Lombardi Comprehensive Cancer Center, Developmental Therapeutics Program, Washington, DC 20007, USA.
Cancer Chemother Pharmacol. 2012 Dec;70(6):843-53. doi: 10.1007/s00280-012-1969-9. Epub 2012 Sep 27.
Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.
Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.
Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks).
This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.
临床前数据表明，将伊马替尼与传统细胞毒性化疗联合使用可能会提高伊马替尼的疗效。我们进行了一项伊马替尼联合紫杉醇治疗晚期或转移性实体瘤患者的 I 期研究。
患者按标准的 3+3 设计入组。每两个周期对患者进行重新分期，如果患者疾病稳定（SD）或更好，则继续不中断研究治疗。评估联合使用伊马替尼和紫杉醇的最大耐受剂量（MTD）和药代动力学特征。
共入组 58 例患者，其中 40 例进入 I 期剂量递增部分。在 28 天的周期中，伊马替尼和紫杉醇交替递增剂量，结果得出的 MTD 为：每天 800mg 伊马替尼，在第 1-4、8-11、15-18 和 22-25 天服用；每周 100mg/m2 紫杉醇，在第 3、10 和 17 天服用。两个扩展队列共入组了 10 例乳腺癌患者和 8 例软组织肉瘤患者，这些患者接受了 MTD 治疗。最常见的不良反应是流感样症状（64%）和恶心/呕吐（71%）。最常见的 3/4 级毒性是中性粒细胞减少（26%）、流感样症状（12%）和疼痛（12%）。与单独使用相比，联合使用两种药物时，药物的药代动力学特征没有明显差异。38 例患者可评估疗效，其中 18 例（47.4%）患者有临床获益。5 例患者（13.2%）有部分缓解（PR），13 例患者（34.2%）疾病稳定（SD）；有临床获益的患者的平均进展时间为 17 周（7-28 周）。
伊马替尼联合紫杉醇联合使用合理安全，耐受性良好，并显示出抗肿瘤活性的证据。需要在特定疾病的 II 期试验中进一步探索。
