title: Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer.
abstract: OBJECTIVE
  The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study.
  
  
  METHODS
  This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40mg for 5 consecutive days followed by a 2day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.
  
  
  RESULTS
  31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.
  
  
  CONCLUSIONS
  Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada.
authors.forename: Daliah
authors.initials: D
authors.lastname: Tsoref
authors.affiliation: London Regional Cancer Program, London ON Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Welch
authors.affiliation: McGill University, Dept. Oncology, Montréal, QC, Canada.
authors.forename: Susie
authors.initials: S
authors.lastname: Lau
authors.affiliation: Cancer Centre of Southeastern Ontario, Kingston, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Biagi
authors.affiliation: Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Katia
authors.initials: K
authors.lastname: Tonkin
authors.affiliation: BCCA, Fraser Valley Cancer Centre, Surrey, BC, Canada.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: BCCA, Cancer Centre for the Southern Interior, Kelowna, BC, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Tom Baker Cancer Centre, Calgary, AB, Canada.
authors.forename: Prafull
authors.initials: P
authors.lastname: Ghatage
authors.affiliation: Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Elit
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Allo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eisenhauer
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto ON Canada. Electronic address: amit.oza@uhn.ca.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Cancer; Endometrial; Metastatic; Phase II; Recurrent; Ridaforolimus