PDF(Pubmed)
Abstract：
Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701).
Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT).
Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response.
The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT).
Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response.
The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
摘要：
目的：在横纹肌肉瘤（RMS）患者中，抗IGF-1R抗体显示出有意义但短暂的肿瘤反应。SRC家族成员YES已被证明介导IGF-1R抗体获得性抗性，在小鼠RMS模型中，共定位IGF-1R和YES导致持续反应。我们进行了抗IGF-1R抗体加尼单抗联合达沙替尼的I期试验，一种针对YES的多激酶抑制剂，RMS患者（NCT03041701）。
方法：患有复发性/难治性肺泡型或胚胎型RMS和可测量疾病的患者是合格的。所有患者每2周静脉注射甲尼单抗18mg/kg。达沙替尼剂量为60mg/m2/剂量(最大100mg)每日一次口服[剂量水平(DL)1]或60mg/m2/剂量(最大70mg)每日两次(DL2)。使用3+3剂量递增设计，最大耐受剂量(MTD)基于第1周期剂量限制性毒性(DLT)确定。
结果：13名符合条件的患者，纳入的中位年龄18岁(范围8-29岁).先前的全身治疗的中位数为3；所有人都接受过先前的辐射。在11名毒性可评估的患者中，1/6在DL1（腹泻）有DLT，2/5在DL2（肺炎，血尿）确认DL1为MTD。在九名可评估反应的患者中，一个有四个周期的确认部分反应（PR），其中1人病情稳定（SD）6个周期。来自无细胞DNA的基因组研究与疾病反应相关。
结论：达沙替尼每天60mg/m2/剂和加尼单抗每两周18mg/kg的组合是安全且可耐受的。这种组合在五个月时的疾病控制率为22％。
方法：患有复发性/难治性肺泡型或胚胎型RMS和可测量疾病的患者是合格的。所有患者每2周静脉注射甲尼单抗18mg/kg。达沙替尼剂量为60mg/m2/剂量(最大100mg)每日一次口服[剂量水平(DL)1]或60mg/m2/剂量(最大70mg)每日两次(DL2)。使用3+3剂量递增设计，最大耐受剂量(MTD)基于第1周期剂量限制性毒性(DLT)确定。
结果：13名符合条件的患者，纳入的中位年龄18岁(范围8-29岁).先前的全身治疗的中位数为3；所有人都接受过先前的辐射。在11名毒性可评估的患者中，1/6在DL1（腹泻）有DLT，2/5在DL2（肺炎，血尿）确认DL1为MTD。在九名可评估反应的患者中，一个有四个周期的确认部分反应（PR），其中1人病情稳定（SD）6个周期。来自无细胞DNA的基因组研究与疾病反应相关。
结论：达沙替尼每天60mg/m2/剂和加尼单抗每两周18mg/kg的组合是安全且可耐受的。这种组合在五个月时的疾病控制率为22％。
