Polatuzumab vedotin结合immunochemotherapy以前未经治疗弥漫型大b细胞淋巴瘤患者:一个非盲、non-randomised, 1 b - 2期研究。

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蒂莉H, Morschhauser F, Bartlett问,梅塔,萨勒斯G, Haioun C,穆尼奥斯J,陈AI, Kolibaba K,陆D,严米,毗努伊勒E, Hirata J,李C,沙曼JP

Polatuzumab vedotin结合immunochemotherapy以前未经治疗弥漫型大b细胞淋巴瘤患者:一个非盲、non-randomised, 1 b - 2期研究。

柳叶刀杂志。2019年5月14日。pii: s1470 - 2045 (19) 30091 - 9。doi: 10.1016 / s1470 - 2045 (19) 30091 - 9。

PubMed ID
31101489 (在PubMed
]
文摘

背景:Polatuzumab vedotin,抗体药物共轭针对CD79b组件b细胞受体的活动作为一个单一的代理和结合利妥昔单抗复发或难治性弥漫型大b细胞淋巴瘤。在这项研究中,我们评估的安全性和初步活动polatuzumab vedotin结合利妥昔单抗或obinutuzumab和环磷酰胺、阿霉素、强的松(CHP)以前未经治疗的患者弥漫型大b细胞淋巴瘤。方法:这是一个非盲、non-randomised研究由一个阶段1 b剂量升级和扩张阶段2剂量11家医院和保健中心在美国和法国。与b细胞非霍奇金淋巴瘤患者18岁或以上资格。排除标准包括周围神经病变与品位大于1,大手术前4周内招生,中枢神经系统淋巴瘤的参与,和不受控制的心脏疾病。阶段1 b剂量升级了3 + 3设计和建立了推荐阶段2剂量。第二阶段扩展评价推荐的第二阶段剂量的polatuzumab vedotin新诊断患者弥漫型大b细胞淋巴瘤有国际预后指数(IPI) 2 - 5。患者接受环磷酰胺750毫克/ m(2)第一天静脉注射阿霉素50毫克/ m(2)静脉注射1天,1 - 5和强的松100毫克每天一次天每21天的周期口头(CHP)加美罗华375毫克/ m(2)静脉注射在每个周期的第1天(R-CHP)或1000毫克obinutuzumab静脉注射1天,8,15个周期1和1天以下的周期(G-CHP)。Polatuzumab vedotin是管理周期1和2的第2天,在第一天的周期在1.0 - -2.4毫克/公斤在升级阶段,第二阶段推荐剂量在扩张阶段。治疗可能会持续6或8个周期,根据调查员偏好。 The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analysed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01992653. FINDINGS: Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1.8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1.8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21.5 months (IQR 16.7-24.3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). INTERPRETATION: The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and managable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP. FUNDING: F Hoffmann-La Roche/Genentech.

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