Leahy Michael, Ray-Coquard Isabelle, Verweij Jaap, Le Cesne Axel, Duffaud Florence, Hogendoorn Pancras C W, Fowst Camilla, de Balincourt Christine, di Paola Eugenio Donato, van Glabbeke Martine, Judson Ian, Blay Jean-Yves
Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK, and Erasmus University Medical Center, Rotterdam, Netherlands.
Eur J Cancer. 2007 Jan;43(2):308-15. doi: 10.1016/j.ejca.2006.09.014. Epub 2006 Nov 13.
The study aimed to assess the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10mg/m2, intravenous (i.v.) every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy. Two groups were recruited: (1) GIST following treatment with imatinib; (2) other STS following treatment with single agent doxorubicin or ifosfamide or a single line of combination therapy. The primary end-point was overall response rate (ORR) as defined by response evaluation criteria in solid tumours (RECIST). Progression free survival (PFS) was a secondary end-point. In the GIST group, a Simon two step design was planned: first step 18 patients, total 32 patients (p1=20% p0=5% alpha=beta=0.1). In the non-GIST group, planned sample size was 40 in a standard Fleming one-step design (p0=10%, p1=25%, alpha=beta=0.1). Forty-three patients with non-GIST and 21 patients with GIST were recruited. In general, the drug was well tolerated. Common Toxicity Criteria (CTC) grade 3 or grade 4 toxicity was granulocytopenia: 70% of patients, 50% of cycles; fatigue: 25% of patients, 8% of cycles; febrile neutropenia: 14% of patients, 4% of cycles. There was one confirmed toxic death due to neutropenic septicaemia. Three patients had clinically significant allergic reactions in 249 cycles delivered. In the GIST group, no patients had a confirmed response and recruitment was discontinued at the first step. In the non-GIST group, there were two confirmed partial responses. The 3 month PFS was 46% in the non-GIST group and 33% in the GIST group. In the non-GIST group, this PFS is in the range of other agents considered active in STS, and may predict for more substantial first line activity. Further investigation in STS other than GIST appears warranted.
本研究旨在评估新型DNA小沟结合剂溴司他丁（brostallicin），以10mg/m²的剂量、每三周静脉注射一次，用于一线治疗失败的晚期或不可切除软组织肉瘤（STS）和胃肠道间质瘤（GIST）患者的疗效和安全性。研究招募了两组患者：（1）接受伊马替尼治疗后的GIST患者；（2）接受单药阿霉素或异环磷酰胺治疗或一线联合治疗后的其他STS患者。主要终点是实体瘤疗效评价标准（RECIST）所定义的总缓解率（ORR）。无进展生存期（PFS）是次要终点。在GIST组中，计划采用西蒙两步设计：第一步18例患者，共32例患者（p1 = 20%，p0 = 5%，α = β = 0.1）。在非GIST组中，计划样本量为40例，采用标准的弗莱明一步设计（p0 = 10%，p1 = 25%，α = β = 0.1）。招募了43例非GIST患者和21例GIST患者。总体而言，该药物耐受性良好。常见毒性标准（CTC）3级或4级毒性为粒细胞减少：70%的患者、50%的周期；疲劳：25%的患者、8%的周期；发热性中性粒细胞减少：14%的患者、4%的周期。有1例因中性粒细胞减少性败血症导致的确诊毒性死亡。在249个给药周期中有3例患者出现具有临床意义的过敏反应。在GIST组中，无患者有确诊缓解，第一步时停止招募。在非GIST组中，有2例确诊部分缓解。非GIST组3个月的PFS为46%，GIST组为33%。在非GIST组中，该PFS处于其他被认为对STS有效的药物范围内，可能预示着更显著的一线活性。对非GIST的STS进行进一步研究似乎是有必要的。
