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Pamela Munster,1 Monica Mita,2 Amit Mahipal,3 John Nemunaitis,4 Christophe Massard,5 Tom Mikkelsen,6 Cristina Cruz,7 Luis Paz-Ares,8 Manuel Hidalgo,9 Dana Rathkopf,10 George Blumenschein Jr,11 David C Smith,12 Barbara Eichhorst,13 Tim Cloughesy,14 Ellen H Filvaroff,15 Shaoyi Li,16 Heather Raymon,17 Hans de Haan,15 Kristen Hege,15 Johanna C Bendell18 1UCSF Helen Diller Family Comprehensive Cancer Center, Department of Medicine, San Francisco, CA, USA; 2Samuel Oschin Comprehensive Cancer Institute, Internal Medicine Medical Oncology Department, Los Angeles, CA, USA; 3Mayo Clinic, Medical Oncology Department, Rochester, MN, USA; 4University of Toledo College of Medicine and Life Sciences, Hematology/Oncology Department, Toledo, OH, USA; 5Institut Gustave Roussy, Drug Development Department, Paris, France; 6Henry Ford Health System, Neurology Department, Detroit, MI, USA; 7Vall d’Hebron University Hospital, Medical Oncology Department, Barcelona, Spain; 8University Hospital 12 de Octubre, CNIO, Universidad Complutense & Ciberonc, Medical Oncology Department, Madrid, Spain; 9Centro Integral Oncológico Clara Campal, Oncology Department, Madrid, Spain; 10Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY, USA; 11The University of Texas MD Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology, Houston, TX, USA; 12University of Michigan, Urology Oncology, Ann Arbor, MI, USA; 13University Hospital of Cologne, Department I for Internal Medicine, Cologne, Germany; 14David Geffen School of Medicine, Neurology Department, UCLA, Los Angeles, CA, USA; 15Celgene Corporation, Translational Development Department, San Francisco, CA, USA; 16Celgene Corporation, Department of Statistics, Summit, NJ, USA; 17Celgene Corporation, Department of Pharmacology, San Diego, CA, USA; 18Sarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, Nashville, TN, USACorrespondence: Johanna C BendellSarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, 250 25th Ave North, Suite 110, Nashville, TN 37203, USATel +1 615 329 7274Email jbendell@tnonc.comPurpose: 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.Keywords: CC-115, mTORC1/mTORC2, mTOR inhibitor, DNA-PK inhibitor, Phase I study