Trial Information

A Randomized Phase II Study Evaluating Vandetanib (ZD6474) in Combination With Docetaxel and Carboplatin Followed by Placebo or Maintenance Therapy With Vandetanib in Patients With IIIb, IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the number one cause of cancer-related mortality in the United States, with
an estimated 160,390 deaths in 2007. Over 80% of these patients will have non-small cell
lung cancer (NSCLC), and the majority of these patients have advanced disease at the time of
diagnosis.

Patients with advanced disease who have an adequate performance status clearly benefit from
systemic chemotherapy, and many clinical trials have been carried out to determine the most
effective regimen. Comorbidities associated with NSCLC preclude the use of cisplatin in
doublet therapies, and, a meta-analysis comparing platinum-based doublet regimens to
non-platinum based, third generation regimens revealed that survival outcomes between these
regimens were equivalent. Despite poor response and overall survival benefits in this
patient population with accepted treatment doublets, the addition of a third cytotoxic agent
did not improve survival and demonstrated increased toxicity. Therefore, it appears a
threshold maximum response can be gained with cytotoxic chemotherapy alone. However, the
poor outcomes still associated with advanced NSCLC clearly demanded the need for continued
improvements in treatment. It was postulated that anticancer therapy could be significantly
improved by not only targeting the tumor cells directly, but also by targeting
neo-angiogenesis. A randomized phase II trial demonstrated a significant improvement in time
to progression (TTP) in patients receiving carboplatin, paclitaxel and bevacizumab compared
to chemotherapy alone. Due to life-threatening and fatal hemorrhage patients with squamous
cell histology, as well as those with a prior history of hemoptysis and brain metastases
were excluded from all further clinical trials using bevacizumab. The definitive study of
bevacizumab in NSCLC was a randomized phase III clinical trial conducted by ECOG (E4599) in
which patients with advanced non-squamous NSCLC received carboplatin + paclitaxel with or
without bevacizumab which met the clinical endpoint of improvement in survival and led to
the approval of bevacizumab in first line treatment in patients with advanced NSCLC with
non-squamous histology.

The epidermal growth factor receptor (EGFR) protein activation leads to TK activation and
results in cell proliferation, motility, adhesion, invasion, survival, and angiogenesis.
The EGFR is over expressed in many solid tumors, including non-small cell lung cancer
(NSCLC), and multiple studies have suggested a shortened survival in NSCLC patients whose
tumor over expresses EGFR . Although studies using small-molecule TK inhibitors (TKIs) in
NSCLC did not meet efficacy endpoints, a phase III trial demonstrated the benefit of EGFR
TKI monotherapy. Patients with advanced NSCLC who have received 2 or 3 prior therapies were
randomized to erlotinib or placebo, and those receiving erlotinib demonstrated a survival
benefit that led to FDA approval of this drug in 2004.

The studies above clearly demonstrated a benefit to combining anti-angiogenic factors with
chemotherapy, and as a monotherapy using anti-EGFR agents, in patients with advanced NSCLC.
The potential benefit to simultaneously targeting these 2 pathways has been addressed in the
recurrent disease setting.

Vandetanib is a novel oral molecule (anilinoquinazoline) that has dual activity against both
the VEGFR and EGFR pathways. Specifically, this compound has potent and reversible
inhibitory activity against VEGFR-2 (KDR), VEGFR-3 (Flt-4), EGFR and RET . Vandetanib is a
TKI and thus acts through inhibition of ATP binding to the tyrosine kinase domains of these
receptors. Recombinant enzyme assays have demonstrated that vandetanib is highly selective
for both VEGFR-2 (IC50=40 nm) with only slightly lower affinity for VEGFR-3 (2.7 fold). EGFR
tyrosine kinase activity is inhibited with an IC50=500 nm. The results of a second-line
setting phase II trial were presented by Heymach et al at the ASCO meeting in 2006. In this
trial, patients were randomized to receive either docetaxel alone, or docetaxel with either
100mg or 300mg of vandetanib. Patients with squamous cell histology, controlled brain
metastases and prior history of hemoptysis were allowed on study. The primary endpoint of
prolongation of progression-free survival (PFS) was met in the 100mg arm (Hazard Ratio(HR)
0.64, p=0.07). There was no increased incidence of hemoptysis in patients receiving
vandetanib, and no CNS hemorrhage events were observed, and side effects commonly attributed
to EGFR inhibition (rash, diarrhea) were higher on the 300mg arm. Early combination studies
suggest that in patients with NSCLC, vandetanib is safe in combination with chemotherapy,
may improve the outcomes of chemotherapy when used at the 100 mg dose, and has activity as
monotherapy at the 300mg dose. In addition, none of the observed hemorrhagic complications
seen with bevacizumab were observed, even in patients at high risk for this complication.

In this study, our main goal is to study the combination of docetaxel + carboplatin and
vandetanib, followed by a double-blind randomized assignment to maintenance therapy with
vandetanib 300 milligrams (mg) or placebo by mouth daily until disease progression to
determine if maintenance therapy can prolong progression-free survival. In addition to
clinical efficacy outcomes we will monitor for safety and tolerability, as well as explore
any differences in outcome based on age and gender.