Healthcare Industry News: cardiac monitor
News Release - May 23, 2006
Recruitment Planned to Resume in AVANT International Phase III Trial in Adjuvant Colon CancerInterim Safety Data Analysis Reveals Acceptable Safety Profile Across All Trial Arms
NUTLEY, N.J., May 23 (HSMN NewsFeed) -- Roche announced today its intention to resume patient recruitment into all treatment arms of the AVANT trial, a study of the different combination chemotherapy treatments FOLFOX-4, FOLFOX-4 + Avastin, and XELOX (XELODA + oxaliplatin) with and without AvastinŽ for post-surgical adjuvant colon cancer.
The decision to lift the temporary recruitment hold was based on the findings from the AVANT independent Data Safety Monitoring Board's (DSMB) analysis of safety data, including 60-day safety data of all patients enrolled in the study prior to the temporary recruitment hold. The DSMB concluded that the current safety profile of AVANT is consistent with that seen in other adjuvant colon cancer trials -- as are the 60-day and overall mortality rates -- and is similar across all treatment arms of the trial.
Additionally, the AVANT study protocol will be amended to include a cardiac monitoring Plan (CMP) in order to gain further insights into the trial, such as the potential occurrence of cardiac events and sudden deaths across all arms of the trial(1). Patient recruitment will resume upon clearance by the relevant Independent Review Boards and Health Authorities.
"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 patients' outcomes," said Professor Aimery de Gramont, Principal Investigator for AVANT. "We are confident that the AVANT study results will open new avenues for patients with colon cancer."
"We are committed first and foremost to the safety of the patients in our clinical trials and welcome the DSMB recommendation," said Lars E. Birgerson, Vice President, Medical Affairs, Roche. "We look forward to resuming recruitment for AVANT, which is an important component of Roche's ongoing oncology clinical trial program exploring the potential of cornerstone therapies such as Xeloda in combination with anti-angiogenic therapies."
About the safety review of the AVANT study
Since the AVANT trial began in December 2004, approximately two-thirds of the trial's target enrollment of 3,450 patients has been enrolled. On February 14, 2006, patient recruitment was temporarily halted to enable the DSMB to undertake a review of 60-day safety data. This action was taken as a result of potential safety concerns and the rapid pace of recruitment in the AVANT trial, and a concern to assure adequate and timely intervention. Patients who were already enrolled into the AVANT trial prior to the recruitment suspension continued treatment according to the study protocol throughout the 60-day review period.
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.
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 (XELODA + 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.
Xeloda is the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Inactive in pill form, Xeloda is enzymatically activated within the body; when it comes into contact with a naturally occurring protein called thymidine phosphorylase, or TP, Xeloda is transformed into 5-FU, a cytotoxic (cell-killing) drug. Because many cancers have higher levels of TP than does normal tissue, more 5-FU is delivered to the tumor than to other tissue. A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Xeloda is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required.
The most common adverse events (greater than or equal to 20%) of Xeloda monotherapy were diarrhea, nausea, stomatitis and hand-foot syndrome. As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.
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, nephroticsyndrome 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. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world's leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years, the Roche Group has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. An employer of choice, in 2005, Roche was named one of Fortune magazine's Best Companies to Work For in America, one of the Top 20 Employers (Science magazine), ranked as the No. 3 Best Company to Work For in NJ (NJ Biz magazine), the No. 1 Company to Sell For (Selling Power), and one of AARP's Top Companies for Older Workers. For additional information about the U.S. pharmaceuticals business, visit our websites: http://www.rocheusa.com or http://www.roche.us.
(1) The added CMP will include an enhanced (ECG and blood tests) cardiac assessment at the baseline, at cycle 1 and 2, and after completion of chemotherapy for all new patients entering the trial.
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