Sustainable Efficacy and Safety Results from Lummicar Study 1: A Phase 1/2 Study of Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Chinese Subjects with Relapsed and/or Refractory Multiple Myeloma

Abstract Background: CT053 is a fully human autologous chimeric antigen receptor (CAR) T-cell therapy comprising a B-cell maturation antigen (BCMA)-specific single-chain variable fragment (25C2). A clinical trial of CT053 is ongoing in LUMMICAR STUDY 1 (NCT03975907) for patients with relapsed and refractory multiple myeloma (RRMM) in China. The pivotal Phase 2 of LUMMICAR STUDY 1 is actively enrolling patients. Here, we report clinical data from Phase 1 with 12 months of follow-up. Methods: Subjects with RRMM who had received ≥3 prior therapies, including at least one proteasome inhibitor and one immunomodulatory drug were enrolled in Phase 1 study. Adverse events (AEs) were graded according to CTCAE, v5.0; Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per IMWG 2016 criteria. Minimal residual disease (MRD) was tested by next-generation flow cytometry on bone marrow aspirates by the EuroFlow assay with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher, and CAR copies in the subject peripheral blood were monitored by quantitative real-time polymerase chain reaction (qPCR). Results: Fourteen subjects with a median age of 54 years (range 34-62) received CT053 infusion. Three subjects received 1.0×10 8 CAR+ T cells and eleven subjects received 1.5×10 8 CAR+ T cells. As of July 8, 2021, 14 subjects with a median follow-up of 13.6 months since infusion. Of the 14 subjects, 11 (78.6%) had received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, 2 (14.3%) had ISS stage III, and 5 (35.7%) had high-risk cytogenetics. The median prior therapies was 6 (range 3-7) and no subject received bridging therapy. The most common AEs were expected hematological toxicities. All subjects (100%) experienced ≥ grade 3 neutropenia, 91.7% experienced ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No dose limiting toxicity or treatment-related death was reported. Additionally, no ≥ grade 3 CRS or neurotoxicity was observed, 92.9% subjects (13/14) experienced grade 1 or 2 CRS (9 grade 1, 4 grade 2). CRS occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days. No severe infections were reported except one case of grade 3 lung infection. A 100% overall response rate was achieved in 14 subjects, with 11 stringent complete responses (sCR, 78.6%), 2 very good partial responses (VGPR), and 1 partial response, with a ≥VGPR rate of 92.9%. Four subjects achieved sCR at week 52. As of July 8, 2021, 12 subjects with at least 12 months of efficacy assessment were still in the study, and the 12-month progression-free survival (PFS) rate was 85.7%. With a median follow-up of 13.6 months, the median duration of response and the median PFS had not been reached. All 11 subjects with sCR were MRD-negative, and 9 subjects reached sustained CR/sCR for more than 12 months (Figure 1). Three subjects had disease progressed including two subjects with extramedullary disease progressed at week 16. Interestingly, the CR/sCR rate for the subjects without extramedullary disease is 91.7% (11/12). The 1-year PFS rate for subjects without extramedullary disease reached 100%。 CT053 cells expanded and persisted well. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 CAR T cells at a dose of 1.0-1.5×10 8 cells achieve a deep and durable response, including a high MRD-negative sCR rate, with an acceptable safety profile in subjects with heavily pretreated RRMM. Figure 1 Figure 1. Disclosures Li: CARsgen: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Xiao: CARsgen Therapeutics Corp: Current Employment. Wang: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Tang: CARsgen Therapeutics Corp: Current Employment.

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Results from Lummicar-1: A Phase 1 Study of Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Chinese Subjects with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-140727 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-50

Author(s):

Wenming Chen ◽

Chengcheng Fu ◽

Zhen Cai ◽

Zonghai Li ◽

Huijuan Wang ◽

...

