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weimeiandy铁虫 (正式写手)
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[求助]
求助给位专家翻译一下如下临床医学专业英语 已有1人参与
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Context The study continues to evaluate safety, PK, activity and pharmacodynamics of GDC-0919 at a continuous dosing schedule (BID 28/28) to enable greater flexibility in future dosing regimens. GDC-0919 also is being evaluated in a Phase Ib study in combination with atezolizumab (PD-L1 inhibitor) in patients with recurrent or advanced solid tumors. Design Per the abstract, this open-label, single center, Phase Ia study with a 3+3 design assesses safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of GDC-0919 in patients (pts) with recurrent/advanced solid tumors. GDC-0919 is administered at doses 50–800mg BID on a 21 days on/7 days off schedule, for up to 12 months. PK parameters and PD markers (plasma Kyn: Trp ratio) were evaluated after single and multiple doses. Tumor assessments are performed every 2 cycles (RECIST v1.1 and immune related response criteria [irRC]). Results The data showed an acceptable safety profile, disease stabilization and preliminary evidence of peripheral pharmacodynamic modulation. GDC-0919 was well tolerated up to 800 mg BID (twice daily) on a 21/28 day cycle. Thirty seven percent of patients available for tumor assessments (7/17) achieved stable disease. The MTD was not reached. Single and multiple dose exposure from 50 to 800 mg of GDC-0919 increased in approximately dose-proportional manner, and higher doses of GDC-0919 modulated plasma Kynurenine in a manner consistent with the half-life of GDC-0919. Per the abstract, as of March 26, 2015, 19 pts were treated and 3 remained active (16 pts discontinued treatment due to progressive disease). Pts received a median of 3 cycles (range 1–11) of GDC-0919 and remained 77 days on treatment (range 13–289 days). Preliminary PK results up to 600mg BID suggest that GDC-0919 is rapidly absorbed and demonstrates dose proportional increases in exposure, with a half-life supportive of BID dosing. Best RECIST responses among 16 pts with on-treatment tumor assessments were 7 (44%) stable disease (SD, lasting ≥4 cycles in 4 pts) and 9 (56%) progressive disease. irRC and PD marker data are pending. Most Common Adverse Events The most common adverse events related to GDC-0919 were lower grade and included pruritus or itching (37%), fatigue, (26%) and decreased appetite (21%). Per the abstract, one DLT of Grade 4 lower gastrointestinal hemorrhage was reported at 800mg in 69 yo male w/mRCC with extensive GI serosal metastasis (the only Grade ≥3 AE assessed as related to GDC-0919). Adverse events (AEs) regardless of causality and reported in ≥4 pts