Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study
Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study
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DOI：
10.1007/s11523-014-0320-2
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发表时间：
2015-03-01
影响因子：
5.4
通讯作者：
Calvo, Emiliano
中科院分区：
文献类型：
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作者：
Brana, Irene;Calles, Antonio;Calvo, Emiliano
C-C趋化因子配体2(CCL2)刺激肿瘤生长、转移和血管生成。卡鲁单抗是一种人免疫球蛋白(1)kappa抗CCL2单抗，已在临床前和临床试验中显示出抗肿瘤活性。我们用四种化疗方案(多西紫杉醇、吉西他滨、紫杉醇+卡铂和聚乙二醇化脂质体盐酸阿霉素[PLD])中的一种对卡鲁单抗进行了首次人类1b期研究。患者患有晚期实体肿瘤，这些治疗方案中千分之一的部分被认为是标准治疗方案，或者对他们没有其他治疗选择。剂量限制毒性包括1例4级发热性中性粒细胞减少症(多西他赛组)和1例3级中性粒细胞减少症(吉西他滨组)。卡鲁单抗联合治疗对多西他赛(n=15)、吉西他滨(n=12)、紫杉醇或卡铂(n=12)或PLD(n=14)无临床相关药代动力学效应。单独使用卡鲁单抗治疗后，血清总CCL2浓度升高，与卡鲁单抗-CCL2结合一致，并且在所有化疗方案的存在下持续增加。卡鲁单抗治疗后游离CCL2立即下降，但随着所有药物的进一步化疗而增加，这表明卡鲁单抗只能在很短的时间内隔离CCL2。既没有观察到抗卡鲁单抗，也没有观察到循环肿瘤细胞(CTCs)和循环内皮细胞(CECs)计数的一致变化。19例可评估患者中有3例较基线尿I型胶原N-端肽(UNTx)下降30%。观察到1例部分缓解和18例(38%)稳定的疾病反应。最常见的甲级药物不良反应是多西他赛手臂中性粒细胞减少(6/15)和发热中性粒细胞减少(4/15)；吉西他滨手臂中性粒细胞减少(2/12)；紫杉醇+卡铂手臂中性粒细胞减少(4/12)和贫血(2/12)；PLD手臂贫血(3/14)和口腔炎(2/14)。卡鲁单抗在10或15 mg/kg的剂量下与标准护理化疗结合使用是安全的，耐受性良好，尽管没有观察到血清CCL2的长期抑制或显著的肿瘤反应。
C-C chemokine ligand 2 (CCL2) stimulates tumor growth, metastasis, and angiogenesis. Carlumab, a human IgG(1)kappa anti-CCL2 mAb, has shown antitumor activity in preclinical and clinical trials. We conducted a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel + carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Patients had advanced solid tumors for which a parts per thousand yen1 of these regimens was considered standard of care or for whom no other treatment options existed. Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on docetaxel (n = 15), gemcitabine (n = 12), paclitaxel or carboplatin (n = 12), or PLD (n = 14). Total serum CCL2 concentrations increased post-treatment with carlumab alone, consistent with carlumab-CCL2 binding, and continued increase in the presence of all chemotherapy regimens. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). One partial response and 18 (38 %) stable disease responses were observed. The most common drug-related grade a parts per thousand yen3 adverse events were docetaxel arm-neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm-neutropenia (2/12); paclitaxel + carboplatin arm-neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm-anemia (3/14) and stomatitis (2/14). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serum CCL2 or significant tumor responses were observed.