Keyword(s):

T Cells ◽

Phase 1 ◽

Private Company ◽

Phase 1 Study ◽

Car T Cells ◽

Car T ◽

Post Infusion ◽

Efficacy Assessment ◽

Grade 3 ◽

Experienced Grade

Background: CT053 are autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects were previously treated in investigator-initiated (IIT) studies with 87.5% overall response rate (ORR), 79.2% complete response (CR) and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. We report herein the first disclosed results from the ongoing phase 1 study (LUMMICAR-1) in China (NCT03975907). Methods: The phase 1 study included subjects with relapsed/refractory multiple myeloma (RRMM) who had received ≥3 prior therapy regimens including a proteasome inhibitor and an immunomodulatory drug, and had measurable disease per 2016 International Myeloma Working Group (IMWG) criteria. All subjects received conditioning treatment of cyclophosphamide (300 mg/m2/day ×3 days) and fludarabine (25 mg/m2/ day × 3 days). After conditioning, subjects received a single infusion of CT053 at the 1.0-1.5×108 CAR+ T-cell dose. Primary objectives for phase 1 were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per 2016 IMWG criteria. Results: As of July 20, 2020, a total of 14 subjects have been enrolled in the study. All 14 subjects have been apheresed and received CT053 infusion, including 3 subjects who received 1.0×108 CAR+ T cells and 3 subjects who received 1.5×108 CAR+ T cells at dose escalation, followed by 8 subjects who received 1.5×108 CAR+ T cells at dose expansion. The 14 batches of CT053 were manufactured in a median of 8 days (range 7-10). Treated subjects had a median age of 54 years (range 34-62) and had received a median of 6 (range 3-7) prior lines of therapy. Of the 14 subjects, 10 (71.4%) received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, and 5 (35.7%) had high-risk cytogenetics. No subject received bridging therapy. At data cutoff, 12 subjects had at least 4 weeks of safety and efficacy assessment with median follow-up of 5 months (range, 1-11). No dose-limiting toxicities were detected. The most common ≥ grade 3 AE was hematological toxicity. Of the 12 subjects with at least 4 weeks follow-up, all experienced ≥ grade 3 neutropenia (100%), 91.7% of subjects had ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No grade 3 or higher CRS or neurotoxicity was observed. Eleven of 12 subjects (91.7%) experienced grade 1 or 2 CRS, including 3 subjects who experienced grade 2 CRS and 8 subjects who experienced grade 1 CRS. CRS events occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days, following a generally predicable onset pattern. Eight subjects received tocilizumab treatment, of whom one subject with grade 2 CRS received both tocilizumab and steroid. At the data cutoff, among 12 subjects with at least 4 weeks of efficacy assessment, a 100% ORR was observed, with 4 stringent complete responses (sCR), 1 CR, 3 very good partial responses and 4 partial responses. All 5 subjects with CR/sCR were minimal residual disease (MRD)-negative at the 10 5 sensitivity level. Responses were independent of baseline BCMA expression in bone marrow. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after dosing in all subjects, with peak copies 45,469 (range 11,825-258,574). Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 at a target dose of 1.0-1.5×108 CAR+ T cells delivers early and deep responses, including MRD negativity in all complete responders, with an acceptable safety profile in subjects with heavily pretreated RRMM. The results from this LUMMICAR-1 study are consistent with the previous IIT phase 1 studies and the ongoing North American LUMMICAR-2 study and support the launch of pivotal LUMMICAR-1 study in China. Updated results will be presented at this conference. Disclosures Li: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Wang:CARsgen Therapeutics Corp.: Current Employment. Xiao:CARsgen Therapeutics Corp.: Current Employment. Wang:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Ma:CARsgen Therapeutics Corp.: Current Employment.

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JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

Blood ◽

10.1182/blood-2018-99-113548 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 957-957 ◽

Cited By ~ 48

Author(s):

Sham Mailankody ◽

Myo Htut ◽

Kelvin P. Lee ◽

William Bensinger ◽

Todd Devries ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Car T Cells ◽

Car T ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

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Safety and Efficacy of AUTO1, a Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)

Blood ◽

10.1182/blood-2021-146316 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3823-3823

Author(s):

Claire Roddie ◽

Juliana Dias ◽

Maeve A O'Reilly ◽

Amaia Cadinanos Garai ◽

Louisa Green ◽

...

