TY - JOUR
T1 - First-in-human phase i study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy
AU - Munster, Pamela
AU - Mita, Monica
AU - Mahipal, Amit
AU - Nemunaitis, John
AU - Massard, Christophe
AU - Mikkelsen, Tom
AU - Cruz, Cristina
AU - Paz-Ares, Luis
AU - Hidalgo, Manuel
AU - Rathkopf, Dana
AU - Blumenschein, George
AU - Smith, David C.
AU - Eichhorst, Barbara
AU - Cloughesy, Tim
AU - Filvaroff, Ellen H.
AU - Li, Shaoyi
AU - Raymon, Heather
AU - de Haan, Hans
AU - Hege, Kristen
AU - Bendell, Johanna C.
N1 - Publisher Copyright:
© 2019 Munster et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 transa-minases. 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.
AB - 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 transa-minases. 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.
KW - CC-115
KW - DNA-PK inhibitor
KW - MTOR inhibitor
KW - MTORC1/mTORC2
KW - Phase I study
UR - http://www.scopus.com/inward/record.url?scp=85076901020&partnerID=8YFLogxK
U2 - 10.2147/CMAR.S208720
DO - 10.2147/CMAR.S208720
M3 - Article
AN - SCOPUS:85076901020
SN - 1179-1322
VL - 11
SP - 10463
EP - 10476
JO - Cancer Management and Research
JF - Cancer Management and Research
ER -