title: Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma.
abstract: BACKGROUND
  We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination.
  
  
  METHODS
  Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used.
  
  
  RESULTS
  RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%).The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively.
  
  
  CONCLUSIONS
  The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastoma.
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Ulrik
authors: U
authors: Lassen
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Olivier L
authors: OL
authors: Chinot
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Catherine
authors: C
authors: McBain
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Morten
authors: M
authors: Mau-Sørensen
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Vibeke Andrée
authors: VA
authors: Larsen
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Maryline
authors: M
authors: Barrie
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Patrick
authors: P
authors: Roth
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Oliver
authors: O
authors: Krieter
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Ka
authors: K
authors: Wang
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Kai
authors: K
authors: Habben
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Jean
authors: J
authors: Tessier
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Angelika
authors: A
authors: Lahr
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark (U.L., M.M.-S.); Department of Radiology, Rigshospitalet, Copenhagen, Denmark (V.A.L.); Aix-Marseille University A.P.-H.M., Department of Neuro-Oncology, University Hospital Timone, Marseille, France (O.L.C., M.B.); Department of Clinical Oncology, The Christie Hospital N.H.S Foundation Trust, Manchester, England (C.M.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (P.R., M.W.); Roche Diagnostics GmbH, Penzberg, Germany (O.K., K.H., A.L.); Hoffmann La Roche Pharmaceuticals, Nutley, NewJersey (K.W.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (J.T.).
authors: Michael
authors: M
authors: Weller
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D000068258:Bevacizumab; C569915:TB-403
keywords: RO5323441; bevacizumab; dose-escalation study; glioblastoma, placental growth factor