Shah, Bijal

TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.

7010 Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adult R/R B-ALL based on the ZUMA-3 study. The overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) was 71% (95% CI, 57-82) after 16.4 mo median follow-up (N = 55; Shah et al. Lancet 2021). Here, we report updated outcomes with longer follow-up in these pts and in a larger pooled analysis of Phase (Ph) 1 and 2 pts who received the pivotal dose of KTE-X19. Methods: Eligible adults (≥18 years) had R/R B-ALL and received a single infusion of KTE-X19 at the pivotal dose (1×106 CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was CR/CRi rate by central review. Results: As of 23 July 2021, median follow-up was 26.8 mo (range, 20.7-32.6) for treated Ph 2 pts (N = 55). The CR/CRi rate per central review was 71% (95% CI, 57-82; 56% CR; 15% CRi). Eleven pts (20%; 8 CR and 2 CRi) proceeded to subsequent allogeneic stem cell transplant (alloSCT). Median duration of remission (DOR) censored at subsequent alloSCT was 14.6 mo (9.4-not estimable [NE]); not censored: 18.6 mo (9.6-NE); 6/39 responders (15%) had ongoing responses at data cutoff. Median (95% CI) relapse-free survival (RFS) was 11.6 mo (2.7-20.5) censored at subsequent alloSCT and 11.7 mo (2.8-20.5) not censored at subsequent alloSCT; 18-mo RFS rates (95% CI) were 35% (20.5-50.6) and 42% (28.0-55.0), respectively. Median (95% CI) overall survival (OS) was 25.4 mo (16.2-NE) among all KTE-X19-treated pts and not reached (25.4-NE) in pts with CR (n = 31). For Ph 1/2 pts (N = 78) who received the pivotal KTE-X19 dose (median follow-up: 29.7 mo; range 20.7-58.3), the CR/CRi rate by independent review was 73% (95% CI, 62-82). Medians (95% CI) for DOR, RFS, and OS were 18.6 mo (9.6-NE), 11.7 mo (6.1-20.5), and 25.4 mo (16.2-NE), respectively. A subgroup analysis revealed that in pts aged 18-39 (n = 36), 40-59 (n = 27), and ≥60 (n = 15) years, the CR/CRi rates (95% CI) were 69% (52-84), 70% (50-86), and 87% (60-98); 24-mo OS rates (95% CI) were 48% (30-64), 54% (33-71), and 57% (28-78), respectively. In pts with pre-KTE-X19 infusion marrow blast percentages > 25 to ≤50 (n = 12), > 50 to ≤75 (n = 14), and > 75 to 100 (n = 30), CR/CRi rates (95% CI) were 83% (52-98), 86% (57-98), and 57% (37-75); 24-mo OS rates (95% CI) were 58% (27-80), 55% (26-77) and 37% (19-55), respectively. There were no new safety signals; the proportion of treated Ph 2 pts with Gr ≥3 treatment emergent adverse events was unchanged since prior data cutoff. One pt had an ongoing neurologic event of Gr 1 finger numbness. Conclusions: With longer follow-up and an expanded data set by independent review, outcomes remain durable in adults with R/R B-ALL, most of whom were heavily pretreated, with median OS not yet reached in pts with CR. Long-term safety was favorable. Clinical trial information: NCT02614066.

