title: Randomized Phase II Trial of Ridaforolimus in Advanced Endometrial Carcinoma.
abstract: OBJECTIVE
  The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR inhibitors show clinical activity in endometrial cancer.
  
  
  METHODS
  An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review.
  
  
  RESULTS
  One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021).
  
  
  CONCLUSIONS
  Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA. amit.oza@uhn.ca.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Andres
authors.initials: A
authors.lastname: Poveda
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Mary
authors.initials: M
authors.lastname: McCormack
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clamp
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Li
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dodion
authors.affiliation: Amit M. Oza, Princess Margaret Cancer Centre, Toronto, ON, Canada; Sandro Pignata, Istituto Nazionale Tumori "Fondazione G Pascale"-Istituto Di Ricovero e Cura a Carattere Scientifico, Naples, Italy; Andres Poveda, Instituto Valenciano de Oncologia, Valencia, Spain; Mary McCormack, University College Hospital, London; Andrew Clamp, Institute of Cancer Sciences-University of Manchester and the Christie National Health Service Foundation Trust, Manchester, United Kingdom; Benjamin Schwartz, Island Gynecologic Oncology, Brightwaters, NY; Jonathan Cheng, Xiaoyun Li, and Kristy Campbell, Merck, Kenilworth, NJ; and Pierre Dodion and Frank G. Haluska, ARIAD Pharmaceuticals, Cambridge, MA.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011372:Progestins / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D011372:Progestins; C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus