By Lisa Seachrist
SILVER SPRING, Md. - The first liposomal drug to gain approval from the FDA received a recommendation from an FDA advisory panel as a treatment for metastatic ovarian cancer that is resistant to other therapies.
The Oncologic Drugs Advisory Committee voted 9-to-2 to endorse accelerated approval for Alza Corp.'s Doxil (doxorubicin HCL liposome injection) as a treatment for patients whose ovarian cancer is refractory to both paclitaxel and platinum-based therapies. Palo Alto, Calif.-based Alza acquired Doxil from Sequus Pharmaceuticals Inc., following the purchase of Sequus in October 1998.
"We're pleased with the recommendation," said Edward Schnipper, vice president for clinical research at Alza. "There's going to be some discussion with the agency on what will be required for Phase IV."
Doxil was approved in December 1995 as a treatment for refractory Kaposi's sarcoma, a cancer associated with immunosuppression. It was the first liposomal formulation to gain FDA approval. Doxil is the common chemotherapy drug, doxorubicin, encapsulated in a polyethylene glycol coat. The formulation allows the drug to circulate in the blood stream longer than it would without the liposomal encapsulation. As a result, it is more likely that the drug will reach its disease target.
The company presented data on three Phase II studies testing the drug in metastatic ovarian cancer and a prespecified interim analysis of a Phase III study testing Doxil against another chemotherapy agent, topotecan, in metastatic ovarian cancer. Patients had to be refractory to both paclitaxel and platinum-based therapy, which was defined as having progressive disease while on therapy or within six months of completing treatment.
In the first Phase II study conducted in the U.S., patients received infusions of 50 milligrams per meter squared every three weeks. In all subsequent studies, patients received infusions once every four weeks to limit certain side effects. The company examined how many patients responded to treatment with Doxil, which was defined as a 50 percent reduction in tumor burden.
Twenty-one percent of the patients in the first Phase II study responded to therapy with Doxil while 18 percent of patients in the second study responded to the drug. However, none of the patients in the European Phase II study, which is still ongoing, has responded to treatment with Doxil. The Phase III study showed a 13.6 percent response rate. Overall, combining all of the studies of Doxil in ovarian cancer, the response rate was 14.4 percent.
As for side effects, the most disturbing to the panel was a condition known as palmar-plantar-erythordysesthesia (PPE), which can cause severe blistering of the hands and feet in its most advanced state. However, the company showed that the condition could be easily managed and only 3 percent of patients dropped out as a result of PPE. Doxil showed no serious cardiac toxicity or bone marrow toxicity, which is common in doxorubicin treatment.
Accelerated approval allows a company to submit surrogate endpoints such as tumor response rate rather than endpoints like survival advantage in return for conducting clinical studies to confirm the drug's clinical benefit in the postmarket arena. The panel had to decide whether a 14.4 response rate merited a recommendation for accelerated approval.
"I would feel much more comfortable if it weren't for that European trial," said panel member Robert Ozols, senior vice president of medical sciences at Fox Chase Cancer Center in Philadelphia.
Nevertheless, the panel did ultimately agree that Doxil should receive accelerated approval for use in ovarian cancer patients who are refractory to paclitaxel and platinum-based drugs.
"We look at this response rate and shudder," said panel member Stacy Nerenstone, associate clinical professor at the Hartford Hospital in Connecticut. "Although, I think in this population, that this response rate is meaningful."
Should the agency approve Doxil, which it is not bound to do based on this recommendation, Alza is hoping that the FDA will use the final results of the Phase III study as the Phase IV requirement. Schnipper said that those results should be available by the end of this year.
Alza's marketing partner, Schering-Plough Corp., is conducting trials of Doxil in metastatic breast cancer. Schering-Plough, of Madison, N.J., is planning to submit an application for approval in Europe for breast cancer this year.