Nanobody-based Biepitope CAR-T Cells Targeting BCMA in the Treatment of R/RMM

A Multicenter Clinical Study on the Safety and Efficacy of Nanobody-based Biepitope CAR-T Cells Targeting BCMA in the Treatment of Relapsed/Refractory Multiple Myeloma

To explore the safety and efficacy of nanobody-based BCMA-targeting biepitope CAR-T cells in the treatment of relapsed/refractory multiple myeloma，this study will be conducted in multiple study centers, with 60 patients openly enrolled to receive CAR-T cell therapy. Patients participating in clinical trials will be tested and evaluated for treatment safety, efficacy, duration of response, and long-term survival.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Nanobody-based biepitope BCMA-targeting CAR-T cells

Detailed Description

This study is a multicenter, open-label, prospective, single-arm clinical study with patients with relapsed/refractory multiple myeloma as the test subjects, in order to evaluate the safety and efficacy of nanobody-based biepitope CAR-T cells targeting BCMA in the treatment of R/RMM, and to collect CAR-T PK/PD indicators. The structure of BCMA target CAR-T is designed to identify two different epitopes of BCMA protein with two recognition domains, in order to killig MM cells without secreting more pro-inflammatory factors and avoiding escape caused by the limitations of single BCMA antigen recognition.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yun Kang; Phone Number: 17362995329; Email: cloudykang@hust.edu.cn
• Study Contact Backup: Name: Mei Heng, M.D., Ph.D; Phone Number: 027-8572600; Email: hmei@hust.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Principal Investigator: Heng Mei, M.D., Ph.D
      • Contact: Heng Mei, M.D., Ph.D; Phone Number: 027-8572600; Email: hmei@hust.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
• Aged ≥ 18 years and ≤ 75 years.
• Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG 2014).
• Diagnosed as relapsed/refractory disease or primary refractory disease; relapse is defined as disease progression within 60 days of the most recent treatment with three or more lines of therapy with different mechanisms of action; refractory is defined as failure to achieve MR or above efficacy with prior treatment and disease progression with recent treatment, or disease progression within 60 days of treatment.
• Flow cytometry or immunohistochemistry showed positive BCMA expression in myeloma cells.
• Have not been treated with antibody-based drugs within 2 weeks prior to cell therapy.
• ECOG score 0-2 points.
• HGB≥70g/L，PLT≥30×10^9/L.

• Liver, kidney and cardiopulmonary functions meet the following requirements:

  1. Serum creatinine ≤ 1.5× ULN or creatinine clearance (Cockcroft-Gault) >30 ml/min；
  2. Left ventricular ejection fraction (LVEF) ≥50%,
  3. Baseline peripheral oxygen saturation > 90%;
  4. Total bilirubin ≤ 1.5×ULN; ALT and AST ≤2.5×ULN.

Exclusion Criteria:

