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 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 (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 2013

Fingerprint

src-Family Kinases
Castration
Tubulin
Prostate-Specific Antigen
Polymerization
Disease-Free Survival
Prostatic Neoplasms
Bone
Bone and Bones
Toxicity
Pharmacokinetics
Chemotherapy
Osteocalcin
Medical Futility
Circulating Neoplastic Cells
Bone Remodeling
Alkaline Phosphatase
Tumors
Constipation
Bone Resorption

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 4, 04.2013, p. 883-892.

Research output: Contribution to journalArticle

Antonarakis, E, Heath, EI, Posadas, EM, Yu, EY, Harrison, MR, Bruce, JY, Cho, SY, Wilding, GE, Fetterly, GJ, Hangauer, DG, Kwan, MFR, Dyster, LM & Carducci, MA 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, vol. 71, no. 4, pp. 883-892. https://doi.org/10.1007/s00280-013-2079-z
Antonarakis, Emmanuel ; Heath, Elisabeth I. ; Posadas, Edwin M. ; Yu, Evan Y. ; Harrison, Michael R. ; Bruce, Justine Y. ; Cho, Steve Y. ; Wilding, Gregory E. ; Fetterly, Gerald J. ; Hangauer, David G. ; Kwan, Min Fun R ; Dyster, Lyn M. ; Carducci, Michael A. / 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. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 4. pp. 883-892.
@article{2b962c69c7cf4b00b2ade67aecdcdf1a,
title = "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",
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-na{\"i}ve 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 (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.",
keywords = "KX2-391, Prostate cancer, Src inhibitor, Tubulin polymerization",
author = "Emmanuel Antonarakis and Heath, {Elisabeth I.} and Posadas, {Edwin M.} and Yu, {Evan Y.} and Harrison, {Michael R.} and Bruce, {Justine Y.} and Cho, {Steve Y.} and Wilding, {Gregory E.} and Fetterly, {Gerald J.} and Hangauer, {David G.} and Kwan, {Min Fun R} and Dyster, {Lyn M.} and Carducci, {Michael A}",
year = "2013",
month = "4",
doi = "10.1007/s00280-013-2079-z",
language = "English (US)",
volume = "71",
pages = "883--892",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - 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

AU - Antonarakis, Emmanuel

AU - Heath, Elisabeth I.

AU - Posadas, Edwin M.

AU - Yu, Evan Y.

AU - Harrison, Michael R.

AU - Bruce, Justine Y.

AU - Cho, Steve Y.

AU - Wilding, Gregory E.

AU - Fetterly, Gerald J.

AU - Hangauer, David G.

AU - Kwan, Min Fun R

AU - Dyster, Lyn M.

AU - Carducci, Michael A

PY - 2013/4

Y1 - 2013/4

N2 - 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 (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.

AB - 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 (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.

KW - KX2-391

KW - Prostate cancer

KW - Src inhibitor

KW - Tubulin polymerization

UR - http://www.scopus.com/inward/record.url?scp=84878871141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878871141&partnerID=8YFLogxK

U2 - 10.1007/s00280-013-2079-z

DO - 10.1007/s00280-013-2079-z

M3 - Article

VL - 71

SP - 883

EP - 892

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -