European Celecoxib Trial in Primary Breast Cancer

It has been found that the chemical changes that take place in a patient's body during the development of inflammation may provide an environment which stimulates cancer cells. One step in the development of inflammation is the production of certain chemical substances which are important in the formation and spread of tumours. These are called prostaglandins. Cyclo-oxygenase II (COX-2) is an enzyme (a substance that speeds up chemical changes in the body) involved in the production of these prostaglandins and although it is not usually present in most tissues it is made at the sites of inflammation. Celecoxib is a selective Non-Steroidal Anti Inflammatory Drug (NSAID) which works by blocking the action of the COX-2 enzyme, leading to a decrease in the production of prostaglandins and a reduction in inflammation.

The purpose of this study is therefore to find out if celecoxib can be used after breast cancer treatment (chemotherapy and/ or radiotherapy) to reduce inflammation and thus reduce the ability of new tumours to grow and survive.

2590 women with primary breast cancer will be recruited in this study from several locations in the United Kingdom and Germany. Eligible patients will be randomly allocated a treatment group, which can be celecoxib or placebo. Both treatments are taken orally (celecoxib 400mg daily, placebo 2 tablets daily) for a total of 2 years. In addition, hormone receptor positive patients will receive endocrine treatment as per local practice. Patients will prematurely discontinue treatment with celecoxib/placebo if disease progression is confirmed or if patients experience unacceptable toxicity.

Patients will be seen every 6 months for the first 3 years and then off treatment follow-up is carried out annually. Participating patients will also be given the option to take part in the pathology sub-study by donating a sample of the tumour tissue collected at the time of the primary surgery.

It has long been recognised that there is an association between chronic immune activation and cancer but the mechanisms behind this observation are not fully understood. The inflammatory process may provide an environment for development of malignant disease, with mediators of inflammatory response such as the cyclo-oxygenases playing an important role and providing a target for therapeutic intervention.

Prostaglandins (PGs) are synthesised from phospholipids by the action of phospholipase A2 and cyclo-oxygenases. Cyclo-oxygenase (COX) -1 differs from COX-2 in that the latter is inducible and its expression is induced by a large range of oncogenes and growth factors. Celecoxib is a selective COX-2 inhibitor that does not cause the effects of COX-1 inhibition, namely gastrointestinal ulceration.

The key regulatory step in this process is the enzymatic conversion of fatty acids to PGG2 and PGH2 by COX. PGH2 is subsequently converted to one of several structurally related PGs including PGE2, PGD2, PGF2, and thromboxane A2 (TxA2), by the activity of specific PG synthases. PGs have important functions in every organ system and regulate a variety of physiological functions such as immunity, maintenance of vascular integrity and bone metabolism. COX-2 is not normally expressed in most tissues, but is induced by a wide spectrum of growth factors and pro-inflammatory cytokines in specific pathophysiological conditions. The expression of COX-2 is highly induced in cells transformed with the oncogene v-src or treated with phorbol esters.

Several studies have suggested an association between non-steroidal anti-inflammatory drug (NSAID) consumption and decreased breast cancer risk.

Elevated COX expression in breast cancer was suggested some time ago by the finding of elevated PG production in breast tumours.

There is pharmacological and genetic evidence to indicate that a significant component of the anticancer property of NSAIDs is due to their ability to inhibit the COX-2 enzyme.

This phase III randomised study assesses the impact on disease free survival and overall survival of the Cox-2 inhibitor Celecoxib as maintenance therapy following surgery and chemotherapy in the treatment of primary breast cancer.

2590 women with primary breast cancer will be recruited in this study from several locations in the United Kingdom and Germany.

Prior to randomization all patients should have completed at least 4 cycles of (neo) adjuvant chemotherapy. Patients who satisfy all the eligibility criteria for the study will be informed and consented to join the study. The Local Investigator will then contact the ICCG randomization centre to randomize the patient by fax or by telephone.

1. Assessments required pre-randomisation

   * Complete history and physical examination (within 4 weeks before randomisation)
   * Haematology (Hb, WBC or ANC, platelets) \& Biochemistry \[serum bilirubin, creatinine, alkaline phosphatase\] (within 4 weeks before randomisation)
   * Mammogram, Chest X-ray, liver ultrasound, bone scan (at a maximum 00 months prior to diagnosis of breast cancer). In case of clinical symptoms metastatic disease has to be excluded before randomisation by the appropriate investigations
   * Collection of tissue blocks for the central tumour banks at Glasgow Royal Infirmary (for sites managed by ICCG) land Studienzentrale in Frankfurt (for sites managed by GBG)
2. Treatment

   Treatment must begin within 14 working days after randomisation and within 12 weeks of day 1 of the last cycle of adjuvant chemotherapy. Radiotherapy should be given according to local policy (concomitant trial treatment and radiotherapy is permitted). Patients will be randomised 2: 1 (in favour of celecoxib) to receive:

   Two Placebo capsules twice daily with food or Two Celecoxib 200mg capsules twice daily (800mg per day) with food The duration of celecoxib/placebo treatment is 2 years. In addition all postmenopausal ER + and/or PgR+ postmenopausal patients will receive exemestane (25mg daily) for 5 years. The start of the treatment will be at same time as starting celecoxib or placebo.
3. Routine Follow up Visits During the course of the trial all patients will be followed up every 3 months in the first year, every 6 months in !years 2 and 3 and annually from year 4 onwards.

