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New Study Shows Initial Treatment With 800 mg/day Imatinib Mesylate Significantly Improved Progression-Free Survival in Group of High-Risk Patients With Rare Form of Gastrointestinal Cancer

• Investigation of high-dose Gleevec regimen significantly reduces relative risk of progression by 61% in patients with specific mutation
• Authors recommend these patients receive 800 mg/day at start of therapy

EAST HANOVER, GERMANY -- May 15, 2006 -- A higher, investigational starting dose of GleevecŪ (imatinib mesylate)* tablets can improve outcomes for high-risk patients with advanced Kit-positive gastrointestinal stromal tumor (GIST) expressing exon 9 mutation, according to new findings from the largest clinical trial to evaluate the drug's effects by mutation. The study findings are now available online and are expected to be published in May.

The clinical trial, an EORTC (European Organisation for Research and Treatment of Cancer) phase 3 study, compared two doses of Gleevec in patients with unresectable and/or metastatic Kit (CD117) positive GIST. While the majority of patients derived benefit from taking 400 mg/day of Gleevec, the study showed that patients whose tumors expressed a mutation on a certain gene segment called exon 9 had significantly superior progression-free survival (P =.0013) when administered Gleevec at the investigational dose of 800 mg/day.

"This latest study provides further evidence that Gleevec is a highly effective therapy for patients with advanced Kit-positive GIST, and offers insight into potential ways to improve long-term outcomes for these patients," said Diane Young, Vice President and global head of Clinical Development at Novartis Oncology. "These data also highlight that the investigational dose of 800 mg/day may be more effective for high-risk patients expressing the exon 9 mutation."

In this study, investigators analyzed data from a recent randomized EORTC Phase III trial comparing two doses of Gleevec (400 mg/day vs. 800 mg/day) in patients with unresectable and/or metastatic Kit-positive GIST, to assess whether tumor genotype correlated with the dose-dependent clinical response to Gleevec. Pre-treatment samples of GISTs from 377 patients enrolled in the clinical trial were analyzed for mutations of Kit and platelet-derived growth factor receptor alpha.

The presence of a Kit exon 9 mutation was the strongest adverse prognostic factor for response to Gleevec, increasing relative risk of progression by 171% (P <.0001) compared to Kit exon 11 mutations. In patients whose tumors expressed a Kit exon 9 mutation, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P =.0013), with a reduction of the relative risk of 61%.

About Gleevec Tablets
Gleevec (imatinib mesylate) tablets are indicated for the treatment of patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST. The effectiveness of Gleevec 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 Information1
Severe (NCI Grades 3/4) lab abnormalities (400mg/day; 600mg/day) -- including neutropenia (10%; 11%), anemia (3%; 9%), and hepatotoxicity (6%; 8%) -- and severe adverse experiences (NCI Grades 3/4), including fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (7%; 12%), hemorrhage (6%; 11%), and musculoskeletal pain (6%; 1%), were reported among Gleevec patients. 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 perforation.

Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing cases note a resolution or improvement of bullous reaction following dose reduction with or without supportive care.

Some patients (5%) were reported to have severe GI bleeds or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.

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 8% of patients at both dose levels.

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 tablets should increase by at least 50% and clinical response should be carefully monitored in patients receiving Gleevec tablets 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 800mg and above, dosing should be accomplished using the 400mg 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

Because of the potential for serious adverse reactions in nursing infants, women should be advised to avoid breast-feeding while taking Gleevec tablets

Common Side Effects1
The majority of patients who received Gleevec in the clinical study experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades, 400mg/day; 600mg/day) were superficial edema (81%; 77%), diarrhea (59%; 70%), nausea (63%; 74%), fatigue (48%; 53%), muscle cramps (47%; 58%), abdominal pain (40%; 37%), rash (38%; 53%), vomiting (38%; 35%), musculoskeletal pain (37%; 30%), and hemorrhage (26%; 34%)*

Supportive care may help the management of most mild to moderate adverse events so that the prescribed dose can be maintained whenever possible

Gleevec tablets should be taken with food and a large glass of water to minimize gastrointestinal (GI) irritation. Gleevec tablets should not be taken with grapefruit juice.


* Known as GlivecŪ (imatinib) outside the U.S.

* Numbers indicate the range of percentages in 5 studies among adult patients with Ph-positive CML and KIT-positive GIST. For more detailed study information, please see the full prescribing information for Gleevec.


SOURCE: Novartis Pharmaceuticals Corporation

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