In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 2061-2061
Abstract:
2061 Background: In vitro studies show synergy between Cp and Ir. Since both drugs are metabolized by carboxyl esterases (CE), the potential for competitive inhibition is possible. We conducted a study to identify a safe dose and potential drug-drug interactions of this combination. Methods: This was an open-label phase I dose escalation trial. Ir was given as a 30 min infusion on days 1 and 8, and Cp on days 1–14 of a 21 day cycle. Plasma for pk analyses was drawn on days 1 and 8, at 0, 15, 30, 45, 60, 90, 120, 240, 360 min, and 24 hr, for total CPT-11, SN-38, SN-38-glucuronide (G), and APC. Results: 47 patients (pt) - median age 60 (32–83) years; performance status 0–1 (96%); diagnoses- ovarian (10), breast (5), cervical (5), colorectal (10) and others (17) received 202 (median 4, range 1–18) cycles in 6 dose cohorts - Ir (mg/m 2 )/Cp (mg/m 2 /day in 2 divided doses) 75/1500, 85/1500, 85/1750, 100/1750, 100/2000, 115/2000. At the highest dose tested (115/2000), 1 of 3 pt developed grade (G) 4 neutropenia with fatal gram-negative sepsis. At dose level 5 (100/2000), 2 of 21 patients developed cycle 1 DLT - G 3 diarrhea/vomiting and G 3 diarrhea. Across all doses and patients, the G 3–4 toxicities observed were diarrhea (12 pt), vomiting (2 pt), fatigue (5 pt), hand-foot syndrome (1 pt), neutropenia (6 pt), anemia (4 pt), thrombocytopenia (2 pt) and elevation of AST/ALT (1 pt). Anti-tumor responses include partial response in 8 of 35 evaluable (23%) pts (3 breast, 4 ovarian, 1 cervical), a minimal response (1 breast), and a 90% decline in PSA (1 pt). Detailed pk analyses show that AUC (0-∞) of Ir, SN-38G, and APC were similar on days 1 and 8. However, SN-38 T max was longer on Day 8 (0.87 hr vs. 1.22 hr, p = 0.012). While SN-38 AUC (0-∞) was higher on day 1 by 45%, this was not statistically significant (p = 0.167). Conclusions: Cp results in a delayed conversion of Ir to SN-38, suggesting competitive inhibition of CE at a molecular level without clinical significance. This could portend a drug-drug interaction when Ir is combined with substrates of CE, and warrants further study. The combination of Ir and Cp is safe and well tolerated at 100/2000, and warrants further evaluation in breast, cervical, ovarian and other malignancies. [Table: see text]
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2006.24.18_suppl.2061
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2006
detail.hit.zdb_id:
2005181-5
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