CART-19 Post-ASCT for Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: CART-19 cells
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This will be a single-arm, open-label study. Patients will be enrolled during induction
      therapy for multiple myeloma, prior to standard-of-care consolidation with autologous stem
      cell transplantation (ASCT). T cells will be harvested for T cell manufacturing prior to
      ASCT, and CART-19 will be infused at day ~60 post-ASCT, 3 days after lymphodepleting
      chemotherapy. The primary endpoint is progression-free survival (PFS) after ASCT. As detailed
      below, the study is powered to detect an increase in two-year PFS to ~75% from a baseline
      expectation of 55% based on historical data. Secondary endpoints will evaluate CART-19
      persistence and function, minimal residual disease, immune correlative endpoints, and
      associations of progression-free survival (PFS) with CART-19 persistence and clinical and
      biologic characteristics of multiple myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must be age 18-70, inclusive, at time of enrollment.

          -  Subjects must have ECOG performance status of 0-2.

          -  Subjects must have a confirmed diagnosis of active multiple myeloma according to IMWG
             criteria, summarized below in Table 6. For circumstances not encompassed by this
             summary of the diagnostic criteria, reference can be made to the full publication of
             the IMWG criteria67. In addition, subjects must have "high-risk" multiple myeloma
             according to one of the following criteria:

               1. Any of the following high-risk cytogenetic features, documented by FISH or
                  metaphase karyotyping: deletion 17p, t(4;14), t(14;16), t(14;20).

               2. Standard-risk cytogenetics but elevated LDH and beta-2-microglobulin > 5.5 mg/L
                  (i.e., R-ISS stage III).

          -  At time of enrollment, subjects must be within 9 months of initiation of systemic
             therapy for multiple myeloma.

          -  Requirements for pre-enrollment therapy: Subjects must have received or be receiving,
             at time of enrollment, "RVD" therapy (combination therapy with lenalidomide,
             bortezomib, and dexamethasone). Patients must have received ≤6 cycles of RVD at time
             of enrollment and must not have progressed (by IMWG criteria65) on RVD. Patients may
             have received other regimens prior to RVD if such therapy was limited to ≤3 cycles.
             Patients may have received radiation therapy prior to enrollment. Patients must not
             have received infusional chemotherapy (e.g., VTD-PACE or similar regimen) prior to
             enrollment.

          -  Subjects must be eligible for ASCT and to receive a melphalan dose of 200 mg/m2 as
             defined by the following criteria:

               1. Left ventricular ejection fraction ≥ 40%,

               2. AST/ALT ≤2.5 times the upper limit of normal

               3. Total bilirubin ≤1.5 mg/dL, unless hyperbilirubinemia is attributable solely to
                  Gilbert's syndrome.

               4. Estimated (by CKD-EPI or Cockgroft-Gault equations) or calculated CrCl ≥40
                  ml/min.

               5. DLCO ≥50% of predicted after correction for anemia.

          -  Subjects must have measurable disease by standard serum and urine tests to enable
             post-transplant monitoring for progression-free survival. Any of the following
             criteria are sufficient to define measurable disease.

               1. Serum M-spike ≥ 0.5 g/dL

               2. 24 hr urine M-spike ≥ 200mg

               3. Involved serum FLC ≥ 50 mg/L with abnormal ratio

               4. For IgA multiple myeloma, total serum IgA level elevated above normal range.
                  Note: Measurable disease does not need to be documented at enrollment but can be
                  based on historical lab results obtained at or since diagnosis with multiple
                  myeloma. For example, a patient who does not have measurable disease at
                  enrollment due to complete remission after induction therapy is eligible if the
                  disease was previously measurable by one of the above criteria.

          -  Subjects must have signed written, informed consent.

          -  Subjects of reproductive potential must agree to use acceptable birth control methods

        Exclusion Criteria:

          -  Subjects must not:

        Be pregnant or lactating. Have inadequate venous access for or contraindications to
        leukapheresis. Have any active and uncontrolled infection. Any uncontrolled medical or
        psychiatric disorder that would preclude participation as outlined.

        Have NYHA Class III or IV heart failure (see Appendix 2), unstable angina, or a history of
        recent (within 6 months) myocardial infarction or sustained (>30 seconds) ventricular
        tachyarrhythmias.

        Have undergone allogeneic stem cell transplantation. Have received prior gene therapy or
        gene-modified cellular immunotherapy. Have active auto-immune disease, including connective
        tissue disease, uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or
        have a history of severe (as judged by the principal investigator) autoimmune disease
        requiring prolonged immunosuppressive therapy.

        Have prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease,
        parenchymal masses) with myeloma. Screening for this (e.g. with lumbar puncture) is not
        required unless suspicious symptoms are present.

        Have a contraindication to post-ASCT maintenance lenalidomide. Have active infection with
        HIV (negative HIV 1/2 antibody screen), hepatitis C (negative hepatitis C antibody screen),
        or hepatitis B (negative hepatitis B surface antigen). Any positive serologies for HIV or
        viral hepatitis should be confirmed with appropriate confirmatory testing before concluding
        that an active infection is present. Subjects with positive hepatitis core antibody are
        also excluded since the effect of long-term B cell depletion on the risk of hepatitis B
        reactivation is unknown.

        Patients with a known history or prior diagnosis of optic neuritis or other immunologic or
        inflammatory disease affecting the central nervous system.