Gleevec(R) Approved in the US for Five Rare Life-Threatening Disorders With Limited Treatment Options

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Gleevec® Approved in the US for Five Rare Life-Threatening Disorders

With Limited Treatment Options

Thursday October 19, 7:25 pm ET

* Approvals Represent First Time a Regulatory Authority has

Simultaneously Approved One Targeted Medicine for Five Disorders

* Now Approved for the Solid Tumor Cancer, Dermatofibrosarcoma

Protuberans

* US Approval Also Granted for Treatment of Four Blood Diseases:

- Relapsed/Refractory Philadelphia Chromosome-Positive Acute

Lymphoblastic Leukemia

- Myelodysplastic/Myeloproliferative Diseases

- Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

- Aggressive Systemic Mastocytosis

* Multiple Approvals in Only Five Years Highlight new Approach of

Developing Treatments Based on Common Molecular Pathways

EAST HANOVER, N.J., Oct. 19 /PRNewswire-FirstCall/ -- In another

important milestone, Gleevec/GlivecR (imatinib mesylate)* tablets has

received US regulatory approval to help patients with five distinct and

potentially life-threatening disorders, representing the first time that

a regulatory authority has ever simultaneously approved one targeted

medicine for so many disorders.

With today's decision, and in only five years, Gleevec has now been

approved in the US for seven diseases, including two solid tumors and

five blood disorders with molecular targets known to be inhibited by the

drug.

All of the diseases covered in the new approval by the US Food and Drug

Administration (FDA) are rare and potentially life threatening. For many

of the patients who suffer from them, few, if any approved treatments

were available prior to Gleevec.

" The effectiveness of Gleevec in these five diseases further underscores

how cancers and diseases of different origin and location can share

common pathways that often respond to the same targeted treatment, " said

Diane Young, MD, Vice President and global head of Clinical Development

at Novartis Oncology. " These approvals further build and demonstrate our

historical commitment to developing therapies for patients with rare

diseases such as acromegaly, carcinoid syndrome and gastrointestinal

stromal tumors. "

The FDA approvals are based on data from Novartis-sponsored clinical

studies and clinical data from independent medical researchers showing

the efficacy of Gleevec in the treatment of these diseases, in which

there is a suggested connection between a Gleevec-sensitive pathway and

a disease.

Gleevec targets the activity of proteins called tyrosine kinases that

appear to play important roles within some cancer cells. Gleevec has

been shown to inhibit the function of the tyrosine kinase Bcr-Abl in

patients with certain forms of blood cancer -- Philadelphia

chromosome-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia

chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) -- and the

receptor tyrosine kinase Kit in Kit-positive GIST (gastrointestinal

stromal tumor).

Researchers have found Gleevec also inhibits other tyrosine kinases,

including platelet-derived growth factor receptor (PDGFR), which have

been shown to be activated in disease pathways that underlie a number of

rare hematologic diseases, as well as some solid tumors.

The new diseases for which Gleevec received approval include one solid

tumor and various rare blood disorders. The solid tumor is

dermatofibrosarcoma protuberans (DFSP), a type of tumor that begins as a

hard lump found in the skin of the chest, abdomen or leg. The four blood

diseases include:

* Relapsed/refractory Philadelphia chromosome-positive acute

lymphoblastic

leukemia (Ph+ ALL), a rapidly progressive blood cancer

characterized by

the presence of the Philadelphia chromosome

* Certain forms of myelodysplastic/myeloproliferative diseases

(MDS/MPD),

which involve certain blood cells made in the bone marrow

* Hypereosinophilic syndrome/chronic eosinophilic leukemia

(HES/CEL),

which is characterized by the persistent overproduction of

eosinophils,

a certain type of white blood cell

* Aggressive systemic mastocytosis (ASM), which is marked by the

presence

of too many mast cells, a certain type of white blood cell.

An approval for newly diagnosed patients is still under review by the

FDA. In the European Union (EU), Gleevec was recently approved for

treatment of certain patients with Ph+ ALL as well as for adult patients

with a form of DFSP. The EU is also reviewing applications for approval

of Gleevec as a treatment for the three other diseases MDS/MPD, HES/CEL

and ASM.

About Gleevec Tablets

In addition to these new indications, Gleevec (imatinib mesylate)

tablets are indicated for the treatment of newly-diagnosed adult and

pediatric patients with Philadelphia chromosome-positive chronic myeloid

leukemia (Ph+ CML) in chronic phase. Follow-up is limited. Gleevec

tablets are also indicated for the treatment of patients with Ph+ CML in

blast crisis, in accelerated phase, or in chronic phase after failure of

interferon-alpha (IFN-a) therapy. Gleevec is also indicated for the

treatment of pediatric patients with Ph+ chronic phase CML whose disease

has recurred after stem cell transplant or who are resistant to IFN-a

treatment. There are no controlled trials in pediatric patients

demonstrating a clinical benefit, such as improvement in disease-related

symptoms or increased survival.