were fatigue (9 pts, 47%), cough, decreased appetite, and nausea (8 pts, 42% each), pruritis (7 pts, 37%), vomiting (6 pts, 32%), increased AST (5 pts, 26%), and hypokalemia and dyspnea (4 pts, 21% each). Grade ≥3 AEs regardless of causality occurred in 11 pts (58%), and those in ≥2 pts were neoplasm progression (3 pts, 16%) and increased AST (2 pts, 10.5%). Grade 3 AST elevations coincided with progression of liver metastases (2 pts, 10%) and were reported as unrelated; a 3rd pt with Grade 2 AST/ALT elevations at Cycle 2 Day 1 was assessed as related to GDC-0919. No AEs led to treatment discontinuation. Conclusion Per the abstract, GDC-0919 has been well tolerated up to 800mg BID on 21 days on/7 days off. PK was linear and dose-proportional. Prolonged SD was reported in 4 patients. Updated results will be presented. |
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sqlg888
铁虫 (正式写手)
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4楼2015-11-24 21:50:28
sqlg888
铁虫 (正式写手)
- SFL-EPI: 1
- 应助: 163 (高中生)
- 金币: 4544.2
- 红花: 27
- 帖子: 995
- 在线: 191.8小时
- 虫号: 4176864
- 注册: 2015-10-27
- 专业: 民族药学
【答案】应助回帖
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weimeiandy: 金币+10, ★★★★★最佳答案 2015-12-14 08:50:58
weimeiandy: 金币+10, ★★★★★最佳答案 2015-12-14 08:50:58
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【项目背景与意义】 本研究将继续评价GDC-0919的安全性、药代动力学、在连续给药时间表活性和药效学的（每日两次28 / 28），加大未来给药方案服药剂量的灵活性。同时，也评价GDC-0919在临床Ib期联合atezolizumab（PD-L1抑制剂）治疗复发性或晚期实体肿瘤进行研究。 【试验设计】 据摘要，临床Ia期研究实验采用非盲、单中心、3 + 3设计，评价GDC-0919药物安全性、药代动力学（PK）、药效学（PD）和该药治疗复发性或晚期实体肿瘤患者初步的抗肿瘤活性（PTS）。GDC-0919剂量在50–800mg（每日两次）连续服药21天/停7天日程管理，连续服药治疗12个月以上。单剂量给药组和多剂量给药组的药代动力学和药效学参数指标（血浆犬尿氨酸：色氨酸比值）进行评价。 每2个周期对肿瘤疗效进行评价，评价标准参照《实体瘤疗效评价标准（RECIST） 1.1版和免疫治疗相关疗效评价分类体系（irRC）》。 【结果】 数据显示，GDC-0919是一个可以接受的安全性，病情稳定和初步证据的外周药效调制。GDC-0919耐受性良好，高达800mg（两次/日）在21天服药，28天为一疗程。37%的患者（7 / 17）达到了病情稳定。最大耐受剂量（MTD）没有达到。单剂量组和多剂量组暴露剂量从50-800mg按剂量比例方式增加GCD-0919进行控制，调节高剂量组GCD-0919剂量后血浆的犬尿氨酸与GCD-0919半衰期一致。 据摘要，截至2015年3月26日，19例参与治疗和3例保持活跃（16例停止治疗，由于疾病进展）。患者接受了3周期的中位数（范围1–11）的GDC-0919并维持77天的治疗（范围13–289天）。初始的PK结果显示到GDC-0919600mg（两次/日）迅速吸收，表明在暴露剂量比例增加条件下，半衰期支持每日两次剂量。最好的实体瘤疗效评价标准(RECIST) 响应间的16例参与治疗肿瘤的评估，7例（44%）病情稳定（SD，持续稳定的≥4周期4例）和9例（56%）疾病进展。IRRC和PD标记数据待定。 【常见的不良反应 】 据摘要，与GCD-0919治疗相关最常见的较低等级的不良反应包括瘙痒（37%）、疲劳（26%）、食欲下降（21%）。剂量限制性毒性（DLT）4级不良反应以下，有一例69岁男性患者W /m肾癌且广泛的胃肠浆膜转移时消化道出血的报道（只有一例≥3级不良反应评估与GCD-0919治疗相关）。不良事件（AE）无论与本药治疗是否关联的报道≥4例，疲劳（9例，47%），咳嗽、食欲下降、恶心（共8例，42%），皮肤瘙痒（7例，37%），呕吐（6例，32%），谷草转氨酶上升（AST）（5例，26%） 低钾血症和呼吸困难（4例，21%）。≥不良反应3级无论与本药是否关联发生的11例（58%），及≥2例患者肿瘤恶化（3例，16%）和谷草转氨酶升高（2例，10.5%）。3级的谷草转氨酶升高正好与肝转移的恶化（2例，10%）和报道无关；与2级的AST / ALT（谷草转氨酶 /谷丙转氨酶）升高在2周期1天第三例评估相关的GCD-0919。没有因不良反应停药 【讨论】 据摘要，GCD-0919有很好的耐受性高达800mg（两次/日）服药21天/ 停7天。药效学的线性与剂量成正比。4例患者病情持续稳定。更新数据将被陆续提交。 |
2楼2015-11-23 16:28:59
5楼2015-11-25 07:36:21
