Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer.
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer.
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PLX4032 的 I 期研究：V600E BRAF 突变作为人类癌症治疗靶点的概念证明。
DOI：
10.1200/jco.2009.27.15_suppl.9000
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
P. Chapman
中科院分区：
文献类型：
--
作者：
K. Flaherty;I. Puzanov;J. Sosman;K. Kim;A. Ribas;G. McArthur;R. J. Lee;J. Grippo;K. Nolop;P. Chapman
9000背景：PLX 4032是一种具有临床前活性的致癌V600 E突变型BRAF激酶的口服选择性抑制剂。V600 E BRAF是黑色素瘤（60%）中最常见的激酶突变，也见于结直肠癌（10%）、大多数未分化和乳头状甲状腺癌以及低级别浆液性卵巢癌。
方法
I期、剂量递增研究，旨在确定3至6名患者（pts）的连续队列中PLX 4032的最大耐受剂量（MTD）、安全性、药代动力学（PK）/药效学（PD）和疗效（每8周进行一次RECIST评价）。在第1、8和15天采集血浆PK样本。
结果
54例患者入组：转移性黑色素瘤（n=49）、甲状腺癌（n=3）、直肠癌（n=1）或卵巢癌（n=1）。26例患者连续接受100 mg BID至1600 mg BID剂量的结晶制剂（CF），相关暴露量低于目标血浆水平。28例患者接受了生物利用度增加的优化制剂，预计生物利用度增加10倍，剂量为160 mg BID至1120 mg BID。AUC与剂量成比例，在240 mg BID和更高剂量下高于目标水平。720 mg BID组发生1例DLT（G4全血细胞减少症）;以360 mg BID重新开始治疗，无骨髓抑制。在1120 mg BID剂量下，5例患者中有3例发生DLT（皮疹和疲乏）。360 mg BID组1例患者发生3级ALT升高。以240 mg BID或更高剂量的增加生物利用度的制剂治疗的13名黑素瘤患者（77%M1C）具有至少8周的随访。接受≥ 240 mg BID治疗的7例BRAF V600 E+患者中，5例发生肿瘤消退，高达83%，1例确认部分缓解（PR），1例未确认PR（过早）; 4例V600 E状态未知的患者中，2例发生肿瘤消退，高达50%，1例确认PR; 2例BRAF野生型患者发生疾病进展。所有7例肿瘤消退的患者保持无进展，范围为4至14个月。3例V600 E突变的甲状腺癌患者肿瘤消退（范围9-16%），无进展（4-7个月）。
结论
PLX 4032的剂量递增在1120 mg BID时达到DLT。720 mg BID是目前的MTD，但可探索960 mg BID。PLX 4032在V600 E BRAF突变型肿瘤中表现出抗肿瘤活性。这些观察结果证实V600 E BRAF是人类癌症的有效治疗靶标。[表：见正文]。
9000 Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase with preclinical activity. V600E BRAF is the most common kinase mutation in melanoma (60%), also found in colorectal carcinomas (10%), most anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas.
METHODS
Phase I, dose-escalation study designed to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic (PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and 15.
RESULTS
54 pts have been enrolled: metastatic melanoma (n=49), thyroid (n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with associated exposures below target plasma levels. 28 pts received an optimized formulation with increased bioavailability, predicted to have 10-fold greater bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-proportional and above target levels at 240 mg BID and higher. There was 1 DLT at 720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at doses of 240 mg BID or higher of the increased bioavailability formulation have a minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at ≥ 240 mg BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1 unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to 14 months. 3 thyroid cancer pts with V600E mutations have tumor regression (range 9-16%) and are progression-free (4-7 months).
CONCLUSIONS
Dose escalation of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960 mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic target in human cancer. [Table: see text].