TY - JOUR
T1 - A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer
AU - Hong, David S.
AU - Kurzrock, Razelle
AU - Oh, Yun
AU - Wheler, Jennifer
AU - Naing, Aung
AU - Brail, Les
AU - Callies, Sophie
AU - Andre, Valerie
AU - Kadam, Sunil K.
AU - Nasir, Aejaz
AU - Holzer, Timothy R.
AU - Meric-Bernstam, Funda
AU - Fishman, Mayer
AU - Simon, George
PY - 2011/10/15
Y1 - 2011/10/15
N2 - Purpose: The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors. Experimental Design: A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein. Results: Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). Conclusions: LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.
AB - Purpose: The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors. Experimental Design: A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein. Results: Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). Conclusions: LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.
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U2 - 10.1158/1078-0432.CCR-11-0430
DO - 10.1158/1078-0432.CCR-11-0430
M3 - Article
C2 - 21831956
AN - SCOPUS:80054114844
SN - 1078-0432
VL - 17
SP - 6582
EP - 6591
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -