A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.
A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.
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RO6870810（一种新型溴结构域和额外末端蛋白抑制剂）在 NUT 癌、其他实体瘤或弥漫性大 B 细胞淋巴瘤患者中进行的 1 期研究。
DOI：
10.1038/s41416-020-01180-1
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发表时间：
2021-03
影响因子：
8.8
通讯作者：
Armand P
中科院分区：
文献类型：
--
作者：
Shapiro GI;LoRusso P;Dowlati A;T Do K;Jacobson CA;Vaishampayan U;Weise A;Caimi PF;Eder JP;French CA;Labriola-Tompkins E;Boisserie F;Pierceall WE;Zhi J;Passe S;DeMario M;Kornacker M;Armand P
溴结构域和额外末端（BET）蛋白是表观遗传的读者，可以驱动致癌和治疗耐药性。RO 6870810是一种新型的小分子BET抑制剂。我们在睾丸癌（NC）、其他实体瘤或伴有MYC失调的弥漫性大B细胞淋巴瘤（DLBCL）核蛋白患者中进行了一项RO 6870810皮下给药21或14天（28或21天为一个周期）的I期研究。疲乏（42%）、食欲减退（35%）和注射部位红斑（35%）是最常见的治疗相关不良事件。药代动力学参数在检测的剂量范围内呈线性，支持每日一次给药。药效学评估表明外周血单核细胞中的CD 11b水平持续降低。NC、其他实体瘤和DLBCL患者的客观缓解率分别为25%（2/8）、2%（1/47）和11%（2/19）。有反应的肿瘤有MYC表达失调的证据。本试验确定了RO 6870810的安全性、有利的药代动力学、靶点结合证据和初步单药活性。NC、其他实体瘤和DLBCL患者的缓解为BET抑制MYC驱动的癌症提供了原理证明。结果支持进一步探索RO 6870810作为单药治疗和联合治疗。NCT 01987362。
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. NCT01987362.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
4.6
作者：
Kumar K;Raza SS;Knab LM;Chow CR;Kwok B;Bentrem DJ;Popovic R;Ebine K;Licht JD;Munshi HG
通讯作者：
Munshi HG
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
11.5
作者：
Jang, Ji Eun;Eom, Ju-In;Min, Yoo Hong
通讯作者：
Min, Yoo Hong
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE