title: A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC-223 in patients with advanced cancer.
  
  
  METHODS
  Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5-60 mg of CC-223, followed by oral daily dosing in 28-day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy.
  
  
  RESULTS
  Twenty-eight patients were enrolled and received ≥1 dose of CC-223. The most common treatment-related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose-limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC-223 demonstrated a mean terminal half-life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC-223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC-223 ≥30 mg/d with an exposure-response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30-mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36-168 days), and progressive disease (12 patients). The disease control rate was 32%.
  
  
  CONCLUSIONS
  CC-223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed.
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Kelley
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Kent C
authors.initials: KC
authors.lastname: Shih
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Grabowsky
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Emily
authors.initials: E
authors.lastname: Bergsland
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: Martin
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Matsutani
authors.affiliation: Celgene Corporation, San Diego, California.
authors.forename: Shuichan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Celgene Corporation, San Diego, California.
authors.forename: Lilly
authors.initials: L
authors.lastname: Wong
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Celgene Corporation, Berkeley Heights, New Jersey.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Celgene Corporation, San Diego, California.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Mortensen
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Celgene Corporation, San Francisco, California.
authors.forename: Kristen
authors.initials: K
authors.lastname: Hege
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
keywords: AKT; mTOR; mTORC1/mTORC2; rapalogs