• Previous diagnosis and treatment of other malignancies within 3 years;
• Presence of one of the following cardiac criteria: atrial fibrillation; Myocardial infarction within the last 12 months; Prolonged QT syndrome or secondary QT prolongation, as judged by the investigator. Echocardiogram LVSF <30% or LVEF <50%; Clinically significant pericardial effusion; Cardiac insufficiency NYHA (New York Heart Association) III or IV (absence of this symptom confirmed by echocardiography within 12 months of treatment);
• Patients with active GVHD;
• Patients with a history of severe pulmonary impairment disease;
• Combined with other malignant tumors in the advanced stage;
• Co-infection with severe or persistent infection that cannot be effectively controlled;
• Combined with severe autoimmune disease or congenital immunodeficiency;
• Active hepatitis (hepatitis B virus deoxyribonucleic acid [HBV-DNA ≥ 500 IU/ml and abnormal liver function] or hepatitis C antibody [HCV-Ab] positive, HCV-RNA above the lower limit of detection of the analytical method and abnormal liver function);
• Human immunodeficiency virus (HIV) infection or syphilis infection;
• Patients with a history of severe allergy to biological products (including antibiotics);
• Patients with central nervous system disorders such as uncontrolled epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, etc;
• Pregnant or Lactating Women; Patients and his or her spouses have a fertility plan within 12 months after CAR-T cell infusion;
• Other conditions considered inappropriate by the researcher.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Effective of nanobody-based biepitope BCMA-targeting CAR-T cells; The recommended reinfusion dose of biepitope BCMA-targeting CAR-T cells in this trial is: 1 × 10^6/kg, 2 × 10^6/kg CAR-T cells.	Drug: Nanobody-based biepitope BCMA-targeting CAR-T cells; Each patient will receive nanobody-based biepitope BCMA-targeting CAR-T cell by intravenous infusion on day 0.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-related Adverse Events	Therapy-related adverse events (AE), including severe adverse events (SAE) and laboratory outliers with clinical significance, will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).	within 3 years after infusion
Overall response rate (ORR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM	Disease overall response rate (ORR) will be assessed from CAR-T cell infusion to death or last follow-up (censored). The rates of stringent complete response (sCRs), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR) will be assessed from CAR T cell infusion to death or last follow-up (censored). ORR will be assessed from CAR T cell infusion to death or last follow-up.	within 3 years after infusion
The rates of complete response (CR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM	CR will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion
Very good partial response (VGPR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM	VGPR will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion
Partial response rate (PR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM	PR will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion
Stable diseases (SD) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM	SD will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma	OS will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion
Progression-free survival (PFS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma	PFS will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion
Event-free survival (EFS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma	EFS will be assessed from CAR-T cell infusion to death or last follow-up (censored).	within 3 years after infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
In vivo expansion and survival of nanobody-based biepitope CAR-T cells targeting BCMA	Quantity of CAR copies in bone marrow, peripheral blood and cerebrospinal fluid will be determined by using flow cytometry and quantitative polymerase chain reaction.	within 3 years after infusion

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China
• Collaborators: The Seventh Affiliated Hospital of Sun Yat-sen University; Huazhong University of Science and Technology Union Shenzhen Hospital; Hebei Taihe Chunyu Biotechnology Co., Ltd

Publications and helpful links

General Publications

• Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, Vogl DT, Weiss BM, Dengel K, Nelson A, Plesa G, Chen F, Davis MM, Hwang WT, Young RM, Brogdon JL, Isaacs R, Pruteanu-Malinici I, Siegel DL, Levine BL, June CH, Milone MC. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019 Mar 21;129(6):2210-2221. doi: 10.1172/JCI126397.
• Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, Lesokhin A, Deol A, Munshi NC, O'Donnell E, Avigan D, Singh I, Zudaire E, Yeh TM, Allred AJ, Olyslager Y, Banerjee A, Jackson CC, Goldberg JD, Schecter JM, Deraedt W, Zhuang SH, Infante J, Geng D, Wu X, Carrasco-Alfonso MJ, Akram M, Hossain F, Rizvi S, Fan F, Lin Y, Martin T, Jagannath S. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021 Jul 24;398(10297):314-324. doi: 10.1016/S0140-6736(21)00933-8. Epub 2021 Jun 24. Erratum In: Lancet. 2021 Oct 2;398(10307):1216. doi: 10.1016/S0140-6736(21)02132-2.
• Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-528. doi: 10.1016/S0140-6736(14)61403-3. Epub 2014 Oct 13.
• Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, Fellowes VS, Hakim FT, Gress RE, Kochenderfer JN. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016 Sep 29;128(13):1688-700. doi: 10.1182/blood-2016-04-711903. Epub 2016 Jul 13.

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2024
• Primary Completion (Estimated): April 18, 2026
• Study Completion (Estimated): October 18, 2026

Study Registration Dates

• First Submitted: June 17, 2024
• First Submitted That Met QC Criteria: July 9, 2024
• First Posted (Actual): July 16, 2024

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 9, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T; BCMA; Relapsed / Refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: biepitope BCMA CAR-T

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No