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

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ClinicalTrials.gov Identifier: NCT03716856
Recruitment Status : Recruiting
First Posted : October 23, 2018
Last Update Posted : October 23, 2018
Sponsor:
Collaborator:
Carsgen Therapeutics, Ltd.
Information provided by (Responsible Party):
First Affiliated Hospital of Zhejiang University

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.

Condition or disease Intervention/treatment Phase
Refractory or Relapsed Multiple Myeloma Genetic: CAR-BCMA T cells Drug: Fludarabine Drug: Cyclophosphamide Phase 1

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Study of Redirected Autologous T Cells With a BCMA-targeted Chimeric Antigen Receptor in Patients With Refractory or Relapsed Multiple Myeloma
Actual Study Start Date : December 26, 2017
Estimated Primary Completion Date : April 30, 2019
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Fludarabine

Arm Intervention/treatment
Experimental: 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.

Genetic: CAR-BCMA T cells
Single dose of CAR-BCMA T cells will be infused, and classic "3+3" dose escalation will be applied.
Other Name: BCMA-redirected autologous T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion




Primary Outcome Measures :
  1. Safety and effectivity - Incidence of study related adverse events [ Time Frame: 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.

  2. Engraftment [ Time Frame: 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 :
  1. Statistical parameter of efficacy assessment:PFS [ Time Frame: 2 years ]
    Statistical parameter:Progression-free Survival (PFS)

  2. Statistical parameter of efficacy assessment:DCR [ Time Frame: 2 years ]
    Statistical parameter:Disease Control Rate (DCR)

  3. Statistical parameter of efficacy assessment:ORR [ Time Frame: 2 years ]
    Statistical parameter:Objective Remission Rate (ORR)

  4. Statistical parameter of efficacy assessment:OS [ Time Frame: 2 years ]
    Statistical parameter:Overall survival (OS)


Other Outcome Measures:
  1. Number of RNA copies of CAR-BCMA T cells in tissue samples [ Time Frame: 2 years ]
    Number of RNA copies of CAR-BCMA T cells in lymph node samples or bone marrow samples at regular intervals from 24 hours after the initial infusion.

  2. Positive incidence of anti-drug antibody [ Time Frame: 2 years ]
    Positive incidence of anti-BCMA anti-drug antibody (ADA).

  3. Change of T cell subsets from baseline counts [ Time Frame: 2 years ]
    Change of T cell subsets from baseline counts after infusion(Tcm, central memory T lymphocytes; Tem, effector memory T lymphocytes; Treg, regulatory T lymphocytes).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients aged between 18 ~ 70 with relapsed or refractory multiple myeloma.
  • Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination.
  • Patients with relapsed or refractory multiple myeloma who meet the following conditions:

    1. Curative efficacy is little or disease progressed after 2 courses of standard treatment regimen;
    2. Disease relapsed after chemotherapy or HSCT. Curative efficacy is little or disease progressed after 2 courses of original treatment regimen;
    3. More than 60 days between last treatment and disease progression;
    4. Autologous or allogeneic SCT is not available at present, or patient refuses to receive SCT;
    5. No response to treatment is defined according to International Myeloma Working Group 2014 version as not achieving CR (including CR, sCR, ICR, MCR) or PR (including VGPR, PR, MR) after 2 consecutive cycles of treatment with current therapy, and the interval between the 2 cycles is no more than 60 days. Disease progression is defined as per 《Chinese Guidelines for Diagnosis and Treatment of Multiple Myeloma》 (Revision in 2015). At least one of the following conditions should be met:Serum M-protein increases ≥ 25% (absolute increase should be ≥ 5 g/L); If serum M protein is ≥ 50 g/L at baseline, increase of serum M protein can be ≥ 10 g/L; Urine M-protein increases ≥ 25% (absolute increase should be ≥ 200 mg/24 h); If the serum and urine M-protein are not detectable, a ≥ 25% increase in the difference between involved and uninvolved FLC levels is required (absolute increase should be ≥ 100 mg/L); Bone marrow plasma cell percentage increases ≥ 25% (absolute increase should be ≥ 10%); Size of existing bone lesions or soft tissue plasmacytomas increases by ≥ 25%, or development of new lytic bone lesions or soft tissue plasmacytomas; Development of hypercalcemia that can be attributed to plasma cell proliferative disorder (corrected calcium is > 2.8 mmol/L or 11.5 mg/dL); Disease progression must be confirmed by 2 sequential assessments.
  • Expected survival > 12 weeks.
  • Disease is measurable, and at least one of the following conditions should be satisfied:
  • Serum M-protein is ≥ 10 g/L;
  • 24-hour urine M-protein is ≥ 200 mg;
  • Serum FLC is ≥ 5 mg/dL;
  • Plasmacytomas that can be evaluated by tests or imaging;
  • Bone marrow plasma cell percentage is ≥ 20%.
  • ECOG scores 0 - 1.
  • Adequate venous access for apheresis and venous blood sampling, and no other contraindications for leukapheresis.
  • WBC ≥ 1.5×10^9/L;PLT ≥ 45×10^9/L; Hb≥9.0g/dL
  • Serum creatinine ≤ 1.5 ULN.
  • ALT ≤ 2.5 ULN;AST ≤ 2.5 ULN. The above lab results should not include those obtained from continuous supportive treatment that is ongoing.

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.).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03716856


Contacts
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Contact: Jie Jin, MD +86-0571-87236896 jiej0503@163.com
Contact: Haitao Meng, MD +86-0571-87236896 menghait2004@163.com

Locations
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China, Zhejiang
First Affiliated Hospital of Zhejiang University Recruiting
Hangzhou, Zhejiang, China, 310006,
Contact: Jin Jie, MD    +86-0571-87236896    jiej0503@163.com   
Contact: Haitao Meng, MD    +86-0571-87236896    menghait2004@163.com   
Sponsors and Collaborators
First Affiliated Hospital of Zhejiang University
Carsgen Therapeutics, Ltd.
Investigators
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Principal Investigator: Jie Jin, MD First Affiliated Hospital of Zhejiang University
Principal Investigator: Haitao Meng, MD First Affiliated Hospital of Zhejiang University

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Responsible Party: First Affiliated Hospital of Zhejiang University
ClinicalTrials.gov Identifier: NCT03716856     History of Changes
Other Study ID Numbers: CG6003
First Posted: October 23, 2018    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: October 2017

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

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites