title: Phase 1 study of dalotuzumab monotherapy and ridaforolimus-dalotuzumab combination therapy in paediatric patients with advanced solid tumours.
abstract: Dalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours.
  
  
  
  Dalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m(2) and escalating to 1200 and 1500 mg/m(2). Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m(2) daily (days 1-5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D.
  
  
  
  Twenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC0-∞]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m(2) dose levels, respectively), maximum serum concentration (Cmax) (392, 643, and 870 mg/ml), and serum trough concentration (Ctrough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m(2). Time to response was 41 d, and progression occurred at 126 d.
  
  
  
  Dalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. The RP2D of dalotuzumab is 900 mg/m(2) (ClinicalTrials.gov identifier: NCT01431547, Protocol PN062).
authors.affiliation: Institut d'Hématologie et d'Oncologie pédiatrique, Place Professeur Joseph Renaut, 69008 Lyon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Frappaz
authors.affiliation: Department of Oncology, MS 260, Room C6067, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Federico
authors.affiliation: The Institute of Cancer Research, The Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, 13001 East 17th Place, Aurora, CO 80045, USA; Childrens Hospital of Colorado, 13123 East 16th Avenue, B115, Aurora, CO 80045-7106, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, 13001 East 17th Place, Aurora, CO 80045, USA; Childrens Hospital of Colorado, 13123 East 16th Avenue, B115, Aurora, CO 80045-7106, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Macy
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: Department of Pediatric Oncology, Institut Curie, 26, rue d'Ulm, 75248 Paris cedex 05, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Clinical Research, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
authors.affiliation: Clinical Research, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Geschwindt
authors.affiliation: Quantitative Solutions B.V., Pivot Park Molenweg 79, 5349 AC Oss, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: Van Schanke
authors.affiliation: BARDS, MSD R&D (China) Co. Ltd., Universal Business Park, No. 10 Jiu Xianqiao Road, Chao Yang District, Beijing 100015, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pediatric and Adolescent Oncology, Gustave Roussy, Univ. Paris-Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France. Electronic address: birgit.geoerger@gustaveroussy.fr.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C515074:ridaforolimus; C569480:dalotuzumab; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Dalotuzumab; IGF1-R; Paediatrics; Pharmacokinetics; Phase 1; Ridaforolimus; mTOR