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 - Funding Information:
We thank the patients whose findings are described in this study, together with the families who supported them. Appreciation is shown for all the investigational staff at all 15 sites; the dedication such professionals show for their patients is too infrequently acknowledged. The same is true for the very many nameless researchers at Celgene who, despite their remoteness from clinical practice, are also motivated to relieve patient suffering. We would like to acknowledge Angela Joubert James and Torsten Trowe, who were employees of Celgene at the time of the CC-115 study. Dr. Paz-Ares was funded by ISCIII: PI1401964, PIE15/00076, RTICC (R12/0036/0028) and CIBERONC (C16/12/00442), co-funded by FEDER from Regional Development European Funds (European Union). We also thank Stephanie K. Doerner, PhD, at The Lockwood Group (Stamford, CT), for providing writing and editorial assistance, funded by Celgene Corporation. This study was presented, in part, at the annual meeting of the American Society of Clinical Oncology, Chicago, IL, June 2–6, 2016. This study was supported by Celgene Corporation.
Funding Information:
This study was supported by Celgene Corporation.
Funding Information:
We thank the patients whose findings are described in this study, together with the families who supported them. Appreciation is shown for all the investigational staff at all 15 sites; the dedication such professionals show for their patients is too infrequently acknowledged. The same is true for the very many nameless researchers at Celgene who, despite their remoteness from clinical practice, are also motivated to relieve patient suffering. We would like to acknowledge Angela Joubert James and Torsten Trowe, who were employees of Celgene at the time of the CC-115 study. Dr. Paz-Ares was funded by ISCIII: PI1401964, PIE15/00076, RTICC (R12/0036/0028) and CIBERONC (C16/12/00442), co-funded by FEDER from Regional Development European Funds (European Union). We also thank Stephanie K. Doerner, PhD, at The Lockwood Group (Stamford, CT), for providing writing and editorial assistance, funded by Celgene Corporation. This study was presented, in part, at the annual meeting of the American Society of Clinical Oncology, Chicago, IL, June 2–6, 2016.
Publisher Copyright:
© 2019 Munster et al.
PY - 2019
Y1 - 2019
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
UR - http://www.scopus.com/inward/citedby.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 -