PMID- 27039387
OWN - NLM
STAT- MEDLINE
DCOM- 20171219
LR  - 20230120
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 34
IP  - 3
DP  - 2016 Jun
TI  - Exposure-safety-efficacy analysis of single-agent ixazomib, an oral proteasome 
      inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 
      maintenance study.
PG  - 338-46
LID - 10.1007/s10637-016-0346-7 [doi]
AB  - Background Ixazomib is the first oral, small molecule proteasome inhibitor to 
      reach phase 3 trials. The current analysis characterized the exposure-safety and 
      exposure-efficacy relationships of ixazomib in patients with relapsed/refractory 
      multiple myeloma (MM) with a purpose of recommending an approach to ixazomib 
      dosing for maintenance therapy. Methods Logistic regression was used to 
      investigate relationships between ixazomib plasma exposure (area under the 
      curve/day; derived from individual apparent clearance values from a published 
      population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic 
      [grade >/= 3 vs </= 2] or non-hematologic [grade >/= 2 vs </= 1] adverse events [AEs], 
      and clinical benefit [>/=stable disease vs progressive disease]) using phase 1 data 
      in relapsed/refractory MM (NCT00963820; N = 44). Results Significant 
      relationships to ixazomib exposure were observed for five AEs (neutropenia, 
      thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). 
      Dose-response relationships indicated a favorable benefit/risk ratio at 3 mg and 
      4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the 
      model predicted that: 37 % of patients will achieve clinical benefit; incidence 
      of grade >/= 3 neutropenia and thrombocytopenia will be 10 % and 23 %, 
      respectively; and incidence of grade >/= 2 rash, fatigue, and diarrhea will be 8 %, 
      19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the 
      phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, 
      increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum 
      clinical benefit balanced with adequate tolerability.
FAU - Gupta, Neeraj
AU  - Gupta N
AD  - Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned 
      subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, 
      Cambridge, MA, 02139, USA. Neeraj.Gupta@takeda.com.
FAU - Labotka, Richard
AU  - Labotka R
AD  - Clinical Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
      Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 
      02139, USA.
FAU - Liu, Guohui
AU  - Liu G
AD  - Biostatistics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
      Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 
      02139, USA.
FAU - Hui, Ai-Min
AU  - Hui AM
AD  - Clinical Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
      Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 
      02139, USA.
FAU - Venkatakrishnan, Karthik
AU  - Venkatakrishnan K
AD  - Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned 
      subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, 
      Cambridge, MA, 02139, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160402
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boron Compounds)
RN  - 0 (Protease Inhibitors)
RN  - 71050168A2 (ixazomib)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Area Under Curve
MH  - Boron Compounds/*administration & dosage/adverse effects/pharmacokinetics
MH  - Disease Progression
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Glycine/administration & dosage/adverse effects/*analogs & 
      derivatives/pharmacokinetics
MH  - Humans
MH  - Logistic Models
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Multiple Myeloma/*drug therapy/pathology
MH  - Protease Inhibitors/*administration & dosage/adverse effects/pharmacokinetics
PMC - PMC4859859
OTO - NOTNLM
OT  - 20S proteasome
OT  - Exposure-response
OT  - Ixazomib
OT  - Maintenance
OT  - Multiple myeloma
OT  - Proteasome inhibitor
EDAT- 2016/04/04 06:00
MHDA- 2017/12/20 06:00
PMCR- 2016/04/02
CRDT- 2016/04/04 06:00
PHST- 2016/02/23 00:00 [received]
PHST- 2016/03/15 00:00 [accepted]
PHST- 2016/04/04 06:00 [entrez]
PHST- 2016/04/04 06:00 [pubmed]
PHST- 2017/12/20 06:00 [medline]
PHST- 2016/04/02 00:00 [pmc-release]
AID - 10.1007/s10637-016-0346-7 [pii]
AID - 346 [pii]
AID - 10.1007/s10637-016-0346-7 [doi]
PST - ppublish
SO  - Invest New Drugs. 2016 Jun;34(3):338-46. doi: 10.1007/s10637-016-0346-7. Epub 
      2016 Apr 2.