Clinical Trials /

Immunotherapy With BCMA CAR-T Cells in Treating Patients With BCMA Positive Relapsed or Refractory Multiple Myeloma

NCT03338972

Description:

This phase I trial studies the side effects and best dose of BCMA CAR-T cells in treating patients with BCMA positive multiple myeloma that has come back or does not respond to treatment. T cells are a type of white blood cell and a major component of the immune system. T-cells that have been genetically modified in the laboratory express BCMA and may kill cancer cells with the protein BCMA on their surface. Giving chemotherapy before BCMA CAR-T cells may reduce the amount of disease and to cause a low lymphocyte (white blood cell) count in the blood, which may help the infused BCMA CAR-T cells survive and expand.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With BCMA CAR-T Cells in Treating Patients With BCMA Positive Relapsed or Refractory Multiple Myeloma
  • Official Title: A Phase I Study of Adoptive Immunotherapy for Advanced B-Cell Maturation Antigen (BCMA)+ Multiple Myeloma With Autologous CD4+ and CD8+ T Cells Engineered to Express a BCMA-Specific Chimeric Antigen Receptor

Clinical Trial IDs

  • ORG STUDY ID: 9762
  • SECONDARY ID: NCI-2017-01932
  • SECONDARY ID: 9762
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9217023
  • NCT ID: NCT03338972

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
  • TNFRSF17 Positive

Interventions

DrugSynonymsArms
Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes FCARH143Autologous Anti-BCMA-CAR CD4+/CD8+ Cells, Autologous Anti-BCMA-CAR-expressing CD8+ and CD4+ T-lymphocytes, BCMA CAR-CD4+/CD8+ T-cells, BCMA-specific CAR-expressing CD4+/CD8+ T-lymphocytes, FCARH143Treatment (chemotherapy, BCMA CAR-T cells)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (chemotherapy, BCMA CAR-T cells)
FludarabineFluradosaTreatment (chemotherapy, BCMA CAR-T cells)

Purpose

This phase I trial studies the side effects and best dose of BCMA CAR-T cells in treating patients with BCMA positive multiple myeloma that has come back or does not respond to treatment. T cells are a type of white blood cell and a major component of the immune system. T-cells that have been genetically modified in the laboratory express BCMA and may kill cancer cells with the protein BCMA on their surface. Giving chemotherapy before BCMA CAR-T cells may reduce the amount of disease and to cause a low lymphocyte (white blood cell) count in the blood, which may help the infused BCMA CAR-T cells survive and expand.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety of adoptive therapy with ex vivo expanded autologous CD8+ plus CD4+
      T cells transduced to express a human B cell maturation antigen (BCMA-)-targeting chimeric
      antigen receptor (CAR) for patients with relapsed or treatment refractory multiple myeloma.

      SECONDARY OBJECTIVES:

      I. To determine the degree to which adoptively transferred T cells traffic to multiple
      myeloma (MM) cells in the bone marrow (BM) and function in vivo.

      II. To determine the degree to which adoptively transferred T cells traffic to MM cells in
      the BM and function in vivo.

      III. To estimate the antitumor activity of adoptively transferred BCMA-specific
      CAR-expressing T lymphocytes (BCMA CAR-T cells).

      OUTLINE: This is a dose-escalation study of BCMA-specific CAR-expressing T lymphocytes.

      Patients undergo leukapheresis to obtain their immune cells, from which CAR-T cells are
      produced. A few weeks later, patients then receive cyclophosphamide and fludarabine on days
      -4 to -2. Beginning 36-96 hours after chemotherapy, patients receive BCMA-specific
      CAR-expressing T lymphocytes intravenously (IV) over 20-30 minutes on day 0.

      After completion of study treatment, patients are followed up at 60, 90, 120, 180, and 365
      days and then up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, BCMA CAR-T cells)ExperimentalPatients undergo leukapheresis. Patients then receive cyclophosphamide and fludarabine on days -4 to -2. Beginning to 36-96 days after chemotherapy, patients receive BCMA-specific CAR-expressing T lymphocytes IV over 20-30 minutes on day 0. Patients may receive a second BCMA-specific CAR-expressing T lymphocytes infusion at the highest cell dose or the next highest dose level.
  • Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes FCARH143
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Have the capacity to give informed consent

          -  Have measurable disease by International Myeloma Working Group (IMWG) criteria based
             on one or more of the following findings:

               -  Serum M-protein >= 1 g/dL

               -  Urine M-protein >= 200 mg/24 hour

               -  Involved serum free light chain (sFLC) level >= 10 mg/dL with abnormal
                  kappa/lambda ratio

               -  Measurable biopsy-proven plasmacytomas (>= 1 lesion that has a single diameter >=
                  2 cm)

               -  Bone marrow plasma cells >= 30%

          -  Have a diagnosis of BCMA+ MM (>= 5% BCMA+ by flow cytometry on CD138 co-expressing
             plasma cells obtained within 45 days of study enrollment); the MM diagnosis must be
             confirmed by internal pathology review of a fresh biopsy specimen at the Fred
             Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA)

          -  Have relapsed or treatment refractory disease with >= 10% CD138+ malignant plasma
             cells (IHC) on BM core biopsy, either:

               -  Following autologous stem cell transplant (ASCT)

