PMID- 33442015
OWN - NLM
STAT- MEDLINE
DCOM- 20210122
LR  - 20230127
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 27
IP  - 1
DP  - 2021 Jan
TI  - Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a 
      phase 2 trial.
PG  - 165-173
LID - 10.1038/s41591-020-01193-6 [doi]
AB  - Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, 
      multicellular neoplasms that cause morbidity and may transform to sarcoma. 
      Treatment of Nf1(fl/fl);Postn-Cre mice with cabozantinib, an inhibitor of 
      multiple tyrosine kinases, caused a reduction in PN size and number and 
      differential modulation of kinases in cell lineages that drive PN growth. Based 
      on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a 
      phase II, open-label, nonrandomized Simon two-stage study to assess the safety, 
      efficacy and biologic activity of cabozantinib in patients >/=16 years of age with 
      NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met 
      its primary outcome, defined as >/=25% of patients achieving a partial response 
      (PR, defined as >/=20% reduction in target lesion volume as assessed by magnetic 
      resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included 
      adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality 
      of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial 
      cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a 
      PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no 
      patients had disease progression while on treatment. Nine patients required dose 
      reduction or discontinuation of therapy due to AEs; common AEs included 
      gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar 
      erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. 
      Patients with PR had a significant reduction in tumor pain intensity and pain 
      interference in daily life but no change in global QOL scores. These data 
      indicate that cabozantinib is active in NF1-associated PN, resulting in tumor 
      volume reduction and pain improvement.
FAU - Fisher, Michael J
AU  - Fisher MJ
AUID- ORCID: 0000-0003-3408-3839
AD  - Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, 
      USA.
FAU - Shih, Chie-Schin
AU  - Shih CS
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
AD  - Merck & Co., Inc., Kenilworth, NJ, USA.
FAU - Rhodes, Steven D
AU  - Rhodes SD
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Armstrong, Amy E
AU  - Armstrong AE
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
AD  - Division of Pediatric Hematology/Oncology, Washington University School of 
      Medicine, St. Louis, MO, USA.
FAU - Wolters, Pamela L
AU  - Wolters PL
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      NIH, Bethesda, MD, USA.
FAU - Dombi, Eva
AU  - Dombi E
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      NIH, Bethesda, MD, USA.
FAU - Zhang, Chi
AU  - Zhang C
AD  - Department of Medical and Molecular Genomics, Indiana University, Indianapolis, 
      IN, USA.
FAU - Angus, Steven P
AU  - Angus SP
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
AD  - Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel 
      Hill, NC, USA.
AD  - Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Johnson, Gary L
AU  - Johnson GL
AD  - Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel 
      Hill, NC, USA.
FAU - Packer, Roger J
AU  - Packer RJ
AD  - Center for Neuroscience and Behavioral Medicine, Children's National Medical 
      Center, Washington, DC, USA.
FAU - Allen, Jeffrey C
AU  - Allen JC
AD  - Department of Pediatrics, New York University School of Medicine, New York, NY, 
      USA.
FAU - Ullrich, Nicole J
AU  - Ullrich NJ
AD  - Department of Neurology, Dana Farber/Boston Children's Hospital, Boston, MA, USA.
FAU - Goldman, Stewart
AU  - Goldman S
AD  - Division of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of 
      Chicago, Chicago, IL, USA.
FAU - Gutmann, David H
AU  - Gutmann DH
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO, 
      USA.
FAU - Plotkin, Scott R
AU  - Plotkin SR
AD  - Department of Neurology and Neuro-Oncology, Massachusetts General Hospital, 
      Boston, MA, USA.
FAU - Rosser, Tena
AU  - Rosser T
AD  - Division of Neurology, Children's Hospital of Los Angeles, Los Angeles, CA, USA.
FAU - Robertson, Kent A
AU  - Robertson KA
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
FAU - Widemann, Brigitte C
AU  - Widemann BC
AD  - Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      NIH, Bethesda, MD, USA.
FAU - Smith, Abbi E
AU  - Smith AE
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Bessler, Waylan K
AU  - Bessler WK
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - He, Yongzheng
AU  - He Y
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Park, Su-Jung
AU  - Park SJ
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Mund, Julie A
AU  - Mund JA
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Jiang, Li
AU  - Jiang L
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA.
FAU - Bijangi-Vishehsaraei, Khadijeh
AU  - Bijangi-Vishehsaraei K
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA.
FAU - Robinson, Coretta Thomas
AU  - Robinson CT
AD  - Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, 
      USA.
FAU - Cutter, Gary R
AU  - Cutter GR
AD  - Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, 
      USA.
FAU - Korf, Bruce R
AU  - Korf BR
AD  - Department of Genetics, University of Alabama Birmingham, Birmingham, AL, USA.
CN  - Neurofibromatosis Clinical Trials Consortium
FAU - Blakeley, Jaishri O
AU  - Blakeley JO
AD  - Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. 
      jblakel3@jhmi.edu.
FAU - Clapp, D Wade
AU  - Clapp DW
AD  - Division of Hematology/Oncology, Department of Pediatrics, Indiana University 
      School of Medicine, Riley Hospital for Children at Indiana University Health, 
      Indianapolis, IN, USA. dclapp@iu.edu.
AD  - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana 
      University School of Medicine, Indianapolis, IN, USA. dclapp@iu.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT02101736
GR  - W81XWH-12-01-0155/US Army Medical Research and Development Command/International
GR  - U54 CA196519/CA/NCI NIH HHS/United States
GR  - K12-HD000850/U.S. Department of Health & Human Services | NIH | Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development 
      (NICHD)/International
GR  - K12 HD000850/HD/NICHD NIH HHS/United States
GR  - U54-CA196519-04/U.S. Department of Health & Human Services | NIH | National 
      Cancer Institute (NCI)/International
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20210113
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Anilides)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 1C39JW444G (cabozantinib)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anilides/adverse effects/pharmacokinetics/*therapeutic use
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Genes, Neurofibromatosis 1
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Neurofibroma, Plexiform/*drug therapy/genetics/pathology
MH  - Neurofibromatosis 1/*drug therapy/genetics/pathology
MH  - Pain Measurement
MH  - Prospective Studies
MH  - Protein Kinase Inhibitors/adverse effects/pharmacokinetics/therapeutic use
MH  - Pyridines/adverse effects/pharmacokinetics/*therapeutic use
MH  - Quality of Life
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Translational Research, Biomedical
MH  - Young Adult
PMC - PMC8275010
MID - NIHMS1705876
COIS- COMPETING INTERESTS The authors declare the following competing interests: C-S.S. 
      is currently employed at Merck Research Laboratories (MRL) within Merck and Co. 
      in Late Stage Oncology Clinical Development, and is a consultant for the 
      Selumetinib NF program at MRL. P.L.W. has holdings in Bristol-Myers Squibb under 
      the amount allowable by the NIH. The remaining authors have no competing 
      interests to declare.
FIR - Shih, Chie-Schin
IR  - Shih CS
FIR - Armstrong, Amy E
IR  - Armstrong AE
EDAT- 2021/01/15 06:00
MHDA- 2021/01/23 06:00
PMCR- 2021/07/13
CRDT- 2021/01/14 05:44
PHST- 2019/12/19 00:00 [received]
PHST- 2020/11/25 00:00 [accepted]
PHST- 2021/01/14 05:44 [entrez]
PHST- 2021/01/15 06:00 [pubmed]
PHST- 2021/01/23 06:00 [medline]
PHST- 2021/07/13 00:00 [pmc-release]
AID - 10.1038/s41591-020-01193-6 [pii]
AID - 10.1038/s41591-020-01193-6 [doi]
PST - ppublish
SO  - Nat Med. 2021 Jan;27(1):165-173. doi: 10.1038/s41591-020-01193-6. Epub 2021 Jan 
      13.