A phase i trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies

Aung Naing, Roger Cohen, Grace K. Dy, David S. Hong, Lyn Dyster, David G. Hangauer, Rudolf Kwan, Gerald Fetterly, Razelle Kurzrock, Alex Adjei

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Summary: 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.

Original languageEnglish (US)
Pages (from-to)967-973
Number of pages7
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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src-Family Kinases
Neoplasms
Maximum Tolerated Dose
Pancreatic Neoplasms
Tubulin Modulators
Pharmacokinetics
Binding Sites
Taxoids
Failure to Thrive
Carcinoid Tumor
Anorexia
Tubulin
Head and Neck Neoplasms
N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide
Neutropenia
Polymerization
Ovarian Neoplasms
Prostate
Prostatic Neoplasms
Thyroid Gland

Keywords

  • KX2-391
  • Ovarian
  • Phase I
  • Prostate
  • Src kinase

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

A phase i trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies. / Naing, Aung; Cohen, Roger; Dy, Grace K.; Hong, David S.; Dyster, Lyn; Hangauer, David G.; Kwan, Rudolf; Fetterly, Gerald; Kurzrock, Razelle; Adjei, Alex.

In: Investigational New Drugs, Vol. 31, No. 4, 01.08.2013, p. 967-973.

Research output: Contribution to journalArticle

Naing, Aung ; Cohen, Roger ; Dy, Grace K. ; Hong, David S. ; Dyster, Lyn ; Hangauer, David G. ; Kwan, Rudolf ; Fetterly, Gerald ; Kurzrock, Razelle ; Adjei, Alex. / A phase i trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 967-973.
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T1 - A phase i trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies

AU - Naing, Aung

AU - Cohen, Roger

AU - Dy, Grace K.

AU - Hong, David S.

AU - Dyster, Lyn

AU - Hangauer, David G.

AU - Kwan, Rudolf

AU - Fetterly, Gerald

AU - Kurzrock, Razelle

AU - Adjei, Alex

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Summary: 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.

AB - Summary: 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.

KW - KX2-391

KW - Ovarian

KW - Phase I

KW - Prostate

KW - Src kinase

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