Abstract Introduction: Brexucabtagene autoleucel (brexu-cel) was approved by US FDA for relapsed/refractory (R/R) mantle cell lymphoma (MCL) on July 24, 2020 based on results from the pivotal ZUMA-2 (NCT02601313) study, in which an objective response rate (ORR) of 93% and a complete response (CR) rate of 67% were achieved among the 60 treated patients with at least 7 months of follow-up. The study had stringent eligibility criteria, including prior treatment with a BTK inhibitor (BTKi), and only allowed BTKi and/or corticosteroid for bridging therapy. We report here the safety and efficacy of brexu-cel in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: Fourteen centers participated in this retrospective study. Patients who underwent leukapheresis by 6/15/2021 with an intent to manufacture brexu-cel were included. Baseline clinical characteristics, bridging therapy, adverse events after brexu-cel infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined based on characteristics at the time of leukapheresis. Duration of response (time from initial response to disease progression or death from any cause), progression-free survival (PFS; time from infusion to disease progression or death from any cause) and overall survival (OS; time from infusion to death from any cause) were analyzed using the Kaplan-Meier method. Results: At the data cut-off date of 7/9/2021, 107 patients underwent leukapheresis, among whom 93 (87%) completed brexu-cel infusion, 2 (2%) were waiting for infusion, and 12 (11%) did not receive infusion (manufacture failure n=6, organ dysfunction n=1, death n=5). Baseline clinical characteristics of the 93 infused patients are shown in Table 1. The median age was 67 years and 81% were male. 32% had high risk simplified MIPI, 77% had Ki-67≥30%, 45% had blastoid or pleomorphic variant, 46% had TP53 alteration, 29% had complex karyotype, and 7% had CNS involvement. The median number of prior lines of therapy was 3. Eighty-two percent had prior BTKi treatment, and 44% had refractory disease to the last line of therapy. Sixty-eight (73%) patients would not have met ZUMA-2 eligibility criteria. Reasons for ineligibility included ECOG PS ≥2 (n=8), CNS involvement by lymphoma (n=6), prior therapies (n=33), cytopenia (n=11), renal or hepatic dysfunction (n=13), other medical conditions (n=18), and active infection (n=2). Sixty (65%) of the 93 patients received bridging therapy, which included BTKi (n=27), venetoclax (n=14), chemotherapy (n=19), CD20 antibody (n=26), lenalidomide (n=3), corticosteroid (n=9), and radiotherapy (n=13). Only 13 (14%) patients received BTKi or corticosteroid alone as in ZUMA-2. Among 93 infused patients, cytokine release syndrome (CRS) rate was 88% (8% grade ≥3), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 58% (33% grade ≥3). No grade 5 CRS or ICANS occurred. Medications used to manage CRS and ICANS were 71 (76%) for tocilizumab, 64 (69%) for steroid, and 16 (17%) for anakinra. Twenty-four (26%) patients required ICU admission, 9 patients required vasopressors, and 4 patients required mechanical ventilation. With a median follow-up of 3.0 months (range 0.1-9.6), day 30 response was evaluable in 81 patients, and the ORR was 86%, with 64% CR (Table 2). The ORR/CR rates were 94%/70% for blastoid or pleomorphic variants, 82%/50% for TP53 altered, 84%/61% for BTKi-exposed, 94%/76% for BTKi-naïve, and 88%/67% for those not meeting ZUMA-2 eligibility criteria. The ORR/CR rates were 87%/69% for patients who received bridging therapy and 85%/56% for those who did not. For patients who achieved a response at day 30, the rate of continued response at 3-month was 83.7% (95% CI 68.3%-92.0%). The 3-month PFS rate was 80.6% (95% CI 68.6%-88.4%), and the 6-month OS rate was 82.1% (95% CI 67.7%-90.5%). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of brexu-cel in R/R MCL in the real world practice. The CRS and ICANS incidences were comparable to those reported in ZUMA-2, but use of tocilizumab and steroid was more frequent than in ZUMA-2. Although 73% of the patients would have been ineligible for ZUMA-2, the ORR and CR rate were comparable to those reported in ZUMA-2. Longer follow-up is necessary to confirm long term safety and efficacy. YW, PJ and FLL are co-first authors, and YL, MW and MDJ are co-senior authors. Figure 1 Figure 1. Disclosures Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Jain: Kite: Consultancy; Lilly: Membership on an entity's Board of Directors or advisory committees. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Umoja: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Munoz: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Beitinjaneh: Kite/Gilead: Other: Ad Board Event Attendee. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Dahiya: Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Jazz Pharmaceuticals: Research Funding; Atara Biotherapeutics: Consultancy; BMS: Consultancy. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; EcoR1 Capital: Consultancy. Goy: Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Phamacyclics: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Incyte: Honoraria; Hoffman la Roche: Consultancy; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Xcenda: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Shah: Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Paludo: Karyopharm: Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding. Lin: Legend: Consultancy; Novartis: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Wang: Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; InnoCare: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Genentech: Consultancy; OMI: Honoraria; Physicians Education Resources (PER): Honoraria; Clinical Care Options: Honoraria; CAHON: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; CStone: Consultancy; Loxo Oncology: Consultancy, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; BGICS: Honoraria; Bayer Healthcare: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Molecular Templates: Research Funding; Imedex: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Lilly: Research Funding; Celgene: Research Funding; Anticancer Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy.

