Clinical trial NCT03716856: Clinical Study of CAR-BCMA T in Patients With Refractory or Relapsed Multiple Myeloma
Official title: Clinical Study of Redirected Autologous T Cells With a BCMA-targeted Chimeric Antigen Receptor in Patients With Refractory or Relapsed Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Refractory or Relapsed Multiple Myeloma
Lead sponsor: First Affiliated Hospital of Zhejiang University
Sponsor class: OTHER
Collaborators: name: CARsgen Therapeutics Co., Ltd.
First posted: 2018-10-23
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility 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.).

Primary outcomes:
measure: Safety and effectivity - Incidence of study related adverse events
timeFrame: 24 weeks
measure: Engraftment
timeFrame: 2 years
Secondary outcomes:
measure: Statistical parameter of efficacy assessment：PFS
timeFrame: 5 years
measure: Statistical parameter of efficacy assessment：DCR
timeFrame: 2 years
measure: Statistical parameter of efficacy assessment：ORR
timeFrame: 2 years
measure: Statistical parameter of efficacy assessment：OS
timeFrame: 5 years
Other outcomes:
measure: Number of DNA copies of CAR-BCMA T cells in tissue samples
timeFrame: 2 years
measure: Positive incidence of anti-drug antibody
timeFrame: 2 years
measure: Change of T cell subsets from baseline counts
timeFrame: 2 years
Locations:
city: Hangzhou
country: China
facility: First Affiliated Hospital of Zhejiang University
state: Zhejiang
Study officials:
affiliation: First Affiliated Hospital of Zhejiang University
name: Jie Jin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: First Affiliated Hospital of Zhejiang University
name: Haitao Meng, MD
role: PRINCIPAL_INVESTIGATOR
References: