Zhitao Ying1, Haiyan Yang2, Ye Guo3, Wenyu Li4, Dehui Zou5, Daobin Zhou6, Zhao Wang7, Mingzhi Zhang8, Jianqiu Wu9, Hui Liu10, Pian Zhang11, Su Yang11, Zisong Zhou11, Hongxia Zheng11, Yuqin Song1, Jun Zhu1. 1. Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China. 2. Department of Lymphatic Medical, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang, China. 3. Department of Oncology, Shanghai East Hospital, Shanghai, China. 4. Department of Lymphoma, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong, China. 5. Lymphoma Center, Institute of Hematology & Blood Diseases, Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Hematology and Blood Diseases Hospital (IH), Tianjin, China. 6. Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. 7. Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 8. Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 9. Department of Medical Oncology, Jiangsu Institute of Cancer Research, Jiangsu Red Cross Cancer Center, Jiangsu Cancer Hospital, the Affiliated Hospital of Nanjing Medical University, Nanjing, China. 10. Department of Hematology, Beijing Hospital, Beijing, China. 11. JW Therapeutics (Shanghai) Co. Ltd, Shanghai, China.
Abstract
BACKGROUND: Despite numerous chimeric antigen receptor T-cell (CAR-T) trials conducted in China, no CAR-T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR-T manufacture abroad. Relma-cel (JWCAR029), an anti-CD19 product produced with a commercial-ready process in China, was evaluated in the first prospective, single-arm, multicenter, pivotal study of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215). METHODS: Patients were randomized to receive either 100 × 106 (low dose, n = 27) or 150 × 106 (high dose, n = 32) CAR+ T-cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics. RESULTS: As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy-evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6-73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%. CONCLUSIONS: Relma-cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR-T-associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.
RCT Entities:
BACKGROUND: Despite numerous chimeric antigen receptor T-cell (CAR-T) trials conducted in China, no CAR-T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR-T manufacture abroad. Relma-cel (JWCAR029), an anti-CD19 product produced with a commercial-ready process in China, was evaluated in the first prospective, single-arm, multicenter, pivotal study of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215). METHODS:Patients were randomized to receive either 100 × 106 (low dose, n = 27) or 150 × 106 (high dose, n = 32) CAR+ T-cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics. RESULTS: As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy-evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6-73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%. CONCLUSIONS:Relma-cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR-T-associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.
Authors: Michael Crump; Sattva S Neelapu; Umar Farooq; Eric Van Den Neste; John Kuruvilla; Jason Westin; Brian K Link; Annette Hay; James R Cerhan; Liting Zhu; Sami Boussetta; Lei Feng; Matthew J Maurer; Lynn Navale; Jeff Wiezorek; William Y Go; Christian Gisselbrecht Journal: Blood Date: 2017-08-03 Impact factor: 22.113
Authors: Felicitas Hitz; J M Connors; R D Gascoyne; P Hoskins; A Moccia; K J Savage; L H Sehn; T Shenkier; D Villa; R Klasa Journal: Ann Hematol Date: 2015-08-07 Impact factor: 3.673
Authors: Michael Crump; John Kuruvilla; Stephen Couban; David A MacDonald; Vishal Kukreti; C Tom Kouroukis; Morel Rubinger; Rena Buckstein; Kevin R Imrie; Massimo Federico; Nicola Di Renzo; Kang Howson-Jan; Tara Baetz; Leonard Kaizer; Michael Voralia; Harold J Olney; A Robert Turner; Jonathan Sussman; Annette E Hay; Marina S Djurfeldt; Ralph M Meyer; Bingshu E Chen; Lois E Shepherd Journal: J Clin Oncol Date: 2014-09-29 Impact factor: 44.544
Authors: Zi-Xun Yan; Li Li; Wen Wang; Bin-Shen OuYang; Shu Cheng; Li Wang; Wen Wu; Peng-Peng Xu; Muharrem Muftuoglu; Ming Hao; Su Yang; Mu-Chen Zhang; Zhong Zheng; James Li; Wei-Li Zhao Journal: Clin Cancer Res Date: 2019-08-23 Impact factor: 12.531
Authors: Shannon L Maude; Noelle Frey; Pamela A Shaw; Richard Aplenc; David M Barrett; Nancy J Bunin; Anne Chew; Vanessa E Gonzalez; Zhaohui Zheng; Simon F Lacey; Yolanda D Mahnke; Jan J Melenhorst; Susan R Rheingold; Angela Shen; David T Teachey; Bruce L Levine; Carl H June; David L Porter; Stephan A Grupp Journal: N Engl J Med Date: 2014-10-16 Impact factor: 91.245
Authors: Bruce D Cheson; Beate Pfistner; Malik E Juweid; Randy D Gascoyne; Lena Specht; Sandra J Horning; Bertrand Coiffier; Richard I Fisher; Anton Hagenbeek; Emanuele Zucca; Steven T Rosen; Sigrid Stroobants; T Andrew Lister; Richard T Hoppe; Martin Dreyling; Kensei Tobinai; Julie M Vose; Joseph M Connors; Massimo Federico; Volker Diehl Journal: J Clin Oncol Date: 2007-01-22 Impact factor: 44.544
Authors: Daniel W Lee; Rebecca Gardner; David L Porter; Chrystal U Louis; Nabil Ahmed; Michael Jensen; Stephan A Grupp; Crystal L Mackall Journal: Blood Date: 2014-05-29 Impact factor: 22.113
Authors: Frederick L Locke; Sattva S Neelapu; Nancy L Bartlett; Tanya Siddiqi; Julio C Chavez; Chitra M Hosing; Armin Ghobadi; Lihua E Budde; Adrian Bot; John M Rossi; Yizhou Jiang; Allen X Xue; Meg Elias; Jeff Aycock; Jeff Wiezorek; William Y Go Journal: Mol Ther Date: 2017-01-04 Impact factor: 11.454
Authors: Andrew M Stein; Stephan A Grupp; John E Levine; Theodore W Laetsch; Michael A Pulsipher; Michael W Boyer; Keith J August; Bruce L Levine; Lori Tomassian; Sweta Shah; Mimi Leung; Pai-Hsi Huang; Rakesh Awasthi; Karen Thudium Mueller; Patricia A Wood; Carl H June Journal: CPT Pharmacometrics Syst Pharmacol Date: 2019-03-07