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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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: Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, USA. eantona1@jhmi.edu
authors: Emmanuel S
authors: ES
authors: Antonarakis
authors: Elisabeth I
authors: EI
authors: Heath
authors: Edwin M
authors: EM
authors: Posadas
authors: Evan Y
authors: EY
authors: Yu
authors: Michael R
authors: MR
authors: Harrison
authors: Justine Y
authors: JY
authors: Bruce
authors: Steve Y
authors: SY
authors: Cho
authors: Gregory E
authors: GE
authors: Wilding
authors: Gerald J
authors: GJ
authors: Fetterly
authors: David G
authors: DG
authors: Hangauer
authors: Min-Fun R
authors: MF
authors: Kwan
authors: Lyn M
authors: LM
authors: Dyster
authors: Michael A
authors: MA
authors: Carducci
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050257:Tubulin Modulators / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000081:Acetamides; D009025:Morpholines; D011725:Pyridines; D050257:Tubulin Modulators; C000713668:tirbanibulin; D019061:src-Family Kinases