Keyword(s):

T Cells ◽

Single Dose ◽

Clinical Activity ◽

Publicly Traded ◽

Car T Cells ◽

18Fdg Pet ◽

Car T ◽

Remission Rates ◽

Grade 3

Abstract INTRODUCTION We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR-T immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL. Cumulatively, this data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Recently, CAR-T therapy has been explored in indolent lymphomas such as follicular (FL) and mantle cell lymphoma (MCL), but a high incidence of toxicity including Grade 3-4 ICANS has been reported. We have initiated testing of AUTO1 in the setting of indolent and high-grade B-NHL and CLL (NCT02935257). METHODS Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m 2 x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x10^6 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x10^6 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. RESULTS As of 17th May 2021, we recruited 13 patients: 7 with FL, 4 with MCL, 1 DLBCL and 1 CLL. Apheresis and product manufacture was successful in all 13 patients and 9 patients were infused: 7 with FL and 2 with MCL. Three patients (1 DLBCL, 1 CLL and 1 MCL) were pending infusion at time of data cut-off and 1 patient (MCL) died due to Covid-19 prior to infusion. Patients treated with AUTO1 had a median age of 56 years (range 39-68y), had received a median of 3 prior lines of treatment (range 2-5) and all patients had stage IV disease at screening. Grade 1 CRS was reported in 4/9 and Grade 2 CRS in 1/9. 1/9 developed MAS which resolved with anakinra/dexamethasone. No ICANS was observed on study. Excellent CAR engraftment was observed and 9/9 patients were in CMR by 18FDG PET-CT post-treatment. At a median of 6.1 months (range 4.0-8.1m), 8/9 patients were disease free at last follow-up. One patient died in CMR at month 5.6 of COVID-19. CONCLUSION AUTO1 has a tolerable safety profile in adult patients with r/r B-NHL despite high disease burden. Early data shows 100% complete remission rates and excellent CAR engraftment/expansion. Additional MCL, CLL and DLBCL patients, updated data and longer follow up will be presented. Disclosures Roddie: Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau. Hartley: Astra Zeneca: Ended employment in the past 24 months; ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Farzaneh: Autolus: Consultancy, Current equity holder in publicly-traded company. Lowdell: Autolus: Consultancy, Current equity holder in publicly-traded company. Linch: Autolus: Consultancy, Current equity holder in publicly-traded company. Pule: Autolus: Current Employment, Current equity holder in publicly-traded company. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company.

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ALLCAR19: Updated Data Using AUTO1, a Novel Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies

Blood ◽

10.1182/blood-2020-137768 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Claire Roddie ◽

Maeve A O'Reilly ◽

Maria A V Marzolini ◽

Leigh Wood ◽

Juliana Dias ◽

...

