Up-Front CART-BCMA With or Without huCART19 in High-Risk Multiple Myeloma

Overview

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.
SparkCures ID 955
Trial Phase Phase 2
Enrollment 39 Patients
Treatments
Trial Sponsors
  • University of Pennsylvania
Trial Collaborators
  • Novartis
NCT Identifier

NCT03549442

Am I Eligible?

The following criteria is a partial list of reasons why patients may or may not be eligible to participate in this clinical trial. Further evaluation with a medical professional will be required to determine full eligibility.

The following criteria is provided for health care professionals.

Inclusion Criteria:

  • 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.
  • 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.
  • Metaphase karyotype with >3 structural abnormalities except hyperdiploidy
  • Plasma cell leukemia (>20% plasma cells in peripheral blood) at any time prior to enrollment
  • 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).
    1. Early progression on first-line therapy, defined as progression (according to IMWG 2016 criteria1)Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106 with any of the following high-risk features:
      1. Within one year of starting first-line therapy with an "imid/PI"combination
      2. 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)
      3. Within one year of a high-dose melphalan and autologous stem cell transplantation (Phase A subjects only)
  • Subjects must meet the following criteria with respect to prior myeloma therapy:
    • Phase A and Phase A Expansion:
      • 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.
      • Subjects must have achieved at least a minimal response (as defined by IMWG 2016 criteria1) to their current regimen.
      • 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).
    • Phases B and C:
      • 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.
      • Subjects must not have received cytotoxic chemotherapy (e.g., doxorubicin, cyclophosphamide, etoposide, cisplatin) with the following exceptions:
        • Low-dose weekly cyclophosphamide (≤500 mg/m2/week)
        • Continuous infusion cyclophosphamide, if limited to a single cycle.
  • Subjects must not have undergone autologous or allogeneic stem cell transplantation.
  • Subjects must have initiated systemic therapy for multiple myeloma ≤1 year prior to enrollment.
  • 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.
  • 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).
  • Subjects must have signed written, informed consent.
  • Subjects must be ≥ 18 years of age.
  • Subjects must have adequate vital organ function:
    • Serum creatinine ≤ 2.5 or creatinine clearance ≥30 ml/min (measured or estimated according to CKD-EPI) and not dialysis-dependent.
    • Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if bone marrow plasma cells are ≥50% of cellularity).
    • 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).
    • Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been performed within 8 weeks of enrollment.
  • 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.
  • Subjects must have an ECOG performance status of 0-2.
  • Subjects must be willing to forego first-line ASCT.
  • Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.

Exclusion Criteria:

  • Pregnant or lactating women
  • Inadequate venous access for or contraindications to leukapheresis.
  • Active hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection.
  • Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.
  • 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 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.
  • 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.

US Trial Locations

Accepting Patients

The following is a listing of trial locations that are open and accepting patients.

Pennsylvania

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