Bayer Initiates Phase III Trial of Stivarga® (regorafenib) Tablets in Patients with Colorectal Cancer after Resection of Liver Metastases

WHIPPANY, N.J., Feb. 20, 2014 /PRNewswire/ -- Bayer HealthCare today announced that the company has begun to enroll patients in the COAST trial studying Stivarga^® (regorafenib) tablets in colorectal cancer (CRC) patients with resected liver metastases. The randomized, double-blind, placebo-controlled Phase III trial is designed to determine the effects of Stivarga as adjuvant treatment following surgical removal of liver metastases.¹

"Patients with more advanced colorectal cancer often develop liver metastases – meaning the disease has spread to the liver," said Joseph Germino, Vice President of Medical Affairs, Oncology, Bayer HealthCare. "The COAST trial will investigate treatment with Stivarga in these patients following surgery to remove liver tumors and completion of chemotherapy."

Stivarga is approved by the U.S. Food and Drug Administration (FDA) to treat two different tumor types. In September 2012, Stivarga was first approved for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. In February 2013, the FDA also approved Stivarga to treat patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.²

About Colorectal Cancer
Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States, in both men and women. It is estimated that almost 143,000 people will be diagnosed with CRC in 2013, and nearly 51,000 people will die from the disease.³ Approximately 50% of colon cancer patients will be diagnosed with liver metastases, either at the time of diagnosis or due to recurrent disease.⁴

About the COAST Study
The COAST [Patients with Stage IV COlorectal Cancer treated with Adjuvant Regorafenib Versus Placebo after Curative Treatment of Liver Metastases in a Randomized, Double-blind, Placebo-controlled Phase-III STudy] clinical trial is studying Stivarga in patients with colorectal cancer after surgical removal of liver metastases and completion of all planned chemotherapy. The primary endpoint of the study is Disease Free Survival (DFS) as assessed by the investigator. DFS is defined as the time (in days) from date of randomization to date of first observed disease recurrence or death. The trial will enroll approximately 750 patients who will be randomized in a 1:1 ratio to receive either Stivarga or placebo. Patients will receive 160 mg Stivarga or placebo. Both treatments will be followed by a low-fat meal for 3 weeks of treatment followed by 1 week without treatment. Safety and tolerability of the treatment groups will be continuously monitored.¹

The study will be conducted in North America, Brazil, Europe, Asia, Israel and Australia. For further information about the study, please visit www.clinicaltrials.gov.

About Stivarga (regorafenib)
In the United States, Stivarga is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. It is also indicated for the treatment of patients with locally advanced, unresectable or metastatic GIST who have been previously treated with imatinib mesylate and sunitinib malate.²

Stivarga is an inhibitor of multiple kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment.²

Stivarga is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx Pharmaceuticals, Inc., an Amgen subsidiary (NASDAQ: AMGN), under which Onyx receives a royalty on all global net sales of Stivarga in oncology.

Important Safety Information for Stivarga^® (regorafenib) tablets:

WARNING: HEPATOTOXICITY

• Severe and sometimes fatal hepatotoxicity has been observed in clinical trials.
• Monitor hepatic function prior to and during treatment.
• Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 Stivarga-treated patients across all clinical trials. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the Stivarga arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the Stivarga arm. 

Obtain liver function tests (ALT, AST, and bilirubin) before initiation of Stivarga and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue Stivarga, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% with Stivarga vs 8% and 3% with placebo in mCRC and GIST patients, respectively. Fatal hemorrhage occurred in 4 of 632 (0.6%) Stivarga -treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence was 45% and 67% with Stivarga vs 7% and 12% with placebo in mCRC and GIST patients, respectively. Incidence of Grade 3 HFSR (17% vs 0% in mCRC and 22% vs 0% in GIST), Grade 3 rash (6% vs <1% in mCRC and 7% vs 0% in GIST), serious adverse reactions of erythema multiforme (0.2% vs 0% in mCRC), and Stevens-Johnson syndrome (0.2% vs 0% in mCRC) was higher in Stivarga-treated patients. Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga -treated patients across all clinical trials. Withhold Stivarga, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

Stivarga caused an increased incidence of hypertension (30% vs 8% in mCRC and 59% vs 27% in GIST with Stivarga vs placebo, respectively). Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. Do not initiate Stivarga until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension.

Stivarga increased the incidence of myocardial ischemia and infarction in mCRC (1.2% with Stivarga vs 0.4% with placebo). Withhold Stivarga in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) occurred in 1 of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.

Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across clinical trials. In GIST, 2.1% (4/188) of Stivarga-treated patients developed gastrointestinal fistula or perforation: of these, 2 cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.

Treatment with Stivarga should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. Stivarga should be discontinued in patients with wound dehiscence.

Stivarga can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The most frequently observed adverse drug reactions (greater than or equal to 30%) in Stivarga-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

The most frequently observed adverse drug reactions (greater than or equal to 30%) in Stivarga-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 15%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

For full prescribing information, including BOXED WARNING, visit www.stivarga-us.com.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare provides products for General Medicine, Hematology, Neurology, Oncology and Women's Healthcare. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

Stivarga^® is a trademark of Bayer^®. Bayer^® and the Bayer Cross^® are registered trademarks of Bayer AG.

Forward Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer Web site at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References:

1. A Randomized, Double-blind, Placebo-controlled Phase-III Study of Adjuvant Regorafenib Versus Placebo for Patients With Stage IV Colorectal Cancer After Curative Treatment of Liver Metastases (COAST). Available at http://clinicaltrials.gov/ct2/show/NCT01939223?term=regorafenib+and+liver+metastases&rank=1. Accessed February 17, 2014.
2. STIVARGA^® (regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, February 2013.
3. American Cancer Society. Key statistics for colorectal cancer. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003096-pdf.pdf. Accessed on October 30, 2013.
4. National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional/page9. Stage IV and. Recurrent Colon Cancer Treatment. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional/page9. Accessed October 30, 2013.

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SOURCE Bayer HealthCare Pharmaceuticals Inc.