Bayer开始第三期肝癌试验

StephenW

Bayer Begins Phase III Liver Cancer Trial


Bayer Initiates Phase III Trial of Stivarga® (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.

StephenW

拜耳启动III期临床试验中晚期肝癌患者的Stivarga®（regorafenib）的片

WAYNE，NJ，5月15日，2013日电/美通社亚洲/  - 拜耳医药保健公司今天宣布，该患者的招生正在进行RESORCE（Regorafenib后，索拉非尼在肝癌患者），国际III期临床试验，以评估疗效和安全性的Stivarga®（ regorafenib）片剂用于治疗进展多吉美（索拉非尼）片剂，用于治疗不能手术切除的肝癌患者的抗癌药物与肝细胞癌（HCC）患者。 stivarga是涉及多种激酶的抑制剂，在正常的细胞功能和病理过程，如肿瘤发生，肿瘤血管生成和维护肿瘤microenvironment.1的

已被批准stivarga由美国食品和药物管理局（FDA）的两种不同类型的肿瘤。在2013年2月，美国FDA批准Stivarga治疗局部晚期，不可切除或转移性胃肠道间质瘤（GIST）先前已经治疗甲磺酸伊马替尼和舒尼替尼malate.1去年九月，被批准用于治疗转移性患者Stivarga此前已与氟尿嘧啶，奥沙利铂和伊立替康为基础的化疗治疗结直肠癌（MCRC）的抗VEGF治疗，如果KRAS野生型，抗EGFR therapy.1的

A.居鲁士说：“帕梅拉，医学博士，副总裁兼美国医学”肝癌患者病情恶化的索拉非尼治疗后，仅口服全身治疗不能手术切除的肝癌患者，以提高整体的生存有一个未满足的需要，事务，拜耳医药保健。 “我们期待着与科学界分享我们的研究结果。”

关于RESORCE研究
索拉非尼后Regorafenib肝癌（RESORCE）临床试验的患者是一项随机，双盲，安慰剂对照，多中心III期研究在肝癌患者病情恶化的索拉非尼治疗后regorafenib。该试验将招募约530名患者将被随机以2:1的比例接受要么regorafenib加最佳支持治疗（BSC）或安慰剂加BSC.2

该研究的主要终点是总生存期，次要终点是时间的进展，无进展生存期，客观肿瘤反应率，疾病控制率。治疗组的安全性和耐受性也将不断monitored.2

在北美，南美，欧洲，亚洲和澳大利亚将进行RESORCE研究。有关研究的进一步信息，请访问：www.clinicaltrials.gov.2

关于肝癌（HCC）
有几种类型的癌症，就可以开始在肝脏中。肝细胞癌（HCC）是最常见的形式，在成人中占大约80％的癌症起源于肝脏肝癌是肝癌更为常见的男性比妇女

美国癌症协会估计，2013年将超过30,000个新例原发性肝癌的诊断在美国States.4美国人罹患肝癌的比例一直在上升缓慢几decades.4

关于Stivarga（regorafenib）
Stivarga用于治疗局部晚期，不可切除或转移性胃肠道间质瘤（GIST）患者以前治疗甲磺酸伊马替尼和舒尼替尼malate.1表示，这也表明，用于治疗转移性结直肠癌患者此前已处理氟尿嘧啶，奥沙利铂和伊立替康为基础的化疗，抗VEGF治疗，而且，如果KRAS野生型，抗EGFR therapy.1的

stivarga是涉及多种激酶的抑制剂，在正常的细胞功能和病理过程，如肿瘤发生，肿瘤血管生成和维护肿瘤microenvironment.1的

Stivarga是拜耳化合物，由拜耳公司开发的，共同推动了由拜耳和Onyx在美国。在2011年，拜耳与玛瑙，玛瑙接收皇族在全球净销售额为肿瘤Stivarga在订立一项协议。

重要安全信息Stivarga®（regorafenib）的片：

警告：肝毒性

    在临床试验中已观察到严重的，有时甚至是致命的肝毒性。
    之前和治疗期间监测肝功能。
    中断和减少或停止Stivarga表现升高的肝功能检查或肝细胞坏死的肝毒性，根据严重性和持久性。



在0.3％的1200 Stivarga治疗的患者在所有临床试验中发生严重的药物性肝损伤有致命的结果。在转移性结直肠癌（MCRC），在Stivarga臂和安慰剂组0.4％的患者在1.6％的患者发生致命的肝功能衰竭，肝衰竭患者在肝脏转移性疾病。在胃肠道间质肿瘤（GIST），发生致命的肝功能衰竭患者在Stivarga臂0.8％。

