PO.CTP01.01 · 进行中的临床试验

新型靶向微环境以降低高危TNBC的转移复发：四硫钼酸盐（TM）联合卡培他滨治疗高复发风险乳腺癌患者的随机II期研究

Novel targeting of the microenvironment to decrease metastatic recurrence of high-risk TNBC: A randomized phase II study of tetrathiomolybdate (TM) plus capecitabine in patients with breast cancer at high risk of recurrence

编号 CT072 展板 3 时间 4/20 09:00–12:00 区域 Section 51 主讲 Linda Vahdat, MBA;MD

分会场 Phase I Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Linda T. Vahdat¹, Nancy Chan², Ben H. Park³, Jessica M. Sharpe³, Kathy D. Miller⁴, Bryan P. Schneider⁴, Kevin M. Kalinsky⁵, Neelima Vidula⁶, Mark E. Robson⁷, Peter A. Kauffman⁸, Rebecca A. Shatsky⁹, Joyce A. O'Shaughnessy¹⁰, Sujata Patil¹¹, Eileen H. Shinn¹², James Talton¹³, Raven M. Lavoie¹, Naomi T. Kornhauser¹, Christina A. Seymour¹, Rebecca E. Dabrowski¹, Vivek Mittal¹⁴

¹Dartmouth Cancer Center, Lebanon, NH,²New York University Langone, New York, NY,³Vanderbilt Ingram Cancer Center, Nashville, TN,⁴Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN,⁵Winship Cancer Institute of Emory University, Atlanta, GA,⁶Massachusetts General Hospital, Boston, MA,⁷Memorial Sloan Kettering Cancer Center, New York, NY,⁸University of Vermont, Burlington, VT,⁹University of California at San Diego, San Diego, CA,¹⁰Texas Oncology Baylor-Sammons Cancer Center, Dallas, TX,¹¹Cleveland Clinic, Cleveland, OH,¹²MD Anderson Cancer Center, Houston, TX,¹³Nanopharmaceutics, Alachua, FL,¹⁴Weill Cornell Medicine, New York, NY

摘要 Abstract

中文摘要

通过一项随机2期试验，我们旨在克服耐药并改善手术时有显著残留病灶的三阴性乳腺癌（TNBC）患者（pts）的结局。我们及他人已证明，铜（Cu）在支持TNBC耐药通路中发挥关键作用[Ramchandani等 Nat Comm 2021；Shanbhag等 PNAS 2019]。我们完成了一项在75例高复发风险BC患者中以TM进行铜耗竭的先导2期临床试验。我们发现TM安全且耐受性良好。在中位随访10.4年时，TNBC患者的无事件生存期（EFS）在高危辅助治疗（3期BC）中为88%，在4期NED TNBC中为59.3%。肿瘤微环境的三个组成部分受到显著影响：VEGFR2+内皮祖细胞（EPC）和Cu依赖性LOXL-2显著减少，而铜耗竭患者的胶原微环境恢复正常[Chan等 Clin Cancer Res 2017，Liu NPJ Breast 2021]，重现了我们在临床前模型中的观察结果。这些发现引出了如下假说：Cu参与转移的3个方面：(1)介导侵袭/转移/化疗耐药的癌细胞内在线粒体生物能量学；(2)支持播散性转移肿瘤细胞定植和生长的"转移前生态位"；(3)促进免疫逃逸和免疫治疗耐药的基质重塑。我们预期，以铜耗竭策略补充标准化疗-免疫治疗将克服耐药并改善结局。我们将通过一项随机2期试验对此进行检验，在完成新辅助治疗和手术后有RCB 2、3残留病灶的TNBC患者中，比较TM联合卡培他滨（C）与C单药±pembrolizumab（P）。主要终点为远处无复发生存期。次要终点为(i)安全性，(ii)整个队列及完成6个月TM治疗者的浸润性无病生存期（iDFS）和OS，(iii)患者报告结局，(iv)治疗对生物标志物的影响。在随机2期研究之前，将在6至18例患者中进行一项Ib期临床试验，以确立辅助TM、卡培他滨和pembrolizumab联合的安全性。稳健的科学相关性和探索性工作将评估铜耗竭对系列血液学生物标志物的影响。我们计划在10个中心入组186例患者。该研究已在1b期部分于剂量水平1和-1累积8例患者。TM联合C和P似乎安全且耐受性良好。

