Millard Trish, Brenin Christiana, Humphrey Clare, Dhakal Ajay, Falkson Carla, Petroni Gina, Wages Nolan A, Dillon Patrick
Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA.
Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.
Int J Breast Cancer. 2024 Feb 7;2024:5515966. doi: 10.1155/2024/5515966. eCollection 2024.
Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial.
A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m to 1000 mg/m.
Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations.
The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.
在对高危疾病进行新辅助治疗后若发现有任何残留疾病，乳腺癌的复发率高得令人难以接受。基于提示表观遗传修饰剂在乳腺癌中具有辅助作用的临床数据以及提示恩替诺特与卡培他滨具有协同活性的临床前数据，我们开展了一项针对这些药物用于转移性乳腺癌（MBC）的I期开放标签研究。两种药物均已公布联合治疗的使用剂量，但此前尚未在人体试验中将这两种药物相互联合使用。
在两个学术中心进行了一项多中心I期剂量递增研究。纳入经治的HER2阴性MBC且具有可测量病灶的患者。通过贝叶斯偏序连续评估法进行双剂量递增。剂量水平范围为恩替诺特3毫克至5毫克以及卡培他滨800毫克/平方米至1000毫克/平方米。
13例MBC患者入组，既往治疗的中位线数为4线，涉及四种剂量水平组合。最常见的毒性反应为中性粒细胞减少、血小板减少和手足感觉异常，这些均为预期的毒性反应。未观察到新的安全信号。观察到1例剂量限制性毒性反应，未超过预先设定的25%的毒性发生率。中位治疗持续时间为2.37个月。未观察到部分缓解或完全缓解。由于药物供应限制，该研究在进入扩展阶段之前提前终止。
恩替诺特与卡培他滨的受试给药组合在经过大量预处理的转移性乳腺癌中可能是安全的。本研究中对恩替诺特在乳腺癌中的临床研究已终止，但该药物的研发在美国境外仍在继续。对于根治性治疗后有高危残留癌的乳腺癌患者亚群，术后辅助药物治疗仍有需求。本试验在ClinicalTrials.gov注册编号为NCT03473639。
