A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma

Jonathan E. Rosenberg, Richard M. Bambury, Eliezer M. Van Allen, Harry A. Drabkin, Primo N Lara, Andrea L. Harzstark, Nikhil Wagle, Robert A. Figlin, Gregory W. Smith, Levi A. Garraway, Toni Choueiri, Fredrik Erlandsson, Damian A. Laber

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Background: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results: 35 patients were enrolled and treated. One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

Original languageEnglish (US)
Pages (from-to)178-187
Number of pages10
JournalInvestigational New Drugs
Volume32
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Nucleotide Aptamers
Renal Cell Carcinoma
Neoplasms
Medicine
Exome
AGRO 100
nucleolin
Protein Biosynthesis
Missense Mutation
Therapeutics
Tumor Burden
Intravenous Infusions
Protein-Tyrosine Kinases
Disease-Free Survival
Up-Regulation
Biomarkers
Safety
Mutation

Keywords

  • Aptamer
  • AS1411
  • Nucleolin
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Rosenberg, J. E., Bambury, R. M., Van Allen, E. M., Drabkin, H. A., Lara, P. N., Harzstark, A. L., ... Laber, D. A. (2014). A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. Investigational New Drugs, 32(1), 178-187. https://doi.org/10.1007/s10637-013-0045-6

A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. / Rosenberg, Jonathan E.; Bambury, Richard M.; Van Allen, Eliezer M.; Drabkin, Harry A.; Lara, Primo N; Harzstark, Andrea L.; Wagle, Nikhil; Figlin, Robert A.; Smith, Gregory W.; Garraway, Levi A.; Choueiri, Toni; Erlandsson, Fredrik; Laber, Damian A.

In: Investigational New Drugs, Vol. 32, No. 1, 2014, p. 178-187.

Research output: Contribution to journalArticle

Rosenberg, JE, Bambury, RM, Van Allen, EM, Drabkin, HA, Lara, PN, Harzstark, AL, Wagle, N, Figlin, RA, Smith, GW, Garraway, LA, Choueiri, T, Erlandsson, F & Laber, DA 2014, 'A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma', Investigational New Drugs, vol. 32, no. 1, pp. 178-187. https://doi.org/10.1007/s10637-013-0045-6
Rosenberg, Jonathan E. ; Bambury, Richard M. ; Van Allen, Eliezer M. ; Drabkin, Harry A. ; Lara, Primo N ; Harzstark, Andrea L. ; Wagle, Nikhil ; Figlin, Robert A. ; Smith, Gregory W. ; Garraway, Levi A. ; Choueiri, Toni ; Erlandsson, Fredrik ; Laber, Damian A. / A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. In: Investigational New Drugs. 2014 ; Vol. 32, No. 1. pp. 178-187.
@article{f00e904b52084ab09b7d05b2bcd92455,
title = "A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma",
abstract = "Background: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results: 35 patients were enrolled and treated. One patient (2.9{\%}) had a response to treatment. The response was dramatic (84{\%} reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.",
keywords = "Aptamer, AS1411, Nucleolin, Renal cell carcinoma",
author = "Rosenberg, {Jonathan E.} and Bambury, {Richard M.} and {Van Allen}, {Eliezer M.} and Drabkin, {Harry A.} and Lara, {Primo N} and Harzstark, {Andrea L.} and Nikhil Wagle and Figlin, {Robert A.} and Smith, {Gregory W.} and Garraway, {Levi A.} and Toni Choueiri and Fredrik Erlandsson and Laber, {Damian A.}",
year = "2014",
doi = "10.1007/s10637-013-0045-6",
language = "English (US)",
volume = "32",
pages = "178--187",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma

AU - Rosenberg, Jonathan E.

AU - Bambury, Richard M.

AU - Van Allen, Eliezer M.

AU - Drabkin, Harry A.

AU - Lara, Primo N

AU - Harzstark, Andrea L.

AU - Wagle, Nikhil

AU - Figlin, Robert A.

AU - Smith, Gregory W.

AU - Garraway, Levi A.

AU - Choueiri, Toni

AU - Erlandsson, Fredrik

AU - Laber, Damian A.

PY - 2014

Y1 - 2014

N2 - Background: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results: 35 patients were enrolled and treated. One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

AB - Background: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. Methods: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results: 35 patients were enrolled and treated. One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

KW - Aptamer

KW - AS1411

KW - Nucleolin

KW - Renal cell carcinoma

UR - http://www.scopus.com/inward/record.url?scp=84899122500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899122500&partnerID=8YFLogxK

U2 - 10.1007/s10637-013-0045-6

DO - 10.1007/s10637-013-0045-6

M3 - Article

C2 - 24242861

AN - SCOPUS:84899122500

VL - 32

SP - 178

EP - 187

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 1

ER -