查看英文原文 English abstract

Through a randomized phase 2 trial, we aim to overcome resistance and improve outcomes for triple-negative breast cancer (TNBC) patients (pts) with significant residual disease at surgery. We and others have demonstrated that copper (Cu) plays key roles in supporting TNBC resistance pathways [Ramchandani et al. Nat Comm 2021; Shanbhag et al PNAS 2019]. We completed a pilot phase 2 clinical trial of Cu-depletion with TM in 75 BC pts at a high-risk of relapse. We found that TM was safe and well tolerated. Event-free survival (EFS) for TNBC pts is 88% for high-risk adjuvants (stage 3 BC) and 59.3% for stage 4 NED TNBC at a median follow-up of 10.4 yrs. Three components of the tumor microenvironment were significantly affected: VEFGR2+ endothelial progenitor cells (EPCs) and Cu-dependent LOXL-2 were significantly reduced, whereas the collagen microenvironment was normalized in Cu-depleted pts [Chan et al Clin Cancer Res 2017, Liu NPJ Breast 2021], recapitulating our observations in pre-clinical models. These findings have led to the hypothesis that Cu contributes to 3 aspects of metastasis: (1) cancer cell intrinsic mitochondrial bioenergetics that mediate invasion/metastasis/chemoresistance; (2) the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells, and (3) stromal remodeling that promotes immune evasion and immunotherapy resistance. We expect that complementing standard chemo-immunotherapy with a Cu depletion strategy will overcome resistance and improve outcome. We will test this through a randomized phase 2 trial of TM with capecitabine (C) vs C alone +/- pembrolizumab (P), in TNBC pts with RCB 2, 3 residual disease after completion of neoadjuvant therapy and surgery. The primary endpoint is distant relapse free survival. Secondary endpoints are (i) safety, (ii) invasive disease-free survival (iDFS), and OS for both the entire cohort and those who complete 6 months of TM therapy, (iii) Pt-reported outcomes and (iv) effect of therapy on biomarkers. Prior to the randomized phase 2 study, a phase Ib clinical trial in 6 to 18 pts will be done to establish the safety of the combination of adjuvant TM, capecitabine and pembrolizumab. Robust scientific correlative and exploratory work will evaluate the effect of Cu depletion on serial blood-based biomarkers. We plan to enroll 186 pts in this study across 10 sites. The study has 8 pts accrued to the phase 1b portion at dose levels 1 and -1. TM appears safe and well tolerated in combination with C and P.

利益披露 Disclosure

L. T. Vahdat, Osmol Therapeutics Other, Advisory board. BPG bio Other, Advisory board. N. Chan, Eli Lilly and Daiichi Other, Ad board in 2025. B. H. Park, AstraZeneca Other, Paid Consultant. Eli Lilly Other, Paid consultant. Guardant Health Other, Paid consultant. Caris Other, Paid consultant. Casdin Capital Other, Paid consultant. Astrin Biosciences Other, Paid consultant. Artera Other, Paid consultant. Celcuity Inc. Other, Paid scientific advisory board member and has ownership interest. Tempus Inc. Unpaid consultant. Horizon Discovery, LTD, and The Johns Hopkins University Other, entitled to a share of royalties received by the University on sales of products.. J. M. Sharpe, None.. K. D. Miller, None.. B. P. Schneider, None. K. M. Kalinsky, Genentech/Roche Other, Advisory Board. Gilead Other, Advisory Board. Seattle Genetics Other, Advisory Board. AstraZeneca Other, Advisory Board. Daiichi Sankyo Other, Advisory Board. Puma Biotechnology Other, Advisory Board. Mersana Other, Advisory Board. Menarini Silicon Biosystems Other, Advisory Board. Myovant Sciences Other, Advisory Board. Merck Other, Advisory Board. Eli Lilly Other, Advisory Board. Pfizer Other, Advisory Board. Novartis Other, Advisory Board. ProteinQure Other, Advisory Board. bioTheranostics Other, Advisory Board. Regor Other, Advisory Board. Relay Therapeutics Other, Advisory Board. Bicycle Therapeutics; Rayzebio; Jazz Pharmaceuticals Other, Advisory Board. EQRX Other, Spouse is a prior employee. ADC Therapeutics Other, Spouse is an employee. N. Vidula, Pfizer ), Other, Advisory board participation (ended). Novartis ), Other, Advisory board participation (ended). Celcuity Other, Steering Committee Participation. Daehwa ). Merck ). Radius ). Stemline ), Other, Steering Committee participation (ended). Ellipses ). AbbVie Other, Advisory board participation (ended). TerSera Other, Advisory board participation (ended). Aadi Other, Advisory board participation (ended). Gilead Other, Advisory board participation (ended). IDEOlogy Health Other, Advisory Board participation (ended). M. E. Robson, None.. P. A. Kauffman, None.. R. A. Shatsky, None. J. A. O'Shaughnessy, AADI Bioscience; Agendia; Amgen Biotechnology; Aptitude Health; AstraZeneca Other, Consulting. BioNTech; Bristol Myers Squibb Other, Consulting. Daiichi Sankyo; Duality Other, Consulting. Eisai; Eli Lilly; Ellipses; Exact Sciences Other, Consulting. G1 Therapeutics; Genentech; Gilead Sciences; Guardant Health Other, Consulting. Hibercell Other, Consulting. Jazz Pharmaceuticals; J&J Other, Consulting. Menarini-Stemline; Merck; Mersana Other, Consulting. Natera; Novartis Other, Consulting. Pfizer; Pierre Fabre Pharmaceuticals; Puma Biotechnology Other, Consulting. RayzeBio; Roche Other, Consulting. Sanofi; Seagen; Stemline Therapeutics; Summitt Therapeutics Other, Consulting. Tempus; TerSera Therapeutics Other, Consulting. S. Patil, ByHeart Independent Contractor, Consultant. E. H. Shinn, Pfizer Other, Private Equity Stock. Eli Lilly Other, Private Equity Stock. Merck Other, Private Equity Stock. AbbVie Other, Private Equity Stock. Abbott Laboratories Other, Private Equity Stock. J. Talton, Nanopharmaceutics, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Patent. R. M. Lavoie, None.. N. T. Kornhauser, None.. C. A. Seymour, None.. R. E. Dabrowski, None.. V. Mittal, None.

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