Department of Hematology, Hospital Universitario y Politècnico La Fe, Avda. Fernando Abril Martorell, 106-Torre A, 4º planta, 46026, Valencia, Spain.
Department of Medicine: Hematology and Oncology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Cancer Chemother Pharmacol. 2023 May;91(5):441-446. doi: 10.1007/s00280-023-04516-9. Epub 2023 Mar 9.
Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML.
Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc).
Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively.
Fractionated GO dosing regimen (3 mg/m/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues.
Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).
吉妥珠单抗奥佐米星（GO）用于治疗复发/难治性（R/R）急性髓系白血病（AML）。GO 分段剂量方案的 QT 间期、药代动力学（PK）和免疫原性尚未得到评估。这项 IV 期研究旨在为 R/R AML 患者获得这些信息。
年龄≥18 岁的 R/R AML 患者接受 GO 3mg/m 的分段剂量方案，每个周期的第 1、4 和 7 天，最多 2 个周期。主要终点是从基线到第 1 周期的 QT 间期校正后（QTc）的平均变化。
50 名患者在第 1 周期接受了至少 1 次 GO 治疗。Fridericia 公式（QTcF）的最小二乘均值差异的 2 侧 90%置信区间上限在第 1 周期的所有时间点均<10ms。没有患者的 QTcF>480ms 或从基线变化>60ms。98%的患者出现治疗相关不良事件（TEAEs）；54%为 3-4 级。最常见的 3-4 级 TEAEs 是发热性中性粒细胞减少症（36%）和血小板减少症（18%）。共轭和非共轭 calicheamicin 的 PK 特征与总 hP67.6 抗体相似。抗药抗体（ADA）和中和抗体的发生率分别为 12%和 2%。
GO 分段剂量方案（3mg/m/剂量）不会导致 R/R AML 患者 QT 间期延长的临床显著安全性风险。TEAEs 与 GO 已知的安全性特征一致，ADA 的存在似乎与潜在的安全性问题无关。
Clinicaltrials.gov ID：NCT03727750（2018 年 11 月 1 日）。
