Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma.
OBJECTIVE
To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma.


METHODS
Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*).


RESULTS
The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults.


CONCLUSIONS
On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).
Cohen
Martin H
MH
Division of Drug Oncology Products, Office of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. martin.cohen@fda.hhs.gov
Johnson
John R
JR
Massie
Tristan
T
Sridhara
Rajeshwari
R
McGuinn
W David
WD
Abraham
Sophia
S
Booth
Brian P
BP
Goheer
M Anwar
MA
Morse
David
D
Chen
Xiao H
XH
Chidambaram
Nallaperumal
N
Kenna
Leslie
L
Gobburu
Jogarao V
JV
Justice
Robert
R
Pazdur
Richard
R
D000818:Animals; D001087:Arabinonucleosides / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D017277:Drug Approval / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000882:Haplorhini; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D011817:Rabbits; D051381:Rats; D014481:United States; D014486:United States Food and Drug Administration
D001087:Arabinonucleosides; C104457:nelarabine