Lessons learned: Results are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development.
Background: MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging.
Methods: Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles.
Results: Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration ≤5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUVmax (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose.
Conclusion: At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies.
• MBC‐11 通过在疾病部位浓缩阿糖胞苷和依替膦酸钠来靶向和治疗癌症诱发的骨病变，结果与此相符。
• MBC‐11 耐受性良好，最大耐受剂量为每天 5 mg/kg，骨髓抑制为主要毒性。
• MBC‐11 药代动力学和药效学参数与新药设计目标一致，令人鼓舞的结果值得进一步临床开发。
背景。MBC‐11 是与抗代谢物阿糖胞苷 (araC) 共价连接的骨靶向双膦酸盐依替膦酸钠的首选结合物。该项首次人体 I 期剂量递增研究通过氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描 (18F‐FDG‐PET/CT) 影像评估安全性、耐受性、最大耐受剂量 (MTD)、血浆药代动力学、骨转换、肿瘤生物标志物和骨病变活性。
方法。15 名患有晚期实体瘤和癌症诱发的骨病 (CIBD) 的患者每天MBC‐11给药0.5‐10 mg/kg，每 4 周给药 5 天，最多进行 4 个周期。
结果。涉及所有谱系的 1‐2 级骨髓抑制是主要毒性。3 名接受 10 mg/kg 治疗的患者中有 2 名出现剂量限制性 4 级中性粒细胞减少症和血小板减少症 [不良事件 (AE)持续时间 ≤5 天]；MTD 为 5 mg/kg。5 名骨吸收标志物 TRAP5b(抗酒石酸酸性磷酸酶‐5b)治疗前升高的患者中，有 4 名持续降低。基线时报告疼痛的 13 名患者中有 6 名在MBC‐11 给药后，疼痛减少。18F‐FDG‐PET/CT 影像显示了 3 名患者的部分代谢反应和其他 3 名患者的稳定代谢反应。在 211 例骨病变中，有 110 例 (52%) 的 SUVmax(标准化为总摄取量的标准发射单位)减少了至少 25%。在所有剂量情况下，均观察到显著活性，并且骨髓抑制随剂量增加而增加。
结论。在耐受良好的 MBC‐11 剂量下，骨相关癌细胞的代谢活性的显著降低为进一步的疾病效应研究提供了基础。
Trial registration: ClinicalTrials.gov NCT02673060.
© AlphaMed Press; the data published online to support this summary are the property of the authors.