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
Authors: Chen Wenming , Fu Chengcheng , Cai Zhen , Li Zonghai , Wang Huijuan , Yan Lingzhi , Wu Yin , Shi Xiaolan , Gao Wen , Yan Shuang , Wang Wei , Han Xiaoyan , Zheng Gaofeng , Wen Yanling , Xiao Jun , Wang Huamao , Ma Hong 
Published: November 2020

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.