PMID- 29781056
OWN - NLM
STAT- MEDLINE
DCOM- 20200121
LR  - 20221207
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 37
IP  - 1
DP  - 2019 Feb
TI  - Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in 
      combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in 
      patients with advanced solid tumors.
PG  - 87-97
LID - 10.1007/s10637-018-0610-0 [doi]
AB  - Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose 
      (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care 
      chemotherapies in patients with solid tumors. Methods Patients received 
      pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, 
      n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 
      3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin 
      dose. Dose escalation proceeded via continual modified reassessment. Results 
      Pevonedistat MTD was 25 mg/m(2) (arm 1) or 20 mg/m(2) (arm 2); arm 3 was 
      discontinued due to poor tolerability. Fifteen (23%) patients experienced 
      dose-limiting toxicities during cycle 1 (grade >/=3 liver enzyme elevations, 
      febrile neutropenia, and thrombocytopenia), managed with dose holds or 
      reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most 
      common AEs included fatigue (56%) and nausea (50%). One drug-related death 
      occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when 
      co-administered with carboplatin plus paclitaxel; no obvious changes were 
      observed when co-administered with docetaxel or gemcitabine. Among 54 
      response-evaluable patients, two had complete responses (arm 2) and 10 had 
      partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response 
      rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with 
      clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with 
      carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained 
      clinical responses were observed in pretreated patients receiving pevonedistat 
      with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.
FAU - Lockhart, A Craig
AU  - Lockhart AC
AUID- ORCID: 0000-0002-0132-5523
AD  - Division of Medical Oncology, University of Miami/Sylvester Comprehensive Cancer 
      Center, 1120 NW 14th Street, Suite 650L, Miami, FL, USA. 
      aclockhart@med.miami.edu.
FAU - Bauer, Todd M
AU  - Bauer TM
AD  - Drug Development, Sarah Cannon Research Institute/Tennessee Oncology PLLC., 
      Nashville, TN, USA.
FAU - Aggarwal, Charu
AU  - Aggarwal C
AD  - Division of Hematology-Oncology, Department of Medicine, Perelman Center for 
      Advanced Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Lee, Carrie B
AU  - Lee CB
AD  - Division of Hematology and Oncology, University of North Carolina at Chapel Hill, 
      Chapel Hill, NC, USA.
FAU - Harvey, R Donald
AU  - Harvey RD
AD  - Departments of Hematology and Medical Oncology and Pharmacology, Emory University 
      School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, 
      USA.
FAU - Cohen, Roger B
AU  - Cohen RB
AD  - Department of Medicine, Perelman Center for Advanced Medicine, University of 
      Pennsylvania, Philadelphia, PA, USA.
FAU - Sedarati, Farhad
AU  - Sedarati F
AD  - Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Nip, Tsz Keung
AU  - Nip TK
AD  - Biostatistics, Takeda Development Centre EU, London, UK.
FAU - Faessel, Helene
AU  - Faessel H
AD  - Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, 
      MA, USA.
FAU - Dash, Ajeeta B
AU  - Dash AB
AD  - Translational and Biomarker Research, Millennium Pharmaceuticals, Inc., 
      Cambridge, MA, USA.
FAU - Dezube, Bruce J
AU  - Dezube BJ
AD  - Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Faller, Douglas V
AU  - Faller DV
AD  - Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
FAU - Dowlati, Afshin
AU  - Dowlati A
AD  - Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01862328
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20180521
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Cyclopentanes)
RN  - 0 (NEDD8 Protein)
RN  - 0 (NEDD8 protein, human)
RN  - 0 (Pyrimidines)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 15H5577CQD (Docetaxel)
RN  - BG3F62OND5 (Carboplatin)
RN  - P88XT4IS4D (Paclitaxel)
RN  - S3AZD8D215 (pevonedistat)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use
MH  - Carboplatin/administration & dosage
MH  - Cohort Studies
MH  - Cyclopentanes/administration & dosage
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - Docetaxel/administration & dosage
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - NEDD8 Protein/*antagonists & inhibitors
MH  - Neoplasms/*drug therapy/pathology
MH  - Paclitaxel/administration & dosage
MH  - Prognosis
MH  - Pyrimidines/administration & dosage
MH  - Tissue Distribution
MH  - Young Adult
MH  - Gemcitabine
PMC - PMC6510847
OTO - NOTNLM
OT  - Advanced solid tumors
OT  - Clinical research
OT  - Pevonedistat
OT  - Phase Ib study
OT  - Standard-of-care chemotherapies
COIS- CONFLICTS OF INTEREST: ACL has no conflicts of interest to disclose. CA reports 
      honoraria and advisory role fees from Genentech, BMS, and Eli Lilly, and research 
      funding from Macrogenics to the Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA, USA. TMB reports research funding from Daiichi 
      Sankyo, Medpachto Inc., Incyte, Mirati Therapeutics, MedImmune, Abbvie, 
      AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Eli Lilly, 
      GSK, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, 
      Immunogen, Takeda, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, 
      Principa Biopharma, Peleton, Immunocore, Roche, Aileron Therapeutics, BMS, and 
      Amgen to the Sarah Cannon Research Institute/Tennessee Oncology PLLC, Nashville, 
      TN, USA. CBL reports travel/accommodation fees or expenses from Novartis and 
      research funding form Takeda, Novartis, and Genentech to the University of North 
      Carolina at Chapel Hill, Chapel Hill, NC, USA. DH reports research funding from 
      Takeda. R.B.C. reports consulting or advisory roles for Takeda, BMS, Kolltan, 
      Cerulean Pharma Inc., and Constellation Pharmaceuticals, and research funding 
      from Takeda. FS, HF, and ABD report stock ownership in and employment by 
      Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited. FS reports travel/accommodation fees or expenses 
      from Takeda. DVF reports employment by Millennium Pharmaceuticals Inc., a wholly 
      owned subsidiary of Takeda Pharmaceutical Company Limited, and patents or 
      intellectual property interests with Phoenicia BioSciences. TKN and BJD are 
      former employees of Millennium Pharmaceuticals Inc., a wholly owned subsidiary of 
      Takeda Pharmaceutical Company Limited. A.D. reports consulting or advisory role 
      fees from Abbvie and AstraZeneca, and research funding from Abbvie, EMD Serono, 
      Genentech, Eli Lilly, Piqur, Taino, Vertex, and Takeda. ETHICAL APPROVAL: All 
      procedures performed in this study involving human participants were in 
      accordance with the ethical standards of the participating institutions and the 
      1964 Helsinki declaration and its later amendments or comparable ethical 
      standards. INFORMED CONSENT: Written informed consent was obtained from all 
      individual participants included in the study.
EDAT- 2018/05/22 06:00
MHDA- 2020/01/22 06:00
PMCR- 2018/05/21
CRDT- 2018/05/22 06:00
PHST- 2018/03/01 00:00 [received]
PHST- 2018/05/11 00:00 [accepted]
PHST- 2018/05/22 06:00 [pubmed]
PHST- 2020/01/22 06:00 [medline]
PHST- 2018/05/22 06:00 [entrez]
PHST- 2018/05/21 00:00 [pmc-release]
AID - 10.1007/s10637-018-0610-0 [pii]
AID - 610 [pii]
AID - 10.1007/s10637-018-0610-0 [doi]
PST - ppublish
SO  - Invest New Drugs. 2019 Feb;37(1):87-97. doi: 10.1007/s10637-018-0610-0. Epub 2018 
      May 21.