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

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

PR Newswire

WHIPPANY, N.J., Feb. 20, 2014

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 ina
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

  oSevere and sometimes fatal hepatotoxicity has been observed in clinical
    trials.
  oMonitor hepatic function prior to and during treatment.
  oInterrupt 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.

Intended for U.S. Media Only

SOURCE Bayer HealthCare Pharmaceuticals Inc.

Contact: Rose Talarico, +1 862 404 5302, rose.talarico@bayer.com
 
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