获得肝功能检查（ALT，AST，胆红素）前开始Stivarga和监视期间至少每2周前2个月的治疗。此后，监测每月或更频繁的临床指征。监测肝功能检查，每周在患者出现肝功能试验，直到改善小于3倍正常上限（ULN）或基线值。暂时保留，然后减少或永久终止Stivarga的严重性和持久性升高的肝功能检查或肝细胞坏死的肝毒性表现而定。

Stivarga引起出血的发病率增加。 （1-5年级）的总体发病率是21％和11％与Stivarga与8％和3％的转移性结直肠癌和GIST患者与安慰剂组，分别为。 4 632（0.6％）的Stivarga治疗的患者发生致命性出血和涉及呼吸道，胃肠道或泌尿生殖道。永久停止Stivarga的患者更频繁地接受华法林的患者的严重或危及生命的出血，监测INR水平。

Stivarga引起手足皮肤反应（HFSR）（又称掌跖红肿[PPE]），和严重皮疹的发生率增加，经常需要调整剂量。总发病率为45％和67％与Stivarga与7％和12％的转移性结直肠癌和GIST患者与安慰剂组，分别为。三年级HFSR（17％比10％的转移性结直肠癌，22％和0％GIST），3级皮疹（6％VS <转移性结直肠癌的1％和7％和0％的GIST），严重不良反应的红斑的发病率多形（0.2％和0％，转移性结直肠癌），史蒂文斯 - 约翰逊综合征（0.2％和0％，转移性结直肠癌）是在Stivarga治疗的患者。发生在0.17％1200 Stivarga治疗的患者在所有临床试验中毒性表皮坏死松解症。扣压Stivarga，减少剂量，或永久停止取决于皮肤毒性的严重性和持久性。

Stivarga引起高血压（30％比8％的转移性结直肠癌和59％比27％与Stivarga与安慰剂组相比，分别在GIST）的发生率增加。在0.25％的1200 Stivarga治疗的患者在所有临床试验中发生高血压危象。不要启动Stivarga的，直到充分控制血压。监测血压每周的第6个星期的治疗，然后每个周期，或更频繁，有临床指征。暂时或永久隐瞒Stivarga严重或不受控制的高血压。

Stivarga转移性结直肠癌（1.2％与Stivarga相较于0.4％，与安慰剂）心肌缺血和梗死的发病率增加。预扣Stivarga在开发新的或急性心肌缺血或心肌梗死的患者，如果潜在的好处大于风险的进一步心肌缺血，分辨率为急性心脏缺血事件后，才恢复。

1 1200 Stivarga的治疗的患者在所有临床试验中发生可逆性后部白质脑病综合征（RPLS）。 RPLS任何病人出现癫痫发作，头痛，视力障碍，混乱或精神功能改变进行评估。确认与MRI诊断RPLS，并停止Stivarga开发RPLS患者。

发生胃肠穿孔或瘘管在0.6％，1200例患者临床试验与Stivarga跨。 GIST中，2.1％（4/188）的Stivarga治疗的患者胃肠瘘或穿孔：，这些胃肠穿孔，2例是致命的。永久终止Stivarga的胃肠穿孔或瘘管的病人谁开发。

应停止治疗Stivarga择期手术前至少2周。手术后的恢复治疗，应根据足够的伤口愈合的临床判断。 Stivarga应停止患者伤口裂开。

Stivarga会对胎儿造成伤害，当给予怀孕妇女。使用有效的避孕，治疗期间及治疗结束后长达2个月。如果在怀孕期间使用此药，如果病人在怀孕期间服用这种药物，患者应了解对胎儿的潜在危险。

因为许多药物排泄在人类乳汁和因为在哺乳婴儿来自Stivarga潜在的严重不良反应，应做出决策是否终止哺乳或终止药物，考虑到药物对母亲的重要性。

最常观察到的药物不良反应（大于或等于30％）与安慰剂治疗的转移性结直肠癌患者中，分别在的Stivarga治疗的患者，分别为：乏力/疲劳（64％比46％），降低食欲和食物摄入量（ HFSR / PPE（45％比7％），腹泻（43％比17％），黏膜炎（33％比5％），体重减轻（32％比10％），47％比28％），感染（31％对17％），高血压（30％和8％），和发声困难（30％和6％）。

最常观察到的药物不良反应（大于或等于30％）的处理Stivarga的患者比接受安慰剂治疗的GIST患者，分别是：HFSR / PPE（67％比15％），高血压（59％比27 ％），虚弱/疲劳（52％比39％），腹泻（47％比9％），黏膜炎（40％比8％），发声困难（39％比9％），感染（32％比5％），降低食欲和食物摄入量（31％比21％），皮疹（30％比3％）。

完整处方信息，包括黑框警告，请访问www.stivarga-us.com。

MP4

瑞格非尼,已上市,肝毒性?