Adjuvant Celecoxib in Completely Resected pN1-2 NSCLC Patients

Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT00211952
• Other study ID #: 0102 PLCSG
• Status: Suspended
• Phase: Phase 3
• First received: September 13, 2005
• Last updated: September 13, 2005
• Start date: March 2004

Study information

• Verified date: September 2005
• Source: Medical University of Gdansk
• Contact: n/a
• Is FDA regulated: No
• Health authority: Poland: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The aim of the study is 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. A clinical trial addressing the role of celecoxib as adjuvant treatment in radically operated patients with high risk of relapse is warranted.

Description:

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

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 542
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Eligibility criteria:

• Completely resected (R0), histologically confirmed NSCLC with pathological T1-T3 category and pathological proof of N1 or N2 disease

• Adequate pre-surgical disease assessment (chest CT and upper abdominal CT – mandatory; mediastinoscopy or PET mandatory if clinical N2 is suspected on chest CT; other examinations according to signs and symptoms to exclude metastatic disease)

• Adequate lymph node sampling

• Randomization between 14 and 42 days after surgery

• Adequate post-surgical recovery

• Age > 18 years

• WHO Performance Status 0 or 1

• Adequate liver and renal function (ALT < 1.5 ULN, bilirubin within normal limits, creatinine < 1.5 ULN) and adequate haematology (haemoglobin >11g/dL, WBC>2.000/?L, PLT>100.000/?L)

• Written informed consent

• No previous treatment with chemotherapy

• No histological diagnosis of SCLC or mixed NSCLC/SCLC type

• No apparent involvement of mediastinal lymph nodes at preoperative staging (cN2)

• No evidence of metastatic disease (M1)

• Stable medical conditions (e.g. no myocardial infarction within 12 months, unstable angina, active psychiatric disorder)

• No active infection

• No history of malignancy other than basal-cell skin cancer or in situ cervical cancer

• No history of severe renal or liver insufficiency

• No history of a recent gastrointestinal bleeding or active ulcer disease or extensive gastro-intestinal surgery that may affect the drug absorption

• No participation in any investigational study within 30 days prior to enrollment

• No pregnancy or lactation or inadequate contraception

• No known hypersensitivity to celecoxib, other COX-2 inhibitors or aspirin (aspirin triad)

• No chronic use of NSAID’s (selective inhibitors of COX-2 and non- selective COX inhibitors), acetylsalicylic acid (aspirin) nor oral steroids >14 days during one month prior to surgery nor anticipated chronic use of the above drugs during the study

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non-Small Cell Lung Cancer

Intervention

Drug:
• celecoxib

Locations

Country	Name	City	State
Poland	Medical University of Gdansk	Gdansk

Sponsors (4)

Lead Sponsor	Collaborator
Medical University of Gdansk	Central and Eastern European Oncology Group, Pharmacia, Stowarzyszenie Ludzi Wyleczonych z Raka Pluca

Country where clinical trial is conducted

Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	time to progression
Secondary	overall survival
Secondary	toxicity