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

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

PR Newswire

WAYNE, N.J., May 15, 2013

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

  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.

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 better life 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.

Intended for U.S. Media Only

SOURCE Bayer HealthCare Pharmaceuticals Inc.

Website: http://www.bayer.com
Contact: Rose Talarico, +1 973 305 5302, rose.talarico@bayer.com
 
Press spacebar to pause and continue. Press esc to stop.