Bayer HealthCare Pharmaceuticals Initiates Phase III Trial of Stivarga&#0174 (regorafenib) Tablets in Patients with Advanced Liver Cancer

WAYNE, N.J., May 15, 2013 /PRNewswire/ -- Bayer HealthCare announced today that patient enrollment is underway for RESORCE (Regorafenib after Sorafenib in Patients with Hepatocellular Carcinoma), an international Phase III trial to evaluate the efficacy and safety of Stivarga^® (regorafenib) tablets for the treatment of patients with hepatocellular carcinoma (HCC) who have progressed on Nexavar^® (sorafenib) tablets, an anticancer medicine for the treatment of patients with unresectable HCC. 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.¹

Stivarga has been approved by the U.S. Food and Drug Administration (FDA) for two different tumor types. In February 2013, the FDA 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.¹ Last September, Stivarga was 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.¹

"There is an unmet need for HCC patients whose disease has progressed after treatment with sorafenib, the only oral systemic therapy shown to improve overall survival in patients with unresectable HCC," said Pamela A. Cyrus, MD, Vice President and Head of U.S. Medical Affairs, Bayer HealthCare Pharmaceuticals. "We look forward to sharing our findings with the scientific community."

About the RESORCE Study
The Regorafenib after Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) clinical trial is a randomized, double blind, placebo controlled, multicenter Phase III study of regorafenib in patients with hepatocellular carcinoma whose disease has progressed after treatment with sorafenib. The trial will enroll approximately 530 patients who will be randomized in a 2:1 ratio to receive either regorafenib plus best supportive care (BSC) or placebo plus BSC.²

The primary endpoint of the study is overall survival, and secondary endpoints are time to progression, progression-free survival, objective tumor response rate and disease control rate. Safety and tolerability of the treatment groups will also be continuously monitored.²

The RESORCE study will be conducted in North America, South America, Europe, Asia and Australia. For further information about the study, please visit: www.clinicaltrials.gov.²

About Hepatocellular Carcinoma (HCC)
Several types of cancer can start in the liver. Hepatocellular carcinoma (HCC) is the most common form of liver cancer in adults and accounts for about 80 percent of cancers that originate in the liver.³ HCC is much more common in men than in women.⁴

The American Cancer Society estimates that in 2013 more than 30,000 new cases of primary liver cancer will be diagnosed in the United States.⁴ The percentage of Americans developing liver cancer has been rising slowly for several decades.⁴

About Stivarga (regorafenib)
Stivarga is 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.¹ It is also 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.¹

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.¹

Stivarga is a Bayer compound developed by Bayer and jointly promoted by Bayer and Onyx in the United States. In 2011, Bayer entered into an agreement with Onyx, 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.

Important Safety Considerations for Nexavar^® (sorafenib) tablets:

Nexavar in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

Cardiac ischemia and/or myocardial infarction may occur. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or myocardial infarction.

An increased risk of bleeding may occur following Nexavar administration. If bleeding necessitates medical intervention, consider permanent discontinuation of Nexavar.

Hypertension may occur early in the course of treatment. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, if required.

Hand-foot skin reaction and rash are common and management may include topical therapies for symptomatic relief. In cases of any severe or persistent adverse reactions, temporary treatment interruption, dose modification, or permanent discontinuation of Nexavar should be considered. Nexavar should be discontinued if Stevens-Johnson Syndrome or toxic epidermal necrolysis are suspected as these may be life threatening.

Gastrointestinal perforation was an uncommon adverse reaction and has been reported in less than 1% of patients taking Nexavar. Discontinue Nexavar in the event of a gastrointestinal perforation.

Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time (PT), International Normalized Ratio (INR) or clinical bleeding episodes.

Temporary interruption of Nexavar therapy is recommended in patients undergoing major surgical procedures.

Nexavar in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Nexavar has not been established in patients with non-small cell lung cancer.

Nexavar can prolong the QT/QTc interval and increase the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome and monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities.

Drug-induced hepatitis with Nexavar may result in hepatic failure and death. Liver function tests should be monitored regularly and in cases of increased transaminases without alternative explanation Nexavar should be discontinued.

Nexavar may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should be advised to avoid becoming pregnant while on Nexavar and female patients should also be advised against breastfeeding while receiving Nexavar.

Elevations in serum lipase and reductions in serum phosphate of unknown etiology have been associated with Nexavar.

Avoid concomitant use of strong CYP3A4 inducers, when possible, because inducers can decrease the systemic exposure of Nexavar. Nexavar exposure decreases when co-administered with oral neomycin. Effects of other antibiotics on Nexavar pharmacokinetics have not been studied.

Most common adverse reactions reported for Nexavar-treated patients vs. placebo-treated patients in unresectable HCC, respectively, were: diarrhea (55% vs. 25%), fatigue (46% vs. 45%), abdominal pain (31% vs. 26%), weight loss (30% vs. 10%), anorexia (29% vs. 18%), nausea (24% vs. 20%), and hand-foot skin reaction (21% vs. 3%). Grade 3/4 adverse reactions were 45% vs. 32%.

For information about Nexavar including U.S. Nexavar prescribing information, visit www.nexavar.com or call 1.866.NEXAVAR (1.866.639.2827).

About Oncology at Bayer
Bayer is committed to delivering science for a betterlife by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes two 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.

Nexavar^® (sorafenib) tablets is a registered trademark of Bayer HealthCare Pharmaceuticals, Inc.

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.

References:

1. STIVARGA Prescribing Information, February 2013.
2. Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma (RESORCE). ClinicalTrials.gov Identifier: NCT01774344. Available at http://www.clinicaltrials.gov/ct2/show/study/NCT01774344?term=regorafenib&rank=6#locn. Accessed March 1, 2013.
3. American Cancer Society. What is liver cancer? Hepatocellular cancer (HCC). (Last Revised 01/18/2013). Available at http://www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-what-is-liver-cancer. Accessed March 1, 2013.
4. American Cancer Society. What are the key statistics about liver cancer? (Last Revised 01/18/2013). Available at http://www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-what-is-key-statistics. Accessed March 1, 2013.

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SOURCE Bayer HealthCare Pharmaceuticals Inc.