Phase 1/2 clinical trial of interferon α2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma
Phase 1/2 clinical trial of interferon α2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma
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DOI：
10.1097/cji.0b013e31805449a8
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发表时间：
2007-09-01
影响因子：
3.9
通讯作者：
Nanus, David M.
中科院分区：
文献类型：
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作者：
Boorjian, Stephen A.;Milowsky, Matthew I.;Nanus, David M.
目的评价全反式维甲酸(ATRA-IV)联合干扰素α2b(干扰素α2b)治疗晚期肾癌(RCC)的可行性、有效性和生物学效应。26例转移性肾癌患者在1/2期试验中接受每周一次的ATRA-IV和干扰素SQ每日5d/wk的治疗。根据I期方法学，12名患者接受了ATRA-IV三个剂量水平(60、75和90 mg/m(2))的治疗，另外14名患者接受了90 mg/m(2)的治疗。根据意向治疗分析评估疗效。测定血清维甲酸(RA)浓度，检测RA和干扰素诱导基因(RARα、RARβ(2)、IRF1、CRABP2和TRAIL)在外周血单核细胞中的表达。60 mg/m(2)组无剂量限制性毒性，75 mg/m(2)组有1/6患者出现3级白细胞减少，90 mg/m(2)组有3例患者无剂量限制毒性。另外14名患者接受90 mg/m(2)ATRA-IV治疗，没有3/4级毒性。26例患者中有5例(19%)获得较大缓解，中位持续时间为14个月(9~23个月)；另有9例(41%)病情稳定或轻微缓解，持续时间为4个月。治疗1周和8周时，输注全反式维甲酸后血清(RA)水平差异无统计学意义。外周血单个核细胞mRNA的表达与临床疗效无关。在干扰素治疗中加入每周一次的ATRA-IV是可行的，且耐受性良好，从而导致血清(RA)的持续上升。该方案在转移性肾细胞癌中显示出抗肿瘤活性，并提示ATRA-IV可加强干扰素的治疗。
To evaluate the feasibility, efficacy, and biologic effects of weekly liposome-encapsulated all-trans retinoic acid (ATRA-IV) plus interferon alpha 2b (IFN) in patients with advanced renal cell carcinoma (RCC). Twenty-six patients with metastatic RCC were treated on a phase 1/2 trial with weekly ATRA-IV and IFN SQ daily 5d/wk. Twelve patients received ATRA-IV at three dose levels (60, 75, and 90mg/m(2)) according to phase I methodology, and 14 additional patients received 90mg/m(2) . Response was assessed according to an intention-to-treat analysis. Serum retinoic acid (RA) concentrations were assayed and peripheral blood mononuclear cell mRNA expression of RA and IFN-inducible genes (RAR alpha, RAR beta(2), IRF1, CRABP2, and TRAIL) were examined. No dose limiting toxicities 2. occurred at 60mg/m(2), grade 3 leukopenia affected 1/6 patients at 75mg/m(2), whereas 3 patients received 90mg/m(2) 2 without a dose limiting toxicities. Fourteen additional patients received 90mg/m(2) ATRA-IV without grade 3/4 toxicity. Five of 26 (19%) patients achieved a major response, with a median duration of 14 months (range 9 to 23); 9 additional patients (41%) demonstrated stable disease or minor response lasting >= 4 months. No significant differences in serum (RA) after ATRA infusion were detected between weeks 1 and 8 of treatment. Peripheral blood mononuclear cell mRNA expression did not correlate with clinical response. The addition of weekly ATRA-IV to IFN therapy is feasible and well tolerated, resulting in sustainable increased serum (RA). This regimen demonstrates antitumor activity in metastatic RCC, and suggests ATRA-IV augments IFN therapy.