Sequential Infusion of Anti-CD19 and Anti-CD20 CAR-T Cells Against Relapsed and Refractory B-cell Lymphoma

• ClinicalTrials.gov Identifier: NCT03207178
• Recruitment Status: Unknown
• First Posted: July 2, 2017
• Last Update Posted: July 2, 2017
• Sponsor: Shanghai Longyao Biotechnology Inc., Ltd.
• Collaborators: Xuzhou Medical University; Shanghai Jiao Tong University School of Medicine
• Information provided by (Responsible Party): Shanghai Longyao Biotechnology Inc., Ltd.

Tracking Information

• First Submitted Date: June 23, 2017
• First Posted Date: July 2, 2017
• Last Update Posted Date: July 2, 2017
• Actual Study Start Date: March 1, 2017
• Estimated Primary Completion Date: February 28, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2017)

Overall complete remission rate [ Time Frame: Half a year ]

The complete remission rate will be evaluated by routine methods.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: June 29, 2017)

• The initial effect time [ Time Frame: 1 year ]
  The initial effect time will be recorded.
• The one-year survival rate [ Time Frame: 1 year ]
  The one-year survival rate will be recorded.
• The safety and the tolerability(incidence of treatment-emergent adverse events defined as dose-limited toxicity) [ Time Frame: 1 month ]
  Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.
• The time to disease progression [ Time Frame: 1 year ]
  The time to disease progression will be counted after complete remission.
• The one-year recurrence [ Time Frame: 1 year ]
  The one-year recurrence will be counted after complete remission.
• The life quality improvement [ Time Frame: 1 year ]
  The life quality improvement will be evaluated by appetite,sleep,pain and mental state.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sequential Infusion of Anti-CD19 and Anti-CD20 CAR-T Cells Against Relapsed and Refractory B-cell Lymphoma
• Official Title: Sequential Infusion of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor(CAR) T Cells Against Relapsed and Refractory B-cell Lymphoma
• Brief Summary: Cluster of differentiation antigen 19(CD19) specifically presents in B lymphocyte cell lines steadily,while not in most normal tissue,including pluripotent hematopoietic stem cells.Cluster of differentiation antigen 20(CD20) presents in 90% of B-cell lymphomas.CD19 antigen is a well-established target for B-cell lymphomas treatment as well as CD20 antigen.Both CD19-targeting CAR T Cells and CD20-targeting CAR T Cells can be used as adoptive cellular immunotherapies for B-cell lymphomas.Though two kinds of single target treatments were proved can induce recession of B-cell lymphomas, the risk of cancer cells to escape and tumor recurrence are still existed. There are no report about combination transfer of two kinds of single target treatments.This research aimed emphasis on safety and therapeutic efficacy evaluation,as well as if combination transfer can decrease recurrence rate.

Detailed Description

To determine:

Primary Outcome Measure:

The Overall complete remission rate and one-year survival rate of combination transfer of CD19-targeting CAR T Cells and CD20-targeting CAR T Cells is superior to or at least not worse than two kinds of single target treatments in the treatment of CD19+/CD20+ B-cell lymphomas.

The risk of cancer recurrence in a year of combination transfer of CD19-targeting CAR T Cells and CD20-targeting CAR T Cells is inferior to two kinds of single target treatments.

Secondary Outcome Measures:

Evaluate the initial effect time, time to disease progression, and life quality improvement of combination transfer compare to single target treatments.

Evaluate the safety and tolerability of combination transfer compare to single target treatments by observation of high fever duration in patients and testing related cell factor level in peripheral blood.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Recurrent or Refractory B Cell Malignancy

Intervention

Biological: Mixed CD19/CD20 CAR-T Transfer

Autologous CD19 CAR-T cells and CD20 CAR-T cells with average 1-5*10^6 cells/kg body weight,separately.

