Abstract：
Arms E and F of the AcSé-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962).
Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes.
Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients.
NCT2813135.
Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes.
Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients.
NCT2813135.
摘要：
AcSé-ESMARTI/II期平台试验的E和F臂旨在定义双重mTORC1/2抑制剂vistusertib作为单一疗法的推荐剂量和初步活性，并与托泊替康-替莫唑胺一起用于富含分子的儿科患者群体患有复发性/难治性恶性肿瘤。此外,我们在儿科和年轻成人癌症治疗分层(MAPPYACTS)试验的分子分析中评估了磷脂酰肌醇3-激酶(PI3K)/AKT/哺乳动物(或机制)雷帕霉素靶蛋白(mTOR)通路的遗传改变(NCT02613962).
4例患者在E臂接受治疗，10例患者在F臂接受治疗，中位年龄为14.3岁。主要诊断为胶质瘤和肉瘤。按照连续重新评估方法进行剂量递增，在Ensign设计中进行扩展。每周2天，每天两次（BID）以75mg/m2每天两次（BID），每周3天/周给予30mg/m2BID的vistusertib单一药物与替莫唑胺100mg/m2/天和拓扑替康0.50mg/m2/天在每个4周周期的前5天是安全的。治疗耐受性良好，主要毒性为血液学。药代动力学表明儿童与成人的暴露量相等。既没有观察到肿瘤反应，也没有观察到长时间的稳定，包括12例肿瘤显示PI3K/AKT/mTOR通路改变的患者。MAPPYACTS队列中复发/难治性儿科癌症的高级分析显示，28.0％的患者与该途径相关的遗传改变。10.5%的人在核心途径基因中携带突变。
Vistusertib在儿科患者中耐受性良好。由于在成人试验中观察到的肿瘤反应和vistusertib的靶标参与不足，研究组被终止。针对PI3K/AKT/mTOR途径仍然是儿科患者需要探索的治疗途径。
NCT2813135。
4例患者在E臂接受治疗，10例患者在F臂接受治疗，中位年龄为14.3岁。主要诊断为胶质瘤和肉瘤。按照连续重新评估方法进行剂量递增，在Ensign设计中进行扩展。每周2天，每天两次（BID）以75mg/m2每天两次（BID），每周3天/周给予30mg/m2BID的vistusertib单一药物与替莫唑胺100mg/m2/天和拓扑替康0.50mg/m2/天在每个4周周期的前5天是安全的。治疗耐受性良好，主要毒性为血液学。药代动力学表明儿童与成人的暴露量相等。既没有观察到肿瘤反应，也没有观察到长时间的稳定，包括12例肿瘤显示PI3K/AKT/mTOR通路改变的患者。MAPPYACTS队列中复发/难治性儿科癌症的高级分析显示，28.0％的患者与该途径相关的遗传改变。10.5%的人在核心途径基因中携带突变。
Vistusertib在儿科患者中耐受性良好。由于在成人试验中观察到的肿瘤反应和vistusertib的靶标参与不足，研究组被终止。针对PI3K/AKT/mTOR途径仍然是儿科患者需要探索的治疗途径。
NCT2813135。
