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A Phase I and Pharmacokinetic Study of ILX-295501,¹ an Oral Diarylsulfonylurea, on a Weekly for 3 Weeks Every 4-Week Schedule in Patients with Advanced Solid Malignancies

² Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas;
³ Brooke Army Medical Center, San Antonio, Texas; and
⁴ Eli Lilly and Company, Indianapolis, Indiana

Purpose: This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 weeks every 4-week schedule. The study also sought to determine the maximum tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity.

Experimental Design: The initial starting dose of ILX-295501 was 100 mg/m², which was equivalent to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m². Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m²; and a modified continual reassessment model was used for dose assignment to determine the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%.

Results: Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m². The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m², which was determined to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clinically relevant levels of oxidized hemoglobin (methemoglobin) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concentrations (C_max) achieving 6.02 h, on average, after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent volume of distribution at steady state (V_ss/F), averaging 8.02 ± 14.08 liters, and low apparent total body clearance (CL_t/F) rate (mean, 0.036 ± 0.116 liters/h). The initial drug distribution phase was rapid [harmonic mean half-life (t_1/2), 2.1 ± 7.0 min], whereas the terminal elimination phase was slow (harmonic mean t_1/2ß, 150.6 ± 80.2 h).

Conclusions: The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 weeks every 4 weeks is 1000 mg/m²/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematological toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.