Aycock, Jeff

Abstract Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, for the treatment of patients with refractory, aggressive NHL. The objective response rate (ORR) was 82% with a 54% rate of complete response and 44% of responses were ongoing at the time of the primary analysis (Locke et al. AACR 2017. #9986). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of patients, respectively. A safety expansion cohort was added to further characterize mechanisms underlying CRS and NE associated with CAR T cell therapy and to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs). Methods: Patients (≥ 18 years) must have had an Eastern Cooperative Oncology Group performance status of 0-1 and refractory or relapsed transplant ineligible disease. Patients received low-dose conditioning of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice a day on day 0 and 8 mg/kg of tocilizumab on day 2 post axi-cel infusion. To evaluate the mechanisms of NE, paired serum and cerebrospinal fluid (CSF) were obtained for all patients prior to conditioning chemotherapy and after axi-cel infusion (day 5). Results: As of April 26, 2017, 31 patients received axi-cel. Median age was 51 years (range, 21-74), 52% were male, 65% had stage III-IV disease, 74% were refractory to ≥ second-line therapy, and 19% relapsed ≤ 12 months after autologous stem cell transplant. Most patients (97%) experienced at least 1 grade ≥ 3 AE. The most common grade ≥ 3 AEs were neutropenia/neutrophil count decreased (71%), anemia (55%), thrombocytopenia/platelet count decreased (52%), leukopenia/white blood cell count decreased (35%), febrile neutropenia (29%), encephalopathy (23%), and hypotension (23%). One patient (3%) experienced a grade ≥ 3 (grade 4) CRS. Grade 3 and 4 NE occurred in 29% and 6% of patients, respectively. One patient died of cerebral edema; there were no other deaths due to AE. Updated efficacy, safety, subgroups, and paired blood/serum/CSF biomarker associative analyses will be presented. Conclusions : Early use of tocilizumab may reduce the incidence of severe CRS but not NE in patients treated with CAR T cell therapy. These data provide evidence that the underlying pathophysiology of NE may differ from that of CRS. Understanding the mechanisms of NE may help to further improve the benefit:risk profile for CAR T cell therapy. Drs Locke and Neelapu contributed equally to this work. Disclosures Locke: Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Neelapu: Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobson: Pharmacyclics, LLC: Consultancy; Kite Pharma: Consultancy. Braunschweig: Kite Pharma: Equity Ownership. Oluwole: Kite Pharma: Consultancy. Siddiqi: Seattle Genetics: Speakers Bureau; Juno: Other: Steering committee for JCAR017; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman: Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan: Seattle Genetics: Research Funding. Bot: Kite Pharma: Employment, Equity Ownership. Rossi: Kite Pharma: Employment, Equity Ownership. Sherman: Kite Pharma: Employment, Equity Ownership. Navale: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Elias: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Go: Kite Pharma: Employment, Equity Ownership. Miklos: Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria.

