In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 3047-3047
Abstract:
3047 Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing “mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan (I) combined with UCN-01, a nonselective Chk1 inhibitor, showed promising activity in TNBC in our phase I study. The primary objective of the phase II trial was to determine the efficacy and toxicity. Correlatives included assessing tumor molecular subtype, TP53, PTEN and pathways targeted by UCN-01. Methods: Pts with measurable, metastatic (met) TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m 2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m 2 IV on d2 and 35 mg/m 2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial peripheral blood mononuclear cells (PBMC) and optional tumor biopsies were collected. Results: Twenty five pts were enrolled. All had prior A and T. The median no. of prior regimens for met disease was 3 (range 1-4). Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a clinical benefit rate (CR+PR+SD 〉 6 mos) of 3/25 (12%), 95% CI (3, 31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 24h post UCN-01, but close to baseline by d8. Immunostain of cleaved caspase 3 (CC3), pHistone H3 (pHH3), γH2AX, and pS6 were done on serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 was reduced 24h post UCN-01. Results for other markers were variable. One case with TP53 deletion showed an induction of CC3, with an increase in pHH3 and γH2AX, suggesting abrogation of cell cycle arrest and enhanced DNA damage. Among 15 with sufficient specimen for analysis, most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% CI: 2.9, - ) mos in wild type populations (p=0.004). Conclusions: This regimen had limited activity in TNBC. Despite the long half-life, drug activity is not detectable by d8 based on PBMC analysis. Our data indicates that future trials in TNBC should consider p53 status.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.3047
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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