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First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy
- Munster, Pamela;
- Mita, Monica;
- Mahipal, Amit;
- Nemunaitis, John;
- Massard, Christophe;
- Mikkelsen, Tom;
- Cruz, Cristina;
- Paz-Ares, Luis;
- Hidalgo, Manuel;
- Rathkopf, Dana;
- Blumenschein, George;
- Smith, David C;
- Eichhorst, Barbara;
- Cloughesy, Tim;
- Filvaroff, Ellen H;
- Li, Shaoyi;
- Raymon, Heather;
- de Haan, Hans;
- Hege, Kristen;
- Bendell, Johanna C
- et al.
Published Web Location
https://doi.org/10.2147/cmar.s208720Abstract
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.Clinical trial registration
NCT01353625.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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