Mathew Paul, Thall Peter F, Jones Donnah, Perez Cherie, Bucana Corazon, Troncoso Patricia, Kim Sun-Jin, Fidler Isaiah J, Logothetis Christopher
Department of Genitourinary Medical Oncology, Unit 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
J Clin Oncol. 2004 Aug 15;22(16):3323-9. doi: 10.1200/JCO.2004.10.116.
To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel.
Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks.
During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m(2), in three of four patients at docetaxel 45 mg/m(2), and in five of six patients at docetaxel 35 mg/m(2). DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone.
With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m(2) weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.
为了研究血小板衍生生长因子受体（PDGFR）抑制剂甲磺酸伊马替尼在去势抵抗性前列腺癌（AIPC）中的作用，包括单独使用以及与多西他赛联合使用的情况，我们设计了一项模块化的I期试验。我们的目标是：（1）评估多西他赛与伊马替尼联合使用时的毒性和最大耐受剂量；（2）评估单独使用伊马替尼以及伊马替尼与多西他赛联合使用时前列腺特异性抗原（PSA）的下降情况。
28名患有AIPC并伴有骨转移的男性患者入组，先接受每日600mg伊马替尼导入治疗30天，然后每日600mg伊马替尼并联合六种可能剂量之一的多西他赛，每6周进行4周，每周一次。
在伊马替尼导入阶段，观察到1例剂量限制性毒性（DLT）事件，28名患者中有2例（7%）出现PSA下降（均<50%）。在伊马替尼与多西他赛联合使用时，多西他赛剂量为30mg/m²时，12例患者中有3例在第1周期出现DLT；多西他赛剂量为45mg/m²时，4例患者中有3例出现DLT；多西他赛剂量为35mg/m²时，6例患者中有5例出现DLT。DLT（共40例事件）主要为疲劳（35%）和恶心（20%）。21例患者中有8例（38%）的PSA下降超过50%，21例患者中有6例（29%）的PSA下降小于50%。观察到连续18个月以上的PSA下降情况。单独联合治疗时，表达PDGFR的肿瘤在连续骨髓活检中出现消退。
每日服用600mg伊马替尼时，多西他赛的最大耐受剂量确定为每6周一次，每周30mg/m²，共4周。观察到长期反应。伊马替尼在AIPC中对多西他赛治疗效果的调节作用正在一项随机II期试验中进行测试。
