Morris Michael J, Cordon-Cardo Carlos, Kelly William K, Slovin Susan F, Siedlecki Karen, Regan Kevin P, DiPaola Robert S, Rafi Mohamed, Rosen Neal, Scher Howard I
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Appl Immunohistochem Mol Morphol. 2005 Mar;13(1):6-13. doi: 10.1097/00129039-200503000-00002.
G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1, 8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2.
G3139是一种BCL-2反义寡核苷酸，在临床前模型中，当与紫杉烷类化疗联合使用时，其抗肿瘤作用会增强。该试验确定了G3139与紫杉醇和多西他赛联合用于治疗进展期实体瘤的安全性和生物学活性。三组患者在第1、8和15天每周接受100 mg/m²的紫杉醇静脉滴注，同时根据分组情况，连续21天每天以4.1、5.3和6.9 mg/kg的剂量持续输注G3139。随后的两组患者在5天输注G3139（每天5或7 mg/kg）的第5天接受多西他赛（75 mg/m²）治疗。对外周血单个核细胞（PBMC）中的Bcl-2蛋白水平进行了探索性检测。共治疗了15例患者。8例患者总共接受了14个周期的G3139和紫杉醇治疗；7例患者总共接受了22个周期的G3139和多西他赛治疗。8例患者因4级中性粒细胞减少（6例）或1-2级可逆性转氨酶升高（2例）需要调整剂量。虽然6例未接受过紫杉烷治疗的前列腺癌患者中有2例的前列腺特异性抗原下降超过50%，但未观察到影像学反应。通过免疫组织化学评估，PBMC中的Bcl-2蛋白水平随治疗而下降。作者得出结论，无论G3139是5天还是21天输注，与紫杉烷类化疗联合使用时耐受性良好，在剂量高达并包括7 mg/kg/d时，通过免疫组织化学检测具有生物学活性，使用每周一次的紫杉醇（100 mg/m²）或每3周一次的多西他赛（75 mg/m²）。这些数据支持正在进行的G3139剂量为7 mg/kg/d和多西他赛75 mg/m²的2期研究的剂量选择。
