Document Detail


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.
MedLine Citation:
PMID:  23314737     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-13
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  71     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-26     Completed Date:  2013-06-13     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  883-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetamides / adverse effects,  pharmacokinetics,  therapeutic use*
Administration, Oral
Aged
Aged, 80 and over
Bone Neoplasms / secondary*
Bone and Bones / metabolism
Humans
Male
Middle Aged
Neoplastic Cells, Circulating / drug effects
Orchiectomy
Prostatic Neoplasms / drug therapy*,  mortality,  pathology
Pyridines / adverse effects,  pharmacokinetics,  therapeutic use*
Tubulin Modulators / adverse effects,  pharmacokinetics,  therapeutic use*
src-Family Kinases / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
P30 CA014520/CA/NCI NIH HHS; P50 CA058236/CA/NCI NIH HHS; PC051382/PC/NCI NIH HHS; T32 CA009071/CA/NCI NIH HHS; UL1 TR000427/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Acetamides; 0/N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide; 0/Pyridines; 0/Tubulin Modulators; EC 2.7.10.2/src-Family Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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