Novartis files for adjuvant use of Gleevec

[Guest guest]

- Gleevec Receives FDA Priority Review as First Therapy to Reduce

Recurrence

of Gastrointestinal Stromal Tumors After Surgery

- Clinical data showing unprecedented 89% reduction in risk of GIST relapse

with use of Gleevec after surgery are basis for FDA, EMEA, Swissmedic

filings

- Historically, one in two patients experienced recurrence of GIST after

surgery - Regulatory submissions reflect continued commitment to bringing

new

therapeutic approaches to patients with rare diseases

http://www.biospace.com/news_story.aspx?StoryID=107925 & full=1

EAST HANOVER, N.J., Aug 27, 2008 /PRNewswire via COMTEX/ -- Novartis

announced today that Gleevec® (imatinib mesylate) tablets* has been

granted

priority review status by the US Food and Drug Administration (FDA) as the

first

therapy to be reviewed for use after surgery in kit-positive

gastrointestinal

stromal tumors (GIST). FDA priority review status is granted to therapies

that

could potentially fill a currently unmet medical need and accelerates the

standard review timing from ten to six months(1). Similar regulatory

submissions have been filed in the European Union and Switzerland and will

be filed in

other countries shortly.

* Known as Glivec® (imatinib) outside the US, Canada and Israel.

The Gleevec submissions are based on data from a Phase III, double-blind,

randomized, multicenter, international study of more than 700 GIST patients

who

had surgery to remove their tumors. The results showed a dramatic 89%

reduction in risk of kit-positive GIST returning after surgery (adjuvant

setting)

in patients treated with Gleevec versus placebo(2).

In early 2007, the study met its primary efficacy endpoint, showing an

advantage for Gleevec in recurrence-free survival. At that time, following

the

recommendation of the independent study data monitoring committee to stop

the

trial accrual early, the study investigators made public the interim results

and offered Gleevec to patients receiving placebo(3).

Approximately half of all patients with newly diagnosed GIST are considered

candidates for surgical resection, or removal of their tumors. Of those who

have the surgery, about half will suffer a recurrence(4). If approved for

this

indication, Gleevec will be the first treatment option available to GIST

patients after surgery to reduce the risk of disease recurrence or to

possibly

prevent the disease from returning.

" The dramatic clinical results from this study of Gleevec in the adjuvant

GIST setting are especially encouraging when we consider the incremental

benefit we typically see with other adjuvant therapies for solid tumors, "

said

Rainer Boehm, MD, Executive Vice President, North American Region Head,

Novartis

Oncology. " The adjuvant use of Gleevec, if approved, would represent an

important advance in the ongoing post-surgery management of GIST. "

Gleevec is currently indicated in both the US and EU for the first-line

treatment of metastatic or unresectable (inoperable) kit-positive GIST. If

approved, the use of Gleevec for the treatment of GIST in the adjuvant

setting

would add to its eight current indications, which include Philadelphia

chromosome-positive chronic myelogenous leukemia (Ph+ CML) and five other

rare

diseases. Novartis also has a therapy for the treatment of carcinoid tumors

and

acromegaly and multiple treatments in the pipeline targeting rare diseases.

Filing data

The study on which the regulatory filing is based compared the

recurrence-free survival of GIST patients taking Gleevec 400 mg/day versus

placebo for one

year immediately following surgery. The results showed that 98% of patients

receiving Gleevec remained recurrence free at one year following surgery

compared to approximately 82% of those receiving placebo(3). This shows

that as a

result of adjuvant therapy with Gleevec, there was an 89% reduction in risk

of GIST returning(2).

The study, known as ACOSOG Z90001, was conducted at multiple cancer centers

throughout the US and Canada, under a ative Research and Development

Agreement between Novartis and the National Cancer Institute (NCI). The

study

was led by the American College of Surgeons Oncology Group (ACOSOG).

The investigators reported that Gleevec therapy was well tolerated by most

patients, with side effects similar to those observed in previous clinical

trials with Gleevec. These include nausea, diarrhea and swelling

(edema)(3).

