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 Jr; David C Smith; Barbara Eichhorst; Tim Cloughesy; Ellen H Filvaroff; Shaoyi Li; Heather Raymon; Hans de Haan; Kristen Hege; Johanna C Bendell

doi:10.2147/CMAR.S208720

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

Cancer Manag Res. 2019 Dec 13:11:10463-10476. doi: 10.2147/CMAR.S208720. eCollection 2019.

Authors

Pamela Munster¹, Monica Mita², Amit Mahipal³, John Nemunaitis⁴, Christophe Massard⁵, Tom Mikkelsen⁶, Cristina Cruz⁷, Luis Paz-Ares⁸, Manuel Hidalgo⁹, Dana Rathkopf¹⁰, George Blumenschein Jr¹¹, David C Smith¹², Barbara Eichhorst¹³, Tim Cloughesy¹⁴, Ellen H Filvaroff¹⁵, Shaoyi Li¹⁶, Heather Raymon¹⁷, Hans de Haan¹⁵, Kristen Hege¹⁵, Johanna C Bendell¹⁸

Affiliations

¹ UCSF Helen Diller Family Comprehensive Cancer Center, Department of Medicine, San Francisco, CA, USA.
² Samuel Oschin Comprehensive Cancer Institute, Internal Medicine Medical Oncology Department, Los Angeles, CA, USA.
³ Mayo Clinic, Medical Oncology Department, Rochester, MN, USA.
⁴ University of Toledo College of Medicine and Life Sciences, Hematology/Oncology Department, Toledo, OH, USA.
⁵ Institut Gustave Roussy, Drug Development Department, Paris, France.
⁶ Henry Ford Health System, Neurology Department, Detroit, MI, USA.
⁷ Vall d'Hebron University Hospital, Medical Oncology Department, Barcelona, Spain.
⁸ University Hospital 12 de Octubre, CNIO, Universidad Complutense & Ciberonc, Medical Oncology Department, Madrid, Spain.
⁹ Centro Integral Oncológico Clara Campal, Oncology Department, Madrid, Spain.
¹⁰ Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY, USA.
¹¹ The University of Texas MD Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology, Houston, TX, USA.
¹² University of Michigan, Urology Oncology, Ann Arbor, MI, USA.
¹³ University Hospital of Cologne, Department I for Internal Medicine, Cologne, Germany.
¹⁴ David Geffen School of Medicine, Neurology Department, UCLA, Los Angeles, CA, USA.
¹⁵ Celgene Corporation, Translational Development Department, San Francisco, CA, USA.
¹⁶ Celgene Corporation, Department of Statistics, Summit, NJ, USA.
¹⁷ Celgene Corporation, Department of Pharmacology, San Diego, CA, USA.
¹⁸ Sarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, Nashville, TN, USA.

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 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; DNA-PK inhibitor; Phase I study; mTOR inhibitor; mTORC1/mTORC2.

Associated data

ClinicalTrials.gov/NCT01353625

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States