title: Selective activity over a constitutively active RET-variant of the oral multikinase inhibitor dovitinib: results of the CNIO-BR002 phase I-trial.
abstract: BACKGROUND
  Given our preclinical data showing synergy between dovitinib and paclitaxel in preclinical models we conducted this phase I trial aiming to define the recommended phase II-dose (RP2D) on the basis of toxicity and pharmacodynamic criteria while searching for genetic variants that could sensitize patients to the regimen under study.
  
  
  METHODS
  A 3+3 escalation schedule was adopted. Seriated FGF23 and dovitinib and paclitaxel pharmacokinetic profiles were determined along a single-agent dovitinib "priming-phase" followed by a dovitinib + paclitaxel combination phase. RECIST 1.1 criteria and NCI CTCAE V.4.0 were used. In fresh pre-treatment tumor biopsy samples, FGFR1, 2 and 3 amplifications were revealed by FISH probes; 32 missense variants were genotyped in tumors and peripheral blood mononuclear cells with Taqman genotyping assays (FGFR1-3 and RET). Constructs encoding for wild-type and variant genes associated with clinical benefit were transfected into HEK-293 cells for preclinical experiments checking constitutive activation and dovitinib sensitivity of the variants.
  
  
  RESULTS
  twelve patients were recruited in three dose-levels. At level 1B (200 mg dovitinib 5-days-on/2-days-off plus 60 mg/m 2-week of paclitaxel) more than 50% FGF23 upregulation was observed and no dose-limiting-toxicities (DLTs) occurred. The most frequent toxicities were asthenia, neutropenia, nausea/vomiting and transaminitis. Two patients with progressive disease prior to trial inclusion achieved prolonged disease stabilization. Both had the germline variant G2071A in the RET gene, which led to constitutive activation of the protein product and Y-905 phosphorylation, both in transfectants and in patients with the alteration. This variant was sensitive to dovitinib; in addition both patients experienced progression upon medication withdrawal.
  
  
  CONCLUSIONS
  Level 1B was the RP2D as it provided adequate pharmacodynamic exposure to dovitinib. The G2071A germline variant act as a genetic modifier that renders different tumors sensitive to dovitinib.
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain; Medical Oncology Department, Hospital de Fuenlabrada, Madrid, Spain; Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain. Electronic address: mquintela@cnio.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintela-Fandino
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Bueno
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Lombardia
authors.affiliation: Medical Oncology Department, ICO-Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gil
authors.affiliation: Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez-Martin
authors.affiliation: Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Marquez
authors.affiliation: Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Bratos
authors.affiliation: Medical Oncology Department, Hospital de Fuenlabrada, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Guerra
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tan
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain; Medical Oncology Department, Hospital La Princesa, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Colomer
authors.affiliation: Medical Oncology Department, ICO-Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; C000717427:FGF23 protein, human; D015363:Quinolones; D000089703:Fibroblast Growth Factor-23; D017239:Paclitaxel
keywords: Antiangiogenic; Clinical trial; Dovitinib; Phase I; RET genetic variant; Sensitizing genetic variant
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