The tumor-targeting immunocytokine F16-IL2 in combination with doxorubicin: dose escalation in patients with advanced solid tumors and expansion into patients with metastatic breast cancer

A phase Ib/II trial was performed to evaluate safety, tolerability, recommended dose (RD) and efficacy of F16-IL2, a recombinant antibody-cytokine fusion protein, in combination with doxorubicin in patients with solid tumors (phase Ib) and metastatic breast cancer (phase II). Six patient cohorts with progressive solid tumors (n = 19) received escalating doses of F16-IL2 [5–25 Million International Units (MIU) of IL2 equivalent dose] in combination with escalating doses of doxorubicin (0–25 mg/m²) on day 1, 8 and 15 every 4 weeks. Subsequently, patients with metastatic breast cancer (n = 10) received the drug combination at the RD. Clinical data and laboratory findings were analyzed for safety, tolerability, and activity. F16-IL2 could be administered up to 25 MIU, in combination with the RD of doxorubicin (25 mg/m²). No human anti-fusion protein antibodies (HAFA) response was detected. Pharmacokinetics of F16-IL2 was dose-dependent over the tested range, with half-lives of ca. 13 and ca. 8 hours for cohorts dosed at lower and higher levels, respectively. Toxicities were controllable and reversible, with no combination treatment-related death. After 8 weeks, 57% and 67% disease control rates were observed for Phase I and II, respectively (decreasing to 43% and 33% after 12 weeks), considering 14 and 9 patients evaluable for efficacy. One patient experienced a long lasting partial response (45 weeks), still on-going at exit of study. F16-IL2 can be safely and repeatedly administered at the RD of 25 MIU in combination with 25 mg/m² doxorubicin; its safety and activity are currently being investigated in combination with other chemotherapeutics, in order to establish optimal therapy settings.

本研究开展了一项Ib/II期临床试验，以评估重组抗体-细胞因子融合蛋白F16-IL2联合多柔比星用于实体瘤患者（Ib期）及转移性乳腺癌患者（II期）的安全性、耐受性、推荐剂量（Recommended Dose, RD）与疗效。6个纳入19例进展性实体瘤患者的队列，每4周于第1、8、15天接受递增剂量的F16-IL2（等效白细胞介素2剂量为5~25百万国际单位（Million International Units, MIU））联合递增剂量的多柔比星（0~25 mg/m²）治疗。随后，10例转移性乳腺癌患者接受了基于推荐剂量的联合给药方案。对临床数据与实验室检查结果进行安全性、耐受性及抗肿瘤活性分析。F16-IL2的最大给药剂量可达25百万国际单位，联合多柔比星的推荐剂量为25 mg/m²。未检测到人抗融合蛋白抗体（Human Anti-Fusion Protein Antibodies, HAFA）应答。F16-IL2的药代动力学特征在受试剂量范围内呈剂量依赖性，低剂量队列与高剂量队列的半衰期分别约为13小时与8小时。不良反应均可控且可逆，未出现联合治疗相关死亡事件。在14例可评估疗效的Ib期患者与9例可评估疗效的II期患者中，治疗8周后实体瘤队列与转移性乳腺癌队列的疾病控制率分别为57%与67%（治疗12周后分别降至43%与33%）。1例患者获得了持续45周的部分缓解，且在研究截止时仍在持续。F16-IL2以25百万国际单位的推荐剂量联合25 mg/m²多柔比星给药时，可安全且重复给药；目前正开展其与其他化疗药物联合的相关研究，以探索最优治疗方案。