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Phase 1 Clinical Results of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Frederick L. Locke, Sattva S. Neelapu, Nancy L Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Armin Ghobadi, Lihua E. Budde, Lynn Navale, Jeff S. Aycock, Jeff Wiezorek and William Y. Go

Abstract

This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®

Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) (Kochenderfer et al. Blood 2012, J Clin Onc 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). The ZUMA-1 trial 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. Preliminary phase 1 results presented.

Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (minimum 1 x 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 is to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Cytokine release syndrome (CRS) was graded per revised criteria (Lee et al. Blood 2014). Key secondary objectives include evaluating the overall response rate (ORR=CR+PR) per Cheson 2007, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as stable disease or progressive disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Subjects must have received at least prior anti-CD20 therapy and an anthracycline containing regimen.

Results: As of 28 July 2015, 6 subjects were dosed in the phase 1 portion of the study. All subjects are evaluable for safety with a median follow up time of 4.8 weeks post KTE-C19 infusion and 3 subjects have had 1 month tumor assessments. Two subjects experienced only grade (gr) 1-2 KTE-C19 related events. Three subjects had gr 3 KTE-C19 related events as highest gr toxicities; all these events were reversible within 3 days. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. One subject experienced a DLT of gr 4 encephalopathy and gr 4 CRS. This subject died within 30 days of KTE-C19 cell infusion; the death was due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Of the 3 subjects assessed for response at one month, 2 achieved a complete response and one achieved a partial response. Key safety and efficacy findings are summarized in the table. Biomarker and translational endpoints are included in a separate abstract. Enrollment is ongoing and updated trial results will be presented.

Conclusions: Preliminary phase I results ofthe ZUMA-1 study demonstrate that KTE-C19 can be centrally manufactured and administered in a multicenter trial. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease at 1 month after KTE-C19 administration. This potentially pivotal study is the first enrolling multicenter anti-CD19 CAR T cell trial in refractory aggressive NHL. Clinical trial: NCT02348216.

SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsResponse at 1 Month
101-002-001M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved) Partial Response
101-002-003M/69/1DLBCLRefractory to 2nd line chemotherapy Gr 3 tremor (resolved)
Gr 3 delirium (resolved)
Gr 3 agitation (resolved)
Gr 3 restlessness (resolved)
Gr 3 somnolence (resolved)
Complete Response
101-009-001F/29/1PMBCLRefractory to 1st, 2nd, 3rd line chemotherapyGr 4 CRS
Gr 4 encephalopathy
N/A
101-003-001M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Response
101-002-004M/69/0DLBCLRefractory to 4th line chemotherapyGr 3 encephalopathy (resolved)Assessment not yet reached
101-003-002F/34/0DLBCLRelapse ≤ 12 mo after ASCTNoneAssessment not yet reached
Table 1.

mo - months

M - male, F - female

N/A - not applicable

Disclosures Locke: Kite Pharma: Other: Scientific Advisory Boards. Off Label Use: Tocilizumab for CRS per Blood et al. 2014. Bartlett: Kite: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Colgene: Research Funding; Millennium: Research Funding; MERC: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Medimmune: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Siddiqi: Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Navale: Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Go: Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership.

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