Doxil Wins Full Approval for Relapsed Ovarian Ca

ROCKVILLE, Maryland—The 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 Medicine, Phoenix.

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.