First-in-human phase i study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy

Pamela Munster, Monica Mita, Amit Mahipal, John Nemunaitis, Christophe Massard, Tom Mikkelsen, Cristina Cruz, Luis Paz-Ares, Manuel Hidalgo, Dana Rathkopf, George Blumenschein, David C. Smith, Barbara Eichhorst, Tim Cloughesy, Ellen H. Filvaroff, Shaoyi Li, Heather Raymon, Hans de Haan, Kristen Hege, Johanna C. Bendell

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10463-10476
Number of pages14
JournalCancer Management and Research
Volume11
DOIs
StatePublished - 2019

Keywords

  • CC-115
  • DNA-PK inhibitor
  • MTOR inhibitor
  • MTORC1/mTORC2
  • Phase I study

ASJC Scopus subject areas

  • Oncology

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    Munster, P., Mita, M., Mahipal, A., Nemunaitis, J., Massard, C., Mikkelsen, T., Cruz, C., Paz-Ares, L., Hidalgo, M., Rathkopf, D., Blumenschein, G., Smith, D. C., Eichhorst, B., Cloughesy, T., Filvaroff, E. H., Li, S., Raymon, H., de Haan, H., Hege, K., & Bendell, J. C. (2019). First-in-human phase i study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy. Cancer Management and Research, 11, 10463-10476. https://doi.org/10.2147/CMAR.S208720