Clinical Trials /

Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma

NCT03549442

Description:

This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA, with or without huCART19, in patients responding to first- or second-line therapy for high-risk multiple myeloma. The regimen evaluated in this study is based on established safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in combination with huCART19, and (4) as a single rather than split-dose infusion.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma
  • Official Title: Phase 1 Study of CART-BCMA With or Without huCART19 as Consolidation of Standard First or Second-Line Therapy for High-Risk Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 828773
  • NCT ID: NCT03549442

Conditions

  • Multiple Myeloma

Purpose

This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA, with or without huCART19, in patients responding to first- or second-line therapy for high-risk multiple myeloma. The regimen evaluated in this study is based on established safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in combination with huCART19, and (4) as a single rather than split-dose infusion.

Detailed Description

      Phase A: Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions
      after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have
      relapsed/refractory myeloma after two prior regimens but who are responding to their current
      therapy. Phase A Expansion: To occur once safety is demonstrated in Phase A. - Phase B:
      Randomization Phase in which patients responding to first or second-line therapy will receive
      either CART-BCMA alone (Cohort

      1) or CART-BCMA + huCART19 (Cohort 2) as split-dose infusions after lymphodepleting
      chemotherapy with cyclophosphamide + fludarabine. Phase C: Single-dose infusion phase to test
      the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19
      (Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide
      + fludarabine in patients responding to first- or second-line therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Phase AExperimentalSafety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have relapsed/refractory myeloma after two prior regimens but who are responding to their current therapy.
    Phase BExperimentalRandomization Phase in which patients responding to first or second-line therapy will receive either CART-BCMA alone (Cohort 1) or CART-BCMA + huCART19 (Cohort 2) as split-doses after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
      Phase CExperimentalSingle-dose infusion phase to test the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19 (Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients responding to first- or second-line therapy.
        Phase A ExpansionExperimentalOnce safety of CART-BCMA/huCART19 combination therapy is established in Phase A, an expansion of Phase A will occur in which the Phase A target population (patients with relapsed/refractory multiple myeloma responding to a standard salvage therapy regimen) will receive both CART-BCMA and huCART19. Enrollment into the Phase A Expansion may occur concurrently with Phase B once opened.

          Eligibility Criteria

                  Inclusion Criteria:
          
                    -  Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106
                       with any of the following high-risk features:
          
                         1. Beta-2-microglobulin ≥ 5.5 mg/L and LDH greater than upper limit of normal. Note:
                            subjects in whom LDH and/or Beta-2-microglobulin were not measured prior to
                            initiation of systemic therapy may qualify based on measurements obtained after
                            initiation of systemic therapy.
          
                         2. High-risk FISH features: deletion 17p, t(14;16), t(14;20), t(4;14) in conjunction
                            with Beta- 2-microglobulin ≥ 5.5 mg/L (i.e., revised ISS stage 3). Note: subjects
                            in whom Beta-2-microglobulin was not measured prior to initiation of systemic
                            therapy may qualify based on measurements obtained after initiation of systemic
                            therapy.
          
                         3. Metaphase karyotype with >3 structural abnormalities except hyperdiploidy
          
                         4. Plasma cell leukemia (>20% plasma cells in peripheral blood) at any time prior to
                            enrollment
          
                         5. Failure to achieve partial response or better (by IMWG 2016 criteria1) to initial
                            therapy with an "imid/PI" combination (thalidomide, lenalidomide, or pomalidomide
                            in combination with bortezomib, ixazomib, or carfilzomib).
          
                            Early progression on first-line therapy, defined as progression (according to
                            IMWG 2016 criteria1)
          
                       i. Within one year of starting first-line therapy with an "imid/PI"combination ii.
                       Within six months of completing first line therapy with an "imid/PI"combination (i.e.
                       a patient who receives an "imid/PI" combination, transitions to observation or
                       maintenance therapy, and progresses within six months of this transition) iii. Within
                       one year of a high-dose melphalan and autologous stem cell transplantation (Phase A
                       subjects only) 2. Subjects must meet the following criteria with respect to prior
                       myeloma therapy:
          
                       a. Phase A and Phase A Expansion:
          
                       a. i. Subjects must: i. have disease that has relapsed after or has been refractory to
                       at least two regimens, including a proteasome inhibitor and thalidomide analog
                       (thalidomide, lenalidomide, pomalidomide); ii. have disease that has relapsed after or
                       has been refractory to one prior regimen if their prior/current therapy collectively
                       has included all of the following: an "imid/PI" combination, pomalidomide,
                       lenalidomide, daratumumab, and carfilzomib. Refractoriness is defined as disease
                       progression on-therapy or within 60 days of stopping therapy.
          
                       b. Subjects must have achieved at least a minimal response (as defined by IMWG 2016
                       criteria1) to their current regimen.
          
                       c. Subjects must not have received prior treatment with anti-BCMA cellular therapy.
                       Subjects may have received treatment with other BCMA-directed agents (e.g., anti-BCMA
                       antibody-drug conjugates or bispecific antibodies).
          
                       b. Phases B and C:
          
                         1. Subjects must be in their first line of multiple myeloma therapy, with the
                            following exception: subjects who have advanced to second-line therapy due to
                            disease progression during first-line therapy are eligible if such progression
                            occurred within six months of beginning first-line therapy. Lines of therapy are
                            defined by IMWG 2016 criteria1.
          