Abstract Background: Relapsed Acute Lymphoblastic Leukemia (ALL) is not curable with standard therapies. Effective outpatient treatment, allowing patients to maintain a good quality of life, while offering a meaningful chance of remission, is an appealing alternative to prolonged admission required for currently available multi-agent regimens. Vincristine sulfate liposomal injection (Marqibo) was approved in 2012 for treatment Ph-ALL in second or greater relapse, originally developed to overcome pharmacokinetic and pharmacodynamic limitations of vincristine. Approved dosing is 2.25 mg/m 2 without a dose cap. Pre-clinical studies showed it increases plasma circulation time, increases tumor tissue delivery, accumulates in tumor tissue, and slowly releases vincristine in tumor tissues rather than into systemic circulation. In a phase 2 trial, as a weekly administered single agent, CR/CRi rate was 20%, with median duration of 23 weeks and overall response rate of 35%. Blinatumomab is a murine recombinant single-chain antibody construct belonging to a class of bispecific T-cell engager (BITE) immuno-oncology. BITE molecules are designed to direct T-effector memory cells towards target cells, triggering cell-specific cytotoxicity. Blinatumomab specifically targets cells that express CD19 and the presence of both, CD19+ target cells and T cells are required for its cytotoxic activity. In previous phase 2 trials, responses to single agent blinatumomab in the relapsed setting were near 60%, although only 34% (44%, including partial and incomplete hematologic recovery) in the pivotal phase 3. Median duration of remission was only 7.3 months and half were very heavily pretreated. Here, we describe a trial designed to target ALL cells with Marquibo as a microtubule inhibitor and blinatumomab as a BiTE immuno-oncology therapy and evaluate whether this combination results in an effective and safe therapeutic option for relapsed/refractory ALL patients. We anticipate additive benefits of the regimen and define a clinically meaningful outcome as >75% (CR/CRi) rate and median progression-free survival (PFS) of ≥1 year. This higher rate of response is expected as many patients are using blinatumomab at first relapse, and therefore we anticipate less prior therapy than overall in the pivotal phase 3 study. Further, we hypothesize that the combination will result in a high rate of response, allowing enhanced immunologic recovery. Study Design/Methods: This is a phase 2, single arm, trial to evaluate the efficacy of blinatumomab and vincristine sulfate liposomal injection. The study will include up to 35 participants who are ≥18years of age, with Ph-, CD19+ ALL, and are either relapse or refractory to ≥2 prior regimens, have ≥5% blasts in the bone marrow or peripheral blood or persistent extranodal/marrow site or have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The active study period includes a 3-week screening phase, followed by a treatment period (induction phase and consolidation phase) of up to 58 weeks (6 cycles), a safety follow-up 30 days later and a long-term follow-up period of up to 18 months. The induction phase includes two cycles of blinatumomab and liposomal vincristine. A single cycle is defined as 6 weeks in duration, which includes 4 weeks of continuous intravenous infusion (CIVI) of blinatumomab (initial dose 9 μg/day for first 7 days, then escalated to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by a 2-week treatment-free interval and 3 weekly doses of liposomal vincristine, administered intravenously at 2.25 mg/m 2, with no dose cap (per label),in the outpatient setting over 1 hour. Subjects who achieve at least stable disease within 2 induction cycles may continue to the consolidation phase to receive up to a maximum of 6 cycles under the same treatment schedule. The primary objectives are to evaluate whether the combination will result in a median PFS of ≥1 year, and if the CR/CRi rate is ≥75% following 2 cycles and duration of remission. Secondary outcomes will include evaluation of the rate of Minimal Residual Disease (MRD) and duration, the proportion of patients who are able to progress to allogeneic transplantation, the safety of blinatumomab and liposomal vincristine sulfate in combination and the effect of the combination and response on measures of immune reconstitution. Figure 1 Figure 1. Disclosures Rizzieri: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Leonard: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy.

