背景:脾酪氨酸激酶(Syk)抑制剂是原发性免疫性血小板减少症的治疗选择。我们的目的是评估安全性,耐受性,药代动力学,初步活动,并推荐原发性免疫性血小板减少症患者2期剂量的索夫利普尼。
方法:这是随机的,双盲,安慰剂对照,1b/2期研究在中国9家医院进行。符合条件的患者年龄为18-75岁,ECOG表现评分为0-1分,原发性免疫性血小板减少症超过6个月,在先前的一线治疗后无反应或复发,或在脾切除术后反应差或术后复发.剂量递增(100毫克,200毫克,或每天一次口服300mg)和剂量扩展阶段(推荐的2期剂量),每个阶段包括8周,双盲,安慰剂对照期,患者被随机分配(3:1)接受sovleplenib或安慰剂与交互式网络反应系统,然后是16周,使用sovleplenib的开放标签期。患者,调查员,在前8周,申办方对治疗分配进行了掩盖.主要疗效终点是血小板计数达到30×109血小板/L或更高的患者比例,并且在无抢救治疗的情况下连续两次就诊时是基线的两倍。通过意向治疗评价疗效。这项研究在ClinicalTrials.gov注册,NCT03951623。
结果:在2019年5月30日至2021年4月22日之间,对62例患者进行了资格评估,其中45例(73%)被随机分配。患者在8周的双盲期内接受了至少一剂研究药物(安慰剂[n=11]和索夫勒普尼100mg[n=6],200毫克[n=6],300毫克[n=16],和400mg[n=6];该组是在观察到先前剂量无方案指定的安全事件后添加的)。所有参与者均为亚洲人;45人中有18人(40%)为男性,27人(60%)为女性。中位年龄为40·0岁(IQR33·0-50·0)。sovleplenib组34例患者中有10例(29%)与安慰剂组11例患者中有5例(45%)同时接受抗原发性免疫性血小板减少症治疗。推荐的2期剂量被确定为每天一次300mg。在100mg组中,满足主要疗效终点的患者比例为3(50%;95%CI12-88),200mg组中有三个(50%;12-88),300mg组中有10人(63%;35-85),400mg组中有2例(33%;4-78),而安慰剂组中有1例(9%;0-41)。300mg组的总反应率为80%(接受连续sovleplenib的20人中有16人加上从安慰剂中越过的人),在连续sovleplenib中持续反应率为31%(11-59;16个中的5个)300mg和75%(19-99;4个中的3个)在0-24周内从安慰剂到sovleplenib。在28天的安全评估期内,sovleplenib组发生了2个2级或更严重的治疗相关治疗紧急不良事件(高甘油三酯血症和贫血).在0-8周内,最常见的治疗引起的不良事件是血乳酸脱氢酶的增加,血尿,和尿路感染(sovleplenib组34个中的7个[21%]与安慰剂组11个中的1个[9%]);隐血阳性和高尿酸血症(各4个[12%]与3个[27%])。没有记录到因治疗引起的致命不良事件。
结论:Sovleplenib的耐受性良好,推荐的2期剂量在原发性免疫性血小板减少症患者中显示出有希望的持久反应,为今后的调查提供了证据。正在进行一项3期试验(NCT05029635),以确认sovleplenib在原发性免疫性血小板减少症患者中的疗效和安全性。
背景:HUTCHMED.
BACKGROUND: Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia.
METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2
study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 109 platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This
study is registered with ClinicalTrials.gov, NCT03951623.
RESULTS: Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the
study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded.
CONCLUSIONS: Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3
trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia.
BACKGROUND: HUTCHMED.