Giving children access to drug clinical trials is crucial, clofarabine approval shows

May 2 2005

The accelerated approval of the drug clofarabine to treat relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) demonstrates the importance of offering children rapid access to new treatments through clinical trials, according to investigators at St. Jude Children's Research Hospital. Refractory or relapsed ALL is a disease that resists treatment.

Clofarabine was approved for use in the treatment of pediatric patients 1 to 21 years old who have relapsed or refractory ALL that developed after at least two regimens of treatment. Researchers say it has been years since a new anti-cancer drug has received U.S. Food and Drug Administration (FDA) approval for pediatric use before approval for adult use. Most new anti-leukemic drugs were developed for use in adults and only later adapted for the treatment of children, they noted in an article on clofarabine published in the May issue of Nature Reviews/Drug Discovery.

"The addition of clofarabine to the list of drugs approved for treating pediatric ALL is especially significant because it has shown significant activity in different types of leukemias that were no longer responding to standard therapy," said Sima Jeha, MD, director of Developmental Therapeutics for Leukemia and Lymphoma at St. Jude and the lead investigator on the pediatric clofarabine trials. "The lack of overlapping toxicities with current agents warrants adding clofarabine to chemotherapy combinations with the aim of achieving even better responses."

During the past few decades, researchers have made major progress in understanding both the biology of leukemias such as ALL and how the genetic makeup of patients affects the outcome of drug therapy. Parallel with these advances, the cure rate for childhood ALL reached 80 percent. Part of this success is due to the modification of therapy for individual patients based on their risk of treatment failure. However, the most significant contribution to the higher survival rate is the increasingly more effective use of drugs developed between the 1950s and 1970s, according to the authors.

"Despite the great progress we've made by learning how to use drugs more effectively, children who do not achieve or maintain complete remission of their diseases have a dismal outlook," said Ching-Hon Pui, MD, director of the St. Jude Leukemia/Lymphoma Division, and American Cancer Society F.M. Kirby Clinical Research Professor. "In order to give these children hope, we need new drugs such as clofarabine. This drug may also prove effective for acute myeloid leukemia (AML), which is generally more drug resistant than ALL."

The FDA used its accelerated approval process for clofarabine based on results of a multicenter Phase II trial, the authors said. In the trial, 31 percent of 49 patients with ALL responded to the drug, with six of these children achieving complete remission of their cancer, according to Jeha. In addition, four children experienced complete marrow remissions in the absence of platelet recovery, and five had partial remissions. Marrow remission means that the treatment has succeeded in eliminating leukemic cells from the bone marrow. This Phase II trial was conducted based on the activity noted in an initial pediatric Phase I clofarabine trial that Jeha published last year in the journal Blood.

Multi-institutional Phase II studies of clofarabine in combination with other agents will soon be offered to pediatric patients with relapsed ALL and AML. The studies will target patients who have been less heavily treated than were the children in the initial single agent trials.

"Because of clofarabine's proven efficacy as a single agent, we now plan to offer regimens including this new drug to children who have been less heavily pre-treated," Jeha said.

Clofarabine, a type of drug called a purine nucleoside antimetabolite, works by blocking the production and repair of DNA, the building blocks of genes. The drug was developed to improve the efficacy and minimize the toxicity of two similar drugs, cladribine and fludarabine.

The other author of this paper is Peter Kirkpatrick (Nature Reviews/Drug Discovery).