Subramaniam Deepa S, Liu Stephen V, Crawford Jeanette, Kramer Jenna, Thompson Jillian, Wang Hongkun, Giaccone Giuseppe
MedStar Georgetown University Hospital, Washington, DC, United States.
Georgetown University, Washington, DC, United States.
Front Oncol. 2018 Mar 12;8:64. doi: 10.3389/fonc.2018.00064. eCollection 2018.
Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin.
Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m on day 1 in 21-day cycles.
Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m in combination with doxorubicin at a dose of 50 mg/m. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days.
Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC.
https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.
小细胞肺癌（SCLC）占所有肺癌的15%，其特点是对细胞毒性化疗的反应率高，但复发率同样很高。人们提出了许多耐药机制，包括对阿霉素诱导的热休克反应的耐药性。ganetespib是一种新型强效非格尔德霉素热休克蛋白90（Hsp90）抑制剂。临床前研究表明，ganetespib与阿霉素之间存在协同作用。我们开展了一项关于ganetespib与阿霉素联合用药的安全性、耐受性及初步疗效的Ib/II期研究。
符合Ib期研究的患者患有适合阿霉素治疗的晚期肿瘤，而符合II期研究的患者患有复发或难治性SCLC。所有患者的东部肿瘤协作组（ECOG）体能状态评分为0 - 1分，且器官功能良好，包括心脏射血分数≥50%。接受过阿霉素终生累积剂量>150mg/m²或有症状性脑转移的患者被排除。患者在第1天和第8天接受ganetespib治疗，在第1天接受阿霉素50mg/m²治疗，每21天为一个周期。
共入组11例患者，其中9例参与Ib期剂量递增研究，2例参与II期扩大研究。该研究由申办方终止。推荐用于未来研究的剂量为ganetespib 150mg/m²联合阿霉素50mg/m²。联合用药最常见的不良事件为1/2级腹泻、恶心、疲劳和转氨酶升高。未观察到剂量限制性毒性。缓解率为25%，中位缓解持续时间为137天。
Ganetespib加阿霉素是一种耐受性良好的联合用药方案，Hsp90抑制剂在SCLC的临床开发仍具潜力。
https://ClinicalTrials.gov/ct2/show/NCT02261805，标识符NCT02261805。