Abstract Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia or lymphoma (T-ALL or T-LBL respectively) and acute myeloid leukemia (AML) have remained poor despite the availability of newer agents. CD38 is a 45 kDa transmembrane glycoprotein expressed by lymphoid and myeloid cells with several important functions including a role in immune escape from tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in tumor cells of patients with T-ALL and AML and potentially targetable using CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020, Farber M et al. ASH 2018]. XmAb18968 is structurally distinct CD3-CD38 bi-specific T-cell engager with a full fragment crystallizable (Fc) domain modified to minimize Fcγ receptor binding and non-selective activation of T cells and other immune effector cells. XmAb18968 has optimized relative affinities for both CD3 and CD38 which results in reduced cytokine release without compromising target cell killing. We hypothesize targeting CD38 in relapsed/refractory- T-cell ALL/LBL and AML is safe and feasible using XmAb18968, a novel CD3-CD38 bispecific antibody. Study design and methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with T-ALL, T-LBL or AML (including undifferentiated leukemia and bi phenotypic leukemia), in relapsed/refractory status (at least one line of prior therapy) including measurable residual disease relapse, CD38 expression ≥ 20%, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation (HCT) within 6 months of enrollment, active acute GVHD, veno-occlusive disease, and acute promyelocytic leukemia. The study is planned to be conducted at 6 sites in United States. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of responses with genomic profile, assessment of serum cytokine response, identifying the changes in phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design for dose escalation and de-escalation in case of dose limiting toxicity (DLT). Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and T-LBL and Group B for subjects with AML. Patients will be entered sequentially to each dose level, starting with the first dose level. The DLT observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experience a DLT. A minimum of 24 and a maximum of 60 patients will be needed for the dose escalation phase. Disclosures Guru Murthy: Curio Sciences: Honoraria; Techspert: Consultancy; Qessential: Honoraria; CancerExpertNow: Honoraria; DAVA Oncology: Honoraria; TG Therapeutics: Other: Advisory board meeting; Cardinal health: Honoraria; Guidepoint: Consultancy. Johnson: Miltenyi Biotec: Research Funding. Abedin: AltruBio: Research Funding; Amgen: Honoraria; Agios: Honoraria; Helsinn: Research Funding; Pfizer: Research Funding; Astellas Pharma Inc.: Research Funding; Actinium: Research Funding. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Shah: Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Leonard: Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Pratz: Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

7002 Background: ZUMA-3 is a Phase 1/2 multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in adult pts with R/R B-ALL. Phase 1 efficacy results at the recommended Phase 2 dose (1×106 CAR T cells/kg) were encouraging (Shah et al. ASCO 2019 #7006). Here, we present the pivotal Phase 2 results. Methods: Eligible adults had R/R B-ALL, > 5% bone marrow (BM) blasts by local evaluation, and ECOG 0–1. Pts received a single infusion of KTE-X19 after conditioning chemotherapy. The primary endpoint was the overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) by central review. Key secondary endpoints were duration of remission (DOR), relapse-free survival (RFS), overall survival (OS), measurable residual disease negativity (MRD–) rate by flow cytometry, and safety. Data are reported in all treated pts. Results: As of 9/2020, 55 of 71 enrolled pts received KTE-X19, with a median follow-up of 16.4 mo (range, 10.3–22.1). Adverse events (AEs; n = 8) and ineligibility (n = 4) were the most common reasons enrolled pts did not receive KTE-X19 infusion. Median age was 40 y (range, 19–84), median BM blasts at screening were 65% (range, 5–100), and 47% of pts had ≥3 prior therapies, with 45%, 22%, and 42% having previously received blinatumomab, inotuzumab ozogamicin, or allogeneic stem cell transplant (alloSCT), respectively. The CR/CRi rate was 71% (95% CI, 57–82; 56% CR, 15% CRi); 31% of responders had ongoing responses. Median (95% CI) DOR, RFS, and OS were 12.8 mo (8.7–not estimable [NE]), 11.6 mo (2.7–15.5), and 18.2 mo (15.9–NE), respectively. In responders, median (95% CI) RFS and OS were 14.2 mo (11.6–NE) and not reached (16.2–NE). The MRD– rate was 97% among pts with CR/CRi. Among 25 pts with prior blinatumomab treatment, the CR/CRi rate was 60%. Ten pts (18%) received subsequent alloSCT at a median 98 days post–KTE-X19 infusion. Median DOR remained unchanged when not censoring for alloSCT. Grade ≥3 AEs occurred in 95% of pts, most commonly anemia (49%) and neutropenia (49% [febrile 13%]). Grade ≥3 cytokine release syndrome (CRS; per Lee at al. Blood 2014) and neurologic events occurred in 24% and 25% of pts, respectively, and were generally reversible. Two Grade 5 KTE-X19–related events occurred (brain herniation, n = 1; septic shock, n = 1). Median times to onset of CRS and neurologic events were 5 d and 9 d, with median durations of 7.5 d and 7 d, respectively. Median peak CAR T-cell levels (cells/µL) were 40.5 (range, 1.3–1533.4) in pts with CR and 0 in nonresponders. CAR T cells were undetectable by 9 mo in ongoing responders. Conclusions: After a median follow-up of 16.4 mo, KTE-X19 demonstrated compelling clinical benefit in heavily pretreated adults with R/R B-ALL, with the median OS not yet reached for responding pts and a manageable safety profile. Clinical trial information: NCT02614066.

Abstract ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.