Munster, Pamela, Mita, Monica, Mahipal, Amit, Nemunaitis, John, Massard, Christophe, Mikkelsen, Tom, Cruz, Cristina, Paz-Ares, Luis, Hidalgo, Manuel, Rathkopf, Dana, Blumenschein, George, Jr., Smith, David C., Eichhorst, Barbara, Cloughesy, Tim, Filvaroff, Ellen H., Li, Shaoyi, Raymon, Heather, de Haan, Hans, Hege, Kristen and Bendell, Johanna C. (2019). First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy. Cancer Manag. Res., 11. S. 10463 - 10477. ALBANY: DOVE MEDICAL PRESS LTD. ISSN 1179-1322

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Abstract

Purpose: This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase. Patients and Methods: Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy. Results: Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD. Conclusion: CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Munster, PamelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mita, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahipal, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemunaitis, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massard, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mikkelsen, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruz, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paz-Ares, LuisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hidalgo, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rathkopf, DanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blumenschein, George, Jr.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cloughesy, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Filvaroff, Ellen H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, ShaoyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raymon, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Haan, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hege, KristenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bendell, Johanna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-160190
DOI: 10.2147/CMAR.S208720
Journal or Publication Title: Cancer Manag. Res.
Volume: 11
Page Range: S. 10463 - 10477
Date: 2019
Publisher: DOVE MEDICAL PRESS LTD
Place of Publication: ALBANY
ISSN: 1179-1322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ADVANCED SOLID TUMORS; PI3K/AKT/MTOR PATHWAY; ENDOMETRIAL CANCER; DAMAGE RESPONSE; PHARMACOKINETICS; PROLIFERATION; TOLERABILITY; RESISTANCE; CRITERIA; GROWTHMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16019

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