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

Research output: Contribution to journalArticle

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 C max 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 C max of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.

Original languageEnglish (US)
Pages (from-to)883-892
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number4
DOIs
StatePublished - Apr 1 2013

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Keywords

  • KX2-391
  • Prostate cancer
  • Src inhibitor
  • Tubulin polymerization

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Antonarakis, E. S., Heath, E. I., Posadas, E. M., Yu, E. Y., Harrison, M. R., Bruce, J. Y., Cho, S. Y., Wilding, G. E., Fetterly, G. J., Hangauer, D. G., Kwan, M. F. R., Dyster, L. M., & Carducci, M. A. (2013). 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. Cancer Chemotherapy and Pharmacology, 71(4), 883-892. https://doi.org/10.1007/s00280-013-2079-z