Phase 1 Results of ZUMA-3: KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)
Authors: Shah Bijal D. , Stock Wendy , Wierda William G , Oluwole Olalekan , Holmes Houston , Schiller Gary J. , Topp Max S. , Kersten Marie José , Houot Roch , Boissel Nicolas , Mojadidi Michelle , Xue Allen , Mardiros Armen , Jiang Yizhou , Shen Tong , Aycock Jeff S. , Stout Shanna , Wiezorek Jeffrey S. , Jain Rajul 
Published: April 2021

Abstract

Background : Approximately 45% of new ALL cases occur in adults ≥ 20 years of age (Howlader et al. SEER Cancer Statistics. 2015), and approximately 50% of adult patients relapse with poor subsequent outcomes (Oriol et al. Haematologica. 2010; Basson et al. JCO. 2011). Promising early efficacy and manageable safety were previously reported with anti-CD19 CAR T cells (KTE-C19) in adult patients with R/R ALL (Shah et al. ASCO 2017. #3024). Here we report updated results of the ZUMA-3 trial.
Methods : Adult patients (≥ 18 years of age) with R/R ALL (Philadelphia+ eligible), &gt; 5% bone marrow (BM) lymphoblasts; Eastern Cooperative Oncology Group performance status (ECOG) 0-1; and adequate renal, hepatic, and cardiac function were eligible. Patients with active graft-versus-host disease or clinically significant infection were not eligible. Patients received a target dose of 1 × 106 CAR T cells/kg or 2 × 106 CAR T cells/kg after lymphodepletion with 25 mg/m2/day fludarabine for 3 days and 900 mg/m2/day cyclophosphamide given on the last day. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence of adverse events (AEs), incidence of minimal residual disease-negative (MRD-) responses, duration of remission (DOR), relapse-free survival (RFS), and overall survival (OS). Exploratory endpoints included levels of anti-CD19 CAR T cells in blood and levels of cytokines in serum.
Results : As of the data cut-off date (DCO; April 26, 2017), 22 patients have been enrolled, and 16 patients received KTE-C19 on study. Four patients had not received treatment by the DCO, 1 patient did not receive KTE-C19 due to an AE after conditioning, and 1 patient received KTE-C19 under compassionate use. All 16 patients who received KTE-C19 prior to the DCO were included in the safety analysis, and all patients who had the opportunity to be followed for 8 weeks prior to the DCO were included in the efficacy analysis (n = 11). Of the 16 patients dosed with KTE-C19, 63% were male, 56% had ECOG 1, and 50% had received ≥ 2 previous lines of treatment, including 3 patients with prior blinatumomab. Nineteen percent of patients had undergone prior allogeneic stem cell transplant, 31% had R/R to ≥ second-line therapy, 31% had primary refractory disease, and 19% experienced first relapse within 12 months of first remission. Most patients (81%) had baseline BM blasts ≥ 60%.
Six patients received the 2 × 106 cells/kg dose and 10 received the 1 × 106 cells/kg dose. No DLTs were observed. One patient experienced a grade 5 event of cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose, and no other KTE-C19-related grade 5 AEs were observed. In the 16 patients who received KTE-C19, all of whom were followed for at least 4 weeks, the most common grade ≥ 3 AEs were hypotension (56%), anemia (50%), pyrexia (50%), and decreased platelet counts (44%). Grade ≥ 3 CRS and neurologic events (NE) were reported in 25% and 63% of patients, respectively. Tocilizumab (toci) or steroids were given for AE management in 94% and 75% of patients, respectively. In the 11 patients eligible for the efficacy analysis, objective response rate was 82%, including 8 (73%) patients with a complete remission (CR or CR with partial hematopoietic recovery), and 1 (9%) with blast-free BM. All remissions were MRD- as determined by flow cytometry. All 5 (100%) of the other patients who were too early for inclusion in the efficacy analysis had MRD- bone marrow with varying degrees of count recovery at the time of the DCO. Median follow-up was 6.8 months; 4 patients relapsed 63 - 168 days after treatment with KTE-C19. Efficacy was comparable between patients who recieved KTE-C19 doses of 1 × 106 and 2 × 106 CAR T cells/kg. Data from additional patients, including those treated with a lower dose of 0.5 × 106 CAR T cells/kg, as well as updated safety, efficacy, biomarker, and product characteristic analyses across dosing groups will be presented.
Conclusions : In this ongoing phase 1 study, KTE-C19 has shown promising efficacy in adult patients with R/R ALL. The safety profile was generally manageable and additional approaches to improve the benefit:risk profile are being explored. ZUMA-3 continues to enroll additional patients at the 0.5 × 106 CAR T cells/kg dose level.

Disclosures
Wierda: AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Juno: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding. Oluwole: Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Schiller: Kite Pharma: Research Funding. Topp: Regeneron: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Celgene: Other: Travel; Macrogenics: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Research Funding. Kersten: Kite Pharma: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millenium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Mojadidi: Kite Pharma: Employment, Equity Ownership. Xue: Kite Pharma: Employment, Equity Ownership. Mardiros: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Shen: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Stout: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Jain: Kite Pharma: Employment, Equity Ownership.