Thalasila A, Poplin Elizabeth, Shih J, Dvorzhinski Dmitri, Capanna T, Doyle-Lindrud S, Beers S, Goodin S, Rubin Eric, DiPaola Robert S
The Dean and Betty Gallo Prostate Cancer Center at The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
Cancer Chemother Pharmacol. 2003 Aug;52(2):119-24. doi: 10.1007/s00280-003-0644-6. Epub 2003 May 24.
Based on prior studies demonstrating the effect of 13- cis-retinoic acid and interferon alpha (CRA/IFN) in decreasing the expression of the antiapoptotic protein bcl-2, our prior clinical study of CRA/IFN with paclitaxel (TAX) administered every 3 weeks, and data demonstrating increased activity of weekly TAX against prostate cancer, we designed a phase I study of weekly TAX in combination with CRA/IFN in patients with prostate cancer and other advanced malignancies. To develop a marker of drug effect, we assessed bcl-2 downregulation in patient peripheral blood mononuclear cells (PBMC).
Enrolled in the study were 14 patients with prostate cancer or other advanced malignancies, and 13 were treated with 1 mg/kg CRA on days 1 and 2, 6 MU/m(2) IFN subcutaneously on days 1 and 2, and TAX at increasing doses on day 2 each week for 6 weeks out of an 8-week cycle. The effect of CRA/IFN on bcl-2 expression was assessed in PBMCs by immunoblotting.
The combination of CRA/IFN and TAX was well tolerated. Dose-limiting toxicities (DLT) in the first cycle of therapy included one patient with fever and neutropenia, and one patient with grade 4 hypertriglyceridemia. The recommended phase II dose of TAX in this combination was 80 mg/m(2). Of 13 patients assessable by tumor markers or scans, 5 had stable disease and 2 had a biochemical partial response including a patient with a decrease in PSA of >50% while on study. The assessment of patient PBMC bcl-2 was feasible in ten patients.
This is the first study in which the safety and clinical activity of weekly TAX combined with CRA/IFN has been demonstrated. The assessment of PBMC bcl-2 is feasible in this weekly chemotherapy schedule
基于先前研究证明13-顺式维甲酸和干扰素α（CRA/IFN）可降低抗凋亡蛋白bcl-2的表达，我们之前关于每3周给予CRA/IFN联合紫杉醇（TAX）的临床研究，以及表明每周一次TAX对前列腺癌活性增加的数据，我们设计了一项针对前列腺癌和其他晚期恶性肿瘤患者的每周一次TAX联合CRA/IFN的I期研究。为了开发一种药物疗效标志物，我们评估了患者外周血单核细胞（PBMC）中bcl-2的下调情况。
14例前列腺癌或其他晚期恶性肿瘤患者入组本研究，13例患者在第1天和第2天接受1mg/kg CRA治疗，第1天和第2天皮下注射6MU/m² IFN，在为期8周的周期中，每周第2天给予递增剂量的TAX，共6周。通过免疫印迹法评估CRA/IFN对PBMC中bcl-2表达的影响。
CRA/IFN与TAX联合应用耐受性良好。治疗第一周期的剂量限制性毒性（DLT）包括1例发热和中性粒细胞减少的患者，以及1例4级高甘油三酯血症患者。该联合方案中TAX的推荐II期剂量为80mg/m²。在13例可通过肿瘤标志物或扫描评估的患者中，5例病情稳定，2例有生化部分缓解，其中1例患者在研究期间PSA下降>50%。对10例患者评估其PBMC bcl-2是可行的。
这是第一项证明每周一次TAX联合CRA/IFN的安全性和临床活性的研究。在这种每周化疗方案中评估PBMC bcl-2是可行的。
