NeXstar Pharmaceuticals made four DaunoXome-related presentations
at the 9th NCI-EORTC Symposium on New Drugs in Cancer Therapy
in Amsterdam, The Netherlands. Parkash S. Gill, MD, associate
professor medicine and pathology at the University of Southern
California School of Medicine, reported that DaunoXome produces
significant improvement in Kaposi's sarcoma (KS) lesions that
have penetrated the lungs. In a new clinical trial involving 35
patients with pulmonary KS, 15 (43%) showed complete or partial
resolution of symptoms. Another 17 patients (49%) realized some
benefit from DaunoXome treatment.
Kaposi's sarcoma lesions penetrate the lungs of up to 47% of patients
and are potentially life-threatening. Dr. Gill was the principal
investigator of DaunoXome's US phase III clinical trial for advanced
Geoffrey M. Mukwaya, MD, a member of NeXstar's clinical staff,
presented pharmacokinetic data from phase II and III clinical
trials in advanced HIV-associated KS. These data showed that DaunoXome
is cleared from the bloodstream more slowly than free daunorubicin.
This longer circulation half-life of DaunoXome allows for greater
concentration of daunorubin in tumors than is otherwise possible
with free drug. However, circulation half-life is not long enough
to produce side effects associated with continuous infusion of
anthracycline anticancer agents.
Theory for Advanced HIV-Associated KS
Dr. Gill made two other presentations at the Amsterdam meeting.
The first summarized the results of the US randomized phase III
clinical trial in which DaunoXome was compared to the standard
three-drug regimen ABV (Adriamycin, bleomycin, and vincristine)
as a therapy for advanced HIV-associated KS. The phase III data
showed that DaunoXome is as effective as ABV, yet produces significantly
fewer of the side effects that adversely affect a patient's quality
of life. For example, alopecia occurred in 8% of patients treated
with DaunoXome, compared with 36% of the patients who received
ABV. Similarly, only 13% of those treated with DaunoXome experienced
neuropathy, compared with 41% of those treated with the ABV regimen.
In addition, median survival for DaunoXome patients was 366 days,
compared with 338 days for those treated with ABV. Median time
to treatment failure was also longer for DaunoXome-treated patients
than for ABV-treated patients (115 vs 99 days).
Lack of Long-Term Cardiotoxicity
In Dr. Gill's second presentation, he said that there is less
cardiotoxicity seen after long-term DaunoXome therapy. Normally,
cardiotoxicity is the chief treatment-limiting side effect associated
with anthracycline chemotherapy, and its incidence increases exponentially
after cumulative doses of 500 mg/m2. In studies involving 277
patients receiving DaunoXome-therapy for advanced HIV-associated
KS, 53 received cumulative doses totaling over 600 mg/m²,
and none of these patients showed signs of anthracycline-induced
cardiotoxicity. Of the 53 patients, 34 received between 600 and
999 mg/m², 12 received between 1,000 and 1,499 mg/m2, and
7 received more than 1,500 mg/m².
"Taken together, these four presentations demonstrate DaunoXome's
novel therapeutic profile, both in terms of efficacy and safety,"
said Michael E. Ross, md, NeXstar's Vice-President for Medical
and Regulatory Affairs. "The lack of cardiac toxicity seen
at doses more than three-fold higher than the normal safe level
of anthracycline therapy is particularly exciting. Being able
to give high cumulative doses of DaunoXome bodes well not only
for the long-term safety of DaunoXome therapy in the treatment
of advanced HIV-associated KS, but also for potential utility
in the aggressive treatment of other cancers known to respond
to anthracycline therapy, such as breast cancer, lymphoma, leukemia
and small-cell lung cancer."