In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 639-639
Abstract:
639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2015.33.3_suppl.639
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2015
detail.hit.zdb_id:
2005181-5
