title: Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients.
  
  
  METHODS
  Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy.
  
  
  RESULTS
  In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved ≥30, ≥50, and ≥90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination.
  
  
  CONCLUSIONS
  Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.
authors.affiliation: Department of Medicine, Smilow Cancer Center, Yale University Medical Center, 333 Cedar Street, PO Box 208032, New Haven, CT, 06520, USA, daniel.petrylak@yale.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.forename: Jitendra G
authors.initials: JG
authors.lastname: Gandhi
authors.forename: William R
authors.initials: WR
authors.lastname: Clark
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heath
authors.forename: Jianqing
authors.initials: J
authors.lastname: Lin
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
authors.forename: Bradley
authors.initials: B
authors.lastname: Carthon
authors.forename: Susan
authors.initials: S
authors.lastname: Moran
authors.forename: Ning
authors.initials: N
authors.lastname: Kong
authors.forename: Ajit
authors.initials: A
authors.lastname: Suri
authors.forename: Michael
authors.initials: M
authors.lastname: Bargfrede
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011241:Prednisone / Q000008:administration & dosage / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D013739:Testosterone / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009281:Naphthalenes; D043823:Taxoids; D000077143:Docetaxel; D013739:Testosterone; D019314:Dehydroepiandrosterone Sulfate; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; C571806:orteronel; D011241:Prednisone