title: Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies.
abstract: OBJECTIVE
  This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies.
  
  
  METHODS
  Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed.
  
  
  RESULTS
  Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non-small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions.
  
  
  CONCLUSIONS
  The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.
authors.affiliation: Cancer Therapy and Research Center, Institute for Drug Development, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Quincy S
authors.initials: QS
authors.lastname: Chu
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Fetterly
authors.forename: Michelle
authors.initials: M
authors.lastname: Goldston
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Lesley
authors.initials: L
authors.lastname: Mathews
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.forename: Theresa
authors.initials: T
authors.lastname: Mays
authors.forename: Heather
authors.initials: H
authors.lastname: Knowles
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Jeff
authors.initials: J
authors.lastname: Kreisberg
authors.forename: Camille L
authors.initials: CL
authors.lastname: Bedrosian
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; C515074:ridaforolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus