A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors.
A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors.
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DOI：
10.1158/1078-0432.ccr-10-2323
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发表时间：
2011-04-15
期刊：
影响因子：
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通讯作者：
Schwartz GK
中科院分区：
文献类型：
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作者：
Dickson MA;Carvajal RD;Merrill AH Jr;Gonen M;Cane LM;Schwartz GK
1 -磷酸鞘氨醇（S1P）是癌细胞生长和增殖的重要介质。S1P的产生由鞘氨醇激酶1（SphK）催化。沙芬戈（L -苏式 - 二氢鞘氨醇）是一种假定的SphK抑制剂。我们进行了一项沙芬戈（S）单独使用以及与顺铂（C）联合使用的I期试验。
采用3 + 3剂量递增法。为安全起见，在联合用药前1周先单独给予S。然后每3周给予S + C。根据剂量，S在60 - 120分钟（min）内给药。60分钟后，C在60分钟内给药。由于过度疲劳，第4组的顺铂剂量从75 mg/m²降至60 mg/m²。
43例患者接受了治疗。41例可评估毒性，37例可评估疗效。最大耐受剂量（MTD）为每3周120分钟内给予S 840 mg/m²及C 60 mg/m²。归因于顺铂的剂量限制性毒性（DLT）包括疲劳和低钠血症。来自S的DLT是肝酶升高。S的药代动力学参数在整个剂量范围内呈线性，与C无显著相互作用。在MTD或接近MTD治疗的患者，S水平达到>20 µM，并在4小时内维持≥5 µM的水平。最佳疗效为6例患者病情稳定，平均持续3.3个月（范围1.8 - 7.2个月）。1例肾上腺皮质癌患者肝脏和肺部转移灶显著消退，另1例患者病情稳定时间延长。S与血浆中S1P的剂量依赖性降低有关。
沙芬戈是第一种进入临床试验的假定SphK抑制剂，可与顺铂安全联合使用。如临床前数据所预期，观察到可逆的剂量依赖性肝毒性。通过下调S1P实现了靶点抑制。推荐的II期剂量为每3周S 840 mg/m²及C 60 mg/m²。
Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (L-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). A 3+3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60–120 minutes (min), depending on dose. 60 min later, C was given over 60 min. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue. 43 patients were treated. 41 were evaluable for toxicity and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m2 over 120 min C 60 mg/m2, every 3 weeks. DLTs attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of > 20 µM and maintained levels ≥ 5 µM for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8 – 7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma. Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase 2 dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks.