Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Szczegóły
Abstrakt

Tytuł:: Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.
Autorzy:: Fisher MJ; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Shih CS; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.; Merck & Co., Inc., Kenilworth, NJ, USA.
Rhodes SD; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Armstrong AE; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.; Division of Pediatric Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Wolters PL; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Dombi E; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Zhang C; Department of Medical and Molecular Genomics, Indiana University, Indianapolis, IN, USA.
Angus SP; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.; Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Johnson GL; Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Packer RJ; Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, DC, USA.
Allen JC; Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
Ullrich NJ; Department of Neurology, Dana Farber/Boston Children's Hospital, Boston, MA, USA.
Goldman S; Division of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Gutmann DH; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Plotkin SR; Department of Neurology and Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
Rosser T; Division of Neurology, Children's Hospital of Los Angeles, Los Angeles, CA, USA.
Robertson KA; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
Widemann BC; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Smith AE; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Bessler WK; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
He Y; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Park SJ; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Mund JA; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Jiang L; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Bijangi-Vishehsaraei K; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
Robinson CT; Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.
Cutter GR; Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA.
Korf BR; Department of Genetics, University of Alabama Birmingham, Birmingham, AL, USA.
Blakeley JO; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. .
Clapp DW; Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA. .; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. .
Corporate Authors:: Neurofibromatosis Clinical Trials Consortium
Źródło:: Nature medicine [Nat Med] 2021 Jan; Vol. 27 (1), pp. 165-173. Date of Electronic Publication: 2021 Jan 13.
Typ publikacji:: Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.
Język:: English
Imprint Name(s):: Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-
MeSH Terms:: Anilides/*therapeutic use
Neurofibroma, Plexiform/*drug therapy
Neurofibromatosis 1/*drug therapy
Pyridines/*therapeutic use
Adolescent ; Adult ; Anilides/adverse effects ; Anilides/pharmacokinetics ; Animals ; Disease Models, Animal ; Female ; Genes, Neurofibromatosis 1 ; Humans ; Male ; Mice ; Mice, Mutant Strains ; Neurofibroma, Plexiform/genetics ; Neurofibroma, Plexiform/pathology ; Neurofibromatosis 1/genetics ; Neurofibromatosis 1/pathology ; Pain Measurement ; Prospective Studies ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/therapeutic use ; Pyridines/adverse effects ; Pyridines/pharmacokinetics ; Quality of Life ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Translational Research, Biomedical ; Young Adult
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Grant Information:: W81XWH-12-01-0155 International US Army Medical Research and Development Command; U54 CA196519 United States CA NCI NIH HHS; K12-HD000850 International U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); K12 HD000850 United States HD NICHD NIH HHS; U54-CA196519-04 International U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
Contributed Indexing:: Investigator: CS Shih; AE Armstrong
Molecular Sequence:: ClinicalTrials.gov NCT02101736
Substance Nomenclature:: 0 (Anilides)
0 (Protein Kinase Inhibitors)
0 (Pyridines)
1C39JW444G (cabozantinib)
EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
Entry Date(s):: Date Created: 20210114 Date Completed: 20210122 Latest Revision: 20230127
Update Code:: 20240105
PubMed Central ID:: PMC8275010
DOI:: 10.1038/s41591-020-01193-6
PMID:: 33442015
: Czasopismo naukowe

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.

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