PO.CTP01.01 · 进行中的临床试验

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

海报缩略图：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

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

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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