Post Surgical GIST study
Positive results prompt US National Cancer Institute to make Gleevec available to patients in post-surgical GIST study
Gleevec found to dramatically reduce the risk of cancer returning after surgery for Kit-positive gastrointestinal stromal tumors (GIST)
Patients receiving placebo in this trial will now be offered Gleevec
Global regulatory submissions planned for use of Gleevec as adjuvant therapy in GIST patients following surgery to remove primary tumor
Gleevec already approved as effective therapy for patients with advanced metastatic or inoperable Kit-positive GIST
East Hanover, April 12, 2007 Investigators will begin offering Gleevec (imatinib mesylate) tablets to patients receiving placebo in a major North American clinical trial after an interim analysis showed participants with Kit-positive gastrointestinal stromal tumors treated with Gleevec following surgery were significantly less likely to experience a return of their cancer compared to those not taking this innovative therapy.
The interim analysis showed no recurrence of cancer in approximately 97% of patients given Gleevec for a year after surgery to remove tumors, compared to approximately 83% of those who underwent surgery but received a placebo. The investigators made these results public because the study had met its primary endpoint in terms of rate of recurrence-free survival.
The study involving more than 600 patients was sponsored by the National Cancer Institute (NCI), part of the US National Institutes of Health (NIH). It was conducted at multiple cancer centers in the US and Canada, and was led by the American College of Surgeons Oncology Group. Novartis supplied Gleevec for use in the study, and also provided partial funding under a Cooperative Research and Development Agreement with NCI to support the clinical development of Gleevec.
Gleevec has already been confirmed as an effective therapy in its approved use for patients with advanced metastatic or unresectable (inoperable) Kit-positive GIST. In a statement issued today by the NIH, the new findings were heralded as excellent news, with major implications for patients with primary disease.
With these new data, we see that Gleevec may help patients with early GIST, said Diane Young, MD, Head of Global Medical Affairs at Novartis Oncology. We will now work with the investigators on a submission to gain regulatory approval for Gleevec as adjuvant treatment for GIST.
Following the recommendation of a data monitoring committee, the study will be closed and patients in the study who are currently being treated with placebo may choose to receive one year of Gleevec.
In the study, patients were randomized to one of two treatment arms. Neither the patients nor physicians knew which treatment the patients were receiving. One patient group received Gleevec at a dose of 400 milligrams per day for one year, while the second group received placebo for one year. According to the study design, patients who developed a recurrence of their cancer while on a study therapy were unblinded to their treatment assignment. Those receiving placebo subsequently received Gleevec, while those already given Gleevec continued with this therapy but at a higher dose. Study results will be presented at a forthcoming scientific meeting.
Gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas that usually arise from the intestinal tract, with the most common site being the stomach followed by the small intestine. The incidence of GIST is estimated to be 4,5006,000 new cases per year in the US (1520 cases per million population), of which more than 90% are kit-positive.
Investigators in the NCI study reported that Gleevec therapy was well tolerated by most patients, with side effects similar to those observed in other clinical trials with Gleevec. These include nausea, diarrhea and swelling (edema). Information on more than 600 patients enrolled in the study was used in the analysis.
Gleevec (imatinib mesylate) is indicated for the treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). The effectiveness of Gleevec in GIST is based on objective response rate. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival
Important Safety Information
Severe (NCI Grades 3/4) lab abnormalities (400 mg/day; 600 mg/day)including neutropenia (10%; 11%), anemia (3%; 9%), thrombocytopenia (0%; 1%), and hepatotoxicity (6%; 8%)and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion or ascites; 3%; 8%) and superficial edema (6%; 5%), hemorrhage (6%; 11%), abdominal pain (11%; 4%), nausea (6%; 4%), diarrhea (3%; 7%), and musculoskeletal pain (6%; 1%) were reported among patients receiving Gleevec
Some patients (5%) were reported to have severe GI bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds
Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, and gastrointestinal (GI) perforation
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events. Therapy with Gleevec was discontinued for adverse events in 5% of patients at both dose levels studied
Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions)
For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron
Use of Gleevec tablets is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec tablets
Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec tablets and should be advised to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants
Common Side Effects of Gleevec Tablets
The majority of patients who received Gleevec in the GIST study experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (400 mg/day; 600 mg/day) (all Grades) were superficial edema (81%; 77%), nausea (63%; 74%), muscle cramps (47%; 58%), diarrhea (59%; 70%), fatigue (48%; 53%), abdominal pain (40%; 37%), rash and related terms (38%; 53%), vomiting (38%; 35%) musculoskeletal pain (37%; 30%), and hemorrhage (26%; 34%)
Supportive care may help management of some mild to moderate adverse events so that the prescribed dose can be maintained whenever possible. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice
The foregoing release contains forward-looking statements that can be identified by terminology such as will, planned, or similar expressions, or by express or implied discussions regarding potential future regulatory submissions, new indications or new labeling for Gleevec, the long-term impact of a patient’s use of Gleevec or potential future sales of Gleevec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that additional regulatory submissions will be made in any particular jurisdictions, or that Gleevec will be approved for any additional indications or labeling in any market. Nor can there be guarantee regarding the long-term impact of a patients use of Gleevec. Neither can there be any guarantee regarding potential future sales of Gleevec. In particular, managements expectations regarding Gleevec could be affected by, among other things, unexpected clinical trial results, including additional analysis of Gleevec clinical data, and new clinical data; unexpected regulatory actions or delays or government regulation generally; the companys ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry, and general public pricing pressures; and other risks and factors referred to in the Company’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, gastrointestinal and respiratory areas. The company’s mission is to improve people’s lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS), a world leader in offering medicines to protect health, treat disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. Novartis is the only company with leadership positions in both patented and generic pharmaceuticals. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. In 2006, the Group’s businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 101,000 associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.
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