BETHESDA, MdThe FDA’s Oncologic Drugs Advisory Committee (ODAC) has voted 14 to 1 to recommend that the agency grant accelerated approval to Campath (alemtuzumab, Millennium & ILEX Partners) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have been treated with alkylating agents and have failed fludarabine (Fludara) therapy.
Should FDA grant accelerated approval to Campath, it will require that the sponsor conduct a phase IV postmar-keting study to provide additional evidence of the drug’s safety and efficacy.
CLL, a progressive and usually fatal disease, is the most common form of adult leukemia. It strikes about 10,000 people in the United States each year, with a prevalence of about 60,000.
First-line treatment for CLL has been alkylating agents with fludarabine used as second-line therapy. However, in recent years, many oncologists have turned to fludarabine as their first line of attack against CLL. There is no approved drug for patients who fail fludarabine therapy.
Campath is a humanized monoclonal antibody that binds to the CD52 antigen, which is expressed on B and T lymphocytes but not on bone marrow progenitor cells. The initial antibody was developed at Cambridge University in England (Campath stands for Cambridge Pathology). The drug acts by lysing leukemia cells expressing the CD52 antigen, a significantly different mechanism from that of cytotoxic chemotherapies.
The drug’s sponsor presented a pivotal phase II study of 93 CLL patients, designated CAM211, and two smaller phase II trials with a total of 56 patients as supportive evidence. The three studies were multicenter but single-arm and uncontrolled. All 149 patients in the three studies were included in the company’s safety analysis of the drug.
In the pivotal study, Campath was given by intravenous infusion initially at 3 mg on day 1. This was increased to 10 mg when tolerated well, and then to 30 mg, again if well tolerated. Thereafter, it was administered three times a week at 30 mg for up to 12 weeks, depending on response.
The company reported 31 responders (33.3%) in CAM211 (2 complete responders and 29 partial responders). Mean time to response was 1.5 months; median duration of response was 8.7 months; and median survival was 16 months. The FDA medical review team agreed with the company’s assessment of these findings.
"Campath is effective in a population of patients for whom no approved therapies are available, and so represents a significant unmet medical need," said Lee R. Brettman, MD, Millennium Pharmaceuticals’ vice president for medical affairs. "The objective response rate of 33% seen in the pivotal trial significantly exceeded the goal set in the protocol."
Presenting for the FDA review team, Genevieve Schechter, MD, focused much of her attention on the safety profile of Campath that emerged from the FDA analysis of the CAM211 study.
According to the FDA, 90% of patients experience infusional toxicity. Most of these cases were mild, but 13% were grade 3-4. Therapy was interrupted in 47% of patients, and in 32%, the delay lasted 1 week or more. Almost one quarter (24%) of participants discontinued treatment for adverse events.
Dr. Schechter said that 67% of patients experienced serious infusional, infectious, or hematologic adverse events. About half (47%) experienced grade 3-4 anemia; 24% had grade 3 and 55% grade 4 neutropenia; 5% had profound pancytopenia, and three of these patients died prior to hematologic recovery.
She noted that 15% of patients died either possibly or probably as the result of adverse events related to Campath; 32% died in the first 6 months after beginning Campath; about half of these deaths resulted from infections and generally occurred in association with cytopenia.
"I began to realize that there was really a treatment mortality that was of grave concern," Dr. Schechter said.
Dr. Brettman disagreed with some of the FDA’s interpretations of the safety data, and suggested the study findings "represent a reasonable, manageable safety profile in this immunocompromised, refractory-disease population."
Some Unresolved Questions
The pivotal study failed to resolve several significant points, Dr. Schechter said. "Questions that are unanswered are the potential for induction of a second malignancy and the potential for a decrease in survival due to infection and hematologic toxicity related to Campath," she said. "These can only be demonstrated through a comparison trial."
The toxicity issue clearly bothered some members of the committee, as did the lack of a comparison drug in CAM211. Several ODAC members urged specific, clear labeling language to warn physicians of the drug’s toxicity. Yet the lack of an effective alternative treatment for CLL patients who fail fludarabine therapy also weighed heavily in the debate over approval.
Patient representative Barbara Lackritz of St. Louis made a strong plea for getting the drug to market. "I think we tend to get caught up in the numbers, and we forget that CAM211 is really a two-arm trial," she said. "The other arm is death. Patients who are refractory to fludarabine and the alkylating agents don’t have a lot of choice. Something needs to be there for them."