哌立福新（Perifosine）治疗结直肠癌三期临床试验数据

Aeterna Zentaris Inc.公司（Nasdaq：AEZS）（TSX：AEZ）（“本公司”）今天宣布，消化道癌症研究主任和位于田纳西州纳什维尔的莎拉景隆研究所药物开发的副主任，Johanna Bendell博士昨天在芝加哥举行的美国临床肿瘤学会（ASCO）年度会议上报告了哌立福新治疗顽固性结直肠癌三期临床试验结果。Bendell博士是该试验的主要研究者。当哌立福新加入卡培他滨治疗顽固性结直肠癌的给药方案时，数据显示总生存期无获益，确证了2012年04月02日由该公司披露的头条结果。

这是一项由我们以前获得许可的Keryx生物制剂公司在美国实施的随机（1:1），双盲三期临床试验，比较卡培他滨+哌立福新（P-CAP）与卡培他滨+安慰剂（CAP）治疗组的疗效和安全性，涉及对所有标准治疗方案耐受的468例转移性结直肠癌患者。主要终点是总生存期（OS），次要终点包括总缓解率（ORR）（完整（CR）+部分缓解（PR））、无进展生存期（PFS）和安全性（clinicaltrials.gov NCT01002248）。

对于总意向治疗（ITT）患者人群，CAP组中位OS为6.9个月而P-CAP组为6.4个月。CAP组中位PFS为11.4个月而P-CAP组为10.9个月。差异无统计学意义。CAP组有7例完全和部分缓解而P-CAP组有6例。

两个治疗组之间的毒性特征无显著性差异。最常见的血液学不良事件为1级或2级贫血（CAP = 30件与P-CAP =49件相比）。最常见非血液学不良事件为1级或2级乏力（CAP = 95件与P-CAP =125件相比）。

在一个预定义的亚组中，对患者进行分层为表达野生型K-ras原癌基因的患者和曾因奥沙利铂的毒性而不是疾病进展中止治疗的患者，哌立福新治疗的患者在OS（P-CAP = 8个月与 CAP = 6.2个月相比）和PFS（P-CAP = 8 个月与 CAP = 6.2个月相比）方面有获益。目前，对该结果的原因尚不清楚，且进一步的分析包括正在进行的生物标志物研究。

Aeterna Zentaris公司的总裁兼首席执行官，于尔根·恩格尔博士评论道，“在4月份，这些数据证实了令人失望的头条结果。然而，他们不会阻止我们继续进行如前所述的三期多发性骨髓瘤试验，首先是基于现有稳定的临床前和临床数据，其次是该领域重要的领军人物均支持此药。此外，我们认为市场的机遇、其他药物遭遇挫折后获得成功的例子，以及推动该研究达到预定中期分析所需要的合理投资，也需要该公司做出明智的决定。在治疗多发性骨髓瘤中，哌立福新是维持我们深度专注于向未满足医疗需求的癌症患者提供新颖的、靶向治疗选择的重要组成部分。”

摘要号：LBA3501

题目：Results of the X-PECT study: A phase III randomized double-blind placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).

X-PECT研究结果：比较perifosine联合卡培他滨(P-CAP)和安慰剂联合卡培他滨(CAP)治疗难治性转移性结直肠癌(mCRC)患者的随机、双盲、安慰剂对照III期研究

摘要：

Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated.

Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed.

Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238.

Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

编辑: xy 作者:丁香园通讯员

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