title: A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies.
abstract: OBJECTIVE
  This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.
  
  
  METHODS
  Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities.
  
  
  RESULTS
  Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029).
  
  
  CONCLUSIONS
  Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.
authors.affiliation: Department of Pediatrics, Cancer Research Center, and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hartford
authors.forename: Apurva A
authors.initials: AA
authors.lastname: Desai
authors.forename: Linda
authors.initials: L
authors.lastname: Janisch
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Lori
authors.initials: L
authors.lastname: Berk
authors.forename: John W
authors.initials: JW
authors.lastname: Loewy
authors.forename: Hedy
authors.initials: H
authors.lastname: Kindler
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Heather L
authors.initials: HL
authors.lastname: Knowles
authors.forename: Camille
authors.initials: C
authors.lastname: Bedrosian
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C515074:ridaforolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus