A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Pharmacokinetics of once-daily trospium chloride 60 mg extended release and twice-daily trospium chloride 20 mg in healthy adults.

The objective of this study is to characterize the steady-state pharmacokinetics and compare the relative bioavailability of the extended-release capsule formulation of the antimuscarinic trospium chloride, developed for once-daily administration, and trospium chloride immediate-release tablets. This is a single-center, multidose, randomized, open-label, 2-period, 2-arm crossover, bioavailability study in healthy adult male and female subjects who are within 20% of their ideal body weight. Subjects receive trospium 60-mg extended-release capsules once daily and trospium 20-mg tablets twice daily for 10 days, each in a crossover manner. Twenty-four subjects are enrolled in the study. With multiple dosing of trospium 60 mg extended-release once daily versus 20 mg twice daily, lower geometric least squares mean area under the concentration-time curve from 0 to 24 hours (17 360 vs 28 590 pg.h/mL; ratio 61%; 90% confidence interval, 51-72) and maximum plasma concentration (1517 vs 2502 pg/mL; 61%; 90% confidence interval, 49-75) are observed. Furthermore, with trospium 60 mg extended-release versus 20 mg, median time to maximum plasma concentration is later (5.0 vs 4.5 hours) and half-life is longer (35.8 vs 27.2 hours). Trospium exposure is lower with multiple dosing of trospium 60 mg extended-release compared with trospium 20 mg twice daily. Thus, with the extended-release formulation, trospium concentrations are less likely to reach the threshold where adverse events may sometimes occur.