Abstract Background: Patients (pts) with refractory aggressive non-Hodgkin lymphoma (NHL) have poor outcomes with currently available therapies, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months (mo) as demonstrated in the 635 pt SCHOLAR-1 meta-analysis (Crump, ASCO 2016; abstract 7516). ZUMA-1 is the first multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells in refractory, aggressive NHL (NCT02348216). The phase 1 portion of ZUMA-1 showed ongoing CRs at 12+ mos in 43% of pts (Locke, ESMO 2016; abstract 1048O). The pivotal phase 2 portion of ZUMA-1 comprises 2 cohorts based on tumor type: DLBCL (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2). Here, we present results of a prespecified interim analysis from cohort 1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after a low-dose conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint is objective response rate (ORR) per 2007 IWG criteria. Key secondary endpoints include duration of response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. Key inclusion criteria include age ≥18 years, ECOG performance status (PS) 0-1, and refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 mos after autologous stem cell transplant (ASCT). Pts must have received a prior anti-CD20 antibody and an anthracycline-containing regimen. A prespecified interim analysis was to be conducted to determine early efficacy with a nominal alpha level of 0.017 in 50 treated pts in cohort 1 with a minimum follow-up of 3 mos. Results: In total, 111 pts from 22 institutions were enrolled and leukapheresed, and 101 pts received KTE-C19. As of August 24, 2016, 51 pts in cohort 1 were eligible for analysis. Median age was 58 years (range, 25-76), 73% were male, 71% had ECOG PS 1, 78% were refractory to ≥2 lines of therapy, 20% relapsed ≤12 mos of ASCT, and 61% were treated with ≥3 lines of prior therapy. KTE-C19 was successfully manufactured in 99% of pts enrolled. Average turnaround time from apheresis to receipt of KTE-C19 at the clinical site was 17.4 days. With an ORR of 76%, the study met the primary endpoint (P<0.0001; exact binomial test comparing observed ORR to a historical control assumption of 20%), with 47% CRs and 29% PRs. 92% of responses occurred within the 1st mo, and 39% of pts had ongoing responses (CR in 33%) at 3 mos. Responses were seen across key covariates, including refractory subgroup (refractory to chemotherapy=76%, relapse post ASCT=80%). Kaplan-Meier estimates of progression-free survival at 1 and 3 mos were 92% and 56%, respectively. The most common grade ≥3 treatment-emergent AEs were neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 20% and 29% of pts, respectively. There was 1 grade 5 KTE-C19-related event of hemophagocytic lymphohistiocytosis. CAR T cells expanded within 14 days of KTE-C19 infusion, and peak expansion was associated with ongoing response at mo 3 (P=0.008). Pts who developed grade ≥3 neurological events had increased serum levels of IL-15 (P=0.0002), IL-6 (P=0.003); IL-10 (P=0.009) and IP-10 (P=0.0003). Cytokines/chemokines returned to baseline levels in most pts by day 28. Data from 93 pts with at least 1 mo of follow-up at the data cutoff will be presented. Conclusions: ZUMA-1 is the first reported multicenter trial of CAR T cell therapy in pts with refractory aggressive NHL. KTE-C19 induced a nearly 6-fold higher CR rate compared to historical outcomes in SCHOLAR-1. Efficacy strongly associated with peak CAR T levels. Central manufacturing, logistics, and AE management were successfully implemented across 22 sites, most with no prior CAR T therapy experience. Results from cohort 2 of ZUMA-1 are also presented (Abstract #998). KTE-C19 demonstrated significant clinical benefit in pts with no curative treatment options. Supported in part by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program®. Drs Neelapu and Locke contributed equally to this study. Disclosures Neelapu: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke:Kite: Membership on an entity's Board of Directors or advisory committees. Miklos:pharmacyclics: Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Siddiqi:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lin:Mayo Clinic: Employment; Janssen: Research Funding. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Goy:COTA: Membership on an entity's Board of Directors or advisory committees; Janssen/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Other: Research funding for clinical trials through institution. Smith:Abbvie: Research Funding; Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria. Deol:Jazz Pharmaceuticals: Consultancy. Avivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche. Westin:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Levy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.

7512 Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]

Abstract Introduction: Outcomes for pts with refractory aggressive NHL are poor with current therapies (Crump, ASCO 2016). Results from the interim analysis of (n=62) of ZUMA-1, the 1st multicenter trial of an anti-CD19 chimeric antigen receptor (CAR) T cell, axi-cel, in refractory aggressive NHL, showed an objective response rate (ORR) of 79% (complete response [CR] 52%; Blood 2016;128:LBA-6). Here we present results from the primary analysis of ZUMA-1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after lowdose conditioning with cy/flu. Eligible pts (≥18 y) had diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL); an ECOG performance status (PS) 0-1; and refractory disease (progressive or stable disease as best response to last prior therapy, or relapsed ≤12 m of autologous stem cell transplant [ASCT]). The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), and frequency of adverse events (AEs). The primary analysis was triggered when 92 pts had at least 6 m of follow-up. Results: As of January 27, 2017, 111 pts from 22 institutions were enrolled; 101 pts (91%) received axi-cel. Median age was 58 y (range, 23-76), 67% male, 85% stage IIIIV, 47% IPI 3-4, 77% refractory to ≥2nd line of therapy, and 21% relapsed ≤12 m of ASCT. Axi-cel was successfully manufactured in 110/111 (99%) pts with an average turnaround time from apheresis to the clinical site of 17 d. With an ORR of 82% (n = 92; P&lt;.0001) the study met the primary endpoint. The ORR in the mITT analysis set of 101 pts was 82% (CR 54%, PR 28%), and was consistent across key covariates including disease subtype, refractory status, stage, and IPI score. At a median follow up of 8.7 m, 44% of pts were in response and 39% were in CR. The median DOR was 8.2 m overall and not reached for pts who achieved a CR. Median OS was not reached; 80% of pts remained alive at 6 m. The most common Gr ≥3 treatmentemergent AEs were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), and encephalopathy (21%). Gr ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of pts, respectively. All CRS and all NE resolved except 1 Gr 1 memory impairment. As previously reported, there were 3 Gr 5 AEs (3%). Peak and cumulative CAR T levels post-axi-cel were associated with durable responses. Conclusions: Axi-cel significantly improved ORR in patients with refractory aggressive NHL. The CR rate was 7-fold higher compared to historical controls (Crump, ASCO 2016) and nearly half the patients have an ongoing response. Axi-cel demonstrated significant clinical benefit with a manageable safety profile in pts lacking curative treatment options.[F.L.L. and S.S.N. contributed equally to this study.] Funding source: Kite Pharma and in part by funding from the Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program treatment options. Citation Format: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Jonathan W. Friedberg, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, Jeff Wiezorek, William Y. Go. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT019. doi:10.1158/1538-7445.AM2017-CT019