Study Arms

Experimental: Mixed CD19/CD20 CAR-T Transfer

Subjects with CD19+/CD20+ B-cell lymphomas will be infused with CD19-targeting CAR T Cells and CD20-targeting CAR T Cells in one time or in parts

Intervention: Biological: Mixed CD19/CD20 CAR-T Transfer

Publications *

• Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ, Chen MX, Feng KC, Wang QS, Fu XB, Han WD. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol. 2014 Dec;155(2):160-75. doi: 10.1016/j.clim.2014.10.002. Epub 2014 Oct 16.
• Witkowska M, Smolewski P. Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2015;7(1):37-46. doi: 10.2217/imt.14.93.
• Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, Gea-Banacloche JC, Pavletic SZ, Hickstein DD, Lu TL, Feldman SA, Iwamoto AT, Kurlander R, Maric I, Goy A, Hansen BG, Wilder JS, Blacklock-Schuver B, Hakim FT, Rosenberg SA, Gress RE, Kochenderfer JN. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. J Clin Oncol. 2016 Apr 1;34(10):1112-21. doi: 10.1200/JCO.2015.64.5929. Epub 2016 Jan 25.
• Hay KA, Turtle CJ. Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies. Drugs. 2017 Mar;77(3):237-245. doi: 10.1007/s40265-017-0690-8.
• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Sang W, Shi M, Yang J, Cao J, Xu L, Yan D, Yao M, Liu H, Li W, Zhang B, Sun K, Song X, Sun C, Jiao J, Qin Y, Sang T, Ma Y, Wu M, Gao X, Cheng H, Yan Z, Li D, Sun H, Zhu F, Wang Y, Zeng L, Li Z, Zheng J, Xu K. Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma. Cancer Med. 2020 Aug;9(16):5827-5838. doi: 10.1002/cam4.3259. Epub 2020 Jul 1.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 29, 2017): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 28, 2020
• Estimated Primary Completion Date: February 28, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 18 Years to 70 Years, Male and female
• Survival time>12 weeks
• B cell lymphomas diagnosed by Physical examination,pathological examination,Laboratory tests and imaging tests
• Chemotherapy failure or recurrent B cell lymphomas
• Creatinine< 2.5mg/dl
• Glutamic-pyruvic transaminase, glutamic oxalacetic transaminase< 3 fold of normal level
• Bilirubin<2.0mg/dl
• Karnofsky Performance Status>50% at the time of screening
• Adequate pulmonary, renal, hepatic, and cardiac function
• Fail in autologous or allogenic haemopoietic stem cell transplantation
• Free of leukocytes removal contraindications
• Voluntarily join CAR-T clinical trial
• Understand and sign written informed consent

Exclusion Criteria:

• Pregnant or nursing women or women with pregnancy plan in half a year
• Any infectious disease (HIV, active tuberculosis, ect.)
• Active hepatitis B, active hepatitis C infection
• Feasibility assessment proves that the efficiency of transduction of lymphocyte is below 10% or the lymphocyte amplification is below 5 fold with the costimulation of cluster of differentiation 3(CD 3)and cluster of differentiation 8(CD 8)
• Abnormal vital signs or cannot cooperate with the inspectors
• mental or psychological disease cannot cooperate with treatment and curative effect evaluation
• Highly allergic constitution or history of severe allergies, especially allergy to interleukin-2(IL-2)
• General infection or local severe infection, or other infection that is not controlled
• Dysfunction in lung, heart, kidney and brain
• Severe autoimmune diseases
• Other symptoms that are not applicable for CAR-T

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT03207178
• Other Study ID Numbers: LYCT-1701
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Shanghai Longyao Biotechnology Inc., Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Shanghai Longyao Biotechnology Inc., Ltd.
• Original Study Sponsor: Same as current

Collaborators

• Xuzhou Medical University
• Shanghai Jiao Tong University School of Medicine

Investigators

• Principal Investigator: Shengqin Ye, M.D.; Shanghai Longyao Biotechnology Inc., Ltd.

• PRS Account: Shanghai Longyao Biotechnology Inc., Ltd.
• Verification Date: June 2017