A randomized, placebo-controlled phase II trial of ZD6474 plus docetaxel, in patients with NSCLC

Abstract

3023 Background: ZD6474 selectively targets two key pathways in tumor growth by inhibiting VEGFR-dependent tumor angiogenesis and EGFR-dependent tumor cell proliferation and survival. The optimal dose of ZD6474 for use in combination with docetaxel (Doc) is being assessed in a two-part randomized, double-blind, placebo-controlled trial of ZD6474/Doc vs Doc alone. Methods: Patients (pts) with locally advanced or metastatic NSCLC after failure of 1st-line platinum-based chemotherapy were recruited to an open-label safety run-in phase, which has now been completed. In the subsequent randomized phase, adult pts received once-daily oral treatment with ZD6474 (100 mg or 300 mg) or placebo, in combination with Doc (75 mg/m2 by i.v. infusion every 21 days). The primary objective is to compare progression-free survival (PFS), and will require a minimum of 40 evaluable pts per treatment arm. PFS will be determined from objective tumor assessments (revised RECIST). Secondary objectives include tolerability, objective response rate and survival. Results: The completed run-in phase comprised 15 pts treated with ZD6474 100 or 300 mg (n = 4 and 11, respectively) plus Doc. The combined use of ZD6474 and Doc did not significantly increase toxicity, or change the exposure to either agent. Doc-related myelosuppression (grade 3 or 4) was experienced by eight pts. Four serious adverse events (AEs) were possibly related to study therapy (toxic-induced encephalopathy, nail infection, non-Q-wave myocardial infarction and bacteremia). Two partial responses were seen in the ZD6474 300 mg cohort, and seven pts exhibited stable disease for ≥12 weeks. Overall median time to disease progression was 15.1 weeks and 19.8 weeks in the ZD6474 100 and 300 mg cohorts, respectively. A total of 127 pts (73 male/54 female; median age 59 years, range 29–82), recruited between May 2003 and July 2004, have received treatment in the randomized phase. Conclusions: The run-in phase demonstrated that combined use of ZD6474 and Doc was generally well tolerated and that AEs were manageable. The randomized phase has completed accrual. When ≥90 progression events have occurred (anticipated by the end of 2004), the randomized phase will be unblinded and the data presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Genentech, Ligand AstraZeneca Amgen, AstraZeneca, Genentech Amgen, AstraZeneca, Eli Lilly, Genentech, Genta