New Study Shows Initial Treatment With 800 mg/day GLEEVEC- Significantly Improved Progression-Free Survival in Group of High-Risk Patients With Rare Form of Gastrointestinal Cancer-Note the side effect descriptions

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New Study Shows Initial Treatment With 800 mg/day Imatinib Mesylate

(GLEEVEC) 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 GleevecR (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

s- 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 GlivecR (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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