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 S.
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.
N1 - Funding Information:
Conflict of interest E.S.A, E.I.H, E.M.P, M.R.H, J.Y.B, E.Y.Y., S.YC., and G.J.F. have no relevant conflicts of interest. G.E.W. is a paid consultant/advisor for Kinex Pharmaceuticals. D.H.G is the Chief Scientific Officer of Kinex Pharmaceuticals, and has stock ownership in Kinex Pharmaceuticals. M.R.K. is the Chief Medical Officer of Kinex Pharmaceuticals, and has stock ownership in Kinex Pharmaceuticals. L.M.D. is the Vice President of Operations of Kinex Pharmaceuticals, and has stock ownership in Kinex Pharmaceuticals. M.A.C. received research funding from Kinex Pharmaceuticals.
Funding Information:
Acknowledgments We thank the patients who volunteered to participate in this study and their families, as well as the staff members who cared for them at each site. Supported by Kinex Pharmaceuticals LLC; a Conquer Cancer Foundation 2009 Young Investigator Award; an NIH/NCI training grant (T32 CA009071); the Department of Defense Prostate Cancer Research Program (PC051382); and the Prostate Cancer Foundation.
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 (<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.
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 (<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.
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
C2 - 23314737
AN - SCOPUS:84878871141
SN - 0344-5704
VL - 71
SP - 883
EP - 892
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -