A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors

Carolyn D. Britten, Elizabeth Garrett-Mayer, Steven H. Chin, Keisuke Shirai, Besim Ogretmen, Tricia A. Bentz, Alan Brisendine, Kate Anderton, Susan L. Cusack, Lynn W. Maines, Yan Zhuang, Charles Smith, Melanie B. Thomas

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

Original languageEnglish (US)
Pages (from-to)4642-4650
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

Fingerprint

Neoplasms
Sphingolipids
Drug-Related Side Effects and Adverse Reactions
Nausea
Vomiting
Cholangiocarcinoma
sphingosine kinase
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
Fatigue
Research Design
Pharmacokinetics
Biomarkers
Lipids
Safety
Growth
sphingosine 1-phosphate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Britten, C. D., Garrett-Mayer, E., Chin, S. H., Shirai, K., Ogretmen, B., Bentz, T. A., ... Thomas, M. B. (2017). A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. Clinical Cancer Research, 23(16), 4642-4650. https://doi.org/10.1158/1078-0432.CCR-16-2363
Britten, Carolyn D. ; Garrett-Mayer, Elizabeth ; Chin, Steven H. ; Shirai, Keisuke ; Ogretmen, Besim ; Bentz, Tricia A. ; Brisendine, Alan ; Anderton, Kate ; Cusack, Susan L. ; Maines, Lynn W. ; Zhuang, Yan ; Smith, Charles ; Thomas, Melanie B. / A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4642-4650.
@article{f363562b988946d99c933b6bf688adc9,
title = "A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors",
abstract = "Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.",
author = "Britten, {Carolyn D.} and Elizabeth Garrett-Mayer and Chin, {Steven H.} and Keisuke Shirai and Besim Ogretmen and Bentz, {Tricia A.} and Alan Brisendine and Kate Anderton and Cusack, {Susan L.} and Maines, {Lynn W.} and Yan Zhuang and Charles Smith and Thomas, {Melanie B.}",
year = "2017",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-16-2363",
language = "English (US)",
volume = "23",
pages = "4642--4650",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

Britten, CD, Garrett-Mayer, E, Chin, SH, Shirai, K, Ogretmen, B, Bentz, TA, Brisendine, A, Anderton, K, Cusack, SL, Maines, LW, Zhuang, Y, Smith, C & Thomas, MB 2017, 'A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors', Clinical Cancer Research, vol. 23, no. 16, pp. 4642-4650. https://doi.org/10.1158/1078-0432.CCR-16-2363

A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. / Britten, Carolyn D.; Garrett-Mayer, Elizabeth; Chin, Steven H.; Shirai, Keisuke; Ogretmen, Besim; Bentz, Tricia A.; Brisendine, Alan; Anderton, Kate; Cusack, Susan L.; Maines, Lynn W.; Zhuang, Yan; Smith, Charles; Thomas, Melanie B.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4642-4650.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors

AU - Britten, Carolyn D.

AU - Garrett-Mayer, Elizabeth

AU - Chin, Steven H.

AU - Shirai, Keisuke

AU - Ogretmen, Besim

AU - Bentz, Tricia A.

AU - Brisendine, Alan

AU - Anderton, Kate

AU - Cusack, Susan L.

AU - Maines, Lynn W.

AU - Zhuang, Yan

AU - Smith, Charles

AU - Thomas, Melanie B.

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

AB - Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

UR - http://www.scopus.com/inward/record.url?scp=85028073704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028073704&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-2363

DO - 10.1158/1078-0432.CCR-16-2363

M3 - Article

C2 - 28420720

AN - SCOPUS:85028073704

VL - 23

SP - 4642

EP - 4650

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 16

ER -