title: Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide.
abstract: Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
authors.affiliation: Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 9E, Boston, MA 02114, USA. egerstner@partners.org
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: Colin L
authors.initials: CL
authors.lastname: Doyle
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood*; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011878:Radiotherapy; D042787:Receptor, TIE-2 / Q000097:blood; D000077204:Temozolomide; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C098069:PIGF protein, human; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D003606:Dacarbazine; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077204:Temozolomide
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