A phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies.
BACKGROUND
Src kinase is central to tumor cell proliferation, apoptosis, and metastasis. KX2-391 is a synthetic, orally bioavailable small molecule inhibitor of Src tyrosine kinase (TK) signaling and tubulin polymerization. This compound is distinct from other Src kinase inhibitors by targeting the peptide substrate rather than the ATP binding site; the binding site on hetero-dimeric tubulin is novel and distinct from the taxanes and other known tubulin inhibitors.


METHODS
This multicenter Phase I trial utilized a 4 + 2 study design to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of KX2-391 in patients with refractory solid tumors.


RESULTS
Forty-four (44) patients (18 M, 26 F; median age, 59) were enrolled in 9 dose cohorts. Dose-limiting toxicities, all reversible within 7 days, occurred in 7 patients and consisted of elevated AST (n = 4), ALT (n = 2), neutropenia (n = 1), thrombocytopenia (n = 1), failure to thrive (n = 1) and anorexia (n = 1). The MTD is 40 mg BID continuously. Eleven patients had stable disease for ≥ 4 months, including patients with ovarian, carcinoid, papillary thyroid, prostate, pancreas and head and neck cancer. Patients with prostate and pancreatic cancer also had significant biomarker decreases (PSA, 205 ng/mL to 39 ng/mL; CA19-9, 38,838 U/mL to 267 U/mL). The ovarian cancer patient has had stable disease > 12 months. KX2-391 was orally available, rapidly absorbed, and exposure was proportional to dose across the range investigated.


CONCLUSIONS
KX2-391 has a favorable pharmacokinetic profile, is well tolerated, demonstrates preliminary evidence of biologic activity, and warrants further evaluation in Phase II trials.
Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. anaing@mdanderson.org
Aung
A
Naing
Roger
R
Cohen
Grace K
GK
Dy
David S
DS
Hong
Lyn
L
Dyster
David G
DG
Hangauer
Rudolf
R
Kwan
Gerald
G
Fetterly
Razelle
R
Kurzrock
Alex A
AA
Adjei
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D001665:Binding Sites; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013379:Substrate Specificity / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000081:Acetamides; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000713668:tirbanibulin; D000255:Adenosine Triphosphate; D019061:src-Family Kinases