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukaemia ◽

B Cell ◽

Lymphoblastic Leukaemia ◽

Car T Cells ◽

Car T ◽

Remission Rates ◽

Grade 3 ◽

Experienced Grade

Introduction: Prognosis for adult B-cell Acute Lymphoblastic Leukaemia (B-ALL) is poor and there is currently no licensed CD19 Chimeric Antigen Receptor (CAR) therapeutic. We developed a novel CD19 CAR (CAT-41BBz CAR) with a fast off-rate, designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. We describe updated data from the Phase I ALLCAR19 (NCT02935257) study of AUTO1 in relapsed/refractory adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leukapheresate. The first 6 products were generated using a standard dynabead/WAVE bioreactor process and subsequent products using a semi-automated closed process. Study design: Patients aged >16y underwent lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) followed by split dose CAR T-cell infusion (Day 0: if ≥20% Bone Marrow (BM) blasts, infuse 10 x 106 CAR T-cells; if <20% BM blasts, 100 x 106 CAR T-cells. At Day+9: if no grade 3-5 Cytokine Release Syndrome (CRS)/immune effector cell associated neurotoxicity syndrome (ICANS), infuse Dose 2, to a total dose of 410 x106 CAR T-cells). Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. Results: As of 13 May 2020, 24 patients have been leukapheresed, 23 products manufactured and 19 patients received at least 1 dose of AUTO1. The median age was 43y (range 18-62), 26% had prior blinatumomab, 47% had prior inotuzumab ozogamicin and 63% had prior hematopoietic stem cell transplantation (HSCT). At the time of pre-conditioning, 42% had ≥50% BM blasts. No patients experienced ≥Grade 3 CRS (Lee criteria), 3/19 (16%) experienced Grade 3 ICANS that swiftly resolved with steroids. Of 19 infused patients, 16/19 (84%) achieved Minimal Residual Disease (MRD) negative complete response (CR). Currently 6 patients have died, none related to AUTO1. 11/19 (58%) patients remain on study and continue in MRD negative remission at a median follow up of 12.2 months (range 0.6-24.4m). To date, only 2 patients underwent HSCT whilst in remission. For all treated patients, the event-free survival (EFS) at 6 months was 62% and 76% for those whose products were manufactured using the closed process. Patients exhibited robust CAR expansion (mean peak CAR T levels 716,769 copies/µg DNA). Conclusions: AUTO1 has a tolerable safety profile in adult patients with r/r B-ALL despite high disease burden. Early data shows high remission rates with 84% achieving MRD negative CR. This preliminary data supports the further development of AUTO1 as a standalone treatment in patients with r/r B-ALL. Data from additional patients and longer follow up will be presented. Furthermore, data from extension cohorts of patients with low- and high- grade B-cell Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia will be presented. Figure Disclosures Roddie: Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Linch:Autolus: Consultancy. Pule:UCLB: Patents & Royalties; Mana Therapeutics: Other: entitled to share of revenue from patents filed by UCL; Autolus: Current Employment, Other: owns stock in and receives royalties, Patents & Royalties. Peggs:Autolus: Consultancy.

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A Phase 1/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-152576 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 547-547

Author(s):

Chunrui Li ◽

Di Wang ◽

Yongping Song ◽

Jianyong Li ◽

He Huang ◽

...

Keyword(s):