Gleevec tablets are also indicated for the treatment of patients with

KIT (CD117)-positive unresectable and/or metastatic malignant

gastrointestinal stromal tumors (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 Information(1)

Hematologic Disorders

For Ph+ CML, severe (NCI Grades 3/4) lab abnormalities-including

neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-33%),

and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades

3/4), including severe fluid retention (eg, pleural effusion, pulmonary

edema, and ascites) and superficial edema (1.8%-11%), hemorrhage

(1%-19%), and musculoskeletal pain (2%-9%) were reported among adults

receiving Gleevec. Severe fluid retention appears to be dose related,

was more common in the advanced phase studies (where the dosage was 600

mg/day), and is more common in the elderly. 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.

The overall safety profile of Ph+ CML pediatric patients treated with

Gleevec in 93 children studied was similar to that found in studies with

adult patients, except that musculoskeletal pain was less frequent

(20.5%) and peripheral edema was not reported. Nausea and vomiting were

the most commonly reported individual adverse events with an incidence

similar to that seen in adult patients.

The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM and

HES/CEL were generally similar to Ph+ CML.

The most frequently reported drug-related adverse events reported in the

Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle

cramps and rash, which were easily manageable. Superficial edemas were a

common finding in all studies and were described primarily as

periorbital or lower limb edemas. However, these edemas were rarely

severe and may be managed with diuretics, other supportive measures, or

in some patients by reducing the dose of Gleevec.

Frequently reported adverse events in the seven MDS/MPD patients

assessed were nausea (57%); diarrhea and muscle cramps (43% each);

anemia, fatigue, arthralgia, and periorbital edema (29% each).

All ASM patients experienced at least one adverse event at some time.

The most frequently reported adverse events were diarrhea, nausea,

ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia,

pruritis, rash and lower respiratory tract infection.

All HES/CEL patients experienced at least one adverse event, the most

common being gastrointestinal, cutaneous and musculoskeletal disorders.

Hematological abnormalities were also frequent, with instances of Grade

3 leukopenia, neutropenia, lymphopenia and anemia.

In patients with HES and cardiac involvement, cases of cardiogenic

shock/left ventricular dysfunction have been associated with the

initiation of Gleevec therapy. The condition was reported to be

reversible with the administration of systemic steroids, circulatory

support measures and temporarily withholding Gleevec. MDS/MPD and ASM

may be associated with high eosinophil levels. Monitoring should

therefore be considered in patients with HES/CEL, and in patients with

MDS/MPD or ASM associated with high eosinophil levels.

Solid Tumors

For GIST, severe (NCI Grades 3/4) lab abnormalities-including

neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-33%),

and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades

3/4), including severe fluid retention (eg, pleural effusion, pulmonary

edema, and ascites) and superficial edema (1.8%-11%), hemorrhage

(1%-19%), and musculoskeletal pain (2%-9%) were reported among Gleevec

patients. Severe fluid retention appears to be dose related, was more

common in the advanced phase studies (where the dosage was 600 mg/day),

and is more common in the elderly. 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.

Frequently reported adverse events in the 12 DFSP patients assessed

include nausea and fatigue (42% each); periorbital, peripheral and eye

edema (33% each); diarrhea, vomiting, rash, lacrimation increased, and

anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis and

anorexia (17% each).

Important Safety Information for all Indications(1)

Severe congestive heart failure and left ventricular dysfunction have

occasionally been reported in patients taking Gleevec. Most of the

patients with reported cardiac events have had other co-morbidities and

risk factors, including advanced age and previous medical history of

cardiac disease. In an international randomized phase 3 study of 1,106

patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac

failure and left ventricular dysfunction were observed in 0.7% of

patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C.

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 (e.g., erythema multiforme and

s- syndrome) have been reported. In some cases, the

reaction recurred upon rechallenge. Several post-marketing reports

described cases in which patients tolerated reintroduction of Gleevec

after resolution or improvement of the bullous reaction. In these

instances, Gleevec was resumed at a lower dose 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

non-hematologic adverse events, or hematologic adverse events.

Therapy with Gleevec was discontinued for adverse events in 3% to 5% of

adult patients with Ph+ CML or Kit+ GIST. None of the 5 patients in the

ASM study discontinued Gleevec due to drug-related adverse events or

abnormal laboratory values.

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 tablets 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.

Patients with severe hepatic impairment should be treated at a starting

dose of 300 mg/day and should be closely monitored.

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 Effects of Gleevec Tablets(1)

The majority of the approximately 1700 adult patients who received

Gleevec in clinical studies experienced adverse events at some time, but

most were mild to moderate in severity. The most frequently reported

adverse events were superficial edema (58%-81%), nausea (47%-74%),

diarrhea (39%-70%), muscle cramps (28%-62%), vomiting (21%-58%), rash

(36%-53%), fatigue (30%-53%), musculoskeletal pain (30%-49%), and

abdominal pain (30%-40%).

The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM and

HES/CEL were generally similar to Ph+ CML.

Supportive care may help management of most mild to moderate adverse

events so that prescribed dose can be maintained whenever possible

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.

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