                         2. Subjects must not have received cytotoxic chemotherapy (e.g., doxorubicin,
                            cyclophosphamide, etoposide, cisplatin) with the following exceptions:
          
                       i. Low-dose weekly cyclophosphamide (≤500 mg/m2/week) ii. Continuous infusion
                       cyclophosphamide, if limited to a single cycle. c. Subjects must not have undergone
                       autologous or allogeneic stem cell transplantation. d. Subjects must have initiated
                       systemic therapy for multiple myeloma ≤1 year prior to enrollment.
          
                       e. Subjects must have received at least 3 complete cycles of their current regimen and
                       have achieved at least a minimal response (as defined by IMWG 2016 criteria1) to the
                       most recent line of therapy.
          
                       3. Subjects must not have achieved a complete or stringent complete response according
                       to IMWG 2016 criteria1 at time of enrollment unless clonal plasma cells are detectable
                       in bone marrow by flow cytometry. (I.e., subjects in complete or stringent complete
                       response are eligible if minimal residual disease can be documented by bone marrow
                       flow cytometry). 4. Subjects must have signed written, informed consent. 5. Subjects
                       must be ≥ 18 years of age. 6. Subjects must have adequate vital organ function:
          
                         1. Serum creatinine ≤ 2.5 or creatinine clearance ≥30 ml/min (measured or estimated
                            according to CKD-EPI) and not dialysis-dependent.
          
                         2. Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if
                            bone marrow plasma cells are ≥50% of cellularity).
          
                         3. SGOT ≤ 3x the upper limit of normal and total bilirubin ≤ 2.0 mg/dl (except for
                            patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome).
          
                         4. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been
                            performed within 8 weeks of enrollment.
          
                            7. Toxicities from prior/ongoing therapies, with the exception of peripheral
                            neuropathy attributable to multiple myeloma therapy, must have recovered to grade
                            ≤ 2 according to the CTCAE 4.03 5.0 criteria or to the subject's prior baseline.
          
                            8. Subjects must have an ECOG performance status of 0-2. 9. Subjects must be
                            willing to forego first-line ASCT. 10. Subjects of reproductive potential must
                            agree to use acceptable birth control methods, as described in protocol Section
                            4.3.
          
                            Exclusion Criteria:
          
                              1. Pregnant or lactating women
          
                              2. Inadequate venous access for or contraindications to leukapheresis.
          
                              3. Active hepatitis B, hepatitis C, or HIV infection, or other active,
                                 uncontrolled infection.
          
                              4. Any uncontrolled medical or psychiatric disorder that would preclude
                                 participation as outlined.
          
                              5. 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.
          
                              6. 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 investigator) autoimmune disease
                                 requiring prolonged immunosuppressive therapy.
          
                              7. 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 or
                                 radiographic findings are present. Subjects with calvarial disease that
                                 extends intracranially and involves the dura will be excluded, even if CSF
                                 is negative for myeloma.
                
          Maximum Eligible Age:N/A
          Minimum Eligible Age:18 Years
          Eligible Gender:All
          Healthy Volunteers:No

          Primary Outcome Measures

          Measure:Adverse event reporting
          Time Frame:90 Days
          Safety Issue:
          Description:The number of participants with adverse events that are possibly, probably or definitely related to CAR T cells.

          Secondary Outcome Measures

          Measure:Clinical outcomes after each CAR T cell regimen
          Time Frame:2 years
          Safety Issue:
          Description:Attainment of PET-negative response (absence of detectable FDG-avid disease by PET/CT).
          Measure:CART cell disposition
          Time Frame:2 years
          Safety Issue:
          Description:Evaluate CAR T cell disposition using quantitative molecular methods
          Measure:Evaluate effects of huCART19 on correlative parameters of CART BCMA resistance and clonogenic multiple myeloma cells, such as the following:
          Time Frame:2 years
          Safety Issue:
          Description:Persistence of clonal BCMAdim/neg or CD19+ plasma cells as measured by flow cytometry and immunohistochemistry Depletion of multiple myeloma clonogenicity as measured using in vitro colony formation assays on bone marrow samples Induction of anti-Sox2 and other anti-myeloma immune responses Depletion of clonal CD19+ B cells
          Measure:Composition of investigative products
          Time Frame:2 years
          Safety Issue:
          Description:Evaluate cellular composition of apheresis product and CARTBCMA/ huCART19 cells.
          Measure:Maintenance therapy effects on persistence
          Time Frame:28 days post infusion - 2 years
          Safety Issue:
          Description:Evaluate effects of post-infusion maintenance therapy on CAR T cell persistence using quantitative molecular methods.
          Measure:Maintenance therapy effects on adverse events
          Time Frame:28 days post infusion - 2 years
          Safety Issue:
          Description:Evaluate effects of post-infusion maintenance therapy on CAR T cell adverse events.
          Measure:Immune cell phenotyping
          Time Frame:2 years
          Safety Issue:
          Description:Characterize the cellular phenotype of multiple myeloma cells that persist after CAR T cell treatment using qualitative molecular methods.

          Details

          Phase:Phase 1
          Primary Purpose:Interventional
          Overall Status:Recruiting
          Lead Sponsor:University of Pennsylvania

          Trial Keywords

          • Multiple Myeloma
          • BCMA CART
          • huCART19

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