ZD6474, a novel antiangiogenic agent, in combination with docetaxel in patients with NSCLC: Results of the run-in phase of a two-part, randomized phase II study

Abstract

3051 Background: ZD6474 is a novel, orally available VEGFR-2 TKI that also has activity against EGFR. Objective tumor responses in NSCLC patients (pts) were observed during Phase I evaluation. In this Phase II trial of ZD6474 plus docetaxel (doc), the safety, efficacy, and possible pharmacokinetic (PK) interaction of the combination were assessed. Methods: Eligibility included locally advanced or metastatic NSCLC after failure of 1st line platinum-based chemotherapy, WHO status of 0 or 1, and no significant hematologic or cardiac abnormalities. In the open-label Part 1 phase, pts received doc (75 mg/m2 every 21 days, i.v.) plus ZD6474 (100 mg once daily, p.o.). If no dose-limiting toxicity occurred by week 4, the next cohort received ZD6474 300 mg. Results: At completion of this phase, 15 pts with a WHO status of 0 (N=6) or 1 (N=9) received the ZD6474/doc combination (100 mg N=4, 300 mg N=11). Pts received a median of 4 cycles of doc (range 1–11) and 12 weeks' ZD6474 (range 2–29). Preliminary evaluation in pts who continued to receive ZD6474/doc for ≥ 3 cycles revealed the most common AE to be rash (CTC grade 3 in 6 of 9 pts), classified as acneiform or desquamation, with a photosensitivity component in all affected patients. The rash was reversible, and was manageable by dose interruption followed by a dose reduction. Other AEs such as GI complaints (nausea/vomiting) and laboratory abnormalities also occurred, (CTC grade 1 or 2). Seven pts experienced CTC Grade 3 or 4 myelosuppression thought to be related to doc treatment. Preliminary PK assessment shows that ZD6474 did not appear to affect exposure to doc, with any changes observed being similar to the intra-patient variability for doc alone. No marked effect on the exposure to ZD6474 was seen when administered with doc, with maximal changes of ±20% compared with ZD6474 alone. Conclusions: This phase has confirmed that the combination of ZD6474 and doc is not associated with significant changes in exposure to either drug and the toxicities are manageable. The double-blind, randomized phase comparing doc/placebo with the doc/ZD6474 (100 or 300 mg) combination is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca