title: Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel.
abstract: BACKGROUND
  The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol).
  
  
  METHODS
  Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out.
  
  
  RESULTS
  Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease > or =4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively.
  
  
  CONCLUSIONS
  Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.
authors.affiliation: Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Tosi
authors.affiliation: Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Viganò
authors.affiliation: Department of Medical Oncology, IMAS-Hospital del Mar, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Department of Oncology-Hematology, Kantonsspital St. Gallen, Saint Gallen, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Hess
authors.affiliation: Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Maur
authors.affiliation: Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cresta
authors.affiliation: Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Locatelli
authors.affiliation: Department of Oncology-Hematology, Kantonsspital St. Gallen, Saint Gallen, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Angst
authors.affiliation: Molecular Therapeutics and Biomarkers in Breast Cancer Program, IMIM-Hospital del Mar, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Study Management Unit, Southern Europe New Drugs Organization, Milano, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Coceani
authors.affiliation: Preclinical and Translational Research Unit.
authors.forename: V M
authors.initials: VM
authors.lastname: Rivera
authors.affiliation: Preclinical and Translational Research Unit.
authors.forename: L
authors.initials: L
authors.lastname: Berk
authors.affiliation: Clinical Research Unit, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Haluska
authors.affiliation: Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy. Electronic address: luca.gianni@istitutotumori.mi.it.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C515074:ridaforolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus