title: An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma.
abstract: OBJECTIVE
  This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL).
  
  
  METHODS
  Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics.
  
  
  RESULTS
  Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing).
  
  
  CONCLUSIONS
  JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL.
authors: University Hospital of Cologne, Department I of Internal Medicine, Cologne, Germany. bastian.von-tresckow@uk-koeln.de.
authors: Bastian
authors: B
authors: von Tresckow
authors: Centre Hospitalier Régional Universitaire (CHRU) de Lille, Lille, France.
authors: Franck
authors: F
authors: Morschhauser
authors: Institut Gustave Roussy, Villejuif, France.
authors: Vincent
authors: V
authors: Ribrag
authors: University Hospital of Wurzburg, Medical Clinic and Polyclinic II, Wurzburg, Germany.
authors: Max S
authors: MS
authors: Topp
authors: Janssen Research and Development, LLC., Raritan, New Jersey.
authors: Caly
authors: C
authors: Chien
authors: Janssen Research and Development, LLC., Spring House, Pennsylvania.
authors: Shobha
authors: S
authors: Seetharam
authors: Janssen Research and Development, LLC., Spring House, Pennsylvania.
authors: Regina
authors: R
authors: Aquino
authors: Janssen Research and Development, LLC., Spring House, Pennsylvania.
authors: Sonja
authors: S
authors: Kotoulek
authors: Janssen Biologics B.V., Leiden, the Netherlands.
authors: Carla J
authors: CJ
authors: de Boer
authors: University Hospital of Cologne, Department I of Internal Medicine, Cologne, Germany.
authors: Andreas
authors: A
authors: Engert
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007093:Imidazoles; C000604309:JNJ-40346527; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016186:Receptor, Macrophage Colony-Stimulating Factor