Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer
Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer
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DOI：
10.1093/annonc/mdh092
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发表时间：
2004-03-01
影响因子：
50.5
通讯作者：
Takahashi, K
中科院分区：
文献类型：
--
作者：
Matsumura, Y;Gotoh, M;Takahashi, K
背景：MCC-465是一种免疫脂质体包裹的阿霉素（DXR）。脂质体用聚乙二醇（PEG）和人单克隆抗体GAH的F（ab '）（2）片段标记，其对>90%的癌性胃组织呈阳性反应，但对所有正常组织呈阴性反应。在临床前研究中，与DXR或掺入DXR的PEG脂质体相比，MCC-465显示出对几种人胃癌细胞的上级细胞毒活性。本试验的主要目的是确定MCC-465的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、II期推荐剂量和药代动力学（PK）。初始剂量为6.5 mg/m2。MCC-465每3周1小时输注一次，连续治疗6个周期。结果：23例患者接受了62个周期的MCC-465 6.5-45.5 mg/m2剂量水平的治疗。DLT为45.5 mg/m2剂量水平的骨髓抑制和食欲不振。其他毒性反应轻微。未观察到掌跖红斑感觉迟钝或心脏毒性。在整个剂量范围内，在16例患者中通常观察到与输注相关的急性反应。虽然未观察到抗肿瘤反应，但在18例可评价患者中的10例中观察到疾病稳定（SD）。药代动力学研究显示，MCC-465的AUC和C-max与Doxilo（R）相似。MCC-465的II期研究的推荐剂量为32.5 mg/m2，相当于DXR的剂量。
Background: MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposome is tagged with polyethylene glycol (PEG) and the F(ab')(2) fragment of human monoclonal antibody GAH, which positively reacts to >90% of cancerous stomach tissues, but negatively to all normal tissues. In preclinical studies, MCC-465 showed superior cytotoxic activity against several human stomach cancer cells compared with DXR or DXR-incorporated PEG liposomes. The main purpose of this trial was to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), recommended phase II dose and pharmacokinetics (PK) of MCC-465.Patients and methods: Patients with metastatic or recurrent stomach cancer were eligible for entry. The initial dose was 6.5 mg/m(2). MCC-465 was administered as a 1-h infusion every 3 weeks and the treatment continued for up to six cycles.Results: Twenty-three patients received a total of 62 cycles at the 6.5-45.5 mg/m(2) dose level. DLTs were myelosuppression and appetite loss at the 45.5 mg/m(2) dose level. Other toxicities were mild. Neither palmar-plantar erythrodysesthesia nor cardiotoxicity was observed. Acute reactions related to infusion were observed commonly in 16 patients over the entire dose range. While no antitumor response was observed, stable disease (SD) was observed in 10 out of 18 evaluable patients. The pharmacokinetic study showed a similar AUC and C-max to Doxilo(R).Conclusion: MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m(2) in an equivalent amount of DXR.