A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade™), in combination with paclitaxel and carboplatin in patients with advanced malignancies
A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade™), in combination with paclitaxel and carboplatin in patients with advanced malignancies
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DOI：
10.1007/s00280-006-0259-9
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发表时间：
2007-02-01
影响因子：
3
通讯作者：
Adjei, Alex A.
中科院分区：
文献类型：
--
作者：
Ma, Cynthia;Mandrekar, Sumithra J.;Adjei, Alex A.
目的硼替佐米是一种20 S蛋白酶体的选择性抑制剂，对多种癌症具有活性，与紫杉烷类和铂类药物具有序列依赖性协同细胞毒性。在该I期研究中测试了硼替佐米与紫杉醇和卡铂联合的两种不同治疗方案，以评估方案对毒性、药效学和临床活性的影响。方法晚期恶性肿瘤患者交替接受（方案A）紫杉醇和卡铂（IV d1），然后硼替佐米（IV d2，d5，d8）或（方案B）硼替佐米（IV d1，d4，d8），然后紫杉醇和卡铂（IV d2），21天为一周期。结果53例患者（A组25例，B组28例）接受了A、B方案治疗，中位疗程分别为3个周期（1-8个周期）和3.5个周期（1-10个周期）。所有治疗周期中3级或以上治疗相关血液学不良事件包括中性粒细胞减少（A 52%，B 50%）、贫血（A 12%，B 7.1%）和血小板减少（A 16%，B 17.9%）。非血液学治疗相关不良事件相当轻微（主要为1级和2级）。对于方案A，最大耐受剂量和未来II期试验的推荐剂量为硼替佐米1.2 mg/m（2）、紫杉醇135 mg/m（2）和卡铂AUC=6;对于方案B，硼替佐米1.2 mg/ m（2）、紫杉醇175 mg/m（2）和卡铂AUC=6。在方案B中观察到6例（21.4%）部分缓解（PR）。相比之下，方案A仅实现1例（4%）PR。两种给药方案在MTD时实现了相似的蛋白酶体抑制。结论：序贯硼替佐米联合化疗（方案B）耐受性良好，在这一小部分患者中，客观缓解率令人鼓舞。有必要对该给药方案进行进一步研究。
Purpose Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. Methods Patients with advanced malignancies were alternately assigned to receive ( schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin ( IV d2) on a 21-day cycle. Results Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m(2), paclitaxel 135 mg/m(2) and carboplatin AUC=6 for schedule A and bortezomib 1.2 mg/ m(2), paclitaxel 175 mg/m(2) and carboplatin AUC=6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. Conclusion Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.