A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors

被引：0

作者：

Scott, Susan C. ^{[1
]}

Farago, Anna ^{[2
]}

Lai, W. Victoria ^{[3
]}

Zahurak, Marianna ^{[1
,4
]}

Rudek, Michelle A. ^{[1
,5
]}

Murray, Judy ^{[1
]}

Carducci, Michael A. ^{[1
]}

Uziel, Tamar ^{[6
]}

Takebe, Naoko ^{[7
]}

Gore, Steven D. ^{[7
]}

Rudin, Charles M. ^{[3
]}

Hann, Christine L. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21218 USA

[2] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Krantz Family Ctr Canc Res, Boston, MA USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA

[4] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol Biostat, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[6] AbbVie Inc, Oncol Discovery, N Chicago, IL USA

[7] NCI, IDB, CTEP, Rockville, MD USA

来源：

CANCER CHEMOTHERAPY AND PHARMACOLOGY | 2025年 / 95卷 / 01期

关键词：

BCL-2 FAMILY INHIBITOR; ABT-263; ABT-737; PHARMACOKINETICS; EFFICACY; SAFETY; 1ST-IN-HUMAN; CARCINOMA; APOPTOSIS; POTENT;

D O I：

10.1007/s00280-025-04760-1

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PurposeTo determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor.MethodsPatients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated.Results14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150 mg orally daily plus vistusertib 35 mg orally twice daily). The main dose-limiting toxicity, grade 3 serum aminotransferase elevation, occurred in two of five patients at dose level 2 (navitoclax 250 mg orally daily plus vistusertib 35 mg orally twice daily). Navitoclax and vistusertib exposures appeared consistent with levels reported in prior studies of each agent. No responses were observed among the 8 response evaluable patients.ConclusionsA tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib.Trial registrationNCT03366103 (First posted December 8, 2017).

引用

页数：9

共 44 条

[11] Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer [J].

Faber, Anthony C. ;

Farago, Anna F. ;

Costa, Carlotta ;

Dastur, Anahita ;

Gomez-Caraballo, Maria ;

Robbins, Rebecca ;

Wagner, Bethany L. ;

Rideout, William M., III ;

Jakubik, Charles T. ;

Ham, Jungoh ;

Edelman, Elena J. ;

Ebi, Hiromichi ;

Yeo, Alan T. ;

Hata, Aaron N. ;

Song, Youngchul ;

Patel, Neha U. ;

March, Ryan J. ;

Ah Ting Tam ;

Milano, Randy J. ;

Boisvert, Jessica L. ;

Hicks, Mark A. ;

Elmiligy, Sarah ;

Malstrom, Scott E. ;

Rivera, Miguel N. ;

Harada, Hisashi ;

Windle, Brad E. ;

Ramaswamy, Sridhar ;

Benes, Cyril H. ;

Jacks, Tyler ;

Engelman, Jeffrey A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (11) :E1288-E1296

[12] mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 [J].

Faber, Anthony C. ;

Coffee, Erin M. ;

Costa, Carlotta ;

Dastur, Anahita ;

Ebi, Hiromichi ;

Hata, Aaron N. ;

Yeo, Alan T. ;

Edelman, Elena J. ;

Song, Youngchul ;

Tam, Ah Ting ;

Boisvert, Jessica L. ;

Milano, Randy J. ;

Roper, Jatin ;

Kodack, David P. ;

Jain, Rakesh K. ;

Corcoran, Ryan B. ;

Rivera, Miguel N. ;

Ramaswamy, Sridhar ;

Hung, Kenneth E. ;

Benes, Cyril H. ;

Engelman, Jeffrey A. .

CANCER DISCOVERY, 2014, 4 (01) :42-52

[13]

FDA Label, Venetoclax

[14] Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors [J].

Gandhi, Leena ;

Camidge, D. Ross ;

de Oliveira, Moacyr Ribeiro ;

Bonomi, Philip ;

Gandara, David ;

Khaira, Divis ;

Hann, Christine L. ;

McKeegan, Evelyn M. ;

Litvinovich, Elizabeth ;

Hemken, Philip M. ;

Dive, Caroline ;

Enschede, Sari H. ;

Nolan, Cathy ;

Chiu, Yi-Lin ;

Busman, Todd ;

Xiong, Hao ;

Krivoshik, Andrew P. ;

Humerickhouse, Rod ;

Shapiro, Geoffrey I. ;

Rudin, Charles M. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (07) :909-916

[15] Rapamycin Rescues ABT-737 Efficacy in Small Cell Lung Cancer [J].

Gardner, Eric E. ;

Connis, Nick ;

Poirier, John T. ;

Cope, Leslie ;

Dobromilskaya, Irina ;

Gallia, Gary L. ;

Rudin, Charles M. ;

Hann, Christine L. .

CANCER RESEARCH, 2014, 74 (10) :2846-2856

[16] Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities [J].

Gay, Carl M. ;

Stewart, C. Allison ;

Park, Elizabeth M. ;

Diao, Lixia ;

Groves, Sarah M. ;

Heeke, Simon ;

Nabet, Barzin Y. ;

Fujimoto, Junya ;

Solis, Luisa M. ;

Lu, Wei ;

Xi, Yuanxin ;

Cardnell, Robert J. ;

Wang, Qi ;

Fabbri, Giulia ;

Cargill, Kasey R. ;

Vokes, Natalie, I ;

Ramkumar, Kavya ;

Zhang, Bingnan ;

Della Corte, Carminia M. ;

Robson, Paul ;

Swisher, Stephen G. ;

Roth, Jack A. ;

Glisson, Bonnie S. ;

Shames, David S. ;

Wistuba, Ignacio I. ;

Wang, Jing ;

Quaranta, Vito ;

Minna, John ;

Heymach, John, V ;

Byers, Lauren Averett .

CANCER CELL, 2021, 39 (03) :346-+

[17] Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer [J].

Hann, Christine L. ;

Daniel, Vincent C. ;

Sugar, Elizabeth A. ;

Dobromilskaya, Irina ;

Murphy, Sara C. ;

Cope, Leslie ;

Lin, Xue ;

Hierman, Jared S. ;

Wilburn, Daniel L. ;

Watkins, D. Neil ;

Rudin, Charles M. .

CANCER RESEARCH, 2008, 68 (07) :2321-2328

[18] EXPRESSION OF BCL-2 ONCOGENE PROTEIN IS PREVALENT IN SMALL-CELL LUNG CARCINOMAS [J].

JIANG, SX ;

SATO, YC ;

KUWAO, S ;

KAMEYA, T .

JOURNAL OF PATHOLOGY, 1995, 177 (02) :135-138

[19] Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2 [J].

Jordan, Justin T. ;

Orr, Christina C. ;

Thalheimer, Raquel D. ;

Cambillo, Josephine, V ;

Beauchamp, Roberta L. ;

Shaikh, Ghalib ;

Muzikansky, Alona ;

Stemmer-Rachamimov, Anat ;

Giovannini, Marco ;

Kalamarides, Michel ;

Barker, Fred G. ;

Ramesh, Vijaya ;

Plotkin, Scott R. .

NEURO-ONCOLOGY ADVANCES, 2023, 5 (01)

[20] First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors [J].

Lakhani, Nehal J. ;

Rasco, Drew ;

Wang, Hengbang ;

Men, Lichuang ;

Liang, Eric ;

Fu, Tommy ;

Collins, Mary C. ;

Min, Ping ;

Yin, Yan ;

Davids, Matthew S. ;

Yang, Dajun ;

Zhai, Yifan .

CLINICAL CANCER RESEARCH, 2024, 30 (03) :506-521

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