title: Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas.
abstract: BACKGROUND
  Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma.
  
  
  METHODS
  Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and ≥1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21).
  
  
  RESULTS
  A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]).
  
  
  CONCLUSIONS
  Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma.
authors.affiliation: Department of Neurology, Neuro-Oncology Center, University of Virginia Medical Center, Charlottesville, Virginia.
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.affiliation: Neuro-Oncology Program, University of California at Los Angeles Oncology Center, Los Angeles, California.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cloughesy
authors.affiliation: Division of Neuro-Oncology, Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Department of Neurosurgery, Pennsylvania State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Glantz
authors.affiliation: Department of Neuro-Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Chamberlain
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.|Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001254:Astrocytoma / Q000473:pathology / Q000628:therapy*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods; D003248:Constipation / Q000139:chemically induced; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003967:Diarrhea; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007970:Leukopenia; D060046:Maintenance Chemotherapy / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D060787:Neoplasm Grading; D019635:Neurosurgical Procedures; D009503:Neutropenia; D011725:Pyridines / Q000008:administration & dosage; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D003606:Dacarbazine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077204:Temozolomide
keywords: antiangiogenic therapy; cabozantinib; glioblastoma; high-grade glioma; signal transduction inhibitors