Lerario Antonio M, Worden Francis P, Ramm Carole A, Hesseltine Elizabeth A, Stadler Walter M, Else Tobias, Shah Manisha H, Agamah Edem, Rao Krishna, Hammer Gary D
Division of Metabolism, Endocrinology & Diabetes, Medical School, University of Michigan, 109 Zina Pitcher Place, 1528 BSRB, Ann Arbor, MI, 48109, USA.
Horm Cancer. 2014 Aug;5(4):232-9. doi: 10.1007/s12672-014-0182-1. Epub 2014 May 22.
Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9-79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66-48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.
肾上腺皮质癌（ACC）是一种侵袭性恶性肿瘤，缺乏有效的全身治疗方法。胰岛素样生长因子受体1（IGF1R）的异常激活经常被观察到。临床前研究表明，对ACC中IGF1R信号通路进行药理抑制具有抗增殖作用。先前一项使用IGF1R抑制剂的I期试验已证明其对ACC具有生物学活性。本研究的目的是评估IGF1R抑制剂西妥昔单抗（IMC-A12）联合米托坦作为晚期/转移性ACC一线治疗方案的疗效。我们对不可切除的复发性/转移性ACC患者进行了一项多中心、随机双臂II期试验。原始方案包括两个治疗组：IMC-A12 + 米托坦组和米托坦单药组，在最初使用IMC-A12 + 米托坦进行单臂安全性评估阶段之后。IMC-A12的剂量为每2周静脉注射10 mg/kg。米托坦的起始剂量为每日2 g，随后根据血清水平/症状进行调整。主要终点是根据实体瘤疗效评价标准（RECIST）评估的无进展生存期（PFS）。由于入组缓慢和疗效有限，本研究在随机分组阶段之前终止。20例患者（13例男性，7例女性）入组单臂阶段，中位年龄为50.2岁（范围21.9 - 79.6岁）。20例患者中有8例观察到治疗效果，包括1例部分缓解和7例病情稳定。中位PFS为6周（范围2.66 - 48周）。不良事件包括2例4级（高血糖和低钠血症）和1例5级（多器官功能衰竭）。尽管该方案在一些患者中显示出活性，但相对较低的治疗疗效使得无法进一步研究这种药物组合。
