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A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.

Fracasso PM, Williams KJ, Chen RC, Picus J, Ma CX, Ellis MJ, Tan BR, Pluard TJ, Adkins DR, Naughton MJ, Rader JS, Arquette MA, Fleshman JW, Creekmore AN, Goodner SA, Wright LP, Guo Z, Ryan CE, Tao Y, Soares EM, Cai SR, Lin L, Dancey J, Rudek MA, McLeod HL, Piwnica-Worms H - Cancer Chemother. Pharmacol. (2010)

Bottom Line: There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives.Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu

ABSTRACT

Purpose: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.

Experimental design: Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.

Results: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).

Conclusion: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.

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Related in: MedlinePlus

Significant decrease in pS6 levels in PBMC following UCN-01 treatment. PBMC were collected at baseline (day 1), 24 h post-irinotecan but prior to UCN-01 (day 2), 24 h post-UCN-01 treatment (day 3) and on day 8 prior to the second irinotecan treatment during cycle 1. PBMC were lysed and analyzed by Western blotting with antibodies specific for S6 ribosomal protein, phosphorylated S6 ribosomal protein (pS6), and actin as a loading control. Representative Western blots of PBMC from three patients are shown (a). The arrow indicates total S6 used for normalization. The ratio of phosphorylated S6 to total S6 protein was plotted for each sample at each time point (b). A natural log transformation of the pS6/S6 ratio was required for a normal distribution for the application of standard parametric tests. After log transformation, a paired t-test (c) and one-way ANOVA (d) were used to assess the differences among different time points (days 1, 2, 3, 8). Homogeneity of pS6/S6 ratio variance was assessed by Leveve’s test, and the variances were found to be equal. A P-value of <0.05 is considered significant and is indicated by **. DF degrees of freedom, N number of samples, CI confidence interval
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Fig1: Significant decrease in pS6 levels in PBMC following UCN-01 treatment. PBMC were collected at baseline (day 1), 24 h post-irinotecan but prior to UCN-01 (day 2), 24 h post-UCN-01 treatment (day 3) and on day 8 prior to the second irinotecan treatment during cycle 1. PBMC were lysed and analyzed by Western blotting with antibodies specific for S6 ribosomal protein, phosphorylated S6 ribosomal protein (pS6), and actin as a loading control. Representative Western blots of PBMC from three patients are shown (a). The arrow indicates total S6 used for normalization. The ratio of phosphorylated S6 to total S6 protein was plotted for each sample at each time point (b). A natural log transformation of the pS6/S6 ratio was required for a normal distribution for the application of standard parametric tests. After log transformation, a paired t-test (c) and one-way ANOVA (d) were used to assess the differences among different time points (days 1, 2, 3, 8). Homogeneity of pS6/S6 ratio variance was assessed by Leveve’s test, and the variances were found to be equal. A P-value of <0.05 is considered significant and is indicated by **. DF degrees of freedom, N number of samples, CI confidence interval

Mentions: Western blot analyses for S6 and pS6 were performed on the peripheral blood mononuclear cells (PBMC) isolated from patient blood (Fig. 1). Representative Western blots of pS6 pre- and post-therapy are shown for three patients (one in Dose Level 4 and 2 in Dose Level 5) and in each case, treatment with UCN-01 (day 3) resulted in a reduction in pS6 but did not alter total levels of S6 (Fig. 1a). Results were analyzed for 23 patient samples (Fig. 1b-d). Importantly, a statistically significant decrease in pS6 was observed on day 3 (24 h following UCN-01 treatment) compared with pre-treatment samples (P < 0.0001). Irinotecan treatment alone did not significantly alter pS6 levels (P = 0.29). Interestingly, levels of pS6 rose in PBMC by day 8, six days after the first dose of UCN-01, and levels of pS6 between days 1 and 8 were no longer significantly different (P = 0.015). Taken together, these results indicate that UCN-01 is bioavailable for at least 24 h after the first dose but may not be available at therapeutic levels by day 8.Fig. 1


A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.

