Immunotherapy With BCMA CAR-T Cells in Treating Patients With BCMA Positive Relapsed or Refractory Multiple Myeloma
Condition: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Autologous Anti-BCMA-CAR-expressing CD4+/CD8+ T-lymphocytes FCARH143; Cyclophosphamide; Fludarabine; Leukapheresis
Intervention description: Given IV; Given IV; Given IV; Undergo leukapheresis
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Have the capacity to give informed consent

          -  Eastern Cooperative Oncology Group (ECOG) performance status score =< 2.

          -  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 principal investigator 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

                         -  Patients receiving retreatment do not need to meet the > 10% CD138+
                            malignant plasma cells (immunohistochemistry staining method [IHC]) on
                            BM core biopsy

          -  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 of clinically relevant or active 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 14 days of enrollment) and have no evidence of new
             sites of CNS activity

          -  Pregnant or breastfeeding females

          -  Allogeneic HSCT or donor lymphocyte infusion within 90 days of leukapheresis.

          -  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, or per PI discretion if cytopenia thought
             to be related to underlying myeloma.

          -  Hemoglobin (Hgb) < 8 mg/dl, or per PI discretion if cytopenia thought to be related to
             underlying myeloma.

          -  Platelet count < 50,000/mm^3, or per PI discretion if cytopenia 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