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.
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。