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Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study.

polatuzumab vedotin在日本复发/难治性b细胞非霍奇金淋巴瘤患者中的安全性和药代动力学: 1期剂量递增研究。

  • 影响因子:2.04
  • DOI:10.1093/jjco/hyaa169
  • 作者列表:"Kinoshita T","Hatake K","Yamamoto K","Higuchi Y","Murakami S","Terui Y","Yokoyama M","Maruyama D","Makita S","Hida Y","Saito T","Tobinai K
  • 发表时间:2021-01-01
Abstract

OBJECTIVE:A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. METHODS:Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. RESULTS:Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43-7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. CONCLUSIONS:This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.

摘要

目的: 开展polatuzumab vedotin (pola) 1期剂量递增研究,以评估pola在日本复发性/难治性b细胞非霍奇金淋巴瘤患者中的安全性、药代动力学和初步抗肿瘤活性。 方法: 患者每21天静脉注射pola (1.0或1.8 mg/kg),直至疾病进展或不耐受。禁止患者内剂量递增。通过标准3 + 3规则测定耐受性。进行血液取样以表征药代动力学。通过计算机断层扫描和骨髓取样评价抗肿瘤活性。 结果: 4名患者接受pola 1.0 mg/kg; 3名患者接受1.8 mg/kg。患者患有滤泡性淋巴瘤 (n = 4) 或弥漫性大b细胞淋巴瘤 (n = 3),中位年龄为62岁,接受过3次先前治疗的中位年龄; 6例为女性.Pola在两组中均具有良好的耐受性,未观察到剂量限制性毒性。最常见的不良事件是外周感觉神经病变 (n = 4)。3级不良事件为胆囊炎和中性粒细胞计数降低 (各1例; 均为1.0 mg/kg),以及晕厥和白内障 (各1例; 均为1.8 mg/kg)。抗体缀合物单甲基奥立他汀E的血浆半衰期为4.43-7.98天,未缀合的单甲基奥立他汀E的全身暴露在两个队列中都受到限制。在研究期间,四名患者达到客观反应 (三名完全反应,一名部分反应) 而没有疾病进展。 结论: 1期剂量递增研究表明,pola具有可接受的安全性,并为日本复发性/难治性b细胞非霍奇金淋巴瘤患者提供了令人鼓舞的抗肿瘤活性。Pola 1.8 mg/kg (推荐的2期剂量) 在日本患者中是可耐受的。

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