First-in-human phase I study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy Journal Article
| Authors: | Munster, P.; Mita, M.; Mahipal, A.; Nemunaitis, J.; Massard, C.; Mikkelsen, T.; Cruz, C.; Paz-Ares, L.; Hidalgo, M.; Rathkopf, D.; Blumenschein, G. Jr; Smith, D. C.; Eichhorst, B.; Cloughesy, T.; Filvaroff, E. H.; Li, S.; Raymon, H.; de Haan, H.; Hege, K.; Bendell, J. C. |
| Article Title: | First-in-human phase I study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy |
| 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 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. © 2019 Munster et al. |
| Keywords: | adult; human tissue; aged; unclassified drug; major clinical study; drug tolerability; fatigue; area under the curve; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; side effect; drug targeting; endometrium carcinoma; multiple cycle treatment; pharmacodynamics; nausea; stomatitis; thrombocytopenia; vomiting; cohort analysis; asthenia; drug dose escalation; ewing sarcoma; hyperglycemia; rash; maculopapular rash; cancer regression; food; drug accumulation; drug distribution; glioblastoma; drug clearance; single drug dose; food drug interaction; drug bioavailability; maximum plasma concentration; time to maximum plasma concentration; drug absorption; drug blood level; phase 1 clinical trial; drug half life; mammalian target of rapamycin inhibitor; chronic lymphatic leukemia; drug tumor level; drug excretion; hypertriglyceridemia; drug exposure; dysgeusia; drug urine level; drug elimination; castration resistant prostate cancer; mtor inhibitor; head and neck squamous cell carcinoma; protein serine threonine kinase inhibitor; decreased appetite; hypertransaminasemia; multiple drug dose; body weight loss; phase i study; human; male; female; article; lymphocytic lymphoma; cc-115; dna-pk inhibitor; mtorc1/mtorc2; cc 115 |
| Journal Title: | Cancer Management and Research |
| Volume: | 11 |
| ISSN: | 1179-1322 |
| Publisher: | Dove Medical Press Ltd |
| Date Published: | 2019-01-01 |
| Start Page: | 10463 |
| End Page: | 10476 |
| Language: | English |
| DOI: | 10.2147/cmar.S208720 |
| PROVIDER: | scopus |
| PMCID: | PMC6916675 |
| PUBMED: | 31853198 |
| DOI/URL: | |
| Notes: | Source: Scopus |
