PMID- 25777468
OWN - NLM
STAT- MEDLINE
DCOM- 20160216
LR  - 20231111
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 33
IP  - 3
DP  - 2015 Jun
TI  - Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced 
      non-hematologic malignancies.
PG  - 652-63
LID - 10.1007/s10637-015-0230-x [doi]
AB  - PURPOSE: Ixazomib is an investigational proteasome inhibitor with demonstrated 
      antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and 
      solid tumors. This open-label, phase 1 study investigated intravenous (IV) 
      ixazomib, in adult patients with advanced non-hematologic malignancies. METHODS: 
      Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 
      0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) 
      based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 
      dose-escalation and expansion at the maximum tolerated dose (MTD). Primary 
      objectives included safety and MTD assessment. Secondary objectives included 
      assessment of pharmacokinetics, pharmacodynamics, and disease response. RESULTS: 
      Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); 
      patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 
      20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 
      pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute 
      renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade >/=3 adverse 
      events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue 
      disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and 
      neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal 
      half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and 
      drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity 
      and upregulation of ATF-3 in tumor biopsies demonstrated target engagement. 
      CONCLUSIONS: In patients with solid tumors, ixazomib was associated with a 
      manageable safety profile, limited antitumor activity, and evidence of downstream 
      proteasome inhibition effects.
FAU - Smith, David C
AU  - Smith DC
AD  - University of Michigan Comprehensive Cancer Center, 7302 CC SPC 5948, 1500 E. 
      Medical Center Drive, Ann Arbor, MI, 48109-5948, USA, dcsmith@umich.edu.
FAU - Kalebic, Thea
AU  - Kalebic T
FAU - Infante, Jeffrey R
AU  - Infante JR
FAU - Siu, Lillian L
AU  - Siu LL
FAU - Sullivan, Daniel
AU  - Sullivan D
FAU - Vlahovic, Gordana
AU  - Vlahovic G
FAU - Kauh, John S
AU  - Kauh JS
FAU - Gao, Feng
AU  - Gao F
FAU - Berger, Allison J
AU  - Berger AJ
FAU - Tirrell, Stephen
AU  - Tirrell S
FAU - Gupta, Neeraj
AU  - Gupta N
FAU - Di Bacco, Alessandra
AU  - Di Bacco A
FAU - Berg, Deborah
AU  - Berg D
FAU - Liu, Guohui
AU  - Liu G
FAU - Lin, Jianchang
AU  - Lin J
FAU - Hui, Ai-Min
AU  - Hui AM
FAU - Thompson, John A
AU  - Thompson JA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150318
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Activating Transcription Factor 3)
RN  - 0 (Boron Compounds)
RN  - 0 (Proteasome Inhibitors)
RN  - 71050168A2 (ixazomib)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Activating Transcription Factor 3/metabolism
MH  - Adult
MH  - Aged
MH  - Boron Compounds/adverse effects/pharmacokinetics/pharmacology/*therapeutic use
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Glycine/adverse effects/*analogs & 
      derivatives/pharmacokinetics/pharmacology/therapeutic use
MH  - Hematologic Neoplasms/pathology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Neoplasms/*drug therapy/*pathology
MH  - Proteasome Inhibitors/adverse effects/pharmacokinetics/pharmacology/*therapeutic 
      use
MH  - Treatment Outcome
PMC - PMC4435632
EDAT- 2015/03/18 06:00
MHDA- 2016/02/18 06:00
PMCR- 2015/03/18
CRDT- 2015/03/18 06:00
PHST- 2014/12/10 00:00 [received]
PHST- 2015/03/06 00:00 [accepted]
PHST- 2015/03/18 06:00 [entrez]
PHST- 2015/03/18 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
PHST- 2015/03/18 00:00 [pmc-release]
AID - 230 [pii]
AID - 10.1007/s10637-015-0230-x [doi]
PST - ppublish
SO  - Invest New Drugs. 2015 Jun;33(3):652-63. doi: 10.1007/s10637-015-0230-x. Epub 
      2015 Mar 18.