Bayer Collaborates with U.S. National Surgical Adjuvant Breast and Bowel Project (NSABP) to Investigate Stivarga® (Regorafenib) Tablets as Additional Adjuvant Therapy in Colon Cancer

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Jun 01, 2016, 02:30 ET

WHIPPANY, N.J., June 1, 2016 /PRNewswire/ -- Bayer and the U.S. National Surgical Adjuvant Breast and Bowel Project (NSABP), a leading clinical trials cooperative group, are collaborating on a new Phase III study to investigate Stivarga^® (regorafenib) tablets as an additional adjuvant therapy in colon cancer. The ARGO trial will investigate regorafenib as a single agent for the adjuvant treatment of Stage IIIB and IIIC colon cancer following completion of standard adjuvant chemotherapy. In this stage, the tumor has started to invade the wall of the colon, but not yet spread to other distant organs.

"In 2016, more than 134,000 adults in the United States will be diagnosed with colorectal cancer. Two-thirds of these cases, or more than 95,000, will be cancers of the colon," said Norman Wolmark, M.D., Chairman of the NSABP. "Despite receiving adjuvant chemotherapy, patients with stage IIIB and IIIC colon cancer are at risk of developing metastatic disease, meaning that the disease has spread from the colon to distant organs. We are keen to explore if regorafenib could help patients at earlier stages of the disease."

The Phase III study ARGO, a randomized, double-blind, placebo-controlled study, will be conducted by NSABP, with Bayer offering consultation as well as financial support. If positive, Bayer may use the results as the basis for regulatory filings to health care authorities to support an expanded indication for the use of Stivarga in this earlier stage of disease.

"At Bayer, we are committed to working with research organizations such as NSABP to further investigate the full clinical utility of our cancer treatments such as regorafenib," said Dario Mirski, M.D., Bayer's senior vice president and head of medical affairs, Americas. "Such collaborations help to transform our collective experience into impactful medicines for people battling the toughest cancers."

Regorafenib is approved under the trade name Stivarga^® in 90 countries worldwide, including the United States, countries in the European Union and Japan for the treatment of metastatic colorectal cancer (CRC). The approval of regorafenib was based on data from the pivotal Phase III CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial. Full results from the CORRECT study were published in January 2013 in The Lancet.

About the ARGO Study
The Phase III study ARGO (A Phase III Randomized Placebo-Controlled Study Evaluating ReGOrafenib Following Completion of Standard Chemotherapy for Patients with Stage III Colon Cancer) will investigate whether providing oral regorafenib monotherapy in the adjuvant setting after standard chemotherapy increases disease-free survival (DFS) in patients with Stage IIIB/IIIC colon cancer. The secondary study endpoints include overall survival (OS) and safety. The trial will enroll approximately 1,100 patients from the U.S. who will be randomized in a 1:1 ratio to receive either 120 mg regorafenib or placebo for a planned duration of two years.

About Colon Cancer
The colon is part of the body's digestive system, which is called the gastrointestinal system.¹ Most colon cancers begin as a growth or a polyp on the inner lining of the colon, a part of the large intestine.¹ Some types of polyps can develop into cancer over the course of several years.¹ The cancer occurs when cells in the body begin to grow out of control.¹ Colon cancer is often grouped with rectal cancer because the two diseases share many common features.¹ However, treatment approaches may differ for colon and rectal cancers, especially in the earlier stages.²

In the U.S., colorectal cancer is currently the third most common cancer diagnosed and the second leading cause of cancer-related deaths when estimates for men and women are combined.³ In 2016, an estimated 134,490 Americans will be diagnosed with colorectal cancer.³ General estimates predict that 1 in 20 will be diagnosed with the disease in their lifetime.⁴

About Stivarga (regorafenib)
In the United States, Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) 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 gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.⁵

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.

Hepatotoxicity: 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.

Liver Function Monitoring: 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.

Hemorrhage: 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.

Dermatological Toxicity: 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.

Hypertension: 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.

Cardiac Ischemia and Infarction: 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 Laukoencephalopathy Syndrome (RPLS): 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: 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.

Wound Healing Complications: 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.

Embryo-Fetal Toxicity: 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.

Nursing Mothers: 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.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥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%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in Stivarga-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), 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 the Boxed Warning, visit http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf.

About the National Surgical Adjuvant Breast and Bowel Project
The National Surgical Adjuvant Breast and Bowel Project (NSABP) is a clinical trials cooperative group supported since its inception by the National Cancer Institute (NCI).

Since its beginning the NSABP has enrolled more than 110,000 women and men in clinical trials in breast and colorectal cancer. Headquartered in Pittsburgh, Pennsylvania, the NSABP has research sites at nearly 1000 major medical centers, university hospitals, large oncology practice groups, and health maintenance organizations in the United States, Canada, Puerto Rico, Australia, and Ireland. In addition to federally sponsored studies, the NSABP also conducts research supported by other resources.

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.

Bayer: Science For A Better Life
Bayer is a global enterprise with core competencies in the Life Science fields of health care and agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2015, the Group employed around 117,000 people and had sales of EUR 46.3 billion. Capital expenditures amounted to EUR 2.6 billion, R&D expenses to EUR 4.3 billion. These figures include those for the high-tech polymers business, which was floated on the stock market as an independent company named Covestro on October 6, 2015. For more information, go to www.bayer.us.

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 website 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.

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