mTORC1/2抑制剂BI 860585单药或联合依西美坦或紫杉醇用于晚期实体瘤患者的1期研究。
A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors.
作者信息
de Braud Filippo, Machiels Jean-Pascal H, Boggiani Daniela, Rottey Sylvie W H, Duca Matteo, Laruelle Marie, Salvagni Stefania, Damian Silvia, Lapeire Lore D F, Tiseo Marcello, Dermine Alexandre, Ould-Kaci Mahmoud, Braunger Juergen, Rascher Juliane, Fischer Daniela, Hoefler Josef, Mariani Gabriella L, Cresta Sara
机构信息
Fondazione IRCCS Istituto Nazionale dei Tumori, Medical Oncology Department, University of Milan, via G. Venezian, 1, 20133 Milan, Italy.
Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Avenue Hippocrate 10, 200 Woluwe-Saint-Lambert, 1200 Brussels, Belgium.
出版信息
Cancers (Basel). 2020 May 31;12(6):1425. doi: 10.3390/cancers12061425.
This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5-300 mg/day; Arm A), BI 860585 (40-220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80-220 mg/day; Arm C) with 60-80 mg/m/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash ( = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash ( = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.
这项1期试验（NCT01938846）确定了mTOR丝氨酸/苏氨酸激酶抑制剂BI 860585作为单一疗法以及与依西美坦或紫杉醇联合用于晚期实体瘤患者时的最大耐受剂量（MTD）。这项3+3剂量递增研究评估了BI 860585单一疗法（5 - 300毫克/天；A组）、BI 860585（40 - 220毫克/天；B组）与25毫克/天依西美坦联合，以及BI 860585（80 - 220毫克/天；C组）与60 - 80毫克/平方米/周紫杉醇联合，每28天为一个周期。主要终点是第1周期出现剂量限制性毒性（DLT）的患者数量和MTD。分别有41例、25例和24例患者接受治疗（A、B、C组）。第1周期中分别有4例（皮疹（=2例）、丙氨酸氨基转移酶/天冬氨酸氨基转移酶升高、腹泻）、4例（皮疹（=3例）、口腔炎、γ-谷氨酰转移酶升高）和2例（腹泻、血肌酸磷酸激酶升高）患者出现DLT。BI 860585的MTD在A组为220毫克/天，在B组和C组为160毫克/天。9例患者获得客观缓解（B组：4例部分缓解（PR）；C组：4例PR；1例完全缓解）。疾病控制率在A组、B组和C组分别为20%、28%和58%。最常见的治疗相关不良事件（AE）在A组是高血糖（54%）和腹泻（39%）；在B组是腹泻（40%）和口腔炎（40%）；在C组是疲劳（58%）和腹泻（58%）。所有组均确定了MTD。观察到BI 860585单一疗法以及与依西美坦或紫杉醇联合使用时具有抗肿瘤活性。
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