ODAC Recommends Accelerated Approval of Liposomal Doxorubicin for Kaposi's Sarcoma

ROCKVILLE, Md--After hours of heated debate, the FDA's OncologicDrugs Advisory Committee (ODAC) decided there was sufficient evidenceof efficacy to recommend approval of DOX-SL (pegylated liposomaldoxorubicin) for the treatment of AIDS-related Kaposi's sarcoma(KS) in patients who have failed first-line treatment or who cannottolerate other treatment. The potential benefits of the drug generallyoutweigh the risks, the committee said.

However, their recommendation to the FDA was for accelerated approvalof the drug. A recommendation for unconditional approval was unanimouslyvoted down, due to concerns about possible protocol and safetyviolations and difficulties in measuring improvements in the studies.

Under the accelerated approval status, the drug's sponsor, LiposomeTechnology, Inc. (LTI), of Menlo Park, Calif, will be requiredto collect additional pertinent data to carry out appropriatepostmarketing studies.

'Not Just Another Analog'

I. Craig Henderson, MD, chief of medical oncology, Universityof California, San Francisco, and a director of LTI, referredto DOX-SL as a "new drug" rather than an analog of doxorubicin.He said that liposomes are generally versatile drug carriers,but they may be limited in their ability to reach target cells.However, DOX-SL, a liposome packed with doxorubicin, has provedto be highly stable, with a relatively long half-life and clearancerate.

Because of its long plasma residence time, DOX-SL tends to preferentiallyenter tissues with compromised blood vessels (such as soft-tissuetumors) and therefore provides good therapeutic effect, Dr. Hendersonsaid. In a regimen of 20 mg/m² every 3 weeks, DOX-SL hasdemonstrated the ability to deliver and maintain therapeutic dosesof doxorubicin to KS lesions.

Difficulties in Measuring Outcomes

Susan Krown, MD, of Memorial Sloan-Kettering Cancer Center anda principal investigator for LTI, said that KS is a frustratingdisease to treat and evaluate because its symptoms and manifestationsare often subjective. Lesion changes as a result of treatmentcan be difficult to measure and characterize.

Since AIDS-related Kaposi's sarcoma is not currently curable,the goals of treatment are palliation of symptoms: decrease inthe number of lesions; diminution in their size, shape, and color;lessening of pain and edema; and improvement in the patient'semotional and functional well being.

She noted that there have been no published studies on second-linetreatment for KS, and the experience with conventional doxorubicin,all of which has been anecdotal, has been highly variable.

Rather than relying on patients' perceptions of improvement toanalyze the efficacy of DOX-SL, Dr. Krown devised the IndicatorLesion Assessment, which consists of measurement of the color,size, thickness, and other characteristics of lesions. She acknowledgedthat this method is not perfect, but maintained that it is a "validand consistent" assessment tool.

Donald Northfelt, MD, University of California, San Francisco,Medical Center and another principal investigator, said that studiesusing this assessment showed that DOX-SL "ameliorated symptomsto a very gratifying degree."

Cardiotoxicity Reduced

Richard Mamelok, MD, LTI medical director, reported on the safetyof DOX-SL in 753 patients from a variety of clinical trials. Themost frequent side effects were leukopenia, including neutropenia.There were 18 deaths (2%) that might have been dose related. Otherside effects included infusion-related reactions, and rednessand blistering of hands and feet, which were mostly mild and transitory.

Margaret Billingham, MD, Stanford University Medical Center, presenteddata on several patients showing that at cumulative doxorubicindoses known to cause substantial irreversible cardiotoxicity withthe conventionally administered drug, DOX-SL patients exhibitedcardiotoxicity similar to that seen in patients with advancedHIV disease who had not received an anthracycline.

Members of the committee expressed grave concern about two majorissues: protocol violations, especially the inclusion of ineligiblepatients, and safety violations.

Before-and-After Pictures Lacking

Several members of the committee discussed their confusion abouthow many patients who did not or could not benefit from conventionaldoxorubicin or other chemotherapeutic agents actually improvedon DOX-SL. For example, not all patients in the studies presentedby the sponsoring company had before-and-after pictures taken.

ODAC members were also concerned about the lack of randomizationin the studies, but took into account that the trials were a mechanismfor providing DOX-SL to patients on a "compassionate use"basis.

Charles Schiffer, MD, ODAC chairman and professor of medicineand oncology, University of Maryland Cancer Center, summed upthe committee's refusal to recommend unconditional approval ofDOX-SL while remaining reluctant to withhold a drug with obvioustherapeutic benefit:

"We have acted on imperfect data, but we have acted out ofsympathy for the patients who suffer from this disease."