A phase I study of E7070, a chloroindolyl-sulfonamide, in combination with irinotecan in gastrointestinal and thoracic carcinomas

Abstract

2031 Background: E7070 is a novel sulfonamide cell cycle inhibitor, demonstrating preclinical synergy with irinotecan. A phase I study was designed to determine the MTD of E7070 in combination with irinotecan in patients with GI and thoracic malignancies. Secondary objectives include evaluation of safety and preliminary assessment of antitumor activity.Methods: This is an ongoing study in which either 125 mg/m2 or 100 mg/m2 of irinotecan is followed by E7070 given in escalating doses (250 mg/m2 to 525 mg/m2). The combination is administered on days 1 and 8 of a 21-day cycle. Patients may have been treated with up to two prior regimens, and may have also received capecitabine or cetuximab. Toxicities are graded using NCI CTC version 2.0. Pharmacokinetic analyses have been performed. Results: Thirty-five patients have been treated. The MTD of the regimen is 125 mg/m2 irinotecan plus 325 mg/m2 E7070 or 100 mg/m2 irinotecan plus 400 mg/m2 E7070. Therapy was well tolerated with a dose limiting toxicity of neutropenia. One death occurred, secondary to neutropenic sepsis. Among 14 patients treated with 100 mg/m2 irinotecan plus 400 mg/m2 E7070, 4 have required dose reductions, omissions or delays. Notable treatment toxicities in this group include: grade 4 neutropenia (2), grade 3 diarrhea (1) and grade 3 pneumonitis (1). Of 11 patients with colorectal cancer one PR occurred in an irinotecan-naïve patient, while 6/8 who had received prior irinotecan had stable disease, with a median TTP of 18 weeks (range 12–24). Among 9 irinotecan-naïve SCLC patients, 3 achieved PR, including one with primary refractory disease, durable for 15+, 21 and 36+ weeks, respectively. Four additional SCLC patients had SD, 2 with >20% reduction in tumor burden. Preliminary pharmacokinetic analyses demonstrated decreased clearance of E7070 in the presence of irinotecan, while irinotecan pharmacokinetics were not affected by E7070. Conclusion: The combination of irinotecan with E7070 is tolerable and has promising activity in previously treated GI and thoracic malignancies. Additional cohorts are planned using 100 mg/m2 CPT-11 and E7070 escalation in a bi-weekly schedule. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Medical Research, Eisai Tsubuka AstraZeneca, Eli Lilly, Pfizer Eisai Medical Research