   Follow up Assessments
   * Clinical examination and history
   * Haematology \& biochemistry
   * Metastatic screen -additional tests/investigations (eg. Bone/liver scan etc) are at the investigators discretion if clinically indicated.
   * Serious Adverse Events
4. Follow up upon relapse Any relapse requires treatment to be stopped and patients should have the minimum tests carried out as described in section (c) above.

Relapse is categorized as ipsilateral breast or axillary nodal relapse \[loco regional\] distant relapse (including supraclavicular nodes) \[distant\] and contralateral breast disease (malignant) \[2nd primary\]. In the event of tumor recurrence the relevant recurrence form should be completed and the trials office notified within 4 weeks.

All patients will be followed up long term irrespective o whether they have been withdrawn from treatment prematurely.

Eligibility Criteria:
Inclusion Criteria:

1. Completely resected (greater or equal 1mm), histologically or cytologically proven unilateral breast cancer
2. Female greater or equal 18 years of age
3. If (neo) adjuvant chemotherapy received, patient must have received at least 4 cycles. Chemotherapy must be completed prior to study entry
4. Hormone Receptor negatives must have received prior chemotherapy
5. Study entry must be within any of the following timelines: 3 months of the end of definitive breast surgery OR between 3 weeks and 4 months after day 1 of the last cycle of adjuvant chemotherapy OR 6 weeks of the end of radiotherapy.
6. WHO performance status 0 or 1
7. Pre-treatment haematology and biochemistry values within acceptable local limits: Haemoglobin, white blood cell greater or equal to 3.0 x 109/l or absolute neutrophil count greater or equal to 1.51 x 109/l, Platelets greater or equal to 100 x 109/l, Serum bilirubin less than 1.5 x upper normal limit , Alkaline phosphatase less or equal to 1.5 x upper normal limit , Serum creatinine less than 1.5 x upper normal limit
8. Negative pregnancy test for patients with child-bearing potential
9. Normal baseline ECG and clinical cardiovascular assessment after completion of all (neo) adjuvant chemotherapy
10. No previous or current evidence for metastatic disease
11. Be accessible for and consent to long term follow-up
12. Written informed consent prior to commencement of specific protocol procedures must be obtained and documented according to the local regulatory requirements

Exclusion Criteria

1. Patients with node negative, T1, Grade 1 breast cancer
2. Unresectable, metastatic or bilateral breast cancer
3. Active or previous peptic ulceration or gastrointestinal bleeding in the last year
4. Active or previous history of inflammatory bowel disease
5. A past history of adverse reaction/hypersensitivity to NSAIDs, including celecoxib and salicylates, or sulphonamides
6. On current or planned chronic NSAIDs therapy (except low dose aspirin 100 mg four times per day or 325mg once daily).
7. Current or long-term use of oral corticosteroids
8. Known or suspected congestive heart failure (greater than New York Heart Association I) and/or coronary heart disease, previous history of myocardial infarction, uncontrolled arterial hypertension (ie BP greater than 160/90mmHg) under treatment with two anti-hypertensive drugs, rhythm abnormalities requiring permanent treatment.
9. Patients with diabetes controlled by diet and oral medication are eligible for the study however patients with insulin dependent diabetes are excluded
10. Past history of stroke/Transient ischaemic attack, symptomatic peripheral vascular disease or carotid disease
11. Previously entered into an adjuvant chemotherapy trial for which approval for entry into REACT has not been granted
12. ER receptor status unknown, Human epidermal growth factor receptor 2 or FISH positive, or Human epidermal growth factor receptor 2 status unknown

14. Hormone Receptor negative and not received (neo)adjuvant chemotherapy 15. Use of hormone replacement therapy within the last 6 weeks 16. Pregnant or lactating women or women of childbearing potential unwilling/unable to use non-hormonal contraception 17. No previous or concomitant malignancies except adequately treated squamous cell / basal cell carcinoma of the skin, in situ carcinoma of the cervix or ductal carcinoma in situ/lobular carcinoma in situ of the breast, unless there has been a disease-free interval of 10 years or more 18. Psychiatric or addictive disorders which could preclude obtaining informed consent 19. Clinical evidence of severe osteoporosis and/or history of osteoporotic fracture