title: A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies.
abstract: OBJECTIVE
  The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.
  
  
  METHODS
  This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction.
  
  
  RESULTS
  Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥ 6 months.
  
  
  CONCLUSIONS
  Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Shilpa.Gupta@moffitt.org.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Argilés
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
authors.affiliation: DITEP, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Hollebecque
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Dajani
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey and North Wales, Pennsylvania.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey and North Wales, Pennsylvania.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Wang
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey and North Wales, Pennsylvania.
authors.forename: Ann
authors.initials: A
authors.lastname: Swift
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey and North Wales, Pennsylvania.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosolini
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019233:Retreatment; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C515074:ridaforolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus