title: A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study.
abstract: BACKGROUND
  To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin.
  
  
  METHODS
  Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during cycles 1 and 2.
  
  
  RESULTS
  Thirty-five patients were enrolled. The MTD was reached at the first DL, (pazopanib 400 mg daily + cisplatin 75 mg/m2every 21 days). Main DLTs were pulmonary embolism, neutropenia, thrombocytopenia, and elevation of liver enzymes. Overall, most common adverse events were anemia (83%), fatigue (80%), thrombocytopenia (80%), neutropenia (73%), hypertension (59%), neurotoxicity (56%), and anorexia (53%). Sixteen patients (46%) discontinued the study due to toxicity. One patient (sarcoma) had a complete response, and three patients (one with breast cancer and two with ovarian cancers) had a partial response. Pharmacokinetic (PK) analyses showed interactions with aprepitant, resulting in increased exposure to pazopanib, which might explain partly the poor tolerance of the combination.
  
  
  CONCLUSIONS
  Cisplatin and pazopanib could not be administered at their single agent full doses, partly due to a PK interaction between pazopanib and aprepitant.
  
  
  BACKGROUND
  This work was funded by GlaxoSmithKline and by the charity Ligue Nationale de Lutte Contre le Cancer.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier, NCT01165385.
authors.affiliation: Department of Medical Oncology, Institut Curie, Saint-Cloud, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.affiliation: Department of Medical Oncology, Centre François Baclesse, Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.affiliation: Department of Medical Oncology, Institut Curie, Saint-Cloud, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cassier
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bompas
authors.affiliation: Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Department of Medical Oncology, Centre François Baclesse, Caen, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Noal
authors.affiliation: R&D Department, UNICANCER, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Orsini
authors.affiliation: R&D Department, UNICANCER, Paris, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: Institut Claudius Regaud, Inserm, UMR1037 CRCT, Université Toulouse III-Paul Sabatier, Toulouse, France.
authors.forename: Diane Charlotte
authors.initials: DC
authors.lastname: Imbs
authors.affiliation: Institut Claudius Regaud, Inserm, UMR1037 CRCT, Université Toulouse III-Paul Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
keywords: Aprepitant; Cisplatin; Pazopanib; Phase I trial; Safety; Solid tumors