Clinical and correlative science results in a phase II study of UCN-01in combination with irinotecan in recurrent triple-negative breast cancer (TNBC)

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/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 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

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100–125 mg/m(2) IV days 1, 8, 15, 22) and UCN-01 (70 mg/m(2) IV day 2, 35 mg/m(2) day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1(S296) on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC