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Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer.

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Pubmed体系：
作者：
Westin Shannon N[1] * ; Labrie Marilyne[2] ; Litton Jennifer K[3] ; Blucher Aurora[2] ; Fang Yong[4] ; Vellano Christopher P[5] ; Marszalek Joseph R[6] ; Feng Ningping[7] ; Ma Xiaoyan[8] ; Creason Allison[9] ; Fellman Bryan[10] ; Yuan Ying[10] ; Lee Sanghoon[11] ; Kim TaeBeom[12] ; Liu Jinsong[13] ; Chelariu-Raicu Anca[14] ; Chen Tsun Hsuan[15] ; Kabil Nashwa[16] ; Soliman Pamela T[14] ; Frumovitz Michael[17] ; Schmeler Kathleen M[14] ; Jazaeri Amir[18] ; Lu Karen H[19] ; Murthy Rashmi[3] ; Meyer Larissa[18] ; Sun Charlotte[20] ; Sood Anil K[21] ; Coleman Robert L[22] ; Mills Gordon B[23] ;
单位： [1]Department of Gynecologic Oncology and Reproductive Medicine, U.T. M.D. Anderson Cancer Center swestin@mdanderson.org. [2]Cell, Developmental &amp [3] Cancer Biology, Oregon Health &amp [4] Science University. [3]Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. [4]Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. [5]TRACTION Platform, Therapeutics Discovery, The University of Texas MD Anderson Cancer Center. [6]Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center. [7]Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center. [8]Surgical Oncology, MDACC. [9]Biomedical Engineering Department, Oregon Health &amp [12] Science University. [10]Biostatistics, The University of Texas MD Anderson Cancer Center. [11]Systems Biology, The University of Texas MD Anderson Cancer Center. [12]Bioinformatics and Computational Biology, UT M. D. Anderson Cancer Center. [13]Department of Pathology, The University of Texas MD Anderson Cancer Center. [14]Gynecologic Oncology, The University of Texas MD Anderson Cancer Center. [15]The University of Texas MD Anderson Cancer Center. [16]AstraZeneca (United States). [17]Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center. [18]Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center. [19]Department of Gynecologic Oncology and Reproductive Medicine, M. D. Anderson Cancer Center. [20]Gynecologic Oncology &amp [24] Reproductive Medicine, The University of Texas MD Anderson Cancer Center. [21]Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center. [22]US Oncology Research, US Oncology Research. [23]OHSU Knight Cancer Institute.
出处：
DOI： 10.1158/1078-0432.CCR-21-1656
ISSN：

摘要：
Based on strong preclinical rationale, we sought to confirm recommended phase 2 dose for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.We performed a safety lead in followed by expansion in endometrial, triple negative breast, or ovarian cancers. Olaparib 300mg orally twice daily (BID) and capivasertib orally BID on a four day on three day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400mg (DL1); 320mg (DL-1). Patients underwent biopsies at baseline and 28 days.38 patients were enrolled. 7 (18%) had germline BRCA1/2 mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell cycle alterations and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism and epigenetics.Combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.Copyright ©2021, American Association for Cancer Research.

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外文
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第一作者：
第一作者单位： [1]Department of Gynecologic Oncology and Reproductive Medicine, U.T. M.D. Anderson Cancer Center swestin@mdanderson.org.
推荐引用方式(GB/T 7714)：
Westin Shannon N,Labrie Marilyne,Litton Jennifer K,et al.Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer.[J].Clinical cancer research : an official journal of the American Association for Cancer Research.2021,doi:10.1158/1078-0432.CCR-21-1656.
APA：
Westin Shannon N,Labrie Marilyne,Litton Jennifer K,Blucher Aurora,Fang Yong...&Mills Gordon B.(2021).Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer..Clinical cancer research : an official journal of the American Association for Cancer Research,,
MLA：
Westin Shannon N,et al."Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer.".Clinical cancer research : an official journal of the American Association for Cancer Research .(2021)

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