Takebe Naoko, Coyne Geraldine O'Sullivan, Kummar Shivaani, Collins Jerry, Reid Joel M, Piekarz Richard, Moore Nancy, Juwara Lamin, Johnson Barry C, Bishop Rachel, Lin Frank I, Mena Esther, Choyke Peter L, Lindenberg M Liza, Rubinstein Larry V, Bonilla Cecilia Monge, Goetz Matthew P, Ames Matthew M, McGovern Renee M, Streicher Howard, Covey Joseph M, Doroshow James H, Chen Alice P
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Oncotarget. 2021 Feb 16;12(4):268-277. doi: 10.18632/oncotarget.27887.
Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen.
Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3+3 phase 1 dose escalation format over 8 dose levels (DLs). Safety, pharmacokinetics/pharmacodynamics, and clinical outcomes were evaluated.
Thirty-four of 40 patients were evaluable. No maximum tolerated dose was established. DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it also yielded higher plasma Z-endoxifen concentrations. Three patients had partial responses and 8 had prolonged stable disease (≥ 6 cycles); 44.4% (8/18) of patients at dose levels 6-8 achieved one of these outcomes. Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles (nearly 5 years).
Evidence of antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.
对他莫昔芬的不同反应可能是由于患者间他莫昔芬代谢为具有药理活性的Z-恩杂他芬存在差异。预计给予Z-恩杂他芬可绕过这些差异，提高活性药物水平，并可能使对他莫昔芬反应欠佳的患者受益。
患有难治性妇科恶性肿瘤、硬纤维瘤或激素受体阳性实体瘤的患者，采用3+3一期剂量递增方案，每天口服Z-恩杂他芬，共8个剂量水平（DLs）。评估安全性、药代动力学/药效学及临床结果。
40例患者中有34例可评估。未确定最大耐受剂量。DL8（360mg/天）用于扩展期，高于以往任何研究中的给药剂量；其血浆Z-恩杂他芬浓度也更高。3例患者部分缓解，8例疾病稳定延长（≥6个周期）；6-8剂量水平的患者中有44.4%（8/18）达到其中一项结果。6例他莫昔芬治疗后进展的患者接受Z-恩杂他芬治疗后部分缓解或疾病稳定≥6个周期；1例硬纤维瘤患者在62个周期（近5年）后仍在研究中。
尽管先前接受过他莫昔芬治疗，但Z-恩杂他芬仍显示出抗肿瘤活性和疾病稳定延长的证据，支持对Z-恩杂他芬进行进一步研究，尤其是在硬纤维瘤患者中。