Fracasso PM, Williams KJ, Chen RC, Picus J, Ma CX, Ellis MJ, Tan BR, Pluard TJ, Adkins DR, Naughton MJ, Rader JS, Arquette MA, Fleshman JW, Creekmore AN, Goodner SA, Wright LP, Guo Z, Ryan CE, Tao Y, Soares EM, Cai SR, Lin L, Dancey J, Rudek MA, McLeod HL, Piwnica-Worms H - Cancer Chemother. Pharmacol. (2010)

Significant decrease in pS6 levels in PBMC following UCN-01 treatment. PBMC were collected at baseline (day 1), 24 h post-irinotecan but prior to UCN-01 (day 2), 24 h post-UCN-01 treatment (day 3) and on day 8 prior to the second irinotecan treatment during cycle 1. PBMC were lysed and analyzed by Western blotting with antibodies specific for S6 ribosomal protein, phosphorylated S6 ribosomal protein (pS6), and actin as a loading control. Representative Western blots of PBMC from three patients are shown (a). The arrow indicates total S6 used for normalization. The ratio of phosphorylated S6 to total S6 protein was plotted for each sample at each time point (b). A natural log transformation of the pS6/S6 ratio was required for a normal distribution for the application of standard parametric tests. After log transformation, a paired t-test (c) and one-way ANOVA (d) were used to assess the differences among different time points (days 1, 2, 3, 8). Homogeneity of pS6/S6 ratio variance was assessed by Leveve’s test, and the variances were found to be equal. A P-value of <0.05 is considered significant and is indicated by **. DF degrees of freedom, N number of samples, CI confidence interval
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Related In: Results  -  Collection

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Fig1: Significant decrease in pS6 levels in PBMC following UCN-01 treatment. PBMC were collected at baseline (day 1), 24 h post-irinotecan but prior to UCN-01 (day 2), 24 h post-UCN-01 treatment (day 3) and on day 8 prior to the second irinotecan treatment during cycle 1. PBMC were lysed and analyzed by Western blotting with antibodies specific for S6 ribosomal protein, phosphorylated S6 ribosomal protein (pS6), and actin as a loading control. Representative Western blots of PBMC from three patients are shown (a). The arrow indicates total S6 used for normalization. The ratio of phosphorylated S6 to total S6 protein was plotted for each sample at each time point (b). A natural log transformation of the pS6/S6 ratio was required for a normal distribution for the application of standard parametric tests. After log transformation, a paired t-test (c) and one-way ANOVA (d) were used to assess the differences among different time points (days 1, 2, 3, 8). Homogeneity of pS6/S6 ratio variance was assessed by Leveve’s test, and the variances were found to be equal. A P-value of <0.05 is considered significant and is indicated by **. DF degrees of freedom, N number of samples, CI confidence interval
Mentions: Western blot analyses for S6 and pS6 were performed on the peripheral blood mononuclear cells (PBMC) isolated from patient blood (Fig. 1). Representative Western blots of pS6 pre- and post-therapy are shown for three patients (one in Dose Level 4 and 2 in Dose Level 5) and in each case, treatment with UCN-01 (day 3) resulted in a reduction in pS6 but did not alter total levels of S6 (Fig. 1a). Results were analyzed for 23 patient samples (Fig. 1b-d). Importantly, a statistically significant decrease in pS6 was observed on day 3 (24 h following UCN-01 treatment) compared with pre-treatment samples (P < 0.0001). Irinotecan treatment alone did not significantly alter pS6 levels (P = 0.29). Interestingly, levels of pS6 rose in PBMC by day 8, six days after the first dose of UCN-01, and levels of pS6 between days 1 and 8 were no longer significantly different (P = 0.015). Taken together, these results indicate that UCN-01 is bioavailable for at least 24 h after the first dose but may not be available at therapeutic levels by day 8.Fig. 1

Bottom Line: There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives.Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu

ABSTRACT

Purpose: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.

Experimental design: Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.

Results: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).

Conclusion: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.

Show MeSH
Related in: MedlinePlus