一项评估 KX2-391（Src 激酶和微管聚合口服抑制剂）在伴有骨转移的去势抵抗性前列腺癌男性患者中的Ⅱ期研究。
A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer.
机构信息
Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, USA.
出版信息
Cancer Chemother Pharmacol. 2013 Apr;71(4):883-92. doi: 10.1007/s00280-013-2079-z. Epub 2013 Jan 13.
PURPOSE
KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC).
METHODS
We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin].
RESULTS
The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥ 30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥ 5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C max was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation.
CONCLUSION
KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C max of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.
目的
KX2-391 是一种口服非三磷酸腺苷竞争性Src 激酶和微管聚合抑制剂。在 I 期临床试验中，晚期前列腺癌患者的前列腺特异性抗原（PSA）水平下降。我们进行了一项单臂 II 期研究，评估了 KX2-391 在化疗初治骨转移去势抵抗性前列腺癌（CRPC）男性中的疗效。
方法
我们用 KX2-391（40mg，每日 2 次）治疗 31 例患者，直至疾病进展或出现不可接受的毒性。主要终点是 24 周无进展生存期（PFS）；50%的成功率被定义为具有临床意义。次要终点包括 PSA 无进展生存期（PPFS）和 PSA 缓解率。探索性结局包括药代动力学研究、循环肿瘤细胞（CTC）计数以及骨吸收标志物[尿 N-端肽（uNTx）；C 端肽（CTX）]和骨形成标志物[骨碱性磷酸酶（BAP）；骨钙素]的分析。
结果
由于预先设定的无效规则，在入组 31 例患者后，该试验提前关闭。24 周时 PFS 为 8%，中位 PFS 为 18.6 周。PSA 缓解率（≥30%下降）为 10%，中位 PPFS 为 5.0 周。此外，基线时 CTC 计数≥5（不利）的 18%男性在治疗后转为 CTC 计数<5（有利）。骨转换标志物下降的男性比例分别为 uNTx 占 32%、CTX 占 21%、BAP 占 10%、骨钙素占 25%。在药代动力学研究中，中位 C max 为 61（范围 16-129）ng/mL，中位 AUC 为 156（35-348）ng h/mL。常见的毒性包括肝紊乱、骨髓抑制、疲劳、恶心和便秘。
结论
KX2-391 每日 40mg 剂量在 CRPC 男性中缺乏抗肿瘤活性，但对骨转换标志物有一定影响。由于微管聚合抑制所需的 C max≥142ng/mL（来自临床前研究），因此在未来的试验中将使用更高的每日一次剂量。
Zotero 插件