T Cells ◽

Median Time ◽

Bone Marrow Aspirate ◽

Phase 1 ◽

Phase 2 ◽

Safety And Efficacy ◽

Car T Cells ◽

Car T ◽

Grade 3

Abstract Background： CT103A, a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product showed excellent safety and promising efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM) patients in our previous report [Blood. 2021; 137 (21): 2890-2901]. The unique CAR structure containing fully human single-chain variable fragments (scFvs) may bypass the potential host anti-CAR immunogenicity and retain antitumor activity. Here we reported the safety and efficacy results of 71 patients in 1.0×10 6 CAR+ T cells/kg cohort from the ongoing phase1/2 study (ChiCTR1800018137/ ChiCTR2000033946). Notably, it was the first time that prior BCMA CAR-T exposed patients were eligible to participate in an anti-BCMA CAR-T cell trial. Methods： This phase 1/2 study of CT103A is single-arm designed and is conducted in 13 centers in China. The study enrolled RRMM patients who had received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. 1.0 × 10 6 CAR+ T cells/Kg was previously identified as recommended phase 2 dose (RP2D). Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, patients received CT103A. The primary objectives of this study were to assess the safety and efficacy of CT103A at RP2D. The cellular pharmacokinetic profile of CT103A in peripheral blood was investigated by measuring CAR transgene levels using droplet digital polymerase chain reaction (ddPCR) and CAR-T cells by flow cytometry. Minimal residual disease (MRD) negativity was evaluated in bone marrow aspirate by standardized Euroflow 8-color flow cytometry with a minimum sensitivity of 10 -5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay. Results: As of the July 15, 2021, 71 patients [59.2% male; median age 58.0 years (range 41-71)] with RRMM received CT103A (9 in phase 1a; 17 in phase 1b; 45 in phase 2). The median follow-up time was 147 days (range 31 to 1029). The treated patients had received a median of 4 (range 3-13) lines of prior therapy. 28.2% and 18.3% were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 18.3% had previously received CAR-T therapy. What's more, 7% of the patients had the extramedullary disease at baseline, and 76.1% had high-risk cytogenetics. The most common ≥ grade 3 treatment-related AEs were hematological toxicities. 93.0% of the patients experienced CRS, among which only 2.8% were grade 3. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was 6 days (range 1-12) with a median duration of 4 days (range 1-27). Only one (1.4%) patient experienced grade 2 ICANS which manifested as a transiently decreased level of consciousness and soon recovered without intervention. All 71 patients were evaluable for at least one month of efficacy assessment. The median time to first response was 15 days (range 11-124). A 94.4% ORR was observed, with 50.7% ≥ CR, 26.8% VGPR, and 16.9% PR. Among them, 50 patients who have completed follow-up of 3 months achieved 96.0% ORR, with 54.0% ≥ CR, 28% VGPR, and 14% PR. For 13 patients who have previously been treated with CAR-T therapy, ORR was 76.9%, with ≥ CR rate of 38.5%，VGPR of 15.4%, and PR of 23.1%. Of the 69 patients with evaluable bone marrow aspirate, 92.8% achieved MRD-negativity with a median time to MRD-negative of 17 days (range 13-180), and among them, 75.0% (95%CI 53.1-87.6%) achieved sustained MRD negativity over six months. The expansion of CT103A reached the peak at a median of 12 days (range 5 to 29). CT103A was still detectable in 88.5% (23/26) patients at 6 months and 87.5% (14/16) patients at 12 months after infusion. The first enrolled patient remains in sCR for 34 months with significant persistence of CT103A transgene. In addition, only 2 of 71 patients were detected positive for anti-drug antibody, which was reported to be a high-risk factor for disease relapse/progression after CAR-T therapy. Conclusion: The impressive efficacy of CT103A, including time to response, overall response rate, and durability, was corroborated by robust expansion and prolonged persistence of CT103A. The expansion and clinical benefits of CT103A did not seem to be influenced by prior murine BCMA CAR-T. Disclosures No relevant conflicts of interest to declare.

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Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽

10.1182/blood-2020-137299 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-6

Author(s):

Xian Zhang ◽

Junfang Yang ◽

Wenqian Li ◽

Gailing Zhang ◽

Yunchao Su ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (>40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

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Evolution and Proliferation of CD7 CAR-T Cells Compared to CD19 CAR-T Cells Therapies for Acute Leukemia

Blood ◽

10.1182/blood-2021-149978 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2820-2820

Author(s):

