JCARH125 CAR-T "Highly Active" in Relapsed/Refractory Multiple Myeloma

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Patients saw a deepening of responses over time.
Patients saw a deepening of responses over time.
The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

The focus surrounding JCARH125 during a presentation by Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center, New York, New York, at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, was on the investigational chimeric antigen receptor T-cell's (CAR-T's) manufacturing process.1 Many audience members asked follow-up questions about how the construct was made, with a particular interest in how Dr Mailankody (by way of Celgene) selected the T cells used for the process.

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That interest was likely based on the best overall response rate (ORR) seen by 14 patients enrolled in the study; this ORR was 82%. It was also likely based on the levels of CAR-T measured in patients' peripheral blood over time; there was a robust expansion of JCARH125 observed at all dose levels and a trend for increased long-term persistence past month 2 at dose levels of at least 150 × 106 CAR-positive T cells.

The JCARH125 construct has a fully human binder, and was optimized to deliver “a cell product comprised of purified CD4 and CD8-positive T cells enriched for central memory phenotype cells, potentially increasing persistence and durability,” according to Dr Mailankody.

The phase 1/2 EVOLVE study (ClinicalTrials.org Identifier: NCT03430011) enrolled patients with relapsed/refractory multiple myeloma (R/R MM) who had received at least 3 prior therapies, were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 0 to 1. They were not selected based on BCMA expression.

Primary objectives were to evaluate safety and tolerability of the product and identify a dose for phase 2 studies. Secondary objectives were to determine the investigational product's pharmacokinetics, evaluate its preliminary antitumor activity, and to evaluate minimal residual disease (MRD) of patients enrolled in the trial.

There were 44 patients in the study, of which, 77% were determined to have had high-risk cytogenetics. Patients had a median of 7 prior regimens (range, 3-23). Twenty-seven percent of patients saw an adverse event of any grade; one patient with a history of myeloma-related kidney disease experienced a dose-limiting toxicity of grade 4 cytokine release syndrome (CRS) that occurred at the dose level of 450 × 106 CAR-positive T cells. This patient died on day 19 after JCARH125 infusion. Eighty percent of patients experienced CRS. Grade 3/4 anemias and thrombocytopenias before the start of lymphodepleting chemotherapy occurred in 18% of patients; these dropped to grade 2 (ie, were considered resolved) but not until at least 3.4 months.

Responses to therapy improved over time: 5 of the 14 patients with the best ORR showed a deepening of response past day 29 of therapy, at which time, 6 of 9 evaluable patients were determined to be minimal residual disease-negative by next-generation sequencing.

Complete responses (CRs) and sCRs were achieved by 27%, with a trend of deepening responses over time. JCARH125 was active in patients with high baseline levels of sBCMA.

Read more of Cancer Therapy Advisor's coverage of the ASH 2018 meeting by visiting the conference page.

Reference

  1. Mailankody S, Htut M, Lee KP, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 957.

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