Lin Amy M, Rini Brian I, Derynck Mika K, Weinberg Vivian, Park Margaret, Ryan Charles J, Rosenberg Jonathan E, Bubley Glenn, Small Eric J
UCSF Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Clin Genitourin Cancer. 2007 Jun;5(5):323-8. doi: 10.3816/CGC.2007.n.011.
Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.
A phase I trial of docetaxel/estramustine/ imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m2 to 60 mg/m2 to 70 mg/m2. Thirteen patients were treated.
On dose level 3 (docetaxel 70 mg/m2 and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m2 and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.
The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.
多西他赛/雌莫司汀是治疗转移性激素难治性前列腺癌的常用方案。伊马替尼可抑制前列腺癌中表达的血小板衍生生长因子受体，并且在临床前前列腺癌模型中与紫杉烷具有协同作用。
开展了一项多西他赛/雌莫司汀/伊马替尼的I期试验，以确定该联合用药的安全性和最大耐受剂量。对病情进展、转移性、激素难治性前列腺癌患者每21天进行一次治疗，给予固定剂量的雌莫司汀（第1 - 5天，每日口服280 mg，分3次服用）、伊马替尼（第1 - 21天，每日口服400 mg）、地塞米松（第1 - 3天，每日口服8 mg，分2次服用）以及预防性华法林（第1 - 21天，每日口服2 mg）。每组3 - 6名患者入组，在第2天接受剂量递增的多西他赛，从50 mg/m²增至60 mg/m²再增至70 mg/m²。共治疗了13名患者。
在剂量水平3（多西他赛70 mg/m²且伊马替尼每日400 mg）时，2名患者出现3级凝血酶原时间升高，归因于伊马替尼与华法林的相互作用。方案进行了修订，纳入了一个中间剂量水平（多西他赛60 mg/m²且伊马替尼每日300 mg）。然而，在整个研究中，13名患者出现了5例不可接受的毒性反应（2例脑血管意外、1例心肌梗死、1例肠系膜缺血和1例深静脉血栓形成）；其中2例毒性反应导致死亡。该研究提前终止入组。
伊马替尼与多西他赛/雌莫司汀联合使用时观察到的高血栓栓塞事件发生率排除了对该方案的进一步探索。