Xian Zhang ◽

Gailing Zhang ◽

Wenqian Li ◽

Liyuan Qiu ◽

Dongchu Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Body Temperature ◽

Incidence Rate ◽

Cell Ratio ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Grade 3

Abstract Background In October 2020, we began the clinical trials of CD7 CAR-T treatment for CD7-positive hematological malignancies at our center. We found that the proliferation profile and evolution of CD7 CAR-T cells within 1-month following infusion into patients were quite different from those of CD19 CAR-T cells. From these data, we reasoned that the time to occurrence of CAR-T-cell-related side effects might also differ between the two cellular therapies. Here, we systematically compared the proliferation and CAR-T-cell-related side effects of CD7 CAR-T cells to these of CD19 CAR-T cells. Patients and Methods From October 2020 to June 2021, a total of 30 patients (24 male, 6 female) including 22 with T-cell acute lymphoblastic leukemia (T-ALL), 3 with T-cell lymphoblastic lymphoma (T-LBL), and 5 with mixed phenotype acute leukemia (MPAL) received autologous CD7 CAR-T cells manufactured by the SenlangBio company (https://clinicaltrials.gov NCT04572308, NCT04796441 and NCT04938115). The median follow-up time was 116 days (range: 15-221days). On Day 30, 25/30 patients (83.3%) achieved complete remission (CR)/CR with incomplete blood recovery (CRi). From December 2017 to June 2021, 45 B-ALL patients (19 male, 26 female) received CD19 CAR-T cells, also manufactured by SenlangBio (NCT04792593 and NCT04546893). The median follow-up time was 351 days (range: 15-1110days). On Day 30, 43/45 patients (95.6%) achieved CR/CRi. The median infused CD7 CAR-T cell dose was 1×10 6/kg (range: 0.5-2×10 6/kg), and the median infused CD19 CAR-T cell dose was 3×10 5/kg (range: 0.2-10×10 5/kg). The CD7 or CD19 CAR-T cell ratio in peripheral blood lymphocytes (PBLC) and the CD7 or CD19 B-lymphocyte percentage in PBLC samples from patients were analyzed on days 0, 4, 7, 10, 14, 21, and 30 following CAR-T cell infusion using flow cytometry. Results The presence of CD7 CAR-T cells in the PBLC samples were gradually detected following CD7 CAR-T cell infusion. The CD7 CAR-T cell ratio in PBLC increased significantly on Day 10. CD7 CAR-T cell peak appeared on Day 21 with a peak of 39.14% (range: 0.04%-74.58%), and was still detectable on Day 30 with a high CD7 CAR-T ratio of 7.5% (1.15%-70.41%). The ratio of CD19 CAR-T cells in patient PBLC samples showed a significant increase on Day 7 following infusion, and the CAR-T cell peak appeared on Day 10 with a peak of 14.71% (range: 0.11%-89.33%), and then quickly decreased to 0.23% (range: 0%-82.88%) on Day 21 (Figure 1). As the CAR-T cells increased, the proportion of target cells decreases significantly (Figure 2). However, the rate of decrease of CD19 cells differed from that of CD7 cells. CAR-T cell proliferation is also associated with CAR-T-cell-related adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Observing the adverse effects after CD7 CAR-T infusion, we found that fever (incidence rate of 83.8%) occurred on the first 1-3 days following infusion, with a body temperature among patients of about 38°C. After patients' body temperature dropped to approximately normal levels, fever occurred again on Day 10-21 (incidence rate of 77.4%), and a higher temperature of 38-40°C was observed. The adverse event profile coincided with the proliferation of CD7 CAR-T cells we observed. Among the 30 cases, 5 had Grade 2 CRS, 2 had CRS of Grade ≥3, and 1 patient had Grade 3 ICANS. Fever following CD19 CAR-T infusion consisted mainly on Day 7-14 after the infusion (incidence rate of 86.6%), followed by a gradual drop of body temperature to normal after Day 14. Among the 45 patients, 5 had Grade 2 CRS, 5 had CRS of Grade ≥3 and 7 had Grade ≥3 ICANS. Conclusions In this clinical study, we found that the proliferation and evolution of CD7 CAR-T cells are distinct from that of C19 CAR-T cells. CD7 CAR-T cells began to proliferate significantly later following patient infusion and persisted longer compared to CD19 CAR-T cells. We found that patients experienced two rounds of fever, appearing on Day 1-3 and Day 10-21 following CD7 CAR-T infusion, which required more attention and prevention compared to the fever experienced by patients infused with CD19 CAR-T cells. However, the incidence of CRS and ICANS did not increase following CD7 CAR-T infusion. More patients and long-term observation are needed to confirm these results and to improve clinical management of patients treated with CAR-T cellular therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Deep and Durable Remissions of Relapsed Multiple Myeloma on a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptor (CAR) with a Fully-Human Heavy-Chain-Only Antigen Recognition Domain

Blood ◽

10.1182/blood-2020-138839 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51