About gastrointestinal stromal tumors (GIST)

Gastrointestinal stromal tumors (GIST) belong to a group of cancers known

as

soft tissue sarcomas. They are the most common sarcomas and can be found

most often in the stomach and small intestine. The incidence of GIST is

estimated to be 4,500 - 6,000 new cases per year in the US (15-20 cases per

million

population)(5), of which more than 90% are kit-positive(6). Kit -- also

known

as CD117 -- is a protein that, when mutated, has been identified as one of

the major causes of GIST.

About Gleevec

Gleevec® (imatinib mesylate) tablets are indicated for the treatment of

newly diagnosed adult patients with Philadelphia chromosome-positive

chronic

myeloid leukemia (Ph+ CML) in the chronic phase. Follow-up is limited to 5

years. Gleevec is also indicated for the treatment of patients with Ph+ CML

in

blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after

failure of interferon-alpha (IFN-alpha) therapy; adult patients with

relapsed or

refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL); adult patients with

myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR

(platelet-derived growth factor receptor) gene rearrangements; adult

patients

with aggressive systemic mastocytosis (ASM) without the D816V c-KIT

mutation or

with c-KIT mutational status unknown; adult patients with hypereosinophilic

syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the

FIP1L1-

PDGFR alpha fusion kinase (mutational analysis or FISH demonstration of

CHIC2 allele deletion) and for patients with HES and/or CEL who are

FIP1L1-PDGFR

alpha fusion kinase-negative or unknown; adult patients with unresectable,

recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP);

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(7)

Fetal harm can occur when Gleevec is administered to a pregnant woman;

therefore, women of childbearing potential should be advised to not become

pregnant while taking Gleevec tablets and to avoid breast-feeding while

taking

Gleevec tablets because of the potential for serious adverse reactions in

nursing

infants. Sexually active female patients taking Gleevec should use adequate

contraception. If the patient does become pregnant while taking Gleevec,

the

patient should be advised of the potential hazard to the fetus.

In adult Ph+ CML patients, severe (NCI Grades 3/4) lab abnormalities --

including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia

(<1%-33%) and

hepatotoxicity (approx 5%) -- and severe adverse experiences (NCI Grades

3/4), including severe fluid retention (e.g., pleural effusion, pulmonary

edema,

and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%), and

musculoskeletal pain (2%-9%) were reported among patients 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.

* Numbers indicate the range of percentages in 4 studies among adult

patients with Ph+ CML in blast crisis, accelerated phase, and chronic

phase.

In HES/CEL patients, instances of Grade 3 leukopenia, neutropenia,

lymphopenia, and anemia were reported.

For DFSP, severe (NCI Grades 3/4) lab abnormalities included anemia (17%),

thrombocytopenia (17%), neutropenia (8%) and increased creatinine (8%).

In GIST, 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 (e.g., 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.

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.

Dose adjustments may be necessary due to hepatotoxicity, other

nonhematologic adverse reactions, or hematologic adverse reactions. Therapy

with Gleevec

was discontinued for drug-related adverse reactions in 2.4% to 5% of adult

patients with Ph+ CML and for adverse reactions in 5% of KIT+ GIST

patients.

None of the 5 patients in the ASM study discontinued Gleevec due to

drug-related

events or abnormal laboratory values. Complete blood counts should be

performed weekly for the first month, biweekly for the second month, and

periodically thereafter as clinically indicated (for example, every 2-3

months).

A 25% decrease in the recommended dose should be used for patients with

severe hepatic impairment.

Some GIST patients (5%) were reported to have severe gastrointestinal (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 GI perforation.

In patients with HES and cardiac involvement, cases of cardiogenic

shock/left ventricular dysfunction have been associated with the initiation

of

imatinib therapy. The condition was reported to be reversible with the

administration of systemic steroids, circulatory support measures, and

temporarily etc etc