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

Clinical Study of Redirected Autologous T Cells With a BCMA-targeted Chimeric Antigen Receptor in Patients With Refractory or Relapsed Multiple Myeloma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory or Relapsed Multiple Myeloma
• Intervention / Treatment: Genetic: CAR-BCMA T cells; Drug: Fludarabine; Drug: Cyclophosphamide

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 changes of cell subsets of CAR-BCMA T cells against T cells (Tcm, central memory T lymphocytes; Tem, effector memory T lymphocytes; Treg, regulatory T lymphocytes).

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200092
      • Xin Hua Hospital of Shanghai Jiao Tong University of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients aged between 18 ~ 70 with relapsed or refractory multiple myeloma.
2. Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination.

3. 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) 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:
   • - i. 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;
   • - ii. Urine M-protein increases ≥ 25% (absolute increase should be ≥ 200 mg/24 h);
   • - iii. 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);
   • - iv. Bone marrow plasma cell percentage increases ≥ 25% (absolute increase should be ≥ 10%);
   • - v. Size of existing bone lesions or soft tissue plasmacytomas increases by ≥ 25%, or development of new lytic bone lesions or soft tissue plasmacytomas;
   • - vi. Development of hypercalcemia that can be attributed to plasma cell proliferative disorder (corrected calcium is > 2.8 mmol/L or 11.5 mg/dL);
   • - vii. Disease progression must be confirmed by 2 sequential assessments.
4. Expected survival > 12 weeks.

5. Disease is measurable, and at least one of the following conditions should be satisfied:

   • 1) Serum M-protein is ≥ 10 g/L;
   • 2) 24-hour urine M-protein is ≥ 200 mg;
   • 3) Serum FLC is ≥ 5 mg/dL;
   • 4) Plasmacytomas that can be measured or evaluated by imaging;
   • 5) Bone marrow plasma cell percentage is ≥ 20%.
6. ECOG scores 0 - 1.
7. Adequate venous access for apheresis and venous blood sampling, and no other contraindications for leukapheresis.
8. WBC ≥ 1.5×10^9/L, PLT ≥ 45×10^9/L;
9. Serum creatinine ≤ 1.5 ULN.
10. 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.

1. Transduction of target lymphocytes < 10%, expansion in response to αCD3/CD28 costimulation < 5-fold.
2. Pregnant or lactating women.
3. HIV positive, or HCV positive
4. Uncontrolled active infection, including active tuberculosis and HBV DNA copies ≥ 1×10^3 copies/mL.
5. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary.
6. Allergic to immunotherapies and related drugs.
7. Patients with heart disease for which treatment is needed or with poorly controlled hypertension.
8. Hyponatremia: serum sodium level < 125 mmol/L.
9. Baseline serum potassium < 3.5 mmol/L (taking potassium supplements before participating in the study to raise potassium level is acceptable).
10. Previous treatment with chemoradiotherapy, immunotherapy and tumor-targeting drug conducted 2 weeks prior to participation in this study or blood collection.
11. 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.
12. 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.).

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: 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 Names: BCMA-redirected autologous T cells; Drug: Fludarabine; Fludarabine is used for lymphodepletion.; Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with CAR-BCMA T cell therapy-related adverse events as assessed by CTCAE v4.03	Number of participants with 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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment	Duration of in vivo survival of CAR-BCMA T cells is defined as "engraftment". The primary engraftment endpoint is the number of CAR-BCMA DNA vector copies per mL blood of CAR-BCMA T cells at regular intervals from 24 hours after initial infusion through 2 years of last infusion. PCR for CAR-BCMA T vector sequences will be performed until any 2 sequential tests are negative, documented as engraftment of CAR-BCMA T cells.	2 years
Anti-tumor response of CAR-BCMA T cell infusion	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 years
Statistical parameter of efficacy assessment#PFS	Statistical parameter#Progression-free Survival (PFS)	5 years
Statistical parameter of efficacy assessment#DCR	Statistical parameter:Disease Control Rate (DCR)	2 years
Statistical parameter of efficacy assessment#ORR	Statistical parameter:Objective Remission Rate (ORR)	2 years
Statistical parameter of efficacy assessment#OS	Statistical parameter:Overall survival (OS)	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of DNA copies of CAR-BCMA T cells in tissue samples	The number of DNA 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 years
Anti-drug antibody	Detect titer of anti-BCMA anti-drug antibody (ADA).	2 years
Changes of cell subsets of CAR-BCMA T cells against T cells	Observe the changes of cell subsets of CAR-BCMA T cells against T cells (Tcm, central memory T lymphocytes; Tem, effector memory T lymphocytes; Treg, regulatory T lymphocytes).	2 years

Collaborators and Investigators

• Sponsor: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Collaborators: CARsgen Therapeutics Co., Ltd.
• Investigators: Principal Investigator: Siguo Hao, MD, Xin Hua Hospital of Shanghai Jiao Tong University of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2017
• Primary Completion (Actual): July 2, 2020
• Study Completion (Anticipated): July 2, 2023

Study Registration Dates

• First Submitted: December 11, 2017
• First Submitted That Met QC Criteria: December 15, 2017
• First Posted (Actual): December 20, 2017

Study Record Updates

• Last Update Posted (Actual): October 12, 2020
• Last Update Submitted That Met QC Criteria: October 8, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: XH-17-018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No