Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer

Invest New Drugs. 2015 Apr;33(2):397-408. doi: 10.1007/s10637-014-0199-x. Epub 2015 Jan 4.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols
  • Dehydroepiandrosterone Sulfate / blood
  • Disease Progression
  • Disease-Free Survival
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects
  • Imidazoles / therapeutic use*
  • Male
  • Middle Aged
  • Naphthalenes / administration & dosage
  • Naphthalenes / adverse effects
  • Naphthalenes / therapeutic use*
  • Prednisone / administration & dosage
  • Prednisone / therapeutic use*
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
  • Taxoids / administration & dosage
  • Taxoids / therapeutic use*
  • Testosterone / blood

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Naphthalenes
  • Taxoids
  • Docetaxel
  • Testosterone
  • Dehydroepiandrosterone Sulfate
  • Steroid 17-alpha-Hydroxylase
  • Prostate-Specific Antigen
  • orteronel
  • Prednisone