A phase I trial of E7974 administered on days 1, 8, and 15 of a 28-day cycle in patients with solid malignancies

Abstract

2543 Background: E7974 is a synthetic hemiasterlin analogue exhibiting binding to a and β tubulin. It induces disruption of spindle formation and mitotic arrest characteristic of anti-tubulin cancer drugs. Unlike taxanes and vincas, E7974 is a poor substrate for the PgP drug efflux pump, potentially overcoming this common mechanism of drug resistance. E7974 demonstrates broad anti-tumor activity against a number of human tumor xenografts. Methods: We conducted the initial Phase I trial using an accelerated dose escalation design to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of E7974 administered IV over 2–5 minutes on Days 1, 8, and 15 of a 28-day cycle. Results: Sixteen patients (7 male, 9 female) with a variety of tumor types and a median age of 54 yrs.(range: 33–78 yrs) were treated at doses of 0.15 mg/m2, 0.21 mg/m2, and 0.29 mg/m2. In the accelerated phase, 0.15 mg/m2 and 0.21 mg/m2 were tolerated. At the 0.29 mg/m2 dose level, one patient experienced grade 4 neutropenia after Day 8. Expansion of the 0.21 mg/m2 dose level resulted in one patient experiencing grade 4 neutropenic fever. Two other patients experienced grades 2 and 3 neutropenia, resulting in delayed dosing beyond Cycle 1. Five additional patients were treated at 0.15 mg/m2; none experienced a DLT or dose delay, thus confirming 0.15 mg/m2 as the MTD. Other observed drug- related toxicities included mild to moderate fatigue, nausea, vomiting, constipation, neuropathy, and myalgias. The PK profile of E7974 can be characterized by moderate to large distribution (Vss = 50 - 133 L), slow clearance (CL = 1.4 - 9 L/hr) and moderate to slow elimination (t1/2 = 6.3 - 31 hr). Approximately 34 - 84% of the administered dose was recovered unchanged in the urine 48 hours post-dose. Stable disease was seen in one patient with colorectal cancer (6 cycles). The MTD cohort has been expanded to a total of 16 evaluable patients for confirmation of tolerability and PK. Conclusions: The recommended Phase 2 dose on Days 1, 8, and 15 of a 28-day schedule is 0.15 mg/m2. Observed toxicities were manageable and reversible. Enrollment is ongoing. [Table: see text]