The New England Journal of Medicine (NEJM) today published Phase I data regarding Glivec* [GLEE-vek] (formerly STI571), the oral investigational agent from Novartis Oncology for the treatment of patients with chronic myeloid leukemia (CML). Also featured in this issue of the NEJM is a case history of the treatment of a patient with a gastrointestinal stromal tumor (GIST). GISTs are solid tumors that express an activated protein shown to be inhibited by Glivec. The publication of these studies comes shortly after Novartis Oncology submitted applications with health authorities globally seeking marketing authorization for Glivec for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy.
The applications are supported by data from three large Phase II studies
of approximately 1,230 patients in 32 centers in five countries. To date,
Glivec has been studied in more than 5,000 patients in 30 countries.
Submissions have taken place in the United States, the European Union, Canada,
Switzerland and Australia, with the application to be filed shortly in Japan.
Results Among CML Patients
NEJM cites that in the Phase I clinical trial evaluating Philadelphia
chromosome-positive CML patients in chronic phase who were resistant or
intolerant to interferon, 98 percent of these patients (53 of 54 total)
achieved a complete hematologic response which has been maintained in 96
percent (51 of 53) of patients. A major cytogenetic response was found in
31 percent of patients (17 of 54 total), which thus far have been durable.
Thirteen percent (7 of 54 total) of these patients had a complete cytogenetic
response. A cytogenetic response indicates the disappearance or reduction of
Philadelphia chromosome-positive cells. In the portion of this Phase I study
evaluating Philadelphia chromosome-positive patients in myeloid blast crisis,
55 percent of patients (21 of 38 total) achieved a hematologic response
(11 percent were complete responses). In the study arm evaluating Glivec in
patients with acute lymphoblastic leukemia (ALL), 70 percent (14 of 20 total)
achieved a hematologic response (20 percent were complete responses). Most of
these patients began to relapse after 3 or 4 months.
Activity in GIST
Data from the case history featured in NEJM suggest that Glivec may have a
role in patients with advanced, malignant GIST. The case history indicated
that a considerable reduction in the patient's total tumor size, as assessed
by positron emission tomography (PET)-scan images, was achieved within two
weeks after treatment began. An objective, partial response, with 52 percent
reduction in the total size of liver metastases, was achieved within one month
after starting Glivec. At the time of publication of the data -- slightly
more than one year after the first dose of Glivec -- all sites of tumor
continued to respond to treatment.
As Glivec is still at an early phase of clinical testing for GIST, its
safety and efficacy have not yet been established in this patient population,
and clinical trial participants are being closely monitored.
Glivec represents a new type of antiproliferative agent called a signal
transduction inhibitor (STI), which has been shown to have the potential to
interfere with intracellular signaling pathways that have implications in
tumor development. Glivec molecularly targets an abnormal protein produced by
the specific chromosomal abnormality called the Philadelphia chromosome, which
is present in a majority of patients with CML.
Glivec also has been shown to have the potential to target the c-kit
protein tyrosine kinase receptor. This receptor is present, and in a majority
of cases mutated, causing it to be continually active in GIST. Because Glivec
demonstrated clinical activity in GIST, Novartis has expanded its trials to
include inoperable or metastatic GISTs. These GIST trials are based on a
collaborative, worldwide effort to treat more than 1,000 patients and will
include clinical trials in conjunction with cancer cooperative groups in the
United States, Canada, Europe, Australia, and potentially other organizations
in Latin America and throughout the world.
Additionally, in programs of small-scale (proof-of-concept) studies,
Novartis recently began investigating the role of Glivec in other solid tumors
in which the biological mechanisms suggest potential activity for Glivec,
including hormone refractory prostate cancer, gliomas (a cancer of the brain)
and small-cell lung cancer. These pilot studies are intended to establish the
basis for further investigations in clinical trials.
In clinical trials in CML, Glivec has been well tolerated with side
effects including nausea, muscle cramps, edema, skin rash, diarrhea, heartburn
and headache, which have been largely mild or moderate in intensity. Fewer
than three percent of patients have experienced serious side effects such as
the potential for liver toxicity, fluid retention and hemorrhages.
In the United States, patients and physicians interested in more
information on these studies can contact the Novartis Oncology Clinical Trials
Hotline at 1-800-340-6843, or the company's website,
http://www.novartisoncology.com. Patients outside the United States should
contact the Medical Department of the local Novartis Pharma Company or consult
the "contact us" section of the company's website,