745. Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)
Authors: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Armin Ghobadi, Lihua E. Budde, Adrian Bot, John M. Rossi, Marika Sherman, Lynn Navale, Meg Elias, Jeff Wiezorek, William Y. Go
Journal: Molecular Therapy (2016)

Introduction: Anti-CD19 CAR T cells with CD3-zeta and CD28 signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies at the NCI (Kochenderfer et al. Blood 2012, JCO 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). ZUMA-1 is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Methods: Subjects received KTE-C19 at a target dose of 2 × 106 (minimum 1 × 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day for 3 days. The primary objective of phase 1 was to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Key secondary objectives were overall response rate, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria were ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Results: As of 20 Nov 2015, 7 subjects were dosed in the phase 1 portion of the study. All subjects were evaluable for safety and 6 were evaluable for efficacy with a median follow up time of 13 weeks post KTE-C19 infusion. One subject experienced a DLT of grade (gr) 4 encephalopathy and gr 4 cytokine release syndrome (CRS) and died due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Key safety and efficacy findings are summarized in the table. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. 5 of 7 subjects (71%) had an objective response including 4 complete remissions (57%). Three subjects have ongoing complete remission at 3 months. CAR T cells peaked within two weeks post infusion were detectable 1-3+ months post infusion. Updated clinical and biomarker results will be presented. Conclusions: The KTE-C19 regimen evaluated was safe for further study. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease. KTE-C19 can be centrally manufactured and administered in a multicenter trial. The potentially pivotal phase 2 portion of the study is ongoing. Clinical trial: NCT02348216. Tabled 1SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsBest Response1M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved)Partial Response2M/69/1DLBCLRefractory to 2nd line or later line chemotherapyGr 3 tremor (resolved) Gr 3 delirium (resolved) Gr 3 agitation (resolved) Gr 3 restlessness (resolved) Gr 3 somnolence (resolved)Complete Remission*relapsed and retreated with an ongoing PR3M/69/0DLBCLRefractory to 2nd line or later line chemotherapyGr 3 encephalopathy (resolved)Stable Disease4M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Remission Ongoing 3 mo+5F/34/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 hypoxia (resolved)Complete Remission Ongoing 3 mo+6M/40/0DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Remission Ongoing 3 mo+7F/29/1DLBCLRefractory to 2nd line or later line chemotherapyGr 4 CRS Gr 4 encephalopathyNEmo – months, M – male, F – female, NE – not evaluable,* relapsed and retreated with an ongoing PR Open table in a new tab mo – months, M – male, F – female, NE – not evaluable,