Relapsed/refractory patients

ASH 2018 | CAR T cell clinical trial for patients with relapsed/refractory multiple myeloma using bb21217

The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. On Sunday 2 December 2018, an oral abstract session was held entitled: Gene Therapy and Transfer: Clinical Trials for Hemophilia and Using CAR T Cells Hematology Disease Topics & Pathway. During that session, Nina Shah from UCSF, San Francisco, US, presented results of the CRB-402, a non-randomized phase I clinical trial that uses chimeric antigen receptor (CAR) T cell therapy to target the plasma cell surface molecule BCMA (B-cell maturation antigen).

In this trial, CAR T cells were engineered carrying the bb21217 construct. This next-generation anti-BCMA target has the same design as bb2121. However, bb21217 transduced T cells are cultured in medium with the phosphoinositide 3 (PI3) kinase inhibitor bb007, which significantly increases the percentage of CD27+ and CD62L+ T cells. These T-cell markers seem to be found predominantly on the surface of memory T cells. Pre-clinical studies suggest that memory T cells could have a longer lifespan than other T cell types and enhance the duration of response to CAR T cell therapy.

CRB-402 is the first clinical trial using bb21217 in patients with relapsed/refractory (R/R) multiple myeloma (MM). The primary outcome measures are the incidence of adverse events (AEs) and abnormal laboratory test results, including dose limiting toxicities (DLTs). Secondary endpoints are disease-specific response criteria, including complete response (CR), very good partial response (VGPR), and minimal residual disease (MRD) among others.

Study Design:
  • Number of R/R MM patients = ~ 50
  • Prior treatments: At least three, including a proteasome inhibitor and an immunomodulatory agent, or double refractory patients
  • Dose escalation: Restricted to patients with ≥ 50% BCMA expression, defined by immunohistochemistry on plasma cells
  • T cells are extracted from patients with leukapheresis and sent to a central facility for viral transduction with the bb21217 construct, expansion, and testing prior to infusion
  • Five days before infusion: Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), daily for three days (days -5, -4, -3)
  • On the day of infusion (day 1): Single infusion of bb21217
  • Clinical trial design: 3 + 3 dose escalation
  • Planned dose levels: 150, 350, 450, and 800 x 106 CAR T cells
  • Patients characterized as high tumor burden (HTB) or low tumor burden (LTB) (≥ 50% or < 50% bone marrow [BM] cells per infusion, respectively)
Key Data:
  • Data cut-off = 18 October 2018
  • Median age = 63 (range, 44–69)
  • Gender = 6 male; 6 female
  • Collected samples = 13
  • Dosed samples = 12; dose = 150 x 106 CAR T cells; HTB = 6 samples; LTB = 6 samples
  • Median follow-up = 26 weeks (range, 4–51)
  • ECOG performance status: 0 = 3 patients; 1 = 9 patients
  • International Staging System (ISS) stage: I = 1 patient; II = 2 patients; III = 4 patients
  • Patients with high-risk cytogenetics: n = 7
  • Median number of prior regimens = 7 (range, 4–17)
  • Patients with prior autologous stem cell transplant (ASCT): n = 10/12
  • Prior treatments: 11/12 patients had previously received lenalidomide and bortezomib and 7/11 were refractory to these drugs
  • Patients who developed cytokine release syndrome (CRS): n = 8/12; grade 1, n = 4; grade 2, n = 3; grade 3, n = 1; grade 4, n = 0; CRS was managed with or without tocilizumab
  • Median time to onset of CRS = 4.5 days (range, 2–11)
  • Patients who developed CAR T neurotoxicity, occurring within 90 days after infusion: n = 3/12
    • One patient with HTB and rapidly accelerating disease experienced DLT (grade 3 CRS and grade 4 encephalopathy)
    • After this event, patients were divided into HTB and LTB groups
    • No other DLTs occurred
  • Adverse events (AEs) (grade ≥ 3):
    • Neutropenia: grade 3, 8%; grade 4, 75%
    • Thrombocytopenia: grade 3, 25%; grade 4, 25%
    • Anemia: grade 3, 42%
    • Leukopenia: grade 3, 17%; grade 4, 25%
    • Lymphopenia: grade 3, 8%; grade 4, 17%
    • Hypophosphatemia: grade 3, 17%
  • Patients who experienced serious AEs: n = 4 (one or more serious AE)
  • Severe infections: n = 1, grade 3 catheter-related infection
  • No deaths up to the cut-off date
  • Recovery from grade 3/4 cytopenias:
    • Neutropenia: 11/12 patients had absolute neutrophil count ≥ 1,000/μl by day 65 post-infusion
    • Thrombocytopenia: 10/12 patients had platelet count ≥ 50,000/μl by day 65 post-infusion
  • Clinical responses:
    • Objective response rate (ORR) = 10/12 patients (95% confidence interval [CI], 51.6–97.9)
    • Stringent CR (sCR)/CR = 3 patients
    • VGPR or better (≥ VGPR) = 6 patients
    • Median time to first response = 1 month (range, 1–2)
    • Median time to best response = 1 month (range, 1–10)
    • Response ongoing in all but one responder; the first patient dosed continues to respond more than a year after treatment
    • MRD: 4/4 responders evaluable for MRD status were MRD negative; 2/2 non-responders were MRD positive
  • BM response:
    • BM plasma cell clearance observed by day 15 post-infusion
    • A substantial decline in free light chains in all responders within one month post-infusion
    • Sustained serum BCMA suppression observed up to nine months post-infusion
  • Robust expansion of infused CAR+ T cells enriched for memory-like T cells
  • Detectable CAR+ T cells up to nine months post-infusion
Conclusions

The initial results of this CAR T trial for R/R MM patients show efficacy of bb21217 at a dose of 150 x 106 CAR+ T cells. Participants showed 83% ORR with ongoing responses up to 90%. The safety profile appears consistent with known toxicities of CAR T cell therapies. The dose escalation is ongoing. A longer follow-up in a larger patient population will expand the data regarding the depth and durability of bb21217 tumor responses and dose response.

References

Shah N. et al. Initial Results from a Phase 1 Clinical Study of bb21217, a Next-Generation Anti Bcma CAR T Therapy. 2018 Dec 2; Oral Abstract #488: ASH 60th Annual Meeting and Exposition, San Diego, CA.

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