Author(s):

Lekha Mikkilineni ◽

Elisabet E. Manasanch ◽

Danielle Vanasse ◽

Jennifer N. Brudno ◽

Jennifer Mann ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Research Funding ◽

Cord Compression ◽

Cell Maturation ◽

Car T Cells ◽

B Cell Maturation ◽

Car T ◽

Grade 3 ◽

B Cell Maturation Antigen

T cells expressing chimeric antigen receptors (CAR) that target B-cell maturation antigen (BCMA) recognize and eliminate multiple myeloma (MM). BCMA is expressed by nearly all cases of MM. BCMA has a restricted expression pattern on normal cells. To reduce the risk of recipient immune responses against CAR T cells, we used a novel, fully-human, heavy-chain-only anti-BCMA binding domain designated FHVH33 instead of a traditional single-chain variable fragment (scFv). The FHVH33 binding domain lacks the light chain, artificial linker sequence, and 2 associated junctions of a scFv. We constructed a CAR designated FHVH33-CD8BBZ. FHVH33-CD8BBZ was encoded by a γ-retroviral vector and incorporated FHVH33, CD8α hinge and transmembrane domains, a 4-1BB costimulatory domain, and a CD3ζ domain. T cells expressing FHVH33-CD8BBZ are designated FHVH-BCMA-T. On this clinical trial, patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5 to -3 followed by infusion of FHVH-BCMA-T on day 0. Twenty-one FHVH-BCMA-T infusions have been administered on 5 dose levels (DL), 0.75x106, 1.5x106, 3x106, 6x106 and 12 x106 CAR+ T cells/kg of bodyweight. DL4 (6 x 106 CAR+ T cells/kg) was identified as the maximum feasible dose (MFD) after weighing toxicity, efficacy and manufacturing factors. Patients are now being enrolled on an expansion phase to test the MFD. One patient (Patient 11) received 2 treatments. Four patients have been enrolled who were not ultimately treated. The median age of the patients enrolled is 64 (range 41-72). Patients received a median of 6 prior lines of therapy (range 3-12). Of the 20 FHVH-BCMA-T treatments evaluable for response, 18 (90%) resulted in objective responses (OR). Twelve treatments resulted in VGPR, complete remission (CR) or stringent complete remission (sCR). Ten patients (50%) have ongoing responses that range between 0-80 weeks (6 sCR/CRs, 3 VGPRs, 1 PR). At the highest two DLs (8 patients), 7 patients (88%) have ongoing responses (median duration 20 weeks, range 0+ to 35+ weeks); progressive MM occurred in only 1 patient who had evidence of spinal cord compression on day +5 due to a rapidly expanding plasmacytoma, which required early intervention with high-dose corticosteroid and radiation therapy. Of the 8 patients evaluated for response who had high-risk cytogenetics at baseline, 7 had ORs. Responses are ongoing in 2 patients with TP53 mutations and 1 patient with t(4;14) translocation. Ten treated patients came off study due to progressive MM (9 patients) or death from other causes (1 patient, influenza). Two of 4 patients who had plasmacytomas evaluated for BCMA expression at relapse had evidence of BCMA-negative MM. Four patients had bone marrow aspirates evaluated for BCMA-expression before treatment and at the time of relapse; 3 of these patients had evidence of loss of BCMA expression at relapse. Of 21 FHVH-BCMA-T treatments administered, 20 (95%) were followed by cytokine release syndrome (CRS) with 16 (76%) cases of grade 1 or 2 CRS, 4 cases (19%) of grade 3 CRS, and no cases of grade 4 CRS. Three patients received tocilizumab. The median peak C-reactive protein after all 21 treatments was 196.9 mg/L. Of 21 total treatments, 8 (38%) were followed by neurologic toxicity; there were 5 cases of grade 1-2 neurologic toxicity (headache, dysarthria, confusion, delirium), 2 cases of grade 3 neurologic toxicity (confusion), and 1 patient with grade 4 spinal cord compression due to progressive MM. Two patients received corticosteroids to manage neurologic toxicities. A median of 3.0% (range 0-95%) of bone marrow T cells were CAR+ when assessed by flow cytometry 14 days after FHVH-BCMA-T infusion. We assessed blood CAR+ cells by quantitative PCR. The median peak level of CAR+ cells was 121 cells/µl (range 3-359 cells/µl) and the median day post-infusion of peak blood CAR+ cell levels was 12 (range 7-14). The results from this phase 1 trial demonstrate that FHVH-BCMA-T cells can induce deep and durable responses of relapsed MM with manageable toxicities. Assessment of durability of responses at the maximum feasible dose is a critical future plan. Accrual to the expansion cohort continues. Table Disclosures Manasanch: Novartis: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; JW Pharma: Research Funding; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Sanofi: Research Funding. Rosenberg:Kite, A Gilead Company: Consultancy, Patents & Royalties, Research Funding. Kochenderfer:Kite, a Gilead company: Patents & Royalties, Research Funding; Celgene: Patents & Royalties, Research Funding; bluebird, bio: Patents & Royalties. OffLabel Disclosure: cyclophosphamide 300 mg/m2 fludarabine 30 mg/m2 Conditioning chemotherapy prior to CAR T-cell infusion

