Trial Information

A Randomized, Double Blind, Placebo Controlled Phase III Trial Evaluating the Role of Adjuvant Celecoxib in Completely Resected, High-Risk (pN1-2) Non-Small Cell Lung Cancer (NSCLC) Patients

1. Rationale and objectives

To assess the influence of celecoxib on relapse-free survival in completely resected
patients with poor prognosis indicated by metastatic involvement of
intrapulmonary/hilar (pN1) or ipsilateral mediastinal (pN2) lymph nodes. Celecoxib, a
selective oral COX-2 inhibitor, was found to exert significant anti-proliferative
activity against a variety of tumor cell lines in vitro, including NSCLC. COX-2 is
frequently up-regulated in NSCLC cell lines and archival tumor samples. Its high
expression was also correlated with poor prognosis of the patients. Proposed mechanisms
of action of selective COX-2 inhibitors include inhibition of angiogenesis, inhibition
of matrix metalloproteinase-2 expression and induction of apoptosis. A clinical trial
addressing the role of celecoxib as adjuvant treatment in radically operated patients
with high risk of relapse is warranted.

2. Study design

A multicenter, international, randomized, double-blind, placebo controlled phase III
clinical trial

3. Primary endpoint

The primary endpoint will be relapse-free survival (time to local or distant relapse)
during the study.

4. Other endpoints

Secondary end-points will include:

- overall survival (time to death of any cause)

- the safety of the long-term administration of celecoxib

5. Statistical methods

The primary objective, i.e. relapse-free survival (RFS), will be recorded as time from
randomization to date of local or distant relapse (date of radiological imaging
demonstrating relapse or date of histological confirmation of relapse or date of
relapse on clinical examination, if above data are not available) or death of any
cause, whichever occurs first. Patients alive without relapse at the end of their
follow-up will be considered censored observations.

The study aims at the verification of the null hypothesis Ho : RFS in the control group
= RFS in the treated group vs. the alternative HA : RFS in the control group ≠RFS in
the treated group Primary and secondary efficacy analyses will be performed using
intention-to-treat principle.

The distribution of RFS and OS in the compared treatment arms will be summarized
graphically using the Kaplan-Meier method and compared by the log-rank test. The result
of the test will be assessed using the 5% significance level (two-sided).

The effect of the treatment on the distribution of RFS and OS will be evaluated by the
score test based on the Cox proportional hazards model, which will include
stratification and other relevant clinical factors as covariates.

The proportion of patients experiencing any AE, any serious AE, and specific types of
AEs and proportion of withdrawals will be compared between the treatment arms using the
chi-square test at the 5% significance level (two-sided).

6. Translational research A research project evaluating immunohistochemical expression of
COX-2, VEGF and CD34 as a marker of vascular density will be performed. These
parameters will be analyzed in a central laboratory by two independent pathologists
involved in angiogenesis research. Immunohistochemical methods will be carefully
validated before commencement of translational research part of the study.

The study centers will be requested to provide post-operative tissue samples
(paraffin-embedded blocks or 5 unstained slides) from the primary tumor.

7. Medication

Trt.groups Drug Form Route Dose interval Dosing No. of patients

1. Celecoxib tablets p.o. 400 mg 12 h 271

2. Placebo tablets p.o. 400 mg 12 h 271