title: Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine.
abstract: OBJECTIVE
  Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine.
  
  
  METHODS
  Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m(2) or 1,800 mg/m(2) divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling.
  
  
  RESULTS
  Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m(2) capecitabine and 50 mg ridaforolimus/1,800 mg/m(2) capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus.
  
  
  CONCLUSIONS
  Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.
authors.affiliation: Montabone Unit for New Drug Development, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto dei Tumori di Milano, Milano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Perotti
authors.forename: Alberta
authors.initials: A
authors.lastname: Locatelli
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hess
authors.forename: Lucia
authors.initials: L
authors.lastname: Viganò
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capri
authors.forename: Michela
authors.initials: M
authors.lastname: Maur
authors.forename: Thomas
authors.initials: T
authors.lastname: Cerny
authors.forename: Sara
authors.initials: S
authors.lastname: Cresta
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Irene
authors.initials: I
authors.lastname: Corradino
authors.forename: Lori
authors.initials: L
authors.lastname: Berk
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Frank
authors.initials: F
authors.lastname: Haluska
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001706:Biopsy; D000069287:Capecitabine; D018797:Cell Cycle Proteins; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006097:Granulation Tissue / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C515074:ridaforolimus; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil; D020123:Sirolimus