In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 5019-5019
Abstract:
5019 Background: Notch signalling pathway plays a critical role in regulating cellular differentiation, proliferation, and apoptosis in preclinical cancer models. The Notch receptor, its ligands, and down-stream effectors are over-expressed in OC. Inhibition of γ-secretase-mediated Notch cleavage is a primary focus for the development of targeted therapeutics. Methods: Women (pts) with progressive, measurable (RECIST), Pt-R OC treated with ≤ 2 chemotherapy regimens for recurrent disease were treated with oral RO at 20mg od, 3 days on/4 days off every week, q3w. The primary objective was to determine the antitumor efficacy of RO in Pt-R OC by the progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives were to assess the safety of RO and to explore molecular correlates of outcome in archival tumor tissue. A Simon two-stage design was used. The study would open to second stage accrual if 〉 4 pts of the first 17 accrued remain progression-free at the end of 4 cycles. Results: 39 pts have been enrolled after first-stage criteria were met. Median age was 59 (range 26-81). Median number of cycles was 2 (range 1-18). 30 (83%) pts had high-grade serous OC. 34 pts were evaluable for response. 8 pts (20%) were progression-free after 4 cycles.12 pts (35%) had stable disease, with a median duration of 3.9 months (range 2.5-12.2). Median PFS was 1.3 months (1.2-2.3). The most common drug-related adverse events (AEs) of any grade (% pts) were: nausea (36), fatigue (28), anorexia (15), hypophosphatemia (15), anemia (13), and increased alanine aminotransferase [ALT] (13). There were 5 G3-4 AEs at least possibly related with RO: increased liver transaminases (2), diarrhea (1), headache (1), and hypophosphatemia (1). Intracellular Notch (NIC) and JAG1 protein expression on high-grade serous OC were correlated with response in 17 pts. Median PFS for pts with high NIC (n=6) was 3.3 months (1.0-not reached), compared to 1.3 months (1.1-2.6) for pts with low NIC (n=11), p=0.09. Conclusions: RO has limited clinical activity in unselected Pt-R OC as a single agent. Future studies need to assess potential for cohort enrichment using NIC expression.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.5019
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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