背景:DNA依赖性蛋白激酶(DNA-PK)在通过非同源末端连接修复DNA双链断裂(DSB)中起关键作用。抑制DNA-PK可以增强DNADSB诱导抗癌疗法的效果。Peposertib(以前称为M3814)是一种口服给药,强力,和选择性小分子DNA-PK抑制剂,在异种移植模型中已证明具有放射增敏和抗肿瘤活性,并且在单一疗法中具有良好的耐受性。这项I期试验(NCT02516813)研究了最大耐受剂量,推荐的II期剂量(RP2D),安全,胸或头颈部肿瘤患者(A组)中peposertib联合姑息性放疗(RT)的耐受性和头颈部鳞状细胞癌患者(B组)中peposertib联合顺铂和根治性RT的耐受性。
方法:患者每天一次(QD)以片剂或胶囊的递增剂量分组,联合姑息性RT(A组)或联合强度调节的治愈性RT和顺铂(B组)。
结果:最常见的因治疗引起的不良事件(TEAE)是放射性皮肤损伤,疲劳,A组恶心(n=34)和口腔炎,恶心,放射性皮肤损伤,和B臂的味觉障碍(n=11)。根据对剂量限制性毒性的评估,耐受性,和药代动力学数据,A组的RP2D被宣布为200mgpeposertib片剂QD与RT组合。在B组(n=11)中,50mgpeposertib与治愈性RT和顺铂联合使用被宣布为可耐受。然而,由于该剂量的暴露量不足,因此终止了入组,并且未正式宣布RP2D.
结论:Peposertib与姑息性RT联合使用,对于每个RT部分的200mgQD剂量的片剂,耐受性良好。当与RT和顺铂联合使用时,可耐受的peposertib剂量导致暴露不足。
OBJECTIVE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly \"M3814\") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B).
METHODS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B).
RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared.
CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.