Safety, tolerability, and pharmacokinetics of TAK-701, a humanized anti-hepatocyte growth factor (HGF) monoclonal antibody, in patients with advanced nonhematologic malignancies: First-in-human phase I dose-escalation study.

Abstract

3081 Background: TAK-701 binds to HGF and inhibits HGF/C-MET-mediated human tumor proliferation in preclinical studies. Methods: Patients aged ≥18 y with advanced nonhematologic malignancies for which standard curative or life-prolonging treatment was not available or no longer effective received up to twelve 28-d cycles of TAK-701 at 5 dose levels: 2, 5, 10, 20 and 30 mg/kg. In cycle 1, pts received a single IV infusion of TAK-701 at twice the assigned dose level on day 1; in subsequent cycles pts received TAK-701 at the assigned dose level on days 1 and 15 of 28-d cycles. Dose escalation was based on dose-limiting toxicities (DLTs) during cycle 1. Primary objectives were to assess safety and serum pharmacokinetics (PK), and determine the maximum tolerated dose (MTD). Secondary objectives included blood pharmacodynamics (PD) and response assessments. Results: At data cut-off (Dec 8, 2009), 20 pts had been enrolled to the first 4 dose levels: 3, 3, 3 and 11 to the 2, 5, 10 and 20 mg/kg cohorts, respectively. Pts received a median of 2 cycles (range 1–6). 4 of 8 evaluable pts achieved investigator-assessed stable disease. The most common adverse events (AEs) were cough (4 pts), abdominal pain, constipation and fatigue (3 pts each), all grade 1/2. There were 3 grade 3 AEs (gastrointestinal ileus, pleural effusion, urinary tract infection) and 1 grade 4 AE (dyspnea). There were 4 deaths, all due to progressive disease. There were no DLTs; the MTD has not been reached. No pt discontinued due to AEs. Preliminary PK/PD analyses for the 2, 5 and 10 mg/kg cohorts indicate dose-proportional PK (Cmax and AUC(0–28 d)). Mean (SD) half-life estimates based on day 1 dosing were 9.56 (2.93), 8.64 (4.19) and 14.1 (4.76) days, respectively. All pts showed increases in total serum HGF following TAK-701 administration; no free serum HGF was detected throughout the dosing interval. Human antihuman antibody analyses are ongoing. Conclusions: TAK-701 up to 20 mg/kg bi-weekly was well tolerated; enrolment to the 30 mg/kg dose level is ongoing. Updated safety, PK/PD, and preliminary response data for all phase I pts will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Millennium Millennium Millennium