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New Data Suggest Novel Cellular Agent From Novartis May Show Promise in
Treating Leukemia Patients
Phase II Data of Investigational Agent Amdray(R) (valspodar),
a Multidrug Resistance Modulator
EAST HANOVER, N.J., Feb. 25 /PRNewswire/ -- Data published in a recent
issue of Blood suggest that Amdray(R) (valspodar), a multidrug
modulator being developed by Novartis Pharmaceuticals Corporation, may
promise in treating certain patients with acute myelogenous leukemia
when used in combination with chemotherapy, according to the company.
The data were the results of a phase II multicenter study, coordinated
researchers at Stanford University School of Medicine, that involved
37 patients with AML in whom either chemotherapy had not demonstrated
or who had relapsed after chemotherapy. In this study, patients
combination of mitoxantrone, etoposide and cytarabine (MEC) and Amdray.
Overall, complete or partial remission was achieved in 43% of patients
patients achieved complete remission; four achieved partial remission).
One mechanism through which multidrug resistance (MDR) occurs is
P-glyoprotein (P-gp), overexpression. P-gp is a protein within the
cell membrane that "pumps" out cytotoxic drugs from the cell, thereby
preventing these drugs from reaching toxic levels and destroying the
Amdray (valspodar) works as a potent inhibitor of P-gp. Previously
PSC 833, Amdray is a non-cytotoxic agent that does not suppress the
system or affect the kidneys.
"Multidrug resistance is a significant problem for cancer patients,"
David Parkinson, MD, vice president of clinical research at Novartis
Pharmaceuticals. "The results of this study are encouraging in
the potential role of Amdray in helping to overcome multidrug resistance
patients with AML." Dr. Parkinson continued, "Novartis currently is
completing global, randomized clinical trials of Amdray with
patients with AML. We anticipate the study results to be available by
of 1999, at which point we can more definitively know the role of Amdray
overcoming multidrug resistance."
AML is a rapidly progressing form of leukemia that originates in the
hematopoetic marrow stem cells and results in significant proliferation
these abnormal myeloid cells. While patients with AML usually respond
initially to chemotherapy, afterwards, most become resistant to a broad
of chemotherapeutic agents. The American Cancer Society estimates that
number of new cases of AML diagnosed in 1998 in the United States at
which represents over 30% of all leukemias.
The 37 patients with poor prognosis AML were divided into two groups.
patients were treated with Amdray plus MEC and received Amdray as a
pretreatment loading dose at 2 mg/kg over 4 hours, with subsequent
infusion at 10 mg/kg/d for 120 hours (5 days). Chemotherapy began
after completion of the 4-hour loading dose of Amdray, with the doses of
mitoxantrone and etoposide reduced due to the known pharmacokinetic
interaction between Amdray and these agents.
The six patients in cohort I were treated with mitoxantrone 5 mg/m2/d
intravenous (IV) bolus, days 1 to 5; etoposide 50 mg/m2/d as a one-hour
infusion, days 1 to 5; and cytarabine 1 g/m2/d as a one-hour infusion,
1 to 5. To compensate for pharmacokinetic interactions, which resulted
higher than expected adverse events, the mitoxantrone and etoposide
reduced further to 4 mg/m2/d and 40 mg/m2/d, respectively, in the 31
in cohort II. To test for P-gp function, the uptake and efflux of
rhodamine-123 was monitored by flow cytometry in leukemic cells gated
according to scatter properties and antigen profile. The final study
determined in cohort II is being further investigated in a Phase III
randomized trial by the Eastern Cooperative Oncology Group (ECOG) in the
Overall, 12 patients (32%) achieved complete remission (CR) and four
achieved partial remission (PR). The regimen with Amdray did not
responses in 21 patients. These results were evenly distributed between
disease categories and occurred within both cohorts.
In cohort I, one patient achieved CR, whereas in cohort II, 11 of
31 patients (36%) achieved CR. There was one patient in Cohort I who
PR, and three patients in cohort II who achieved PR.
The study data suggest the possible role of MDR reversal in this patient
group, which is being further evaluated in ongoing Phase III studies.
Thus far, findings from several ongoing studies -- including oral and iv
formulations -- indicate that Amdray is generally well tolerated when
administered in conjunction with chemotherapeutic agents. Side effects
doses currently being studied are transient and reversible. They
dizziness, numbness, tingling of the extremities, nausea,
and increase in liver enzymes. In addition, some patients may
cerebellar dysfunction -- manifested by difficulty in walking or
of coordination -- that is rapidly reversible. When Amdray is used in
combination with chemotherapeutic drugs in clinical trials, the most
clinically significant adverse events are those normally expected from
respected chemotherapeutic regimen.
Products represented by the Novartis oncology franchise include
(pamidronate disodium for injection) for the treatment of osteolytic
metastases in patients with multiple myeloma or breast cancer in
with standard antineoplastic therapy, hypercalcemia of malignancy, and
Paget's disease; Femara(R) (letrozole tablets) for the treatment of
breast cancer in postmenopausal women with disease progression following
antiestrogen therapy; and Sandostatin LAR(R) Depot (octreotide acetate
injectable suspension) and Sandostatin(R) (octreotide acetate injection)
control of symptoms in patients with metastatic carcinoid and vasoactive
intestinal peptide-secreting tumors (VIPomas), and for the treatment of
acromegaly in patients in whom medical therapy is appropriate. In
products to address various hematologic disorders are managed by this
and include Sandoglobulin(R) (Immune Globulin Intravenous (Human) [IGIV]
the maintenance therapy for primary immunodeficiency syndromes and for
treatment of immune thrombocytopenia purpura, and Desferal(R)
mesylate) for treatment of acute iron intoxication and chronic iron
due to transfusion-dependent anemias.
Novartis Pharmaceuticals Corporation researches, develops, manufactures
and markets leading innovative prescription drugs used to treat a number
diseases and conditions, including central nervous system disorders,
transplantation, cardiovascular diseases, dermatological diseases,
respiratory disorders, cancer and arthritis. The company's mission is
improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals
is an affiliate of the Novartis Group, a world leader in Life Sciences
core businesses in Healthcare, Agribusiness and Consumer Health
(Self-Medication and Nutrition). In 1998, Novartis Group sales were CHF
31.7 billion (US B$21.8), of which CHF 17.5 billion (US B$12) were in
Healthcare, CHF 8.4 billion (US B$5.8) in Agribusiness and CHF 5.8
(US B$4.0) in Consumer Health. The group annually invests more than
CHF 3.6 billion (US B$2.5) in R&D. Headquartered in Basel, Switzerland,
Novartis Group employs about 85 000 people and operates in over 100
around the world.
For information, contact:
Gloria Stone Joe Schepers
Novartis Pharmaceuticals Corporation Novartis Corporation
SOURCE Novartis Pharmaceuticals Corporation
CO: Novartis Pharmaceuticals Corporation
ST: New Jersey
IN: MTC HEA
02/25/99 12:31 EST http://www.prnewswire.com
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