Clinical Study of CAR-BCMA T in Patients With Refractory or Relapsed Multiple Myeloma

Phase 1

Interventions: Genetic: CAR-BCMA T cells
Drug: Fludarabine
Drug: Cyclophosphamide

Brief Summary: A single arm, open-label pilot study is designed to determine the safety, efficacy and cytokinetics of CAR-BCMA T cells in patients with BCMA-positive refractory or relapsed multiple myeloma.

Detailed Description: This study is designed to determine the safety, tolerability and engraftment potential of anti-BCMA lentivirus-transduced autologous T cells in patients with refractory or relapsed multiple myeloma.

Primary objectives:

1. Determine the safety and tolerability of CAR-BCMA T cells (autologous T cells transduced with chimeric antigen receptors recognizing BCMA) in patients with refractory or relapsed multiple myeloma.

2. Observe the cytokinetics of CAR-BCMA T cells.

Secondary objectives:

1. Observe the anti-tumor response of CAR-BCMA T cells to refractory or relapsed multiple myeloma (evaluated by diagnostic criteria International Myeloma Working Group (IMWG2014 version) as CR, sCR, ICR, MCR or VGPR).

2. Make an evaluation on the distribution and in vivo survival of CAR-BCMA T cells in peripheral blood, lymph node, and bone marrow.

3. Observe the immunogenicity of CAR-BCMA T cells, and determine if there is anti-BCMA scFv cellular immune response and anti-BCMA scFv humoral immune response.

4. Observe the change of T cell subsets relative to CAR-BCMA T。 (Tcm, central memory T lymphocytes; Tem, effector memory T lymphocytes; Treg, regulatory T lymphocytes).

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Patients with any of the following conditions are not eligible for this study.

Pregnant or lactating women.
HIV positive, or HCV positive
Uncontrolled active infection, including active tuberculosis and HBV DNA copies ≥ 1×10^3 copies/mL.
Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary.
Allergic to immunotherapies and related drugs.
Patients with heart disease for which treatment is needed or with poorly controlled hypertension.
Hyponatremia: serum sodium level < 125 mmol/L.
Baseline serum potassium < 3.5 mmol/L (taking potassium supplements before participating in the study to raise potassium level is acceptable).
Previous treatment with chemoradiotherapy, local treatment ,immunotherapy and tumor-targeting drug conducted 2 weeks prior to participation in this study or blood collection.
Patients have undertaken immunosuppressor for graft-versus-host disease (GVHD) within 4 weeks before participation in this study or blood collection, or the patient is diagnosed with acute or chronic GVHD.
Other severe disease that may restrain patients from participating in this study (e.g. diabetes, severe cardiac dysfunction, myocardial infarction or unstable arrhythmias or unstable angina in recent 6 months, gastric ulcer, active autoimmune disease, etc.).

Arm && Interventions

Group	Intervention	Description
CAR-BCMA T cells	CAR-BCMA T cells	In this study, autologous T cells transduced with a BCMA-targeted chimeric antigen receptor (CAR-BCMA T cells) are used to treat patients with refractory or relapsed multiple myeloma. Route of administration: Intravenous injection. Lymphodepletion conditioning: Lymphodepletion will be conducted several days prior to CAR-BCMA T cells infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.
CAR-BCMA T cells	Fludarabine	In this study, autologous T cells transduced with a BCMA-targeted chimeric antigen receptor (CAR-BCMA T cells) are used to treat patients with refractory or relapsed multiple myeloma. Route of administration: Intravenous injection. Lymphodepletion conditioning: Lymphodepletion will be conducted several days prior to CAR-BCMA T cells infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.
CAR-BCMA T cells	Cyclophosphamide	In this study, autologous T cells transduced with a BCMA-targeted chimeric antigen receptor (CAR-BCMA T cells) are used to treat patients with refractory or relapsed multiple myeloma. Route of administration: Intravenous injection. Lymphodepletion conditioning: Lymphodepletion will be conducted several days prior to CAR-BCMA T cells infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.

Primary Outcome Measures

Name	Time	Method
Safety and effectivity - Incidence of study related adverse events	24 weeks	Incidence of study related adverse events which are defined as laboratory toxicities and clinical events that are possible, likely or definitely related to study treatment at any time from the infusion until week 24, including infusion related toxicity and any toxicity possibly related to CAR-BCMA T cells.
Engraftment	2 years	Duration of in vivo survival of CAR-BCMA T cells is defined as "engraftment". After 24 hours of infusion, the CAR-BCMA DNA sequence was detected by PCR according to the follow-up time point, until the result of any two consecutive tests was negative and recorded as the "engraftment endpoint" of CAR-BCMA T cells.

Secondary Outcome Measures

Name	Time	Method
Statistical parameter of efficacy assessment：DCR	2 years	Statistical parameter:Disease Control Rate (DCR)
Statistical parameter of efficacy assessment：ORR	2 years	Statistical parameter:Objective Remission Rate (ORR)
Statistical parameter of efficacy assessment：OS	5 years	Statistical parameter:Overall survival (OS)
Statistical parameter of efficacy assessment：PFS	5 years	Statistical parameter：Progression-free Survival (PFS)

Locations (1): First Affiliated Hospital of Zhejiang University
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Hangzhou, Zhejiang, China