Basel, 23 May 2006

Recruitment to resume in AVANT international phase III trial in post-surgical adjuvant colon cancer

Temporary suspension of recruitment to be lifted following analysis of safety data

Roche announced today their intention to resume patient recruitment into the AVANT trial, a study of different combination chemotherapies, including two Roche medicines, Xeloda and Avastin, for post-surgical adjuvant treatment of colon cancer.

The decision to lift the temporary hold on recruitment was taken following the recommendation by the AVANT independent Data Safety Monitoring Board (DSMB). The DSMB concluded that the current safety profile and the death rates from all causes in AVANT were consistent with those seen in other adjuvant colon cancer trials. Thus, no concerns were raised about continuing recruitment in AVANT.
Patient recruitment will therefore resume upon clearance by the relevant Independent Review Boards and Health Authorities.

Professor Aimery de Gramont, Principal Investigator for AVANT stated: “We are very pleased to resume recruitment. The AVANT trial provides a unique opportunity to investigate whether combining an anti-angiogenic agent with standard chemotherapy in the adjuvant colon cancer setting will enhance patient outcomes. We are confident that the AVANT study results will open new avenues of treatment for patients with colon cancer.”

Ed Holdener, Head of Global Development at Roche said “We welcome this recommendation from the DSMB. Patient safety is of utmost importance to us and it is essential that safety data are carefully monitored, particularly in the adjuvant treatment setting where patients have an additional chance of being cured of their cancer by post-surgical therapy.”

About the safety review of the AVANT study
Since the AVANT trial began in December 2004, approximately two thirds of the target number of 3,450 patients have been enrolled. On February 14, 2006, patient recruitment was temporarily halted to enable the DSMB to undertake a review of 60-day safety data. Patients who had already enrolled into the AVANT trial prior to the recruitment suspension have continued treatment according to the study protocol. This review was initiated for two reasons: a potential safety signal observed in one of the three study arms and the fast recruitment in the AVANT trial, which could impede adequate and timely intervention. The data review undertaken by the DSMB with a cut-off date of April 25, 2006 revealed that the all cause mortality excluding deaths due to recurrent colon cancer, in the AVANT trial for FOLFOX-4 (Arm A) was 0.8% (6 cases), for FOLFOX-4 + Avastin (Arm B) 0.5% (4 cases) and for XELOX + Avastin (Arm C) 1.05% (8 cases). These rates are consistent with those reported in other adjuvant studies in colon cancer. In order to gain further insights into the potential occurrence of cardiac events and sudden deaths, the AVANT study protocol will be amended to include a Cardiac Monitoring Plan (CMP*) .

About AVANT
The AVANT trial is a 3-arm global study (308 centers from 33 countries) randomizing high-risk stage II and stage III patients with colon cancer to FOLFOX-4 (infused/bolus 5-FU/LV + oxaliplatin), FOLFOX-4 plus Avastin, or XELOX (capecitabine + oxaliplatin) plus Avastin (arms A, B and C respectively). The objectives of AVANT are to assess whether adding Avastin to the chemotherapy regimens FOLFOX-4 or XELOX can prolong disease-free survival (i.e. whether it can reduce the chance of the cancer recurring) in patients who had no evidence of disease after curative surgery and to determine the safety profile of Avastin when used in combination with FOLFOX-4 or XELOX in the adjuvant setting.

About Avastin
Avastin is the first treatment that inhibits angiogenesis – the growth of a network of blood vessels that supply nutrients and oxygen to cancerous tissues. Avastin targets a naturally occurring protein called VEGF (Vascular Endothelial Growth Factor), a key mediator of angiogenesis, thus choking off the blood supply that is essential for the growth of the tumour and its spread throughout the body (metastasis).

Avastin is the first and only anti-angiogenic agent to have demonstrated improved overall and/or progression-free survival in the three major types of cancer leading to death: colorectal cancer, non-small cell lung cancer and breast cancer. In Europe, Avastin was approved early 2005 for first-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with the chemotherapy regimens of intravenous 5-fluorouracil/folinic acid or intravenous 5-fluorouracil/folinic acid/irinotecan. Avastin received approval by the US Food and Drug Administration (FDA) in February 2004. In addition, filing occurred in the US on April 10, 2006, for use of Avastin in previously untreated advanced non-squamous, non-small cell lung cancer and in Japan on April 21, 2006 for use of Avastin in patients with advanced or recurrent colorectal cancer

Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure.  The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia.  

Roche and Genentech are pursuing a comprehensive clinical program investigating the use of Avastin in multiple tumor types (including colorectal, breast, lung, pancreatic cancer, ovarian cancer, renal cell carcinoma, prostate and others) and different settings (advanced and adjuvant ie post-operation). The total development program is expected to include over 25,000 patients worldwide.

About Xeloda
Xeloda is licensed in more than 90 countries worldwide including the EU, USA, Japan, Australia and Canada and has been shown to be effective, safe, simple and convenient oral chemotherapy treating over 1 million patients to date.

Roche received marketing authorisation for Xeloda as a first-line monotherapy (by itself) in the treatment of metastatic colorectal cancer (colorectal cancer that has spread to other parts of the body) in most countries (including the EU and USA) in 2001. Xeloda has also been approved by the European Medicines Agency (EMEA) and U.S. Food and Drug Administration (FDA) for adjuvant (post-surgery) treatment of colon cancer in March and June 2005, respectively.

Xeloda is licensed in combination with Taxotere (docetaxel) in women with metastatic breast cancer (breast cancer that has spread to other parts of the body) and whose disease has progressed following intravenous (i.v.) chemotherapy with anthracyclines. Xeloda monotherapy is also indicated for treatment of patients with metastatic breast cancer that is resistant to other chemotherapy drugs such as paclitaxel and anthracyclines. Xeloda is licensed for the first-line treatment of stomach cancer that has spread, in South Korea.

The most commonly reported adverse events with Xeloda include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As a supplier of innovative products and services for the early detection, prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2005 sales by the Pharmaceuticals Division totalled 27.3 billion Swiss francs, and the Diagnostics Division posted sales of 8.2 billion Swiss francs. Roche employs roughly 70,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Additional information about the Roche Group is available on the Internet (www.roche.com).

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* The added CMP will include an enhanced (ECG and blood tests) cardiac assessment at baseline, cycle 1 and 2 and after completion of chemotherapy for all new patients entering the trial.