Adjuvant Celecoxib in Completely Resected pN1-2 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