Purpose: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients
with advanced solid malignancies.
Experimental Design: OSI-7836 was ...initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities,
the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks
followed by a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte
subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in
earlier patients.
Results: Thirty patients received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose
was defined as 300 mg/m 2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m 2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m 2 in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no
clinically significant hematologic toxicities. Following the initial dose, OSI-7836 was eliminated from plasma with a median
(range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in
B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and
interleukin-10 in all patients who received ≥200 mg/m 2 OSI-7836. Best response was disease stabilization in seven patients.
Conclusion: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did
not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further
studies in specific hematologic malignancies.
Abstract
Background
Tamoxifen (Tam) undergoes extensive biotransformation into several metabolites, including the highly active metabolite endoxifen. Differences in metabolism, influenced by both ...genetic and environmental factors, largely contribute to the inter-individual variability in endoxifen plasma concentrations, potentially affecting the efficacy of Tam. Conflicting results between CYP2D6 genotype/phenotype and endoxifen concentrations have been observed. A reason for this discrepancy may be that CYP3A4 may have a more crucial role in the formation of endoxifen than previously thought (de Graan et al, JCO, in press). Hypothesizing that induction of CYP3A4 and CYP2D6 could lead to increased endoxifen levels, a prospective study was activated evaluating the effects of enzyme induction by rifampicin (Rif) on the plasma pharmacokinetics (PK) of Tam and its metabolites.
Methods: A randomized cross-over study design was used, with each patient serving as her own control. Breast cancer patients on steady state Tam therapy (20 or 40 mg once daily) were included. Patients underwent two periods of plasma sampling covering 24 hrs each, once using Tam alone, and once after 15 days of oral Rif (600 mg daily) taken in combination with Tam. Patients were randomized for sampling sequence 1) Tam alone followed by Rif/Tam versus 2) Rif/Tam followed by Tam alone. PK sampling in sequence 2 was performed after a 30-day wash-out period of Rif. Tam and its main metabolites ND-Tam, 4-OH-Tam and endoxifen were quantitated by a validated LC-MS/MS method. PK parameters, including area under the plasma-concentration time curve (AUC) and maximum concentration (Cmax) of all four compounds were calculated (WinNonLin program) and compared (with or without Rif) using a two-sided paired t-test. For safety reasons an interim-analysis was performed after 4 patients.
Results: The interim-analysis showed that concentrations of Tam and its metabolites were significantly decreased during Rif/Tam co-administration as compared to Tam administration alone (see table). Especially endoxifen exposure was decreased by a mean of 69%. Based on these data it was decided to stop further enrollment in this study.
Conclusions: Concentrations of Tam and its main metabolites decreased significantly after induction by rifampicin. Potentially contributing factors include further metabolism of Tam-metabolites into other inactive metabolites or conjugates (i.e. glucuronides) or a decreased oral availability of Tam. Further pharmacokinetic analyses, including the analysis of glucuronides and other metabolites, will be performed to better understand the mechanism behind these findings. Based upon these data, combining rifampicin with Tam should be avoided. Similar drug-drug interactions may exist between Tam and other strong CYP inducers, such as St John's wort and phenytoin.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-04.
Purpose: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics
of the polyamine synthesis inhibitor SAM486A given in ...combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.
Experimental Design: Patients with advanced colorectal cancer were treated with 5-FU bolus (400 mg/m 2 ) followed by a 22-h infusion (600 mg/m 2 ) and LV (200 mg/m 2 ) and escalating doses of SAM486A, 1–3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics
and pharmacodynamics of the combination
Results: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients
received SAM486A in the combination at doses ranging from 25 to 150 mg/m 2 /day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m 2 /day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen
of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response
8 (30%) of 26 or stable disease 9 (35%) of 26. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance
was similar to that when used as a single agent.
Conclusions: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced
colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m 2 /day. A disease-directed evaluation of SAM486A using this regimen is warranted.
Cytokine secretion profiles of activated T cells are critical for maintaining the immunologic balance between protection and tolerance. In mice, several cytokines have been reported to exhibit ...monoallelic expression. Previously, we found that the human interleukin-1 alpha (IL1A) gene exhibits a stable allele-specific expression pattern in CD4+ T-cell clones. We investigated whether DNA methylation is involved in the allele-specific expression of IL-1α. Here, we show that differential methylation of CpGs in the proximal promoter region is associated with allele-specific expression of IL-1α in CD4+ T cells. The differential methylation pattern is already observed in naive T cells. In keratinocytes, which constitutively produce IL-1α, the proximal promoter is hypomethylated. CpGs located further upstream and in intron 4 were almost all methylated, irrespective of expression. Treatment of nonexpressing cells and of T-cell clones with 5-aza-2′deoxycytidine induced IL-1α expression in the nonexpressing cells and induced expression of the formerly silent allele in T-cell clones. In addition, electrophoretic mobility shift assays showed that methylation of CpGs in the proximal promoter resulted in direct inhibition of binding of nuclear factor(s). Taken together, these results suggest that allele-specific expression of IL-1α in CD4+ cells is achieved, at least in part, by differential methylation of the promoter.
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