Phase 2 study of tamibarotene for relapsed acute promyelocytic leukemia (APL)
CytRx Corporation announced favorable preliminary results from its Phase 2 STAR-1 registration clinical trial for tamibarotene in the treatment of acute promyelocytic leukemia (APL) in patients failing other treatments. 
This study was an open-label, non-randomized trial, with a primary endpoint of determining the rate of durable complete response for tamibarotene therapy when administered as a single agent to adult patients following treatment failure with all-trans retinoic acid (ATRA) and arsenic trioxide.
Trial patients were administered 6 mg of tamibarotene daily until they achieved remission or for a maximum of 56 days. From the results of eleven patients who had received a median of seven prior therapies, three patients (27%) achieved a hematologic complete response, and four (36%) achieved a morphologic leukemia-free state.
Tamibarotene is an orally available, rationally designed, synthetic retinoid compound which was designed to potentially avoid toxic side effects by binding to its molecular target more selectively than all trans-retinoic acid (ATRA), the current first line treatment for APL.

[化学名]：4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid
[分子式]：C22H25NO3
[开发阶段]：临床试验（日本，适应症为急性早幼粒细胞白血病）；临床前研究（美国，适应症为类风湿性关节炎）

[ATC分类]：抗肿瘤药（L01）/治疗银屑病的维甲酸化合物（D05B-B）

[简介]：Tamibarotene [AM 80, retinobenzoic acid]是一种新的合成维甲酸化合物，原由日本的盐野义公司开发，但盐野义公司已不参与该产品开发，目前由东京大学继续该产品的开发。Tamibarotene曾进入治疗银屑病的III期临床开发阶段，但针对该适应症的开发已终止。该产品还在进行治疗类风湿性关节炎的临床前研究。在治疗糖尿病视网膜病变方面也有潜力，但开发进展还未公布。Tamibarotene在日本还在进行治疗急性早幼粒细胞白血病的临床试验。
[不良反应]：2名复发的急性早幼粒细胞白血病患者接受tamibarotene（6mg/m2/day，口服）治疗，两名患者都出现了高脂血症，一名患者在停止治疗后不久出现了头痛症状[1]。24名患者在接受tamibarotene（6mg/m2/day，口服）治疗后，有1名患者出现了维甲酸综合征（表现为发热、呼吸困难、动脉血氧水平降低、弥漫性的肺部阴影）；有1名患者出现了白细胞增多症，白细胞计数达到51.2×105/L；另有3名患者也出现了中度白细胞增多；16名患者出现了高甘油三酯血症；15名患者出现了高胆固醇血症。和tamibarotene治疗有关的不良反应一般比接受维甲酸治疗时出现的类似的不良反应轻。在完全缓解之后仍继续进行药物治疗，如果2周后还未达到理想反应的话，tamibarotene的剂量可提高到9mg/m2/day。如果不良反应严重，剂量减至3mg/m2/day或停药[2]。局部用药：20名银屑病患者局部使用tamibarotene 0.002-0.008%，每日一次，只有1名患者发现了皮肤刺激反应，该患者接受的药物浓度为0.005%，出现了暂时的比较轻的皮肤刺激反应[3]。在另一项研究中，20名患者接受tamibarotene 0.008%或0.005%局部治疗，1名患者出现了皮肤搔痒[4]。

[临床试验]：2名复发的急性早幼粒细胞患者接受tamibarotene
6mg/m2/day口服治疗，2名患者的全血细胞逐渐恢复，骨髓中的白细胞出现了形态学的分化，在治疗的第52和38天2名患者获得了完全缓解，这两名患者之前接受过全反式维甲酸的治疗，但在tamibarotene给药期间未接受过其他抗白血病药物治疗[1]。
24名复发的早幼粒细胞白血病患者接受tamibarotene治疗，14名患者获得了完全缓解，从开始治疗到缓解的中位时间为41天。在未获得完全缓解的10名患者中，有3名病情有了发展，7名患者病情变化不大。在获得完全缓解的患者中有5名随后接受了异基因骨髓移植，14个月后这些患者仍处于完全缓解状态；2名患者病情复发，另7名患者接受附加的化疗，14个月后仍处于完全缓解状态。这些患者起初都接受了维甲酸治疗并获得了完全缓解，以后病情复发。Tamibarotene的起始剂量为6mg/m2/day[2]。
局部用tamibarotene的适宜浓度为0.008%。在银屑病患者参加的临床试验中，tamibarotene 0.008%乳膏局部治疗的患者有52.9%皮肤症状有了“明显的缓解；相应的0.005%浓度的百分比为47.1%，0.002%浓度的百分比为29.4%，安慰剂的百分比为18.8%[5]。

[参考文献]
1、Takeuchi M, Yano T, et al. Re-induction of complete remission with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukaemia previously treated with all-trans retinoic acid. British Journal of Haematology. 97: 137-140, No. 1, Apr 1997.
2、Tobita T, Takeshita A, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukaemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 90: 967-973, 1 Aug 1997.
3、Ishibashi Y, Harada S, et al. A shorttermapplication test of Am-80 ointment in the clinical phase II studies. Rinsho Iyaku. 11: 539-544, No.
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4、Ishibashi Y, Harada S, et al. Preliminary dose-finding study on Am-80 ointment in the clinical phase II studies. Rinsho Iyaku. 11: 545-554, No. 3, 1995. 5、Ishibashi Y, Harada S, et al. Dose-finding study on Am-80 ointment in the clinical phase II studies. Rinsho Iyaku. 11: 555-564, No. 3, 1995 ct 2000.