First‐in‐Human Phase I Study of MBC‐11, a Novel Bone‐Targeted Cytarabine‐Etidronate Conjugate in Patients with Cancer‐Induced Bone Disease

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. 经验教训 • 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。 • 治疗显著降低了基线时检测到的一半以上骨病变的癌细胞活性。 • 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。 摘要 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