Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors.

Autor:	Thomas A; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Redon CE; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Sciuto L; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Padiernos E; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Ji J; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Lee MJ; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Yuno A; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Lee S; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Zhang Y; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Tran L; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Yutzy W; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Rajan A; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Guha U; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Chen H; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Hassan R; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Alewine CC; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Szabo E; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Bates SE; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Kinders RJ; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Steinberg SM; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Doroshow JH; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Aladjem MI; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Trepel JB; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY., Pommier Y; Anish Thomas, Christophe E. Redon, Linda Sciuto, Emerson Padiernos, Min-Jung Lee, Akira Yuno, Sunmin Lee, Arun Rajan, Udayan Guha, Haobin Chen, Raffit Hassan, Christine C. Alewine, Eva Szabo, Seth M. Steinberg, James H. Doroshow, Mirit I. Aladjem, Jane B. Trepel, and Yves Pommier, National Cancer Institute, Bethesda; Jiuping Ji, Yiping Zhang, Lan Tran, William Yutzy, and Robert J. Kinders, Frederick National Laboratory for Cancer Research, Frederick, MD; and Susan E. Bates, Columbia University Medical Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2018 Jun 01; Vol. 36 (16), pp. 1594-1602. Date of Electronic Publication: 2017 Dec 18.
DOI:	10.1200/JCO.2017.76.6915
Abstrakt:	Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m 2 , days 1 to 5; M6620 210 mg/m 2 , days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.
Databáze:	MEDLINE
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