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First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy

Authors Munster P, Mita M, Mahipal A, Nemunaitis J, Massard C, Mikkelsen T, Cruz C, Paz-Ares L, Hidalgo M, Rathkopf D, Blumenschein Jr G, Smith DC, Eichhorst B, Cloughesy T, Filvaroff EH, Li S, Raymon H, de Haan H, Hege K, Bendell JC

Received 16 March 2019

Accepted for publication 16 September 2019

Published 13 December 2019 Volume 2019:11 Pages 10463—10476


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Beicheng Sun

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, USA

Correspondence: Johanna C Bendell
Sarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, 250 25th Ave North, Suite 110, Nashville, TN 37203, USA
Tel +1 615 329 7274

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 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

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