Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 4, pp 883–892

A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer

  • Emmanuel S. Antonarakis
  • Elisabeth I. Heath
  • Edwin M. Posadas
  • Evan Y. Yu
  • Michael R. Harrison
  • Justine Y. Bruce
  • Steve Y. Cho
  • Gregory E. Wilding
  • Gerald J. Fetterly
  • David G. Hangauer
  • Min-Fun R. Kwan
  • Lyn M. Dyster
  • Michael A. Carducci
Original Article

DOI: 10.1007/s00280-013-2079-z

Cite this article as:
Antonarakis, E.S., Heath, E.I., Posadas, E.M. et al. Cancer Chemother Pharmacol (2013) 71: 883. doi:10.1007/s00280-013-2079-z

Abstract

Purpose

KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC).

Methods

We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin].

Results

The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median Cmax was 61 (range 16–129) ng/mL, and median AUC was 156 (35–348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation.

Conclusion

KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a Cmax of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.

Keywords

KX2-391Prostate cancerSrc inhibitorTubulin polymerization

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Emmanuel S. Antonarakis
    • 1
  • Elisabeth I. Heath
    • 2
  • Edwin M. Posadas
    • 3
  • Evan Y. Yu
    • 4
  • Michael R. Harrison
    • 5
  • Justine Y. Bruce
    • 6
  • Steve Y. Cho
    • 1
  • Gregory E. Wilding
    • 7
  • Gerald J. Fetterly
    • 8
  • David G. Hangauer
    • 9
  • Min-Fun R. Kwan
    • 9
  • Lyn M. Dyster
    • 9
  • Michael A. Carducci
    • 1
  1. 1.Prostate Cancer Research ProgramSidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.Barbara Ann Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  3. 3.Samuel Oschin Comp. Cancer InstituteCedars-Sinai Medical CenterLos AngelesUSA
  4. 4.Fred Hutchinson Cancer Research CenterSeattleUSA
  5. 5.Duke Cancer InstituteDurhamUSA
  6. 6.University of Wisconsin Carbone Cancer CenterMadisonUSA
  7. 7.State University of New York at BuffaloBuffaloUSA
  8. 8.Roswell Park Cancer InstituteBuffaloUSA
  9. 9.Kinex Pharmaceuticals LLCBuffaloUSA