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AUTO1, a Novel Fast Off CD19CAR Delivers Durable Remissions and Prolonged CAR T Cell Persistence with Low CRS or Neurotoxicity in Adult ALL

Blood ◽

10.1182/blood-2019-131086 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 226-226 ◽

Cited By ~ 2

Author(s):

Claire Roddie ◽

Maeve A O'Reilly ◽

Maria A V Marzolini ◽

Leigh Wood ◽

Juliana Dias Alves Pinto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Advisory Committees ◽

Split Dose ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Grade 3

Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if <20% BM blasts, infuse 100 x 106 CAR T cells. Day +9: if no Grade 3-5 CRS/CRES, infuse Dose 2, to a total dose of 410 x 106 CAR T cells). Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months Results: As of 24 July 2019, 16 patients have been leukaphresed, 14 products manufactured (one failed leukaphresis and one currently in manufacture) and 13 patients have received at least 1 dose of AUTO1. Of the 16 patients, median age was 35.5 (range 18-63), 10/16 (63%) had prior blinatumomab or inotuzumab ozogamicin and 12/16 (75%) had prior HSCT. At the time of pre-conditioning, 9/13 (69%) patients were in morphological relapse with >5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (median peak expansion 172 CAR/uL blood). Of the 13 patients dosed (1/13 pending 28 day follow up), 10/12 (83%) achieved MRD negative CR at 1 month and all patients had ongoing CAR T cell persistence at last follow up. Two patients experienced CD19 negative relapse (one at M3, one at M6), 1 patient died on D17 before first response evaluation, 1 died in molecular CR from sepsis, and 1 died from persistent disease. Currently, 7/12 remain on study and continue in flow/molecular MRD negative remission with a median follow up of 9.0 months (range 1.2-14.8). Conclusions: AUTO1 delivers excellent early remission rates with initial data showing 83% MRD negative CR and robust CAR expansion and persistence. Despite high tumour burden, the safety profile compares favourably to other CD19 CARs, with no cases of severe CRS and only one case of Gr3 neurotoxicity. This is consistent with experience in the paediatric cohort. Updated results will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

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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)

Blood ◽

10.1182/blood.v130.suppl_1.888.888 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 888-888

Author(s):

Bijal D. Shah ◽

Wendy Stock ◽

William G Wierda ◽

Olalekan Oluwole ◽

Houston Holmes ◽

...

Keyword(s):

T Cells ◽

Research Funding ◽

Phase 1 ◽

Adult Patients ◽

Employment Equity ◽

Efficacy Analysis ◽

Car T Cells ◽

Car T ◽

Equity Ownership ◽

Grade 3

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), > 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.

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