A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.
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.
Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, USA, rosenbj1@mskcc.org.
Jonathan E
JE
Rosenberg
Richard M
RM
Bambury
Eliezer M
EM
Van Allen
Harry A
HA
Drabkin
Primo N
PN
Lara
Andrea L
AL
Harzstark
Nikhil
N
Wagle
Robert A
RA
Figlin
Gregory W
GW
Smith
Levi A
LA
Garraway
Toni
T
Choueiri
Fredrik
F
Erlandsson
Damian A
DA
Laber
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052157:Aptamers, Nucleotide / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D003710:Demography; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D009838:Oligodeoxyribonucleotides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D000097796:Nucleolin
D052157:Aptamers, Nucleotide; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100