Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
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DOI：
10.1158/1078-0432.ccr-08-1223
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Calvert H
中科院分区：
文献类型：
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作者：
Plummer R;Jones C;Middleton M;Wilson R;Evans J;Olsen A;Curtin N;Boddy A;McHugh P;Newell D;Harris A;Johnson P;Steinfeldt H;Dewji R;Wang D;Robson L;Calvert H
肿瘤抵抗细胞毒治疗的一个机制是修复受损的DNA。PARP-1是一种参与碱基切除修复的核酶，碱基切除修复是5条主要修复途径之一。PARP抑制剂作为一类新的化疗和放射治疗药物正在兴起。本文报道了PARP抑制剂AG-014699与替莫唑胺联合治疗成人晚期恶性肿瘤的安全性、有效性、药代动力学和药效学结果。最初，实体瘤患者接受AG-014699递增剂量的治疗，每天服用替莫唑胺100 mg/m2×5，q 28，以建立PARP抑制剂量(PID)。随后，AG-014699剂量固定在Pid，替莫唑胺在肿瘤活检的转移性黑色素瘤患者中升级到最大耐受剂量或200mgm2。评价AG014699和替莫唑胺的药代动力学、PARP活性、DNA单链断裂(SSB)、疗效和毒性。33例患者入选。PARP在所有剂量下均有抑制作用，PID为12 mg/m2，对PBL PARP活性的抑制率为74-97%。推荐剂量为AG014699 12 mg/m2和替莫唑胺200 mg/m2。5h后肿瘤PARP平均抑制率为92%(46~97%)。没有观察到单独由AG014699引起的毒性。AG014699与替莫唑胺无相互作用，呈线性药动学关系。所有在PID治疗的患者都显示出DNA SSB的增加，并看到了令人鼓舞的活动证据。AG014699和替莫唑胺的结合耐受性很好，药效学评估证明了这种新类别药物的作用模式的原理证明。
One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. PARP-1 is a nuclear enzyme involved in base excision repair, one of the 5 major repair pathways. PARP inhibitors are emerging as a new class of agents which can potentiate chemo and radiotherapy. The paper reports safety, efficacy, pharmacokinetic and pharmacodynamic results of the First-in-Class trial of a PARP inhibitor, AG-014699, combined with temozolomide in adults with advanced malignancy. Initially patients with solid tumors received escalating doses of AG-014699 with 100 mg/m2 temozolomide daily x 5 q 28 to establish the PARP-inhibitory dose (PID). Subsequently AG-014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumours were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single strand breaks (SSB), response and toxicity were evaluated. 33 patients were enrolled. PARP inhibition was seen at all doses, PID was 12 mg/m2 based on 74 -97% inhibition of PBL PARP activity. Recommended doses were AG014699 12 mg/m2 and temozolomide 200 mg/m2. Mean tumor PARP inhibition at 5 hours was 92% (range 46 - 97%). No toxicity attributable to AG014699 alone was observed. AG014699 demonstrated linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA SSB and encouraging evidence of activity was seen. The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments demonstrating proof of principle of the mode of action of this new class of agents.