Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome
Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome
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DOI：
10.1038/sj.leu.2404213
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发表时间：
2006-06-01
期刊：
影响因子：
11.4
通讯作者：
Feldman, E. J.
中科院分区：
文献类型：
--
作者：
Roboz, G. J.;Giles, F. J.;Feldman, E. J.
PTK787/ZK 222584(PTK/ZK)是一种口服血管生成抑制剂，靶向血管内皮生长因子受体酪氨酸激酶，包括VEGFR-1/Flt-1、VEGFR-2/KDR、VEGFR-3/Flt-4、血小板衍生生长因子受体酪氨酸激酶和c-kit蛋白酪氨酸激酶。这项I期研究的目的是评价PTK/ZK的安全性、耐受性、生物活性和药理作用。PTK/ZK每天两次，按连续给药方案给药，用于治疗原发难治性或复发性急性髓细胞白血病(AML)、继发性AML、预后不良的初治AML或晚期骨髓增生异常综合征(MDS)。PTK/ZK单药治疗无效的急性髓系白血病患者可接受PTK/ZK联合标准诱导化疗。63例患者接受PTK/ZK 500-1000 mg，2次/d口服。收集安全性和药代动力学数据。根据标准的骨髓和外周血标准评估疗效。剂量限制毒性为嗜睡、高血压、恶心、呕吐和食欲不振。与PTK/ZK相关的其他不良反应包括头晕、虚弱、乏力、腹泻和瘙痒；这些通常是轻微和可逆的。药代动力学数据显示在第14天达到稳定状态，重复给药没有蓄积，稳定状态下的暴露剂量没有显著增加，超过最大耐受量(MTD)。PTK/ZK联合化疗的17例AML患者中有5例完全缓解。结论：PTK/ZK的MTD为750 mg，2次/d。该药物一般耐受性良好，可与MDS和AML患者的化疗结合使用。
PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.