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weimeiandy鐵蟲 (正式寫手)
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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
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weimeiandy: 金幣+10, ★★★★★最佳答案 2015-12-14 08:50:58
weimeiandy: 金幣+10, ★★★★★最佳答案 2015-12-14 08:50:58
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【項(xiàng)目背景與意義】 本研究將繼續(xù)評價(jià)GDC-0919的安全性、藥代動(dòng)力學(xué)、在連續(xù)給藥時(shí)間表活性和藥效學(xué)的（每日兩次28 / 28），加大未來給藥方案服藥劑量的靈活性。同時(shí)，也評價(jià)GDC-0919在臨床Ib期聯(lián)合atezolizumab（PD-L1抑制劑）治療復(fù)發(fā)性或晚期實(shí)體腫瘤進(jìn)行研究。 【試驗(yàn)設(shè)計(jì)】 據(jù)摘要，臨床Ia期研究實(shí)驗(yàn)采用非盲、單中心、3 + 3設(shè)計(jì)，評價(jià)GDC-0919藥物安全性、藥代動(dòng)力學(xué)（PK）、藥效學(xué)（PD）和該藥治療復(fù)發(fā)性或晚期實(shí)體腫瘤患者初步的抗腫瘤活性（PTS）。GDC-0919劑量在50–800mg（每日兩次）連續(xù)服藥21天/停7天日程管理，連續(xù)服藥治療12個(gè)月以上。單劑量給藥組和多劑量給藥組的藥代動(dòng)力學(xué)和藥效學(xué)參數(shù)指標(biāo)（血漿犬尿氨酸：色氨酸比值）進(jìn)行評價(jià)。 每2個(gè)周期對腫瘤療效進(jìn)行評價(jià)，評價(jià)標(biāo)準(zhǔn)參照《實(shí)體瘤療效評價(jià)標(biāo)準(zhǔn)（RECIST） 1.1版和免疫治療相關(guān)療效評價(jià)分類體系（irRC）》。 【結(jié)果】 數(shù)據(jù)顯示，GDC-0919是一個(gè)可以接受的安全性，病情穩(wěn)定和初步證據(jù)的外周藥效調(diào)制。GDC-0919耐受性良好，高達(dá)800mg（兩次/日）在21天服藥，28天為一療程。37%的患者（7 / 17）達(dá)到了病情穩(wěn)定。最大耐受劑量（MTD）沒有達(dá)到。單劑量組和多劑量組暴露劑量從50-800mg按劑量比例方式增加GCD-0919進(jìn)行控制，調(diào)節(jié)高劑量組GCD-0919劑量后血漿的犬尿氨酸與GCD-0919半衰期一致。 據(jù)摘要，截至2015年3月26日，19例參與治療和3例保持活躍（16例停止治療，由于疾病進(jìn)展）。患者接受了3周期的中位數(shù)（范圍1–11）的GDC-0919并維持77天的治療（范圍13–289天）。初始的PK結(jié)果顯示到GDC-0919600mg（兩次/日）迅速吸收，表明在暴露劑量比例增加條件下，半衰期支持每日兩次劑量。最好的實(shí)體瘤療效評價(jià)標(biāo)準(zhǔn)(RECIST) 響應(yīng)間的16例參與治療腫瘤的評估，7例（44%）病情穩(wěn)定（SD，持續(xù)穩(wěn)定的≥4周期4例）和9例（56%）疾病進(jìn)展。IRRC和PD標(biāo)記數(shù)據(jù)待定。 【常見的不良反應(yīng) 】 據(jù)摘要，與GCD-0919治療相關(guān)最常見的較低等級的不良反應(yīng)包括瘙癢（37%）、疲勞（26%）、食欲下降（21%）。劑量限制性毒性（DLT）4級不良反應(yīng)以下，有一例69歲男性患者W /m腎癌且廣泛的胃腸漿膜轉(zhuǎn)移時(shí)消化道出血的報(bào)道（只有一例≥3級不良反應(yīng)評估與GCD-0919治療相關(guān)）。不良事件（AE）無論與本藥治療是否關(guān)聯(lián)的報(bào)道≥4例，疲勞（9例，47%），咳嗽、食欲下降、惡心（共8例，42%），皮膚瘙癢（7例，37%），嘔吐（6例，32%），谷草轉(zhuǎn)氨酶上升（AST）（5例，26%） 低鉀血癥和呼吸困難（4例，21%）。≥不良反應(yīng)3級無論與本藥是否關(guān)聯(lián)發(fā)生的11例（58%），及≥2例患者腫瘤惡化（3例，16%）和谷草轉(zhuǎn)氨酶升高（2例，10.5%）。3級的谷草轉(zhuǎn)氨酶升高正好與肝轉(zhuǎn)移的惡化（2例，10%）和報(bào)道無關(guān)；與2級的AST / ALT（谷草轉(zhuǎn)氨酶 /谷丙轉(zhuǎn)氨酶）升高在2周期1天第三例評估相關(guān)的GCD-0919。沒有因不良反應(yīng)停藥 【討論】 據(jù)摘要，GCD-0919有很好的耐受性高達(dá)800mg（兩次/日）服藥21天/ 停7天。藥效學(xué)的線性與劑量成正比。4例患者病情持續(xù)穩(wěn)定。更新數(shù)據(jù)將被陸續(xù)提交。 |
2樓2015-11-23 16:28:59
sqlg888
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3樓2015-11-23 16:29:54
sqlg888
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4樓2015-11-24 21:50:28
5樓2015-11-25 07:36:21
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