title: A multicenter phase 1/2a dose-escalation study of the antioxidant moiety of vitamin E 2,2,5,7,8-pentamethyl-6-chromanol (APC-100) in men with advanced prostate cancer.
abstract: BACKGROUND
  A phase 1/2a dose escalation study of APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) was conducted to determine maximum tolerated dose (MTD), recommended phase 2 dose, toxicities and efficacy in men with castrate-resistant prostate cancer (CRPC).
  
  
  METHODS
  This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients in cohorts of 3 were treated with escalating doses of APC-100 (900 mg-2400 mg) orally once daily continuously. Cycles were 28 days.
  
  
  RESULTS
  Twenty patients with CRPC were enrolled in the dose escalation cohort. One possible DLT (elevated ALT) was seen at dose level 1. No other DLTs were seen and no dose reductions were required. Most frequent AEs included nausea (grade 1 in 6 patients) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 patients the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules ingested. Five of the 20 patients had stable disease as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8).
  
  
  CONCLUSIONS
  APC-100 is a novel agent with dual mechanism of action functioning both as potent antioxidant as well as antiandrogen. No detectable APC-100 was found in the plasma at dose level 5 (2100 mg) and it was felt that maximal feasibility was nearly reached. APC-100 is being reformulated as a tablet to allow further dose escalation. Once a recommended phase 2 dose is established, future studies in prostate cancer chemoprevention should be conducted.
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA. ckyriako@medicine.wisc.edu.
authors.forename: Christos E
authors.initials: CE
authors.lastname: Kyriakopoulos
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI, 48201, USA.
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Heath
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Mulusew
authors.initials: M
authors.lastname: Yayehyirad
authors.affiliation: Adamis Pharmaceuticals Corporation, 11682 El Camino Real, Suite 300, San Diego, CA, 92130, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI, 53792, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002839:Chromans / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014810:Vitamin E / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002839:Chromans; D014810:Vitamin E; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman
keywords: APC-100; Oxidative stress; Phase I; Prostate cancer