A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia
A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia
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DOI：
10.1182/bloodadvances.2018015677
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发表时间：
2018-08-14
期刊：
影响因子：
7.5
通讯作者：
Bhatia, Mickie
中科院分区：
文献类型：
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作者：
Aslostovar, Lili;Boyd, Allison L.;Bhatia, Mickie
我们完成了1期剂量递增试验，以评估多巴胺受体D2(DRD2)拮抗剂硫代咪嗪(TDZ)与阿糖胞苷联合使用的安全性。13例55岁以上复发或难治性急性髓系白血病(AML)患者入选。口服TDZ剂量为25 mg(n=6)、50 mg(n=4)、100 mg(n=3)，每6h一次，共21天。剂量限制毒性(DLTS)包括1例患者在25 mg TDZ时3级QTC间期延长，2例患者在100 mg TDZ时出现神经事件(步态障碍、意识低落和头晕)。在50 mg TDZ剂量下，循环中DRD2拮抗剂的总水平接近10mU M，这一水平被认为在体外对人AML具有选择性活性。13名患者中有11名患者完成了为期5天的TDZ导入，其中6名患者接受TDZ联合羟基脲治疗，5名患者仅接受TDZ治疗。在此期间，8名患者的原始细胞水平下降了19%至55%，而3名患者表现出进展性疾病。在这5天的间隔中，原始细胞减少的程度与白血病细胞上假定的TDZ靶受体DRD2的表达有关。这些初步结果表明，DRD2是治疗AML疾病的潜在靶点。需要未来的研究来证实这些观察结果，包括在AML患者中使用耐受性提高的改良DRD2拮抗剂。
We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 mu M, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients.