocyte count ≥50/μL or PB B lymphocyte ≥10% of the total lymphocytes; patients are not required to be minimal residual disease negative (MRD)(-). Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status must be ≥50 at screening. Patients treated with prior gene/adoptive T-cell therapy other than tisagenlecleucel and patients with active central nervous system involvement by malignancy are excluded.

The primary efficacy endpoint is the proportion of patients who reestablish B-cell aplasia within 12 months of reinfusion as measured by circulating B lymphocytes (<50/μL) and presence of tisagenlecleucel cells by quantitative polymerase chain reaction (qPCR) in the PB. Secondary outcomes include the ORR (CR + CR with incomplete blood count recovery) during the 12 months post reinfusion, event-free survival, overall survival, MRD status, and safety; immunogenicity and tisagenlecleucel persistence (by qPCR) are exploratory endpoints. Subgroup analysis of efficacy outcomes will include patients with a loss of B-cell aplasia within 9 months of first infusion who are MRD(+) at time of enrollment, as well as patients with very early (<3 mo), early (≤3 to <6 mo), and later (≥6 mo) loss of B-cell aplasia following first infusion. Safety will be assessed throughout the trial.

For the primary analysis, a minimum of 10% of patients reestablishing B-cell aplasia within 12 months after reinfusion is expected with an estimated true rate of 25%. All secondary and exploratory variables will be summarized descriptively. Estimated enrollment is about 54 patients in the United States.

Clinical Trial Information: NCT04225676

Disclosures: Boyer: Thunder Biotech Inc: Consultancy. Grupp: Servier: Research Funding; Cellectis: Other; Roche: Consultancy; Adaptimmune: Other: SAB; Jazz: Other: SSC; TCR2: Other: SAB; GlaxoSmithKline: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Juno/BMS: Other; Janssen/JnJ: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Kite/Gilead: Research Funding; Allogene: Other; Novartis: Consultancy, Other: SSC, Research Funding. Hermiston: Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Kovacs: Novartis: Current Employment. Magley: Novartis: Current Employment. Myers: Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Pulsipher: Bellicum: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding; Novartis: Honoraria; Jasper: Honoraria. Purkayastha: Novartis: Current Employment. Willert: Novartis: Current Employment.

*signifies non-member of ASH