ROCKVILLE, MarylandThe Food and Drug Administration
(FDA) has given full approval to Doxil (doxorubicin HCl liposome injection,
Tibotec Therapeutics, Division of Ortho Biotech Products, L.P.) for the
treatment of ovarian cancer in women whose disease has progressed or recurred
after platinum-based chemotherapy.
FDA granted Doxil accelerated approval in 1999 for the
treatment of metastatic ovarian cancer on the basis of three phase II studies
that showed tumor regression in 20 of a total of 145 women (13.8%) who had
failed paclitaxel- and platinum-based therapy. The accelerated approval for use
in ovarian cancer required further clinical study to prove Doxil’s apparent
benefit was real.
The agency gave the drug full approval on the basis of data
from a phase III trial. The drug’s labeling for ovarian cancer was updated to
remove failed paclitaxel treatment from the indication. The labeling also added
survival, time to progression, and tumor response data.
"The phase III data provide evidence of the product’s
clinical benefit for patients with relapsed ovarian cancer," said lead
investigator Alan N. Gordon, MD, of the University of Arizona School of
Doxil first received accelerated approval in 1995 for the
treatment of Kaposi’s sarcoma. The FDA’s new approval decision does not change
the drug’s labeling or its approval status for that disease.
Doxorubicin HCl, the active ingredient in Doxil, is a
cytotoxic anthracycline antibiotic. Its mechanism of action appears related to
its ability to rapidly penetrate cells because of its liposome encapsulation
and to bind to DNA, which inhibits the synthesis of nucleic acid and induces
mutagenesis and chromosomal aberrations.
The phase III trial, known as Doxil Study 30-49, was funded
by Johnson & Johnson, the parent company of Tibotec Therapeutics, which now
markets the drug in the United States.
The open-label trial involved 474 patients (median age, 60)
with epithelial ovarian cancer that recurred after or failed to respond to
first-line platinum-based chemotherapy (about 73% of patients had also received
a taxane). The researchers randomized 239 patients to Doxil 50 mg/m2
every 28 days and 235 patients to topotecan (Hycamtin) 1.5 mg/m2/d
for 5 consecutive days every 21 days.
Time to progression, the primary endpoint, was comparable in
the two arms, 4.1 months for the Doxil-treated patients and 4.2 months for the
topotecan group (P = .617). Overall median survival was 14.4 months in
the Doxil arm and 13.7 months in the topotecan group (P = .05), yielding
an 18% reduction in risk of death (hazard ratio [HR] = 1.216). Overall tumor
response rates were 19.7% (47 patients) in the Doxil arm, and 17% (40 patients)
in the topotecan arm.
The most common hematologic side effects reported in the
phase III trial of Doxil vs topotecan were, respectively, neutropenia (7.9% and
14%), anemia (5.4% and 25.1%), and thrombocytopenia (1.3% and 17%).
Nonhematologic side effects in the two groups, respectively,
that affected 20% or more of Doxil patients included hand-foot syndrome (50.6%
and 0.9%), with 23.8% grade 3-4 in the Doxil group; nausea (46% and 63%);
stomatitis (41.4% and 15.3%); asthenia (40.2% and 51.5%); abdominal pain (33.5%
and 37.9%); vomiting (32.6% and 43.8%); constipation (30.1% and 45.5%); rash
(28.5% and 12.3%); fever (21.3% and 30.6%); pain (20.9% and 17%); diarrhea
(20.9% and 34.9%); and anorexia (20.1% and 21.7%).
Doxil’s labeling contains a black-box warning that Doxil may
result in myocardial damage that leads to congestive heart failure as the total
cumulative dose approaches 550 mg/m2; acute infusion-related
reactions in up to 10% of patients; and severe myelosuppression. It further
states that dosage should be reduced in patients with impaired hepatic
function; Doxil should not be substituted for doxorubicin on a
milligram-per-milligram basis because of the potential for severe side effects;
and the drug should be administered only under the supervision of a physician
experienced in the use of cancer chemotherapeutic agents.
The results of the study were first published by Dr. Gordon and his
colleagues in 2001 and updated in 2004 (Gynecol Oncol 95:1-8, 2004). Dr.
Gordon also presented the updated findings at the 2004 Chemotherapy Foundation
Symposium XXII, where he described the survival results according to platinum
sensitivity. For patients who had platinum-resistant disease, there was no
significant difference in overall survival between the treatment arms. However,
in the platinum-sensitive subset, there was a significant difference in overall
survival apparent "fairly early" in the trial, he said. Median overall survival
was 107.9 weeks for the Doxil group vs 70.1 weeks for topotecan (HR = 1.432,
P = .017), for a 30% reduction in risk of death.