               -  Or, if a patient has not yet undergone ASCT, the individual must:

                    -  Be transplant ineligible, due to age, comorbidity, patient choice, insurance
                       reasons, concerns of rapidly progressive disease, and/or discretion of
                       attending physician, and,

                    -  Demonstrate disease that persists after > 4 cycles of induction therapy and
                       that is double refractory (persistence/progression) after therapy with both
                       a proteasome inhibitor and immunomodulatory drug (IMiD) administered either
                       in tandem, or in sequence; > 4 cycles of therapy are not required for
                       patients with a diagnosis of plasma cell leukemia

          -  Male and female patients of reproductive potential must be willing to use an effect
             contraceptive method before, during, and for at least 4 months after the CAR T cell
             infusion

        Exclusion Criteria:

          -  History of another primary malignancy that requires intervention beyond surveillance
             or that has not been in remission for at least 1 year (the following are exempt from
             the 1 year limit: non-melanoma skin cancer, curatively treated localized prostate
             cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion
             on papanicolaou [PAP] smear)

          -  Active hepatitis B, hepatitis C at the time of screening

          -  Patients who are (human immunodeficiency virus [HIV]) seropositive

          -  Subjects with uncontrolled active infection

          -  > 1 hospital admission (lasting 5 days or more) for documented infection in prior 6
             months

          -  Presence of acute or chronic graft-versus-host disease (GVHD) requiring active
             treatment unless limited to skin involvement and managed with topical steroid therapy
             alone

          -  History of any one of the following cardiovascular conditions within the past 6
             months: Class III or IV heart failure as defined by the New York Heart Association
             (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or
             other clinically significant cardiac disease as determined by the principal
             investigator (PI) or designee

          -  History or presence of clinically relevant central nervous system (CNS) pathology such
             as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
             Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active
             central nervous system MM involvement and/or carcinomatous meningitis; subjects with
             previously treated central nervous systems involvement may participate, provided they
             are free of disease in the CNS (documented by flow cytometry performed on the
             cerebrospinal fluid [CSF] within one week of enrollment) and have no evidence of new
             sites of CNS activity

          -  Pregnant or breastfeeding females

          -  Use of any of the following:

               -  Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or
                  equivalent) within 7 days prior to leukapheresis; physiologic replacement,
                  topical, and inhaled steroids are permitted

               -  Cytotoxic chemotherapeutic agents within 1 week of leukapheresis; oral
                  chemotherapeutic agents are allowed if at least 3 half-lives have elapsed prior
                  to leukapheresis

               -  Lymphotoxic chemotherapeutic agents within 2 weeks of leukapheresis

               -  Daratumumab (or other anti-CD38 therapy) within 30 days of leukapheresis

               -  Experimental agents within 4 weeks of leukapheresis unless progression is
                  documented on therapy and at least 3 half-lives have elapsed prior to
                  leukapheresis

          -  Absolute neutrophil count (ANC) < 1000/mm^3, per PI discretion if thought to be
             related to underlying myeloma

          -  Hemoglobin (Hgb) < 8 mg/dl, per PI discretion if thought to be related to underlying
             myeloma

          -  Platelet count < 50,000/mm^3, per PI discretion if thought to be related to underlying
             myeloma

          -  Active autoimmune disease requiring immunosuppressive therapy

          -  Major organ dysfunction defined as:

               -  Creatinine clearance < 20 ml/min

               -  Significant hepatic dysfunction (serum glutamic-oxaloacetic transaminase [SGOT] >
                  5 x upper limit of normal; bilirubin > 3.0 mg/dL)

               -  Forced expiratory volume in 1 second (FEV1) of < 50% predicted or diffusion
                  capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% (patients with
                  clinically significant pulmonary dysfunction, as determined by medical history
                  and physical exam should undergo pulmonary function testing)

          -  Anticipated survival of < 3 months

          -  Contraindication to cyclophosphamide or fludarabine chemotherapy

          -  Patients with known AL subtype amyloidosis

          -  Uncontrolled medical, psychological, familial, sociological, or geographical
             conditions that do not permit compliance with the protocol, as judged by the PI; or
             unwillingness or inability to follow the procedures required in the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:22 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT)
Time Frame:Up to 21 days after T cell infusion
Safety Issue:
Description:Observed DLT rates will be summarized based on the DLT-Evaluable analysis set. Final DLT rates at each dose level will be estimated by the Continual Reassessment Method (CRM) algorithm.

Secondary Outcome Measures

Measure:Duration of persistence of adoptively transferred BCMA CAR-T cells
Time Frame:Baseline up to 15 years
Safety Issue:
Description:
Measure:Migration of adoptively transferred BCMA CAR-T cells
Time Frame:Baseline up to 15 years
Safety Issue:
Description:
Measure:Objective response rate (ORR)
Time Frame:Baseline up to 3 months after T cell infusion
Safety Issue:
Description:Proportion of patients with a best response of either complete response or partial response, assessed using modified International Myeloma Working group response criteria.
Measure:Progression-free survival (PFS)
Time Frame:Assessed up to 15 years
Safety Issue:
Description:Assessed using modified International Myeloma Working Group response criteria
Measure:Overall survival (OS)
Time Frame:Assessed up to 15 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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