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
"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
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
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
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,
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."