The Lancet. Haematology · 2025
GPRC5D-targeted CAR T-cell therapy (CT071) in patients with relapsed or refractory multiple myeloma: a first-in-human, single-centre, single-arm, phase 1 trial.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Jin Lina, Gu Sinan, Ruan Qianqi, Lu Jing, Qiang Wanting, He Haiyan, Fan Xiaoqiang, Liu Jin, Guo Pei, Meng Xingxing, Rajakumaraswamy Nishanthan, Chen Deng, Li Zonghai, Du Juan
Аннотация
BACKGROUND: Relapsed or refractory multiple myeloma remains incurable. CT071 is a fully human, autologous, chimeric antigen receptor (CAR) T-cell therapy directed against G protein-coupled receptor class C group 5 member D (GPRC5D), with expedited manufacturing. This trial aimed to assess the preliminary activity, safety, and cellular kinetics of CT071 in relapsed or refractory multiple myeloma.
METHODS: This first-in-human, single-centre, single-arm, phase 1 study was conducted in China at Shanghai Changzheng Hospital. Eligible patients were aged 18 years or older with relapsed or refractory multiple myeloma who had received three or more previous lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or had double-class refractory therapy, and had progressive disease on the last line of therapy. Eastern Cooperative Oncology Group performance status 0-2 was required. Patients received CT071 at 0·1 × 106 CAR T cells per kg or 0·3 × 106 CAR T cells per kg. The primary endpoint was safety, which included dose-limiting toxicities, adverse events, and dose determination. Activity was also evaluated as a secondary endpoint. All patients receiving CT071 were included in the safety and activity analyses. This trial is registered with ClinicalTrials.gov (NCT05838131) and enrolment is complete.
FINDINGS: Between April 28, 2023, and June 21, 2024, 23 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (one discontinued due to rapid disease progression, one due to active infection, and one was withdrawn because of failed manufacture of CAR T cells), thus 20 patients were infused. Median age was 63·0 years (IQR 53·0-65·5). 12 (60%) of 20 patients were male and eight (40%) were female; all patients were Chinese. Median follow-up was 10·71 months (IQR 6·13-12·02). No dose-limiting toxicities were observed, and the recommended phase 2 dose was determined at 0·1 × 106 CAR T cells per kg. Haematological toxicities were the most common grade 3 or worse treatment-related adverse events, occurring in all patients. Cytokine release syndrome occurred in 12 (60%) of 20 patients, all of which were grade 1-2. One (5%) patient had grade 3 immune effector cell-associated neurotoxicity syndrome. Serious treatment-related adverse events were reported in seven (35%) patients; no treatment-related deaths occurred. Skin-related events included onychomadesis reported in four (20%) patients and rash in one (5%) patient, all of which were grade 1. The objective response rate was 100% (95% CI 83·2-100), with a complete response or better rate of 50% (ten of 20 patients).
INTERPRETATION: CT071 demonstrated an encouraging safety profile with compelling activity in patients with relapsed or refractory multiple myeloma.
FUNDING: National Natural Science Foundation of China and Clinical Research Plan of Shanghai Hospital Development Center.
METHODS: This first-in-human, single-centre, single-arm, phase 1 study was conducted in China at Shanghai Changzheng Hospital. Eligible patients were aged 18 years or older with relapsed or refractory multiple myeloma who had received three or more previous lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or had double-class refractory therapy, and had progressive disease on the last line of therapy. Eastern Cooperative Oncology Group performance status 0-2 was required. Patients received CT071 at 0·1 × 106 CAR T cells per kg or 0·3 × 106 CAR T cells per kg. The primary endpoint was safety, which included dose-limiting toxicities, adverse events, and dose determination. Activity was also evaluated as a secondary endpoint. All patients receiving CT071 were included in the safety and activity analyses. This trial is registered with ClinicalTrials.gov (NCT05838131) and enrolment is complete.
FINDINGS: Between April 28, 2023, and June 21, 2024, 23 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (one discontinued due to rapid disease progression, one due to active infection, and one was withdrawn because of failed manufacture of CAR T cells), thus 20 patients were infused. Median age was 63·0 years (IQR 53·0-65·5). 12 (60%) of 20 patients were male and eight (40%) were female; all patients were Chinese. Median follow-up was 10·71 months (IQR 6·13-12·02). No dose-limiting toxicities were observed, and the recommended phase 2 dose was determined at 0·1 × 106 CAR T cells per kg. Haematological toxicities were the most common grade 3 or worse treatment-related adverse events, occurring in all patients. Cytokine release syndrome occurred in 12 (60%) of 20 patients, all of which were grade 1-2. One (5%) patient had grade 3 immune effector cell-associated neurotoxicity syndrome. Serious treatment-related adverse events were reported in seven (35%) patients; no treatment-related deaths occurred. Skin-related events included onychomadesis reported in four (20%) patients and rash in one (5%) patient, all of which were grade 1. The objective response rate was 100% (95% CI 83·2-100), with a complete response or better rate of 50% (ten of 20 patients).
INTERPRETATION: CT071 demonstrated an encouraging safety profile with compelling activity in patients with relapsed or refractory multiple myeloma.
FUNDING: National Natural Science Foundation of China and Clinical Research Plan of Shanghai Hospital Development Center.