title: Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas.
abstract: Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.
authors.affiliation: Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02115, USA, anorden@partners.org.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Lesser
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Nayak
authors.forename: Eudocia Q
authors.initials: EQ
authors.lastname: Lee
authors.forename: Mikael L
authors.initials: ML
authors.lastname: Rinne
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.forename: Benjamin
authors.initials: B
authors.lastname: Purow
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Doherty
authors.forename: Debra C
authors.initials: DC
authors.lastname: LaFrankie
authors.forename: Julee R
authors.initials: JR
authors.lastname: Pulverenti
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Rifenburg
authors.forename: Sandra F
authors.initials: SF
authors.lastname: Ruland
authors.forename: Katrina H
authors.initials: KH
authors.lastname: Smith
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gaffey
authors.forename: Christine
authors.initials: C
authors.lastname: McCluskey
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D015331:Cohort Studies; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007211:Indoles; D000068258:Bevacizumab; D020794:Receptor Protein-Tyrosine Kinases; C530716:nintedanib